The Merck Veterinary Manual [11 ed.] 0911910611, 9780911910612

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THE MERCK VETERINARY MANUAL ELEVENTH EDITION

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Dedicated to all veterinarians and their colleagues in animal health worldwide.

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THE MERCK VETERINARY MANUAL ELEVENTH EDITION

Editor-in-Chief: Susan E. Aiello, DVM, ELS Executive Editor: Michael A. Moses Editorial Board Dana G. Allen, DVM, MSc, DACVIM Peter D. Constable, BVSc (Hons), MS, PhD, DACVIM Andrew Dart, BVSc, PhD, DACVS, DECVS Peter R. Davies, BVSc, PhD Katherine E. Quesenberry, DVM, DABVP (Avian Practice) Philip T. Reeves, BVSc, PhD, FACVSc Jagdev M. Sharma, BVSc, MS, PhD

Published by MERCK & CO., INC. KENILWORTH, NJ, USA 2016

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Editorial and Production Staff Editor-in-Chief: Susan E. Aiello, DVM, ELS Executive Editor: Michael A. Moses Publisher: Melissa Adams Partnership Manager: Michael Wisniewski Subsidiary Rights Coordinator: Sheryl Olinsky-Borg Sales and Service Specialist: Leta S. Bracy Associate Director, Merck Digital Publications: Michael DeFerrari

Library of Congress Control Number: 2016905370 ISBN-13: 978-0911910612 ISSN Number: 0076-6542 Copyright© 2016 by MERCK & CO., INC. All rights reserved. No part of this book may be reproduced or used in any form or by any means, electronic or mechanical, including photocopying, or by any information storage and retrieval system, without permission in writing from the Publisher. Address inquiries to Merck Publishing Group, P.O. Box 2000, RY34A-426, Rahway, NJ 07065 Printed in the USA Designer: Jerilyn Bockorick, Cenveo® Publisher Services Composition by Cenveo® Publisher Services Fort Washington, Pennsylvania Printed and bound at RR Donnelley Crawfordsville, Indiana

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THE MERCK VETERINARY MANUAL

Previous Editions First Edition Second Edition Third Edition Fourth Edition Fifth Edition Sixth Edition Seventh Edition Eighth Edition Ninth Edition Tenth Edition

1955 1961 1967 1973 1979 1986 1991 1998 2005 2010

Foreign Language Editions Chinese China Agriculture Press, Beijing Croatian/Slovakian Komora Vetarinarnich Lekarov, Brno French Editions d'Apres, Paris Italian Cristiano Giraldi Editore, Bologne Japanese Gakusosha, Tokyo Portuguese Editora Roca, Sao Paulo Spanish Editorial Oceano, Barcelona

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OTHER MERCK BOOKS The Merck Index First Edition, 1889 The Merck Manual of Diagnosis and Therapy First Edition, 1899 T he Merck Manual of Medical Information' Home Edition First Edition, 1977 The Merck Manual of Health and Aging First Edition, 2004 The Merck/Merial Manual for Pet Health First Edition, 2007 The Merck Manual of Patient Symptoms First Edition, 2008 The Merck Manual Go-To Home Guide for Symptoms First Edition, 2013 Merck books are published as a service to the scientific community and the public.

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FOREWORD Merck & Co., Inc., has a long history of providing medical information to both human and animal health care professionals. For more than 60 years, the Merck Veterinary Manual (MVM) has provided veterinarians and other animal health professionals with concise and authoritative information on diseases and management of food-producing, c9mpanion, laboratory, and exotic animals. The 11th edition carries on this proud tradition. This new edition has been completely updated and revised to continue to address the many diverse aspects of veterinary medicine. The first half of the book covers all body systems, including discussions of disease etiology, diagnosis, treatment, control, and prevention. The second half addresses special topics, including behavior, clinical pathology, management and nutrition, pharmacology, toxicology, and poultry medicine. Although the contents of the book have expanded with each edition, the MVM remains true to its original objective: a concise, easy-to-use, comprehensive reference that covers the diversity of species and animal diseases worldwide. Coverage is straightforward and practical, with explicit recommendations given for treatment whenever possible. The succinct discussions also serve to give readers a strong foundation for seeking out and understanding more detailed information available elsewhere. The MVM covers all the basics, but it is also often relied on for areas not com­ monly encountered in the daily routine of most animal health professionals. This is no more evident than in the growing responsibility of veterinarians to society, in which general practitioners and specialists alike must vigilantly embrace their role in the international movement of animals, maintaining a safe food supply, and minimizing the spread of infectious animal disease and zoonotic agents. In this vein, a new section is dedicated to public health, covering public health functions and agencies, epidemio­ logic principles, disease outbreak investigations, food safety, and an extensive table of zoonoses. Other significant new information has been added on heart disease, diagnostic imaging, emergency medicine, wound management, and pharmacology, including drug resistance. The emerging area of aquaculture is reflected in new chapters on aquaculture, aquatic systems, and aquarium fish. Veterinary responsibilities under the new Veterinary Feed Directive rule are also summarized. Additional timely new topics have been added throughout, covering subjecl.s as diverse as backyard poultry, equine arboviral encepha­ lomyelitis, neonatal management, smoke inhalation, rhodococcosis, scorpion bites, spider flies, xylitol toxicity, toxicologic hazards in the workplace, and the human-animal bond and service animals. And as medical knowledge of exotic and laboratory animals continues to increase, so does the MVM's coverage of pet birds, rabbits, reptiles, rodents, fish, and other nontraditional species. The contents of the MVM are available online and as an app for handheld devices, providing enhanced capability to quickly access needed information. Digital versions are updated more frequently and include thousands of additional images and other multimedia offerings. As always, we are deeply grateful to the authors and reviewers who have contrib­ uted to the current and past editions of the MVM. The 11th edition of the MVM is an extensive collaboration of the MVM Editorial Board and nearly 400 veterinary experts from academia, government, research organizations, and specialty practices, represent­ ing more than 20 countries worldwide. It is only through their dedication to animal health and their efforts and willingness to share their time and expertise that the MVM is possible.

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FOREWORD

Acknowledgment and thanks are also due to the following individuals for their assistance in the 11th edition of the MVM: Jennifer A. Doyle for business operations and technical troubleshooting, Lisa P. Glinski for index entry coding and other critical tasks, Jean L. Perry for general project administrative support, and Michelle A. Steigerwald for image processing. Appreciation is also expressed to Robert S. Porter, MD, for his manage­ ment support. Lastly, there is nothing more rewarding than hearing directly from our readers. Please continue to share your many thoughts, experiences, and stories about the MVM so that the book and its legacy can continue to improve, evolve, and endure.

SusanE. Aiello, DVM, ELS, Editor-in-Chief MiclwelA. Moses, Executive Editor

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GUIDE FOR READERS • The Contents shows the title of each section of the Merck Veterinary Manual (MVM) and the corresponding thumb tab abbreviation. • Each section has its own Table of Contents that lists chapter and subchapter titles in that section. • Many cross-reference page numbers are found throughout the text to enable the reader to quickly find discussions of related material elsewhere in the book. • A number of abbreviations and symbols used routinely throughout the text are listed beginning on p xiii. Other abbreviations used in the text are defined at their first use. • Generic ( nonproprietary) names of drugs are used in most instances. • Running heads on left-hand pages correspond to the chapter title of the text appearing at the top of that page. Running heads on right-hand pages correspond to the chapter title of the text appearing at the bottom of that page. In other words, running heads are used as in a standard dictionary. • The Index is the best way to locate specific discussions of a disease, condition, or syndrome for which the name is known. • The first half of the MVM is arranged into anatomic systems, and specific conditions are located in the system that is primarily affected. Conditions that may affect more than one system are covered in the section Generalized Conditions (GEN). The second half of the MVM covers special topics or disciplines. • The authors, reviewers, editors, and publisher have made extensive efforts to ensure that treatments, drugs, dosage regimens, and withdrawal times are accurate and conform to the standards accepted at the time of publication. However, constant changes in information resulting from continuing research and clinical experience, reasonable differences in opinions among authorities, unique aspects of individual clinical situations, and the possibility of human error in preparing such an extensive text require that the reader exercise individual judgment when making a clinical decision and, if necessary, consult and compare information from other sources. In particular, the reader is advised to check the product information currently provided by the manufacturer of each drug before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently. Many of the drug dosages given are considered extra-label usages, which require a valid veterinarian-client-patient relationship. Veterinarians should also be familiar and comply with the regulations set forth by the Veterinary Feed Directive.

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CONTENTS Foreword

vii

Guide for Readers

ix

Abbreviations and Symbols Editorial Board Contributors

CIR DIG EE END GEN IMM ITG MET MUS NER REP RES URN

xiii

xv xvii

Circulatory System 147 Digestive System Eye and Ear 487 537 Endocrine System Generalized Conditions 811 Immune System

585

833 lntegumentary System Metabolic Disorders 983 1031 Musculoskeletal System 1207 Nervous System 1321 Reproductive System 1409 Respiratory System Urinary System

1493

BEH CPP EMG EXL MGN PBH PHM POU TOX

Behavior 1533 Clinical Pathology and Procedures 1583 Emergency Medicine and Critical Care 1657

REF IND

Reference Guides

Exotic and Laboratory Animals 1731 Management and Nutrition 2061 Public Health 2389 Pharmacology 2485 2775 Poultry Toxicology

Index

2945 3173

3187 xi

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ABBREVIATIONS AND SYMBOLS adli b ADP ALT AST ATP bid bpm BUN cal CBC(s) CDC CFU cm CNS CK CSF CT cu DIC dL DNA ECG eg ELISA EPA EPG et se q EU F FDA fl. ft g gal. GI GnRH H&E Hg b

hr ie lg

IL

as much as desired adenosine diphosphate alanine aminotransferase aspartate aminotransferase adenosine triphosphate twice a day beats per minute blood urea nitrogen Celsius (Centigrade) calorie(s) complete blood count(s) Centers for Disease Control and Prevention colony-forming unit centimeter(s) central nervous system creatine kinase (CPK, creatine phosphokinase) cerebrospinal fluid computed tomography cubic disseminated intravascular coagulation deciliter(s) deoxyribonucleic acid electrocardiogram for example enzyme-linked immunosorbent assay Environmental Protection Agency eggs per gram (of feces) and the following one(s) European Union Fahrenheit Food and Drug Administration femtoliter(s) foot, feet gram(s) gallon(s) gastrointestinal gonadotropin-releasing hormone hematoxylin and eosin hemoglobin hour(s) that is immunoglobulin (with class following: A, D, E, G, or M) interleukin

intramuscular(ly) inch(es) intraperitoneal(ly) international unit(s) ru IV intravenous(ly) kcal kilocalorie(s) kilogram(s) kg L Jiter(s) LOH lactate dehydrogenase lb pound(s) m meter(s) molar M Meal megacalorie(s) mcg microgram ME metabolizable energy milliequivalent(s) m Eq milligram(s) mg min minute(s) mL milliliter(s) millimeter(s) mm month(s) mo mole(s) mol milliosmole(s) m Osm run nanometer(s) magnetic resonance imaging MRI National Research Council NRC NSAID(s) nonsteroidal antiinflammatory drugcs) OIE Office International des Epizooties oz ounce(s) page/pages p/pp polymerase chain reaction PCR packed cell volume PCV negative logarithm of hydrogen pH ion activity per os, orally PO part(s) per billion ppb part(s) per million ppm qid four times a day quantity sufficient to make qsad RBC(s) red blood cell(s) ribonucleic acid RNA subcutaneous(ly) SC sec second(s) SI units International System of Units specific pathogen free SPF sq square tablespoon(s) tbsp IM in. IP

xiii

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xiv

ABBREVIATIONS AND SYMBOLS

TDN

total digestible nutrients three times a day teaspoon(s) unit(s) United Kingdom United States Department of Agriculture United States of America Union of Soviet Socialist Republics (former) white blood cell(s) week(s) weight year(s)

tid tsp

u

UK

USDA USA USSR WBC(s) wk

wt yr

(}(

�

6 E

"{

A µ K

(T

alpha beta delta epsilon gamma lambda micro, mu kappa sigma

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EDITORIAL BOARD Dana G. Allen, DVM, MSc, DACVIM

Professor Emeritus, Ontario Veterinary College, University of Guelph, Ontario, Canada

Peter D. Constable, BVSc (Hons), MS, PhD, DACVIM

Dean, College of Veterinary Medicine, University of Illinois at Urbana­ Champaign, Urbana, IL

Andrew Dart, BVSc, PhD, DACVS, DECVS

Director, Research and Clinical Trials Unit, and Registered Equine Surgical Specialist, University of Sy dney, NSW, Australia

Peter R. Davies, BVSc, PhD

Allen D. Leman Chair in Swine Health and Productivity, Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN

Katherine E. Quesenberry, DVM, MPH, DABVP (Avian)

Avian and Exotic Pet Service, The Animal Medical Center, New York, NY

Philip T. Reeves, BVSc, PhD, FACVSc

Principal Scientist, Australian Pesticides and Veterinary Medicines Authority, Symonston, Australia

Jagdev M. Shatma, BVSc, MS, PhD

Research Professor, The Biodesign Institute, Visiting Professor, School of Life Sciences, Arizona State University, Tempe, AZ; Professor and Endowed Chair ifl Avian Health Emeritus, University of Minnesota, St. Paul, MN

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CONTRIBUTORS Tahseen Abdul-Aziz, BVMS, MS, PhD, DACPV Veterinary Pathologist, Rollins Animal Disease Diagnostic Laboratory, North Carolina Department of Agriculture and Consumer Services, Raleigh, NC

Avian Encephalomyelitis; Botulism; Listeriosis Stephen B. Adams, DVM, MS, DACVS Professor of Surgery, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN

Arthroscopy; Lameness in Horses: Intro­ duction; Musculoskeletal System: Intro­ duction; The Lameness Examination Andrew J. Allen, DVM, PhD, DACVIM Assistant Professor, Department of Veteri­ nary Clinical Sciences, Washington State University, Pullman, WA

Disorders of Calcium Metabolism: Partu­ rient Paresis in Cows; Metabolic Disor­ ders: Introduction; Transport Tetany in Ruminants. Dana G. Allen, DVM, MSc, DACVIM Professor Emeritus, Ontario Veterinary College, University of Guelph, Ontario, Canada

Congenital and Inherited Anomalies; Systemic Pharmacotherapeutics of the Cardiovascular System: Drugs Acting on the Blood Kelly E. Allen, MS, PhD Lecturer, Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK

Glen W. Almond, DVM, PhD Professor, Swine Health and Production Management, North Carolina State Univer­ sity, Raleigh, NC

Postpartum Dysgalactia Syndrome and Mastitis in Sows Gary C. Althouse, BS, MS, DVM, PhD, DACT Professor of Reproduction. and Swine Health; Marion Dilley and David George Jones Endowed Chair in Animal Repro­ duction, Department of Clinical Studies, New Bolton Center, University of Pennsyl­ vania, Kennett Square, PA

Management of Reproduction: Pigs Claire B. Andreasen, DVM, PhD, DACVP Associate Dean for Academic and Student Affairs and Professor, College of Veterinary Medicine, Iowa State University, Ames, IA

Staphylococcosis Frank M. Andrews, DVM, MS, DACVIM (Large Animal) Louisiana Veterinary Medical Association Equine Committee Professor and Director, Equine Health Studies Program, Depart­ ment of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

Gastrointestinal Ulcers in Large Ani­ mals: Gastrointestinal Ulcers in Horses John A. Angelos, DVM, PhD, DACVIM Associate Professor, Department of Medi­ cine and Epidemiology; Livestock Medicine and Surgery, School of Veterinary Medicine, University of California, Davis, CA

Infectious Keratoconjunctivitis

Blood Parasites: Old World Hepatozo­ onosis and American Canine Hepatozo­ onosis

David A. Ashford, DVM, MPH, DSc Attache, US Department of Agriculture, Office of Agricultural Affairs, Port au Prince, Haiti

Sandra Allweiler, DVM, DACVA Assistant Professor, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Clarke Atkins, DVM, DACVIM Jane Lewis Seaks Distinguished Professor, Professor Emeritus, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Pain Assessment and Management

Heartworm Disease

Foot-and-Mouth Disease

xvii

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CONTRIBUTORS

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Rick Atwell, BVSc, PhD, FACVSc

Honorary Professor, School of Veterinary Science, University of Queensland, Bris­ bane, Queensland, Australia Tick Paralysis David G. Baker, DVM, MS, PhD, DACLAM

Director and Professor, Division of Labo­ ratory Animal Medicine, School of Veteri­ nary Medicine, Louisiana State University, Baton Rouge, LA Eye-worm Disease Lora R. Ballweber, MS, DVM

Professor, Clinical Parasitology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO Fluke Infections in Ruminants; Gastro­ intestinal Parasites of Pigs; Lungw01m Infection Alejandro Banda, DVM, MSc, PhD, DACPV, DACVM

Associate Clinical Professor of Avian Virology, Poultry Research and Diag­ nostic Laboratory, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS Duck Viral Enteritis

Daniela Bedenice, DVM, DACVIM, DACVECC

Assistant Professor, Department of Clini­ cal Sciences, Cummings School of Vet­ erinary Medicine, Tufts University, North Grafton, MA

Hypoxic lschemic Encepha.lopathy; Man­ agement of the Neonate: Large Animals; Sepsis in Foals Sylvia J. Bedford-Guaus, DVM, PhD, DACT

Animal Reproduction Consultant, Barce­ lona, Spain

Breeding Soundness Examination of the Male James K. Belknap, DVM, PhD, DACVS

Professor of Equine Surgery, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH Lameness in Horses: Disorders of the Foot William G. Bickert, PhD

Professor Emeritus, Biosystems and Agricultural Engineering, Michigan State University, East Lansing, Ml Ventilation

Gad Baneth, DVM, PhD, DECVCP

Rob Bildfell, DVM, MSc, DACVP

Lisa G. Barber, DVM

Collection and Submission of Laboratory Samples; Pyrrolizidine Alkaloidosis

Professor, Koret School of Veterinary Medicine, Hebrew University, Rehovot, Israel Leishmaniosis Assistant Professor, Department of Clini­ cal Sciences, Cummings School of Vet­ erinary Medicine, Tufts University, North Grafton, MA Antineoplastic Agents George M. Barrington, DVM, PhD, DACVIM

Professor, Food Animal Medicine and Surgery, College of Veterinary Medicine, Washington State University, Pullman, WA

Congenital Erythropoietic Porphyria; Photosensitization Robert B. Beckstead, PhD

Associate Professor, Department of Poultry Science, University of Georgia, Athens, GA Hexamitiasis; Histomoniasis

Professor, Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR

Patrick Joseph Blackall, BSc, PhD

Principal Research Fellow, Queensland Alliance for Agriculture and Food Itmo­ vation, The University of Queensland, Brisbane, Queensland, Australia Infectious Coryza Barry R. Blakley, DVM, PhD

Professor, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada Copper Poisoning; Fluoride Poisoning; Lead Poisoning; Mercury Poisoning; Metaldehyde Poisoning; Molybdenum Poisoning; Quercus Poisoning; S01·ghum Poisoning

CONTRIBUTORS

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Shauna L. Blois,DVM,DVSc,DACVIM

Assistant Professor, Clinical Studies, Ontario Veterinary College, University of Guelph, Ontario, Canada

Diseases of the Stomach and Intestines in SmaU Animals: Gastrointestinal Neopla­ sia, Gastrointestinal Ulcers, Helicobacter Infections Dawn Merton Boothe,DVM,PhD

Professor, Department of Anatomy, Physiol­ ogy, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL Antibacterial Agents; Antifungal Agents; Antiviral Agents; Chemotherapeutics Introduction; Pharmacology Introduction Manuel Borca,DVM,PhD

Research Microbiologist, Foreign Animal Disease Research, USDA, Orient Point, NY Classical Swine Fever Jane C. Boswell,MA, VetMB,CertVA, CertES (Orth), DECVS, MRCVS

The Liphook Equine Hospital, Liphook, Hampshire, UK Lameness in Horses: Disorders of the Stifle, Disorders of the Tarsus and Metatarsus Joan S. Bowen, DVM

Bowen Mobile Veterinary Practice, Wellington, CO Health-Management Interaction: Goats; Lameness in Goats Perle E. Boyer,DVM

Lecturer, North Carolina State University, Raleigh, NC Postpartum Dysgalactia Syndrome and Mastitis in Sows R. Keith Bramwell, BS,MS,PhD

Extension Poultry Specialist, Cooperative Extension Service, and Associate Profes­ sor, Department of Poultry Science, Uni­ versity of Arkansas, Fayetteville, AR Artificial Insemination (Poultry) Matthew T. Brokken,DVM,DACVS

Clinical Assistant Professor, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH Lameness in Horses: Disorders of the Carpus and Metacarpus, Disorders of the Fetlock and Pastern

xix

Scott A. Brown,VMD,PhD,DACVIM

Josiah Meigs Distinguished Professor and Head, Department of Small Animal Medi­ cine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA Infectious Diseases of the Urinary System in SmaU Animals; Noninfectious Diseases of the Urinary System in Small Animals Cecil F. Brownie,DVM,PhD,DABVT, DABFE,DABFM,FACFEI

Professor Emeritus, College of Veterinary Medicine, North Carolina State University, Raleigh, NC Poisonous Mushrooms; Poisonous Plants Glenn F. Browning,BVSc,DVCS,PhD

Professor in Veterinary Microbiology, Asia-Pacific Centre for Animal Health, Faculty of Veterinary Science, The University of Melbourne, Werribee, Victoria, Australia Infectious Bronchitis David Bruyette,DVM,DACVIM

Medical Director, VCA West Los Angeles Animal Hospital, Los Angeles, CA The Adrenal Glands; The Pancreas Marie S. Bulgin,DVM,MBA, DACVM

Emerita, Caine Veterinary Teaching Cen­ ter, University ofldaho, Caldwell, ID

Health-Management Interaction: Sheep; Lameness in Sheep; Scrapie Kristine E. Burgess,DVM,DACVIM (Oncology)

Assistant Professor, Department of Clini­ cal Sciences, Cummings School of Vet­ erinary Medicine, Tufts University, North Grafton,MA

Antineoplastic Agents Amanda Burling,DVM

Maddie's Shelter Medicine Program, Col­ lege of Veterinary Medicine, University of Florida, Gainesville, FL Feline Leukemia Virus and Related Diseases Raymond Cahill-Morasco,MS,DVM

SeaPort Veterinary Hospital, Gloucester, MA Zinc Toxicosis

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CONTRIBUTORS

Robert J. Callan,DVM,MS,PhD, DACVIM Professor, Department of Clinical Sci­ ences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Bluetongue; Congenital and Inherited Anomalies: Border Disease; Malig­ nant Catarrhal Fever; Sporadic Bovine Ence'J)halomyelitis John Campbell,DVM,DVSc Professor, Large Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Respiratory Diseases of Cattle Wayne W. Carmichael,PhD Professor of Aquatic Biologyffoxicology, Wright State University, Dayton, OH

Algal Poisoning James W. Carpenter,MS,DVM, DACZM Professor, Zoological Medicine, Depart­ ment of Clinical Sciences, College of Veter­ inary Medicine, Kansas State University, Manhattan, KS

Hedgehogs Phillip D. Carter,BVSc,MVS Queensland Department of Agriculture, Fisheries and Forestry, Tick Fever Centre, Wacol, Queensland, Australia

Blood Parasites: Babesiosis Samuel C. Cartner,DVM,PhD, DACLAM Assistant Vice President for Animal Research Services and Director, Animal Resources Program, University of Ala­ bama, Birmingham, AL

Euthanasia Chr istopher K. Cebr a ,VMD, MA,MS, DACVIM Professor, Large Animal Medicine, College of Veterinary Medicine, Oregon State University, Corvallis, OR

He'J)atic Lipidosis: Pregnancy Toxemia in Cows Sharon A. Center,BS,DVM, DACVIM Professor, Department of Clinical Sci­ ences, College of Veterinary Medicine, Cornell University, Ithaca, NY

He'J)atic Disease in Small Animals

Jens Peter Chr istensen,DVM,PhD Associate Professor, Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Denmark

Fowl Cholera; Riemerella anatipestifer Infection Edwin Claer ebout,DVM,PhD, DEVPC Professor, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium

Anthelmintics Peter Clegg,MA,Vet MB,DECVS, PhD,MRCVS Professor of Equine Surgery, Veterinary Teaching Hospital, School of Veterinary Sciences, University of Liverpool, Neston, UK

Lameness in Horses: Disorders of the Back and Pelvis, Disorders of the Hip Johann (Hans) F. Co etzee ,BVSc, CertCHP,PhD,DACVCP Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State Univer­ sity, Ames, IA

Systemic Pharmacotherapeutics of the Ruminant Digestive System Stephen R. Collett,BSc,BVSc, MMedVet Clinical Associate Professor, Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA

Biosecurity; Sudden Death Syndrome of Broiler Chickens Michael T. Collins , DVM,PhD,DACVM Professor of Microbiology, Department of Pathobiological Sciences, School of Vet­ erinary Medicine, University of Wisconsin, Madison, WI

Paratuberculosis Peter D. Constable,BVSc (Hons),MS, PhD,DACVIM Dean, College of Veterinary Medicine, University of Illinois, Urbana, IL

Abdominal Fat Necrosis; Acute Intes­ tinal Obstructions in Large Animals; Bovine Secondary Recumbency; Coc­ cidiosis; Cryptosporidiosis; Diseases of the Abomasum; Disorders of Potassium

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CONTRIBUTORS

Metabolism; Diseases of the Ruminant Forestomach: Bloat in Ruminants, Grain Overload, Simple Indigestion, Traumatic Reticuloperitonitis, Vagal Indigestion Syndrome; Infectious Diseases of the Uri­ nary System in Large Animals: Bovine Cystitis and Pyelone'J)hritis

Gary L Cromwell,PhD Professor, Department of Animal and Food Sciences, University of Kentucky, Lexington, KY

Rhian B. Cope,BVSC, PhD, DABT, ERT,FACTRA Toxicology Section, Office of Scientific Evaluation, Therapeutic Goods Adminis­ tration of Australia, Sy monston, Australian Capital Territory, Australia

Suzanne M. Cunningham, DVM, DACVIM (Cardiology) Assistant Professor of Cardiology, Depart­ ment of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA

Iron Toxicity in Newborn Pigs; Nutri­ tion: Pigs

Cyanide Poisoning; Smoke Inhalation; Toxicologic Hazards in the Workplace

Cardiovascular System Introduction; Thrombosis, Embolism, and Aneurysm

Robert W. Coppock,DVM, MS,PhD, DABVT,DABT President and CEO, Robert W. Coppock, DVM, Toxicologist and Associate Ltd., Vegreville, Alberta, Canada

Andrew Dart,BVSc, PhD,DACVS, DECVS Director of the Research and Clinical Training Unit, Faculty of Veterinary Sci­ ence, The University of Sydney, New South Wales, Australia

Persistent Halogenated Aromatic Poison­ ing Susan M. Cotter, DVM, DACVIM (Small Animal,Oncology) Distinguished Professor of Clinical Sci­ ences Emerita, Cummings School of Vet­ erinary Medicine, Tufts University, North Grafton, MA

Blood Groups and Blood Transfusions; Hematopoietic System Introduction; Hemostatic Disorders Laurent L. Couetil, DVM, PhD, DACVIM (Large Animal) Professor, Department of Veterinary Clini­ cal Sciences, College of Veterinary Medi­ cine, Purdue University, West Lafayette, IN

Pulmonary Emphysema Kate E. Creevy,DVM,MS, DACVIM Associate Professor of Internal Medicine, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA

Canine Distemper; Canine Herpesviral Infection; Infectious Canine He'J)atitis Rocio Crespo,DVM, MSc,DVSc, DACPV Associate Professor and Director, Avian Health and Food Safety Laboratory, Washington Animal Disease Diagnostic Laboratory, Washington State University, Pullman, WA

Miscellaneous Conditions of Poultry: Urate De'J)osition (Gout)

xxi

Congenital and Inherited Anomalies Autumn P. Davidson, DVM,MS, DACVIM Clinical Professor, School of Veterinary Medicine, University of California, Davis, CA

Management of Re'J)roduction: Small Animals; Management of the Neonate: Small Animals; Re'J)roductive Diseases of the Male Small Animal Peter R- Davies,BVSc,PhD Professor, Swine Health and Production, Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN

Exudative Epidermitis; Parakeratosis; Pityriasis Rosea in Pigs; Swine Vesicular Disease; Vesicular Exanthema of Swine Sherrill Davison,VMD,MS,MBA, DACPV Associate Professor, Laboratory of Avian Medicine and Pathology, School of Veteri­ nary Medicine, University of Pennsylvania, Kennett Square, PA

Salmonelloses (Poultry) Scott A. Dee,DVM, MS,PhD Director of Research, Pipestone Applied Research, Pipestone Veterinary Services, Pipestone, MN

Infectious Diseases of the Uri:nary System in Large Animals: Porcine Cystitis­ Pyelonephritis Complex; Porcine Repro­ ductive and Respiratory Syndrome; Pseudorabies; Respiratory Diseases of Pigs

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CONTRIBUTORS

Alice Defarges,DVM,MSc,DACVIM Assistant Professor in Internal Medicine, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Ontario, Canada

Diseases of the Stomach and Intestines in Small Animals: Colitis in Small Animals, Constipation and Obstipation in Small Animals, Inflammatory Bowel Disease in Small Animals Sagi Denenberg,DVM,DACVB, DECAWBM(Behaviour),MACVSc (Behaviour) North Toronto Veterinary Behaviour Spe­ cialty Clinic, Thornhill, Ontario, Canada

Normal Social Behavior and Behavioral Problems of Domestic Animals R. Page Dinsmore,DVM Associate Professor, Department of Clini­ cal Sciences, College of Veterinary Medi­ cine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Health-Management Interaction: Dairy Cattle Stephen J. Divers,BVetMed,DZooMed, DACZM,DECZM(Herpetology), FRCVS Professor of Zoological Medicine, Depart­ ment of Small Animal Medicine and Surgery, College of Veterinary M,edicine, University of Georgia, Athens, GA

Reptiles Thomas J. Divers,DVM,DACVIM, DACVECC Professor of Medicine, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY

Leptospirosis: Horses, Ruminants, Swine; Noninfectious Diseases of the Urinary System in Large Animals Thomas M. Donnelly, BVSc,DVP, DACLAM,DABVP(ECM) The Kenneth S. Warren Institute, Ossining, NY; Adjunct Associate Professor, Cum­ mings School of Veterinary Medicine, Tufts University, North Grafton, MA

Rodents Patricia M. Dowling,DVM,MSc, DACVIM,DACVCP Professor, Veterinary Clinical Pharma­ cology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada

Systemic Pharmacotherapeutics of the Monogastric Digestive System; Systemic Pharmacotherapeutics of the Muscular System; Systemic Pha1macotherapeutics of the Respiratory System; Systemic Phar­ macotherapeutics of the Urinary System Michael W. Dryden, DVM,PhD,DACVM University Distinguished Professor of Veterinary Parasitology, Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS

Ectoparasiticides: Ectoparasiticides Used in Small Animals; Fleas and Flea Allergy Dermatitis; Mange: Mange in Dogs and Cats J.P.Dubey,MVSc,PhD Microbiologist, Animal Parasitic Dis­ eases Laboratory, Beltsville Agricultural Research Center, USDA, Beltsville, MD

Toxoplasmosis Rebecca S.Duerr,DVM,MPVM,PhD Staff Veterinarian, International Bird Res­ cue Research Center, Cordelia, CA

Management of the Neonate: Care of Orphaned Native Birds and Mammals John Dunn,DVM,PhD Veterinary Medical Officer, Avian Disease and Oncology Laboratory, USDA-ARS, East Lansing, MI

Neoplasms (Poultry) Jack Easley,DVM,MS,DABVP (Equine) Equine Veterinary Practice, LLC, Shelbyville, KY

Dentistry: Dentistry in Large Animals Scott H.Edwards,BSc,BVMS,PhD, MANZCVSc Senior Lecturer,Veterinary Pharmacology, Charles Sturt University, Wagga Wagga, New South Wales, Australia

Anti-injl,ammat01y Agents Steve M. Ensley,DVM,PhD Veterinary Toxicologist, Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames,IA

Toxicology Introduction

VetBooks.ir

CONTRIBUTORS

Ronald J. Erskine, DVM,PhD Professor, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI Mastitis in Large Animals Paul Ettestad, DVM,MS State Public Health Veterinarian, Epidemi­ ology and Response Division, New Mexico Department of Health, Santa Fe, NM Plague Timothy M. Fan, DVM,PhD, DACVIM Associate Professor, Department of Veteri­ nary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL Canine Lymphoma Susan E. Fielder, DVM,MS, DACVP (Clinical Pathology) Clinical Assistant Professor, Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State Univer­ sity, Stillwater, OK Reference Guides Scott D. Fitzgerald, DVM,PhD, DACVP, DACPV Professor, Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State Uni­ versity, East Lansing, MI Congenital and Inherited Anomalies of the Urinary System; West Nile Virus Infection in Poultry Sherrill A. Fleming, DVM, DACVIM, DABVP Associate Professor, Food and Animal Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS Pasteurellosis of Sheep and Goats Janet E. Foley, DVM,PhD Professor, Department of Medicine and Epidemiology; Co-Director, Center for Vector-Borne Disease, School of Veterinary Medicine, University of California, Davis, CA Tularemia Jonathan H. Foreman, DVM,MS, DACVIM (Large Animal) Associate Dean, Professor, College of Veterinary Medicine, University of Illinois, Urbana, IL Hepatic Disease in Large Animals

Mark T. Fox, BVetMed,PhD, DEVPC, FHEA,MRCVS Professor of Veterinary Parasitology, Department of Pathology and Pathogen Biology, The Royal Veterinary College, University of London, UK Gastrointestinal Parasites of Ruminants Ruth Francis-Floyd, DVM,MS, DACZM Professor, Department of Large Animal Clini­ cal Sciences, College of Veterinary Medicine, University of F1orida, Gainesville, FL Aquaculture; Aquarium Fishes; Aquatic Systems Robert M. Friendship, DVM,MSc, DABVP Professor, Department of Population Medi­ cine, Ontario Veterinary College, Univer­ sity of Guelph, Ontario, Canada Gastrointestinal Ulcers in Large Ani­ mals: Gastric Ulcers in Pigs; Health­ Management Interaction: Pigs Laurie J. Gage, DVM, DACZM Big Cat and Marine Mammal Specialist, USDA APHIS Animal Care, Center for Animal Welfare, Napa, CA Management of the Neonate: Care of Orphaned Native Birds and Mammals Maricarmen Garcia,PhD Associate Professor, Poultry Diagnostic and Research Center, Department of Popu­ lation and Health, University of Georgia, Athens, GA Infectious Laryngotracheitis Tam Garland, DVM,PhD, DABVT Veterinary Medical Diagnostic Laboratory, Texas A&M University, College Station, TX Arsenic Poisoning; Gossypol Poisoning Jack M. Gaskin, DVM,PhD, DACVM Associate Professor Emeritus, Department of Infectious Disease and Pathology, Col­ lege of Veterinary Medicine, University of F1orida, Gainesville, FL Encephalomyocarditis Virus Infection Kirk N. Gelatt, VMD, DACVO Emeritus Distinguished Professor, Depart­ ment of Small Animal Clinical Sciences, College of Veterinary Medicine, University of F1orida, Gainesville, FL Neoplasia of the Eye and Associated Structures; Ophthalmic Emergencies; Ophthalmology

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CONTRIBUTORS

Richard W. Gerhold,DVM,MS, PhD Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

Louis Norman Gotthelf,DVM Animal Hospital of Montgomery; Mont­ gomery Pet Skin and Ear Clinic, Montgom­ ery, AL

Coccidiosis (Poultry); Cryptosporidiosis (Poultry); Trichomonosis

Tumors of the Ear Canal

E. Paul J. Gibbs,BVSc,PhD,FRCVS Professor Emeritus, College of Veterinary Medicine, University of Florida, Gaines­ ville, FL

Pox Diseases T homas W. G. Gibson,BSc,BEd,DVM, DVSc,DACVS Assistant Professor of Small Animal Surgery, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Ontario, Canada

Marcelo Gottschalk, DVM,PhD Professor, College of Veterinary Medicine, University of Montreal, St-Hyacinthe, Quebec, Canada

Streptococcal Injections in Pigs Gregory F. Grauer,DVM,MS,DACVIM Professor and Jarvis Chair of Small Animal Internal Medicine, Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

Ethylene Glycol Toxicity

Diseases of the Stomach and Intestines in Small Animals: Gastric Dilation and Vol­ vulus in Small Animals, Gastrointestinal Obstruction in Small Animals

Deborah S. Greco,DVM,PhD,DACVIM Senior Research Scientist, Nestle Purina PetCare, New York, NY

Robert 0. Gilbert,BVSc,MMedVet, DACT,MRCVS Professor, Reproductive Medicine, Depart­ ment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY

Paul R. Greenough, FRCVS Professor Emeritus of Veterinary Surgery, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada

Metritis in Large Animals; Retained Fetal Membranes in Large Animals; Systemic Pharmacotherapeutics of the Re-productive System; Uterine Prolapse and Eversion; Vaginal and Cervical Prolapse; Vulvitis and Vaginitis in Large Animals Sabine Gilch,PhD Assistant Professor, Veterinary Medicine, University of Calgary, Alberta, Canada

Chronic Wasting Disease Eric Gonder,DVM,MS,PhD,DACPV Veterinarian, Butterball LLC, Goldsboro, NC; Adjunct Professor, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Miscellaneous Conditions of Poultry: Pendulous Crop

The Pituitary Gland

Lameness in Cattle Tara L. Grinnage-Pulley,DVM,PhD Adjunct Lecturer and Postdoctoral Research Fellow, Department of Epidemi­ ology, College of Public Health, University of Iowa, Iowa City, IA

Blood Parasites: Trypanosomiasis Walter Gruenberg,DMV,MS,PhD, DECAR,DECBHM Assistant Professor, Department of Farm Animal Health, Utrecht University, Utrecht, The Netherlands

Colisepticemia; Disorders of Phosphorus Metabolism; Dystrophies Associated with Calcium, Phosphorus, and Vitamin D; Hepatic Lipidosis: Fatty Liver Disease of Cattle; Intestinal Diseases in Ruminants; Salmonellosis

Sonya G. Gordon,DVM,DVSc, DACVIM (Cardiology) Associate Professor, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX

P. K. Gupta,PhD,Post Doc (USA), PGDCA,MSc VM & AH BVSc, FNA VSc,FASc,AW,FST,FAEB,FACVT (USA),Gold Medalist Editor-in-Chief, Toxicology International, Bareilly-lndia

Systemic Pharmacotherapeutics of the Cardiovascular System

Herbicide Poisoning; Pentachlorophenol Poisoning

VetBooks.ir

CONTRIBUTORS Ramesh C. Gupta,DVM,MVSc,PhD, DABT,FACT,FACN,FAT S

Professor and Head, Toxicology Depart­ ment, Breathitt Veterinary Center, Murray State University, Hopkinsville, KY Insecticide and Acaricide (Organic) Toxicity James S. Guy, DVM,PhD

Professor, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC Coronaviral Enteritis of Turkeys; Viral Encephalitides Sharon M. Gwaltney-Brant, DVM,PhD, DABVT,DABT

Toxicology Consultant, Veterinary Infor­ mation Network and Adjunct Faculty, College of Veterinary Medicine, University of Illinois, Urbana, IL

Food Hazards; Household Hazards; Snakebite; Toad Poisoning

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R. Reid Hanson, DVM,DACVS, DACVECC

Professor of Equine Surgery, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL Congenital and Inherited Anomalies of the Musculoskeletal System; Equine Emergency Medicine: Thermal Injuries Joseph Harari,MS,DVM,DACVS

Veterinary Surgeon, Veterinary Surgical Specialists, Spokane, WA Arthropathies and Related Disorders in Small Animals; Lameness in Small Animals; Myopathies in Small Animals; Osteopathies in Small Animals Billy M. Hargis,DVM,PhD

Professor and Director, JKS Poultry Health Research Laboratory, University of Arkan­ sas; Tyson Sustainable Poultry Health Chair, Department of Poultry Science, University of Arkansas, Fayetteville, AR

Carlton L. Gyles,DVM,PhD

Miscellaneous Conditions ofPoultry: Ascites Syndrome; Necrotic Enteritis; Spontaneous Cardiomyopathy of Turkeys

Edema Disease

Professor, Department of Animal Science, Iowa State University, Ames, IA

Professor Emeritus, Department of Pathobiology, Ontario Veterinary College, University of Guelph, Ontario, Canada Caroline N. Hahn,DVM,MSc,PhD, DECEIM,DECVN,MRCVS

Senior Lecturer in Veterinary Clinical Neuroscience, Royal (Dick) School of Vet­ erinary Studies, University of Edinburgh, Midlothian, UK Dysautonomia Edward J. Hall,MA,VetMB,PhD, DECVIM-CA

Professor of Small Animal Internal Medi­ cine, Department of Clinical Veterinary Science, University of Bristol, Bristol, UK Diseases of the Stomach and Intestines in Small Animals: Malabsorption Syndromes in Small Animals Jean A. Hall,DVM,PhD,DACVIM

Professor, Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR Disorders of Calcium Metabolism: Puer­ peral Hypocalcemia in Small Animals Jeffery 0. Hall,DVM,PhD,DABVT

Professor and Head of Diagnostic Toxicol­ ogy, Utah State University, Logan, UT Selenium To:ricosis

D. L. Hank Harris,DVM,PhD

Intestinal Diseases in Pigs Lynette A. Hart,PhD

Professor, Population Health and Repro­ duction, School of Veterinary Medicine, University of California, Davis, CA The Human-Animal Bond Joe Hauptman, DVM,MS,DACVS

Professor of Surgery, College of Veterinary Medicine, Michigan State University, East Lansing, MI Diaphragmatic Hernia Jan F. Hawkins, DVM,DACVS

Associate Professor, Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN Diseases of the Esophagus in Large Animals; Diseases of the Mouth in Large Animals; Pharyngeal Paralysis; Pharyngitis Marcus J. Head,BVetMed,MRCVS

Senior Associate, Rossdales Equine Hospi­ tal and Diagnostic Centre, Newmarket, UK Lameness in Horses: Disorders of the Shoulder and Elbow

VetBooks.ir

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CONTRIBUTORS J. Jill Heatley,DVM,MS,DACZM, DABVP (Avian) Associate Professor, Zoological Medicine, College of Veterinary Medicine, Texas A&M University, College Station, TX

Vaccination of Exotic Mammals Charles M. Hendrix,DVM,PhD Professor, Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL

CNS Diseases Caused by Helminths and Arthropods; Diagnostic Procedures for the Private Practice Laboratory: Parasi­ tology; Flies; Venomous Arthropods Thomas H. Herdt,DVM,MS, DACVN, DACVIM Professor, Department of Large Animal Clinical Sciences and Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, Ml

Ketosis in Cattle; Nutrition: DainJ Cattle

Frederic J. Hoerr,DVM,PhD,DACVP, DACPV Pathologist, Veterinary Diagnostic Pathol­ ogy, LLC, Fort Valley, VA

Aspergillosis; Miscellaneous Conditions of Poultry: Breast Blisters, Breast Buttons, Cannibalism; Mycotoxicoses (Poultry) Timothy N. Holt,DVM Associate Professor, Clinical Sciences, Livestock Medicine and Surgery, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Bovine High-Mountain Disease Sharman M. Hoppes,DVM,ABVP (Avian) Clinical Associate Professor, Zoological Medicine, Department of Veterinary Small Animal Clinical Sciences, Texas A&M University, College Station, TX

Pet Birds

Laurie Hess,DVM,DABVP Veterinary Center for Birds & Exotics, Bedford Hills, NY

Michael J. Huerkamp,DVM,DACLAM Director, Division of Animal Resources; Professor, Pathology and Laboratory Medi­ cine, Emory University, Atlanta, GA

Sugar Gliders

Laboratory Animals

Michael Hess, DMV Clinic for Poultry and Fish Medicine, Department for Farm Animals and Veterinary Public Health, Urµversity of Veterinary Medicine, Vienna, Austria

Martin E. Hugh-Jones,VetMB,MPH, fhD,MRCVS Professor Emeritus, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

Avian Spirochetosis; Miscellaneous Conditions of Poultry: Fluke Infections

Anthrax

Hugh Hildebrandt,DVM Medford Veterinary Clinic, Medford, WI

Mink W. Mark Hilton,DVM,DABVP Clinical Associate Professor, Veterinary Clinical Sciences, School of Veterinary Med­ icine, Purdue University, West Lafayette, IN

Health-Management Interaction: Beef Cattle; Nutrition: Beef Cattle Katrin Hinrichs,DVM,PhD,DACT Professor and Patsy Link Chair in Mare Reproduction, Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX

Cloning of Domestic Animals

Staci Hutsell,DVM Resident, Maddie's Shelter Medicine Program, College of Veterinary Medicine, University of Florida, Gainesville, FL

Feline Infectious Peritonitis Basil 0. Ikede,BVetMed,DVM,PhD, FCVSN Retired Professor and Chair, Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada

Bovine Petechial Fever Peter G. G. Jackson, MA,BVM&S, DVM&S,FRCVS St. Edmund's College, University of Cambridge, Cambridge, UK

Prolonged Gestation in Cattle and Sheep

CONTRIBUTORS

VetBooks.ir

Daral J. Jackwood, PhD

Professor,Department of Veterinary Preventive Medicine,Ohio Agricultural Research and Development Center,The Ohio State University,Wooster,OH

_Infectious Bursal Disease Mark W. Jackwood, PhD

Professor, Department of Population Health,College of Veterinary Medicine, University of Georgia,Athens,GA

BordeteUosis Eugene D. Janzen,DVM,MVS

Professor, Production Animal Health, Faculty of Veterinary Medicine, University of Calgary,Alberta,Canada

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Peter D. Kirkland,BVSc,PhD

Senior Principal Research Scientist, Officer-in-Charge,Virology Laboratory, Elizabeth Macarthur Agricultural Institute, Menangle, New South Wales, Australia

Congenital and Inherited Anomalies: Akabane Virus Infection Mark D. Kittleson,DVM,PhD, DACVIM (Cardiology)

Professor Emeritus,School of Veterinary Medicine, University of California, Davis, CA

Heart Disease and Heart Failure Kirk C. Klasing, BS,MS, PhD

Histophilosis; Lightning Stroke and Electrocution; Trichomoniasis

Professor of Animal Biology, Department of Animal Science, University of Califor­ nia, Davis, CA

LaRue W. Johnson,DVM, PhD

Nutrition and Management: Nutritional Requirements of Poultri.J

Professor Emeritus, College of Veterinary Medicine and Biomedical Sciences,Colorado State University, Fort Collins,CO

Llamas and Alpacas Richard C. Jones,BSc,PhD,DSc, FRCPath

Emeritus Professor, School of Veterinary Science, University of Liverpool, Leahurst, Neston,Wirral, UK

Malabsorption Syndrome; Viral Arthritis Maureen H. Kemp, BVMS,MVM,PhD, DCHP,MRCVS

Thomas R. Klei, PhD

Boyd Professor and Associate Dean for Research and Advanced Studies, School of Veterinary Medicine and Louisiana Agricultural Experiment Station, Louisiana State University, Baton Rouge, LA

Gastrointestinal Parasites of Horses; Helminths of the Skin Nick J. Knowles, MPhil

Head of Molecular Epidemiology Section, Vesicular Disease Reference Laboratory, The Pirbright Institute,Woking,Surrey, UK

Wern Veterinary Surgeons,Wales,UK

Teschovirus Encephalomyelitis

Laryngeal Disorders

Alexandre Kreiss, BVSc, PhD

Robert J. Kemppainen, DVM, PhD

Professor, Department of Anatomy, Physiology & Pharmacology,College of Veterinary Medicine, Auburn University, Aubum,AL

Endocrine System Introduction; Neuro­ endocrine Tissue Tumors

Research Fellow, Menzies Research Insti­ tute Tasmania, University of Tasmania, Australia

Tasmanian Devils Janice E. Kritchevsky, VMD, MS, DACVIM

Safdar A. Khan,DVM, MS,PhD, DABVf

Professor,Large Animal Medicine,Depart­ ment of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University,West Lafayette, IN

Rodenticide Poisoning; Strychnine Poisoning; Toxicities from Human Drugs

Equine Metabolic Syndrome; The Pituitary Gland: Hirsutism Associated with Adenomas of the Pars Intermedia; The Thyroid Gland: Non-neoplastic Enlargement of the Thyroid Gland

Director of Toxicology Research, ASPCA Animal Poison Control Center,Urbana, Illinois

VetBooks.ir

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CONTRIBUTORS

tomas G. Ksiazek, DVM,PhD ofessor, Department of Pathology,Univer­ Y of Texas Medical Branch, Galveston,TX

imean-Congo Hemorrhagic Fever; ,pah Virus Infection ed F. Kuehn,DVM,MS,DACVIM !Ction Chief,Internal Medicine,Michigan !terinary Specialists, Southfield,MI

3spiratory Diseases of Small Animals; 3spiratory System Introduction iahesh C. Kumar,BVSc,MS,PhD, ACPV onsultant, Poultry Health & Food Safety, t. Cloud, MN

issecting Aneurysm in Turkeys iina Yu-Hsin Kung, PhD,MSc,BVSc, ,VM rincipal Veterinary Epidemiologist, .nimal Biosecurity and Welfare Program, lepartment of Agriculture,Fisheries nd Forestry, Biosecurity Queensland, !ueensland, Australia

lendra Virus Infection ifichelle A. Kutzler, DVM,PhD,DACT lanfield Professor of Companion Animal ndustries, Department of Animal and langeland Sciences,Oregon State Univer­ ;ity, Corvallis, OR

"Janine Transmissible Venereal Tumor; kfammary Tumors; Prostatic Diseases �atalie A. Kwit,DVM,MPH

ri'oot-and-Mouth Disease Gary M. Landsberg,BSc,DVM, MRCVS,DACVB,DECAWBM Veterinary Behaviourist,North Toronto Veterinary Behaviour Specialty Clinic, Thomhill,Ontario,Canada

Behavioral Medicine Introduction; Normal Social Behavior and Behavioral Problems of Domestic Animals Thomas J. Lane,BS, DVM Professor Emeritus, University of Florida, Gainesville,FL

D. Bruce Lawhorn, DVM,MS Relief Veterinarian; Veterinary Informa­ tion Network Swine Consultant, College Station, TX

Potbellied Pigs Andrea S. Lear, DVM Clinical Instructor, Department of Large Animal Clinical Sciences, College of Veterinary Medicine,The University of Tennessee,Knoxville,T N

Bluetongue; Congenital and Inherited Anomalies: Border Disease; Malig­ nant Catarrhal Fever; Sporadic Bovine Encephalomyelitis Margie D. Lee, DVM,PhD Professor of Population Health,Poultry Diagnostic and Research Center,College of Veterinary Me(iicine, University of Geor­ gia,Athens, GA

Avian Campylobacter Infection StevenLeeson, PhD Professor Emeritus, University of Guelph, Ontario,Canada

Fatty Liver Hemorrhagic Syndrome; Nutrition and Management: Nutritional Deficiencies in Poultry MichaelL.Levin,PhD Medical Entomology Laboratory Director, Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, GA

Ticks Julie K. Levy,DVM,PhD,DACVIM Department of Small Animal Clinical Sci­ ences,College of Veterinary Medicine,and Director, Maddie's Shelter Medicine Pro­ gram, University of F1orida, Gainesville, FL

Feline Infectious Peritonitis; Feline Leukemia Virus and Related Diseases MichelLevy,DVM,DACVIM Professor, Department of Veterinary Clini­ cal and Diagnostic Sciences, University of Calgary,Alberta,Canada

Health-Management Interaction: Horses

Polioencephalomalacia

Jimmy C. Lattimer,DVM,MS,DACVR, DACVRO Associate Professor (Radiology and Radia­ tion Oncology),Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia,MO

Alicja E. Lew-Tabor,BSc (Hons),PhD Principal Research Fellow, Queensland Alliance for Agriculture & Food Innova­ tion, The University of Queensland, Brisbane,Queensland,Australia

Diagnostic Imaging; Radiation Therapy

Blood Parasites: Anaplasmosis; Enteric Campylobacteriosis

VetBooks.ir

CONTRIBUTORS

David H. Ley, DVM, PhD Professor, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Mycoplasmosis HuiChu Lin, DVM, MS, DACVAA Professor, Large Animal Anesthesia, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn,AL

Malignant Hyperthermia Dana Lindemann, DVM Resident, Illinois Zoological and Aquatic Animal Residency Program, Wildlife Epidemiology Laboratory, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, IL

Hedgehogs Andrew Linklater, DVM, DACVECC Clinical Instructor, Lakeshore Veterinary Specialists, Glendale, WI

Emergency Medicine Introduction; Evaluation and Initial Treatment of the Emergency Patient; Fluid Therapy; Monitoring the Critically m Animal; Specific Diagnostics and Therapy Jeanne Lofstedt, BVSc, MS, DACVIM (Large Animal) Professor of Large Animal Internal Medicine, Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada

Caprine Arthritis and Encephalitis Maureen T. Long, DVM, PhD, DACVIM Associate Professor, Department of Infec­ tious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL

Equine Arboviral Encephalomyelitis; Meningitis, Encephalitis, and Encepha­ lomyelitis

Ingrid Lorenz, DMV, DMVH, DECBHM Lecturer in Bovine Medicine, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Ireland

Diseases of the Ruminant Forestomach: Ruminal Drinking, Ruminal Parakerato­ sis, Subacute Ruminal Acidosis Jodie Low Choy, BVSc, BVMS, IVAS Cert Menzies School of Health Research; University Avenue Veterinary Hospital, Durack, Northern Territory, Australia

Melioidosis Katharine F. Lunn, BVMS, MS, PhD, MRCVS, DACVIM Associate Professor, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Fever of Unknown Origin; Leptospirosis Robert J. MacKay, BVSc, PhD Professor, Large Animal Medicine, Depart­ ment of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL

Equine Protozoal Myeloencephalitis Charles Mackenzie, BVSc, PhD, ACVM, AO Professor, Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI

Besnoitiosis Kenneth S. Macklin, MSc, PhD Associate Professor, Department of Poul­ try Science, Auburn University, Auburn, AL

Helminthiasis John E. Madigan, DVM, MS Distinguished Professor, Department of Medicine and Epidemiology, School of Vet­ erinary Medicine, University of California, Davis, CA

Equine Granulocytic Ehrlichiosis

Michael R. Loomis, DVM, MA, DACZM Qhief Veterinarian, North Carolina Zoologi­ cal Park, Asheboro, NC

Richard A. Mansmann, VMD, PhD (Hon), DACVIM (Large Animal) Equine Podiatry & Rehabilitation Practice; Clinical Professor Emeritus, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Zoo Animals

?repurchase Examination of Horses

xxix

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CONTRIBUTORS Steven L. Marks, BVSc, MS, MRCVS, DACVIM

Clinical Professor of Emergency and Inter­ nal Medicine; Associate Dean and Director of Veterinary Medical Services, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Anemia; Health-Management Interac­ tion: Small Animats Bret D. Marsh, DVM

Indiana State Veterinarian, Indiana State Board of Animal Health, India­ napolis, IN

?repurchase Examination of Ruminants and Swine Joerg Mayer, DMV, MSc, DABVP (ECM), DECZM (Small Mammal)

Mushtaq A. Memon, BVSc, PhD, DACT

Theriogenologist, Department of Vet­ erinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA

Reproductive Diseases of the Female Small Animal Paula I. Menzies, DVM, MPVM, DECS-RHM

Professor, Ruminant Health Management Group, Department of Population Medi­ cine, Ontario Veterinary College, Univer­ sity of Guelph, Ontario, Canada

Disorders of Calcium Metabolism: Parturi­ ent Paresis in Sheep and Goats; Hepatic Lipidosis: Pregnancy Toxemia in Ewes and Does; Management of Reproduction: Sheep; Posthitis and Vulvitis in Sheep and Goats

Associate Professor of Zoological and Exotic Animal Medicine, Department of Small Animal Medicine & Surgery, College of Veterinary Medicine, University of Geor­ gia, Athens, GA

Professor of Dermatology, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

Rabbits

Dermatophytosis

Milton M. McAllister, DVM, PhD, DACVP

Associate Professor, School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, South Australia, Australia

Neosporosis C. Wayne Mcilwraith, BVSc, PhD, DSc, FRCVS, DACVS, DACVSMR

Department of Clinical Sciences, Oollege of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Arthropathies in Large Animats; Lame­ ness in Horses: Tendinitis

Sandra R. Merchant, DVM, DACVD

Joanne B. Messick, VMD, PhD, DACVP

Associate Professor of Veterinary Clinical Pathology, Department of Comparative Pathobiology, College of Veterinary Medi­ cine, Purdue University, West Lafayette, IN

Blood Parasites: Hemotropic Mycopuismas Samia A. Metwally, DVM, PhD

Senior Animal Health Officer (Virologist), AGAH, AGA Division, Food and Agricul­ ture Organization of the United Nations, Rome, Italy

Nairobi Sheep Disease Patti J. Miller, DVM, PhD

Thomas St. C. McKenna, DVM, PhD

Veterinary Medical Officer, Exotic and Emerging Avian Viral Diseases Research, USDA Agricultural Research Service, Athens, GA

African Horse Sickness

Kelly D. Mitchell, BSc, DVM, DVSc, DACVIM

Assistant Director for New England, Surveillance, Preparedness and Response Services, District 1, USDA, APHIS, Veteri­ nary Services, Sutton, MA

Jennifer H. McQuiston, DVM, MS

Epidemiology Team Leader, Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, GA

Rickettsial Diseases

Newcastle Disease and Other Paramyxo­ virus Infections: Newcastle Disease

Toronto Veterinary Emergency Clinic, Scarborough, Ontario, Canada

Diseases of the Stomach and Intestines in Small Animats: Canine Parvovirus, Feline Enteric Coronavirus, Gastritis in SmaUAnimats, Hemorrhagic Gastroen­ teritis in Small Animats

VetBooks.ir

CONTRIBUTORS Harry W. Momont,DVM,PhD,DACT Clinical Associate Professor, Department of Medical Sciences, School of Veterinary Medi­ cine, University of W1Sconsin, Madison, WI

Reproductive System Introduction Donald R. Monke,DVM,MBA Vice President, Production Operations, Select Sires, Inc., Plain City, Ohio

Seminal Vesiculitis in Bulls James N. Moore,DVM,PhD Distinguished Research Professor, Depart­ ment of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA

Colic in Horses Gaston A. More,MV,DVM Facultad de Ciencias Veterinarias, Labo­ ratorio de Inmunoparasitologia, U niversi­ dad Nacional de La Plata, Buenos Aires, Argentina

Sarcocystosis Karen A. Moriello, DVM,DACVD Professor of Dermatology, Department of Medical Sciences, School of Veterinary Medi­ cine, University of W1Sconsin, Madison, WI

Acantlwsis Nigricans; Atopic Dermatitis; Congenital and Inherited Anomalies of the Integumentary System; Cuterebra Infestation in Small Animals; Derma­ tophilosis; Hygroma; Integumentary System Introduction; Interdigital F'urun­ culosis; Otitis Externa; Otitis Media a.nd Interna; Pyoderma Teresa Y. Morishita,DVM, MPVM,MS, PhD,DACPV Professor of Poultry Medicine & Food Safe­ ty, College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA

Enterococcosis; Streptococcosis James K. Morrisey,DVM,DABVP (Avian) Service Chief, Companion Exotic Animal Medicine Service, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY

Ferrets W. Ivan Morrison,PhD, BVMS Professor, T he Roslin Institute, Royal (Dick) School of Veterinary Studies, Uni­ versity of Edinburgh, Scotland, UK

Blood Parasites: Theileriasis

xxxi

Derek A. Mosier,DVM,PhD,DACVP Professor, Department of Diagnostic Medicine/Pathology, College of Veteri­ nary Medicine, Kansas State University, Manhattan, KS

Hemorrhagic Septicemia Amelia S. Munsterman,DVM,MS, DACVS, DACVECC Clinical Instructor, Equine Emergency and Critical Care, College of Veterinary Medi­ cine, Auburn University, Auburn, AL

Equine Emergency Medicine; Fatigue and Exercise Jeffrey Musser,DVM,PhD Clinical Associate Professor, Department of Veterinary Pathobiology, College of Vet­ erinary Medicine, Texas A&M University, College Station, TX

Vaccination ofExotic Mammals Sofie Muylle,DVM,PhD Faculty of Veterinary Medicine, Depart­ ment of Morphology, Ghent University, Salisburylaan, Merelbeke, Belgium

Dental Development Dusty W. Nagy,DVM,MS,PhD,DACVIM Associate Teaching Professor, Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Mis­ souri, Columbia, MO

Bovine Leukosis T. Mark Neer,DVM,DACVIM Professor and Hospital Director, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK

Demyelinating Disorders; Motion Sickness Robin A. J. Nicholas,MSc,PhD, FRCPath Animal Health and Veterinary Laboratories Agency, Addlestone, Surrey, UK

Contagious Agalactia Paul Nicoletti,DVM,MS,DACVPM

Deceased

Professor Emeritus, College of Veterinary Medicine, University of Florida, Gaines­ ville, FL

Brucellosis in Dogs; Brucellosis in Large Animals

VetBooks.ir

xxxii

CONTRIBUTORS

Michelle Nie Raghnaill, PhD Research Fellow, National Academy of Science, Canberra, Australia

Pharmacology Introduction: Dosage Forms and Delivery Systems, Drug Action and Pharmacodynamics, Nano­ technology Joeke Nijboer, PhD Nutritionist, Rotterdam Zoo, Rotterdam, The Netherlands

Nutrition: Exotic and Zoo Animals Donald L. Noah, DVM, MPH, DACVPM Associate Professor, Public Health, Col­ lege of Veterinary Medicine, Midwestern University,Glendale,AZ

Public Health Primer Lisa K. Nolan, DVM, PhD Dr. Stephen G. Juelsgaard Dean, College of Veterinary Medicine,Iowa State University, Ames,IA

Colibacillosis

Chris Oura, BVetMed, MSc, PhD, MRCVS Senior Lecturer in Veterinary Virology, School of Veterinary Medicine, University of the West Indies, Champ Fleurs,Trinidad

African Swine Fever Rebecca A. Packer, MS, DVM, DACVIM (Neurology) Assistant Professor,Neurology/Neurosur­ gery, Department of Veterinary Clinical Sciences, and Department of Basic Medi­ cal Sciences, School of Veterinary Medi­ cine, Purdue University, West Lafayette,IN

Congenital and Inherited Anomalies of the Nervous System Terri Parrott, DVM Veterinarian, St. Charles Veterinary Hospital, Davenport,FL

Nonhuman Primates Sharon Patton, MS, PhD Professor, Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

Kenneth Opengart, MS, DVM, PhD, DACPV Vice President,Live Operations, Keystone Foods,Huntsville, AL

Amebiasis; Giardiasis

Gangrenous Dermatitis

Vaccines and Immunotherapy

Tanja Opriessnig, DMV, PhD The Roslin Institute, University of Edinburgh, Scotland, UK;; Professor, Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA

Lisa K. Pearson, DVM, MS, PhD, DACT Clinical Instructor,Comparative Therio­ genology, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA

Erysipelothrix rhusiopathiae Jnfection Stephanie R. Ostrowski, DVM, MPVM, DACVPM Associate Professor, Department of Patho­ biology, College of Veterinary Medicine, Auburn University,Auburn,AL

Public Health Primer Gary D. Osweiler, DVM, MS, PhD Professor Emeritus, Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State Univer­ sity, Ames, IA

Coal-Tar Products Poisoning; Mycotoxi­ coses; Petroleum Product Poisoning Raul E. Otalora, DVM Production ManagerNeterinarian, Quail International, Inc., Greensboro, GA

Ulcerative Enteritis

Susan L. Payne, PhD Associate Professor, Veterinary Pathobiology, Texas A&M University, College St.ation, TX

Congenital and Inherited Anomalies of the Digestive System Angela Pelzel-McCluskey, DVM National Epidemiologist for Equine Dis­ eases, USDA,APHIS Veterinary Services, Fort Collins, CO

Vesicular Stomatitis Maurice B. Pensaert, DVM, MS, PhD Emeritus Professor of Animal Virology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium

Porcine Hemagglutinating Encephalo­ myelitis Andrew S. Peregrine, BVMS, PhD, DVM, DEVPC, DACVM Associate Professor, Department of Pathobiology, Ontario Veterinary College, University of Guelph,Ontario, Canada

Gastrointestinal Parasites of Small Animals

VetBooks.ir

CONTRIBUTORS Donald Peter,DVM,MS,DACT Veterinarian/Owner, Frontier Genetics, Hermiston, OR

Bovine Genital Campylobacteriosis; Equine Coital Exanthema Christine Petersen,DVM,PhD Associate Professor, Department of Epidemiology, University of Iowa, Iowa City, IA

Blood Parasites: Trypanosomiasis Mark E. Peterson,DVM,DACVIM Director of Endocrinology and Nuclear Medicine, Animal Endocrine Clinic,New York, NY

The Parathyroid Glands and Disorders of Calcium Metabolism; The Thyroid Gland: Hyperthyroidism, Hypothyroidism Barb ar a D. Petty,DVM North Florida Aquatic Veterinary Services, Fort White,FL

Aquarium Fishes James R. Philips,PhD Associate Professor of Science, Math/ Science Division, Babson College, Babson Park,MA

Air Sac Mite; Ectoparasites of Poultry Carlos R. F. Pinto, MedVet,PhD, DACT Associate Professor, Theriogenology Sec­ tion, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

Embryo Transfer in Farm Animals P aul J. Plummer,DVM,PhD,DACVIM (Large Anim al),DECSRH M Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State Univer­ sity, Ames, IA

Coxiellosis Robert E. Porter,DVM,PhD,DACVP, DACP V Clinical Professor,Veterinary Popula­ tion Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN

Perirenal Hemon·hage Syndrome of Tur­ keys; Poisonings (Poultry)

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Karen W. Post ,DVM,MS,DACVM Director of Laboratories, Veterinary Bacteriologist,North Carolina Veterinary Diagnostic Laboratory System; Consumer Services, Rollins Animal Disease, Diagnos­ tic Laboratory, Raleigh, NC

Diagnostic Procedures for the Private Practice Laboratory: Clinical Microbiol­ ogy David G. Pugh,DVM,MS, MAg, DACT, DACVN,DACVM Department of Pathobiology, College of Veterinary Medicine,Auburn University, Aubum,AL

Nutrition: Goats; Nutrition: Sheep Sarah L. R alston,VMD,PhD,DACVN Professor,Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers University, New Bruns­ wick, NJ

Nutrition: Horses John F. Randolph,DVM,DACVIM Professor,Department of Clinical Sci­ ences, College of Veterinary Medicine, Cornell University,Ithaca,NY

Erythrocytosis and Polycythemia Silke R autenschle in,DVM,PhD Professor,Clinic for Poultry, University of Veterinary Medicine, Hannover, Germany

Avian Metapneumovirus Willie M. Reed,DVM,PhD,DACVP, DACP V Dean, College of Veterinary Medicine, Purdue University, West Lafayette, IN

Quail Bronchitis; Turkey Viral Hepatitis Philip T. Reeves ,BVSc (Hons),PhD, FA NZCVS Chief Regulatory Scientist, Veterinary Medicines and Nanotechnology, Austra­ lian Pesticides and Veterinary Medicines Authority, Canberra, Australia

Phannacology Introduction: Chemical &sidues in Food and Fiber; Dosage Fonns and Delivery Systems, Drug Action and Phannacodynamics, Nanotechnology Mason V. Reichard, PhD Associate Professor, Department of Veteri­ nary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State Univer­ sity,Stillwater,OK

Cattle Grubs; Mange in Large Animals

VetBooks.ir

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CONTRIBUTORS

Hugh W. Reid,MBE,BVM&S,DT VM, PhD,MRCVS Moredun Research Institute, Pentlands, Science Park, Penicuik, UK Louping nz

Guillermo R. Risatti,MV,MS,PhD Associate Professor, Department of Patho­ biology and Veterinary Science, University of Connecticut, Storrs, CT Classical Swine Fever

Douglas J. Reinemann,PhD Professor and Chair, Department of Biological Systems Engineering, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI Stray Voltage in Animal Housing

Narda G. Robinson,DO,DVM,MS College of Veterinary Medicine and Bio­ logical Sciences, Colorado State Univer­ sity, Fort Collins, CO Complementary and Alternative Veteri­ nary Medicine

Christopher D. Reinhardt,BS,MS, PhD Assistant Professor and Extension Feedlot Specialist, Animal Sciences and Industry, Kansas State University, Manhattan, KS Growth Promotants and Production Enhancers

Kursten V. Roderick, DVM Cardiology Resident, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA Cardiovascular System Introduction; Thrombosis, Embolism, and Aneurysm

Petra Reinhold,DVM,PhD Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Jena, Germany Chlamydiosis Alexander M. Reiter,DT, DMv, DAVDC, DEVDC Chief, Dentistry and Oral Surgery Service, Ryan Veterinary Hospital, School.of Veteri­ nary Medicine, University of Pennsylvania, Philadelphia, !'A Dentistry: Dentistry in Small Animals; Diseases of the Mouth in Small Animals Marcio Garcio Ribeiro, DVM,PhD Professor, Infectious Diseases of Domes­ tic Animals, Department of Veterinary Hygiene and Public Health, School of Veterinary Medicine and Animal Sciences, Siio Paulo State University - UNESP, Botu­ catu, Siio Paulo, Brazil Nocardiosis; Rhodococcosis Franklin Riet-Correa,PhD Professor, Veterinary Hospital, Federal University of Campina Grande, Patos, Paraiba, Brazil Cattle Grubs: Lechiguana Yasuko Rikihisa,PhD Professor, Veterinary Biosciences, The Ohio State University, Columbus, OH Rickettsial Diseases: Salmon Poisoning Disease and Elokomin Fluke Fever

Camille Roesch,PhD Nanosafety Pharmacist Consultant, Aus­ tralian Pesticides and Veterinary Medi­ cines Authority, Symonston, Australia Pharmaco'logy Introduction: Dosage Forms and Delivery Systems, Drug Action and Phmmacodynamics, Nano­ technology Peter Rolls,BVSc,MVS Veterinary Officer, Tick Fever Centre, Department of Agriculture, Fisheries and Forestry, Biosecurity Queensland, Waco!, Queensland, Australia Blood Parasites: Babesiosis Juan E. Romano,DVM,MS,PhD, DACT Associate Professor, Department of Large Animal Clinical Sciences, College of Vet­ erinary Medicine, Texas A&M University, College Station, T_X Hormonal Control of Estrus A. Gregorio Rosales,DVM,MS,PhD, DACPV Vice President of Veterinary Services, Aviagen Inc., Huntsville, AL Disorders of the Reproductive System (Poultry) Stanley I. Rubin,DVM,MS,DACVIM Clinical Professor, Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL Digestive System Introduction; Diseases of the Rectum and Anus

VetBooks.ir

CONTRIBUTORS Pamela L. Ruegg, DVM, MPVM Professor, Department of Dairy Science, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI

Udder Diseases Charles E. Ruppr echt, VMD, MS, PhD Director, LYSSA LLC, Lawrenceville, GA

Rabie-s Bonnie R. Rush, DVM, MS, DACVIM Professor, Equine Internal Medicine, Col­ lege of Veterinary Medicine, Kansas State University, Manhattan, KS

Respiratory Diseases of Horses Y. M. Saif, DVM, PhD Professor Emeritus, Food Animal Health Research Program, The Ohio State Univer­ sity, Wooster, OH

Rotaviral Injections in Chickens, Turkeys, and Pheasants Jeremiah T. Saliki, DVM, PhD, DACVM Professor and Director, Athens Veterinary Diagnostic Laboratory, University of Georgia, Athens, GA

Peste des Petits Ruminants; Rinderpest Jean E. Sander, DVM, MAM, DACPV Dean, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK

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Charles M. Scanlan, DVM, PhD Professor, Department of Veterinary Pathobiology, College of Veterinary Medi­ cine and Biomedical Sciences, Texas A&M University, College Station, TX

Meat Inspection Karel A. Schat, DVM, PhD Professor, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY

Chicken Anemia Virus Injection Mary M. Schell, DVM, DABVT, DABT Senior Toxicologist, ASPCA Animal Poison Control Center, Urbana, Illinois

Rodenticide Poisoning David G. Schmitz, DVM, MS, DACVIM (Large Animal) Visiting Associate Professor, Department of Veterinary Large Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, TX

Cantharidin Poisoning T homas Schubert, DVM, DACVIM, DABVP Clinical Professor and Chief of Neurology Service, Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL

Candidiasis; Disposal of Carcasses and Disinfection of Premises; Omphalitis

Facial Paralysis; Limb Paralysis; Nervous System Introduction

Sherry Lynn Sanderson, BS, DVM, PhD, DACVIM, DACVN Associate Professor, Physiology and Phar­ macology, College of Veterinary Medicine, University of Georgia, Athens, GA

James Schumacher, DVM, MS Professor, Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

Nutrition: Small Animals; Urinary System Introduction

Lameness in Horses: Regional Anesthesia

Yuko Sato, DVM, MS, DACPV Assistant Professor, Veterinary Diagnostic & Production Animal Medicine, Poultry Extension and Diagnostics, Iowa State University, Ames, IA

John Schumacher, DVM, MS Professor, Department of Clinical Sci­ ences, College of Veterinary Medicine, Auburn University, Auburn, AL

Backyard Poultry Ashley B. Saunders, DVM, DACVIM (Cardiology) Associate Professor of Cardiology, Depart­ ment of Small Animal Clinical Sciences, College of Veterinary Medicine and Bio­ medical Sciences, Texas A&M University, College Station, TX

Systemic Pharmacotherapeutics of the Cardiovascular System

Lameness in Horses: Regional Anesthesia Philip R. Scott, BVM&S, MPhil, DVM&S, DSHP, DECBHM, FHEA, FRCVS Veterinary Clinical Sciences, University of Edinburgh, Midlothian, UK

Aspiration Pneumonia; Contagious Ecthyma; Listeriosis; Mycotic Pneu­ monia; Respiratory Diseases of Sheep and Goats; Ulcerative Dermatosis of Sheep

VetBooks.ir

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CONTRIBUTORS

Joaquim Segales, DVM, PhD, DECVP, DECPHM Facultat de Veterinaria, Departament de Sanitat i d'Anatomia Animals and Centre de Recerca en Sanitat Animals, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain

Gliisser's Disease; Porcine Circovirus Diseases Patricia L. Sertich, MS, VMD, DACT Associate Professor-Clinician Educator, Department of Clinical Studies, New Bolton Center, School of Veterinary Medi­ cine, University of Pennsylvania, Kennett Square, PA

Management of Reproduction: Horses Torsten Seuberlich, DMV Professor, NeuroCentre, Division of Neurological Sciences, OIE Reference Laboratories for BSE and Scrapie; Vet­ suisse Faculty, Department of Clinical Research and Veterinary Public Health, University of Berne, Berne, Switzer­ land

Bovine Spongiform Encephalopa.thy A. S. Shakespeare, BSc (Eng) (Natal), BVSc (Hons) (Pret), MMedVet (Med) (Pret) Onderstepoort Veterinary Faculty, Univer­ sity of Pretoria, South Africa

Heartwater Linda Shell, DVM, DACVIM (Neurol­ ogy) Professor, Small Animal Internal Medi­ cine, Ross University School of Veterinary Medicine, Basseterre, Saint Kitts and Nevis

H. L. Shivaprasad, BVSc, MS, PhD, DACPV Professor, California Animal Health and Food Safety Laboratory System, University of California, Tulare, CA

Hemon-hagic Enteritis/Marble Spleen Disease Wayne Simpson, MSc (Microbiology), BHort Sc, DHort Scientist, Endophyte Mycology, Forage Improvement Section, AgResearch Lim­ ited, Palmerston North, New Zealand

Ryegrass Toxicity Annette N. Smith, DVM, MS, DACVIM Professor, Department of Clinical Sci­ ences, College of Veterinary Medicine, Auburn University, Auburn, AL

Neopi,asia of the Nervous System; Paraneo­ p/,astic Disorders of the Nervous System Geof W. Smith, DVM, PhD Associate Professor of Ruminant Medi­ cine, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Actinobacillosis; Actinomycosis Joan A. Smyth, PhD Director, Connecticut Veterinary Medi­ cal Diagnostic Laboratory, Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT

Egg Drop Syndrome '76 Victoria Smyth, PhD Senior Scientific Officer for Avian Virology, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast, UK

Systemic Pharmacotherapeutics of the Nervous System

Avian Nephritis Viral Infections

Clifford F. Shipley, DVM, DACT Clinical Associate Professor, Agricultural Animal Care and Use Program and Col­ lege of Veterinary Medicine, University of Illinois, Urbana, IL

Arthur M. Spickett, BSc (Hons) Zoology Parasites, Vectors and Vector-borne Diseases Programme, ARC-Onderstepoort Veterinary Institute, South Africa

Management of Reproduction: Goats

Sweating Sickness

Michael Shipstone, BVSc, FACVSc, DACVD Queensland Veterinary Specialists, Bris­ bane, Queensland, Australia

Anna Rovid Spickler, DVM, PhD Veterinary Specialist, Center for Food Security and Public Health, College of Veterinary Medicine, Iowa State Univer­ sity, Ames, IA

Systemic Pharmacotherapeutics of the Integumentary System

Zoonoses

CONTRIBUTORS

VetBooks.ir

Sharon J. Spier, DVM, PhD, DACVIM

Jamie Lynn Stewart , DVM

Professor,Department of Medicine and Epidemiology, School of Veterinary Medi­ cine, University of California, Davis,CA

Department of Veterinary Clinical Medicine, College of Veterinary Medicine. University of Illinois, Urbana, IL

Disorders of Ca!,eium Metabolism: Hypo­ ca/.cemic Tetany in Horses; Lymphadeni­ tis and Lymphangitis: Corynebacterium pseudotuberculosis Infection of Horses and Cattle

Management of Reproduction: Goats

Richard A. Squires , B VSc (Hons), PhD, DVR, DACVIM, DECVIM-CA, GCert Ed, MR CVS

Nutrition and Management Poultry: Feeding and Management Practices

Head of Veterinary Clinical Sciences, School of Veterinary and Biomedical Sci­ ences, James Cook University, Townsville, Australia

Bruce Stewart-Brown , DVM, DACP V

Senior Vice President of Food Safety, Qm ity, and Live Operations, Perdue Farms, Salisbury, MD

Roger W. Stitch , MS, PhD

Feline Panleukopenia

Professor of Parasitology, Department of Veterinary Pathobiology, College of Vet­ erinary Medicine, University of Missouri, Columbia,MO

Henry R. Stiimpfli, DVM, DMV, DACVIM

Ectoparasiticides: Ectoparasiticides Used in Large Animals

Professor,Large Animal Medicine, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Ontario,Canada

Clostridial Diseases

Michael K. Stoskopf, DVM, PhD, DACZ!

Professor of Wildlife and Aquatic Health, Director of the Environmental Medicine Consortium, College of Veterinary Medicine North Carolina State University, Raleigh, N(

Jonathan Statham , MA, Vet MB , DCHP, MR CVS

Marine Mammals

Cystic Ovary Disease; Management of Reproduction: Cattle

Professor of Neuroscience, Comparative Biomedical Sciences, School of Veterina!J Medicine, Louisiana State University, Baton Rouge, LA

Bryan L. Stegelmeier, DVM, PhD, DACVP

Deafness

Bracken Fern Poisoning; Sweet Clover Poisoning

Professor and Head for Bacteriology and Mycology, Institute for Infectious Dis­ eases and Zoonoses,Faculty of Veterinar: Medicine, Ludwig-Maximilians University Munich, Germany

Veterinarian, Bishopton Veterinary Group, North Yorkshire, UK

Veterinary Pathologist, Poisonous Plant Research Laboratory, USDA-ARS, Logan, UT

Jorg M. Steiner, DMV, PhD, DACVIM, DECVIM-CA, AGAF

Associate Professor and Director, Gas­ trointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX

The Exocrine Pancreas Allison J. Stewart , B VS C (Hons), MS , DACVIM (Large Animal), DACVECC

Professor of Equine Internal Medicine, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Aubum,AL

Disorders of Magnesium Metabolism; Intestinal Diseases in Horses and Foals

George M. Strain , PhD

Reinhard K. Straubinger, DMVH, PhD

Lyme Borreliosis Bert E. Stromberg , PhD

Professor,Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN

Infectious Diseases of the Urinary System in Large Animals: Swine Kidney Worm Infection; Trichinellosis David E. Swayne , DVM, PhD, DACVP, DACP V

Laboratory Director, USDA-ARS, Southeas1 Poultry Research Laboratory, Athens, GA

Avian Influenza; Newcastle Disease and Other Paramyxovirus Infections: Other Avian Paramyxovirus Infections

xxxvii

VetBooks.ir

xxxviii

CONTRIBUTORS

Thomas W. Swerczek, DVM, PhD Professor, Department of Veterinary Sci­ ence, University of Kentucky, Lexington, KY T'yzzer Disease Jane E. Sykes,BVSc (Hons), PhD, DACVIM Professor of Small Animal Medicine, Department of Medicine and Epidemi­ ology, School of Veterinary Medicine, University of California, Davis, CA Chlamydial Conjunctivitis Joseph Taboada, DVM, DACVIM Professor and Associate Dean, Office of Student and Academic Affairs, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA Fungal lrifections Jaime L. Tarigo, DVM, PhD, DACVP Assistant Professor, Veterinary Clinical Pathology, University of Georgia, Athens, GA Blood Parasites: Cytauxzoonosis Marcel Taverne, PhD Emeritus Professor of Fretal and Perinatal Biology, Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Pseudopregnancy in Goats Charles 0. Thoen, DVM, PhD Professor, Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA Tuberculosis and other Mycobacterial lrifections; Tuberqulosis in Poultry Jennifer E. Thomas, DVM Post-Doc Fellow, Department of Veteri­ nary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State Univer­ sity, Stillwater, OK Lice; Mange in Large Animals William B. Thomas, DVM, MS, DACVIM (Neurology ) Professor, Neurology and Neurosurgery, Department of Small Animal Clinical Sci­ ences, University of Tennessee, Knoxville, TN Diseases of the Peripheral Nerves and Neuromuscular Junction; Diseases of the Spinal Column and Cord Sara M. Thomasy, DVM, PhD, DACVO Vision Researcher, Department of Surgical and Radiological Sciences, School of Vet-

erinary Medicine, University of California, Davis, CA Equine Recurrent Uveitis Larry J. Thompson, DVM, PhD, DABVT Senior Research Scientist, Nestle Purina PetCare, St. Louis, MO Nitrate and Nitrite Poisoning; Nonpro­ tein Nitrogen Poisoning; Salt Toxicity Peter N. Thompson, BVSc, MMv, PhD Professor of Veterinary Epidemiology, Faculty of Veterinary Science, University of Pretoria, South Africa Rift Valley Fever; Wesselsbron Disease Ahmed Tibary, DMV, PhD, DACT Professor, Comparative Theriogenology, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA Abortion in Large Animals; Congenital and Inherited Anomalies of the Repro­ ductive System John F. Timoney, MVB, PhD, Dsc, MRCVS Keeneland Chair of Infectious Diseases, Gluck Equine Research Center, Depart­ ment of Veterinary Science, University of Kentucky, Lexington, KY Glanders Peter J. Timoney, MVB (Hons), MS, PhD,FRCVS Professor; Frederick Van Lennep Chair in Equine Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY Equine Irifectious Anemia; Equine Viral Arteritis Ian Tizard, BVMS, PhD, DACVM University Distinguished Professor of Immunology; Director, Richard M. Schubot Exotic Bird Health Center, Department of Veterinary Pathobiology, College of Veteri­ nary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX Amyloidoses; Immunologic Diseases; The Biology of the Immune System; Vaccines and Immunotherapy Sheila M. F. Torres, DVM, MS, PhD, DACVD Associate Professor, Dermatology, College of Veterinary Medicine, University of Min­ nesota, St. Paul, MN Diseases of the Pinna

VetBooks.ir

CONTRIBUTORS Jerry L. Torrison,DVM,PhD,DACVPM

Swine Veterinarian, Zinpro Corporation; Adjunct Professor, College of Veterinary Medicine, University of Minnesota, St. Paul, MN

Lameness in Pigs Sandra P. Tou,DVM,DACVIM

Assistant Clinical Professor of Cardiology, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Congenital and Inherited Anomalies of the Cardiovascular System Josie L. Traub-Dargatz,DVM,MS, DACVIM

Professor of Equine Medicine, Depart­ ment of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Vesicular Stomatitis Robert Tremblay,DVM, DVSc, DACVIM

Bovine/Equine Specialist, Boehringer lngelheim (Canada) Ltd, Burlington, Ontario, Canada

Arnaud J. Van Wettere,DVM,MS,PhD, DACVP

Assistant Professor of Veterinary Pathology, Utah Veterinary Diagnostic Laboratory, Utah State University, Logan, UT

Avian Chlamydiosis; Bloodborne Organ­ isms; Disorders of the Skeletal System (Poultry); Myopathies (Poultry) Jozef Vercruy sse,DVM

Professor, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium

Anthelmintics; Blood Parasites: Shisto­ somiasis Alice E. Villalobos,DVM,DPNAP

Director, Animal Oncology Consultation Service; Director, Pawspice, Hermosa Beach, CA

Tumors of the Skin and Soft Tissues Pedro Villegas,DVM,MS,PhD, DACVM,DACPV

Professor Emeritus, Department of Population Health, College of Veterinary Medicine, Poultry Diagnostic & Research Center, University of Georgia, Athens, GA

Management and Nut1·ition Introduction

Inclusion Body Hepatitis/Hydropericar­ dium Syndrome

Deoki N. Tripathy,DVM,MS,PhD, DACVM,DACPV

Patricia S. Wakenell,DVM,PhD, DACVP

Professor Emeritus, Department of Veteri­ nary Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, IL

Fowlpox Thomas N. Tully,Jr.,BS,DVM,MS, DABVP (Avian), DECZM (Avian)

Head, Avian Diagnostics, Animal Disease Diagnostic Laboratory; Associate Profes­ sor, Department of Comparative Patho­ biology, School of Veterinary Medicine, Purdue University, West Lafayette, IN

Backyard Poultry; Erysipelas

Professor, Zoological Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

Peter J. Walker,BSc,PhD,DSc

Ratites

Bovine Ephemeral Fever

Tracy A. Turner,DVM,MS

Anoka Equine Veterinary Services, Elk River, MN

Lameness in Horses: Imaging Techniques Stephanie J. Valberg,DVM,PhD, DACVIM,ACVSMR

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CSIRO Biosecurity, Australian Animal Health Laboratory, Victoria, Australia

Patricia Walters,VMD,DACVIM, DACVECC

New England Animal Medical Center, West Bridgewater, MA

Diseases of the Esophagus in Small Animals Kevin Washburn, DVM

Professor, Department of Veterinary Popu­ lation Medicine, University of Minnesota Equine Center, St. Paul, MN

Professor, Large Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, TX

Myopathies in Horses; Myopathies in Ruminants and Pigs

Lymphadenilis and Lymphangitis: Gase­ ous Lymphadenitis

VetBooks.ir

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CONTRIBUTORS

Nick Whelan, BVSc, MVSc, MACVSc, DACVCP, DACVO

Thomas Wittek, Univ.-Prof. Dr.med. vet., DECBHM

Animal Eye Clinic of Waterloo Region, Cambridge, Ontario, Canada

University Clinic for Ruminants, Universi­ ty of Veterinary Medicine, Vienna, Austria

Systemic Pharmacotherapeutics of the Eye

Malassimilation Syndromes in Large Animals; Peritonitis

Brent R. Whitaker, MS, DVM

Zerai Woldehiwet, DVM, PhD, DAgric, MRCVS

Vice President of Biological Programs, National Aquarium, Baltimore, MD Amphibians Thevor J. Whitbread, BSc, BVSc, MRCVS, DECVP

Pathologist, Abbey Veterinary Services, Devon, UK Diagnostic Procedures for the Private Practice Laboratory: Clinical Biochem­ ist1y, Clinical Hematology, Cytology, Serology, Urinalysis Stephen D. White, DVM, DACVD

Professor and Chief of Service, Dermatology, Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA Eosinophilic Granuloma Complex; Food Allergy; Miscellaneous Systemic Derma­ toses; Nasal Dermatoses of Dogs; Saddle Sores; Seborrhea; Urticaria Chris Whitton, BVSc, FANZCVS, PhD

Associate Professor, Equine Centre, Uni­ versity of Melbourne, Victoria, Australia Lameness in Horses: Developmental Orthopedic Disease Mark L. Wickstrom, DVM, MS, PhD

Associate Professor, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada Antiseptics and Disinfectants

Professor, Institute of Infection and Global Health and School of Veterinary Science, University of Liverpool, Wirral, UK Tick Pyemia; Tickborne Fever R. Darren Wood, DVM, DVSc, DACVP

Associate Professor, Department of Pathobiology, Ontario Veterinary College, University of Guelph, Ontario, Canada Leukocyte Disorders Peter R. Woolcock, BSc, MSc, PhD

Professor, Clinical Diagnostic Virology, California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, CA Duck Viral Hepatitis Mariko Yamamoto, PhD

Department of Population Health and Reproduction, School of Veterinary Medi­ cine, University of California, Davis, CA The Human-Animal Bond Roy P. E. Yanong, VMD

Associate Professor and Extension Veteri­ narian, Tropical Aquaculture Laboratory, Fisheries and Aquatic Sciences Program, School of Forest Resources and Conserva­ tion, Institute of Food and Agricultural Sci­ ences, University of Florida, Gainesville, FL Aquaculture Laszlo Zsak, DVM, PhD

Surgeon, Georgia Veterinary Specialists, Atlanta, GA

Research Leader, USDA-Agricultural Research Center, South Atlantic Area, Southeast Poultry Research Laboratory, Athens, GA

Wound Management

Goose Parvovirus Infection

Kevin P. Wrnkler, DVM, DACVS

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CIRCULATORY SYSTEM THE BLOOD AND LYMPHATICS

HEMATOPOIETIC SYSTEM IN TRODUCTION 4

Red Blood Cells 4 White Blood Cells 5 Platelets 7

ANEMIA

7

Regenerative Anemias 9 Blood Loss Anemia 9 Hemolytic Anemia 10 Nonregenerative Anemias 12 Nutritional Deficiencies 12 Anemia of Chronic Disease 13 Renal Disease 13 Primary Bone Marrow Diseases 13

BLOOD GROUPS AND BLOOD TRANSFUSIONS 15

Blood Typing 16 Crossmatching 16 Blood Transfusions 17 Blood Substitutes 18

18 Anaplasmosis 18 Babesiosis 21 Cytauxzoonosis · 23 Equine Granulocytic Ehrlichiosis 697 (GEN) Hemotropic Mycoplasmas 26 Feline Infectious Anemia 28 Old World Hepatozoonosis and American Canine Hepatozoonosis 29 Rickettsial Diseases 803 (GEN) Schistosomiasis 31 Theileriases 33 East Coast Fever 34 Tropical Theileriosis 35 Other Theileriases of Cattle 35 Ovine and Caprine Theileriases 35 Equine Theileriasis 35 Trypanosomiasis 35 Tsetse-transmitted Trypanosomiasis 35 Surra 38 Dourine 38 Chagas' Disease 38 Nonpathogenic Trypanosomes 40

BLOOD PARASI TES

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CIRCULATORY SYSTEM

BOVINE LEUKOSIS

743 (GEN)

CANINE LYMPHOMA

40

EQUINE INFECTIOUS ANEMIA 699 (GEN) ERYTHROCYTOSIS AND POLYC YTHEMIA

43

FELINE LEUKEMIA VIRUS AND RELATED DISEASES

790 (GEN)

HEMOSTATIC DISORDERS 44 Coagulation Disorders 46 Platelet Disorders 46 Vascular Disorders 50 Coagulation Protein Disorders 51 Pathologic Thrombosis 54 LEUKOCYTE DISORDERS 56 Physiology of Leukocytes 56 Blood Vascular System 56 Granulocytes 56 Monocytes 57 Lymphocytes 57 Leukogram Abnormalities 57 Specific Interpretive Leukogram Responses

59

LYMPHADENITIS AND LYMPHANGITIS 63 Caseous Lymphadenitis of Sheep and Goats 63 Corynebacterium pseudotuberculosis Infection of Horses and Cattle Epizootic Lymphangitis 639 (GEN) Melioidos.is 661 (GEN) Strangles 1453 (RES) Streptococcus porcinus Infection of Pigs 734 (GEN) THE HEART AND VESSELS CARDIOVASCULAR S YSTEM INTRODUCTION 67 Abnormalities of the Cardiovascular System 70 Common Endpoints of Heart Disease 73 Heart Failure, Congestive Heart Failure, and the Failing Heart 73 Diagnosis of Cardiovascular Disease 73 Principles of Therapy 74 Common Therapeutic Agents 75 CONGENITAL AND INHERITED ANOMALIES Outflow Tract Obstructions 78 Aortic Stenosis 78 Pulmonic Stenosis 78 Coarctation of the Aorta 79 Left-to-Right Shunts 79 Patent Ductus Arteriosus 79

76

66

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CIRCULATORY SYSTEM

Ventricular Septal Defects 81 Atrial Septal Defects 82 Right-to-Left Shunts 83 Tetralogy of Fallot 83 Other Cyanotic Heart Diseases 84 Conditions of the AtrioventricularValves 84 MitralValve Dysplasia 84 Tricuspid Valve Dysplasia 84 MitralValve Stenosis 85 Vascular RingAnomalies 85 Persistent Right �ortic Arch 85 Miscellaneous Congenital Cardiac Abnormalities 86 87 Diagnosis 87 History and Signalrnent 87 Physical Examination 87 Radiography 91 Electrocardiography 92 Echocardiography 98 Cardiac Catheterization 99 Heart Failure 99 Systolic Dysfunction 99 Diastolic Dysfunction 100 Compensatory Mechanisms 100 Cardiac Biomarkers 101 Clinical Manifestations 101 Management 103 Specific Cardiac Diseases 112 MyxornatousAVValve Degeneration 112 Valvular Blood Cysts or Hematomas 115 Cardiomyopathies 115 Myocarditis 119 Other Causes of Myocardial Failure 120 Infective Endocarditis 121 Pericardial Disease 122 Systemic and Pulmonary Hypertension 125 Arterial Thromboembolism 126

HEART DISEASE AND HEART FAILURE

HEARTWORM DISEASE

127

BOVINE HIGH-MOUNTAIN DISEASE

137

THROMBOSIS, EMBOLISM, AND ANEURYSM 141

3

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HEMATOPOIETIC SYSTEM INTRODUCTION

HEMATOPOIETIC SYSTEM INTRODUCTION Blood supplies cells with water, electro­ lytes, nutrients, and hormones and removes waste products. The cellular elements supply oxygen (RBCs), protect against foreign organisms and antigens (WBCs), and initiate coagulation (platelets). Because of the diversity of the hematopoietic system, its diseases are best discussed from a functional perspective. Function may be classified as either normal responses to abnormal situations (eg, leukocytosis and left shift in response to inflammation) or primary abnormalities of the hematopoietic system (eg, pancytopenia from marrow failure). Furthermore, abnormalities may be quantitative (ie, too many or too few cells) or qualitative (ie, abnormalities in function).

RED BLOOD CELLS The function of RBCs is to carry oxygen to the tissues at pressures sufficient to permit its rapid diffusion. This is accomplished through the following mechanisms: a carrier molecule, hemoglobin (Hgb); a vehicle (RBC) capable of bringing the intact Hgb to the cellular level; and a metabolism geared to protect both the RBC and the Hgb from damage. Interference with synthesis or release of Hgb, production or survival of RBCs, or metabolism causes disease. Hgb is a complex molecule, formed of four heme units attached to four globins (two a and two f3 globins). Iron is added in the last step by the ferrochelatase enzyme. Interference with the normal production of heme or globin leads to anemia. Causes include copper or iron deficiency and lead poisoning. Hemoglobinopathies such as thalassemias and sickle cell anemia, important genetic diseases of people, have not been seen in other animals. In these diseases, the production of globins (a or f3 or both) does not balance heme production, and the Hgb is not functional. The only known hemoglobinopathy of animals is porphyria. Although described in several species, it is most important as a cause of photosensitivity in cattle (seep 976). Red cell mass, and thus oxygen-carrying capacity, remains constant over time in healthy animals. Mature RBCs have a finite life span; their production and destruction must be carefully balanced, or disease ensues. Erythropoiesis is regulated by erythropoi­ etin, which increases in the presence of hypoxia and regulates RBC production. In

most species, the kidney is both the sensor organ and the major site of erythropoietin production, so chronic renal failure is associated with anemia. Erythropoietin acts on the marrow in concert with other humoral mediators to increase the number of stem cells entering RBC production, to shorten maturation time, and to cause early release of reticulocytes. Other factors that affect erythropoiesis are the supply of nutrients (eg, iron, folate, or vitamin B 12) and cell-cell interactions between erythroid precursors, lymphoid cells, and other components of the hematopoietic microen­ vironment. Factors that may suppress erythropoiesis include chronic debilitating diseases and endocrine disorders (such as hypothyroidism or hyperestrogenism). 1\vo mechanisms exist for removal of senescent RBCs; both conserve the principal constituents of the cell for reuse. Removal of aged RBCs normally occurs by phagocytosis by the fixed macrophages of the spleen. As the RBC ages it may change antigenically,acquiring senescent antigens and losing its flexibility due to impaired ATP production. Both of these changes increase the risk that the cell will become trapped in the spleen and removed by macrophages. After phagocytosis and subsequent disruption of the cell membrane, Hgb is converted to heme and globin. Iron is released from the heme ni.oiety and either stored in the macrophage as ferritin or hemosiderin or released into the circulation for transport back to the marrow. The remaining heme is converted to bilirubin, which is released by the macrophages into the systemic circulation, where it complexes with albumin far transport to the hepato­ cytes; there, it is cor\jugated and excreted into the bile. In extravascular hemolytic anemias, RBCs have a shortened life span, and the same mechanisms occur at an increased rate. Approximately 1% of normal aging RBCs are hemolyzed in the circulation, and free Hgb is released. This is quickly converted to Hgb dimers that bind to haptoglobin and are transported to the liver, where they are metabolized in the same manner as products from RBCs removed by phagocytosis. In intravascular hemolytic anemia, more RBCs are destroyed in the circulation (hemoglobinemia) than can be bound to haptoglobin. The excess Hgb and, therefore, iron are excreted in the urine (hemoglobinuria).

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HEMATOPOIETIC SYSTEM INTRODUCTION

The principal metabolic pathway of RBC is glycolysis, and the main energy source in most species is glucose. Glucose enters the RBC by an insulin-independent mechanism, and most is metabolized to produce ATP and reduced nicotinamide adenine dinucleotide (NADH). The energy of ATP is used to maintain RBC membrane pumps so as to preseive shape and flexibility. The reducing potential of the NADH is utilized via the methemoglobin reductase pathway to maintain the iron in Hgb in its reduced form (Fe2•). The glucose not used in glycolysis is metabolized via a second pathway, the hexose monophosphate (HMP) shunt. No energy is produced via the HMP shunt; its principal effect is to maintain reducing potential in the form of reduced nicotina­ mide adenine dinucleotide phosphate (NADPH). In conjunction with the glutathione reductase/peroxidase system, NADPH maintains the sulfhydryl groups of globin in their reduced state. Some disorders are the direct result of abnormal RBC metabolism and interference with glycolysis. Inherited deficiency of pyruvate kinase, a key glycolytic enzyme, causes ATP deficiency, which leads to reduced RBC life span and hemolytic anemia. Excessive oxidant stress may overload the protective HMP shunt or methemoglobin reductase pathways, causing Heinz body hemolysis or methemo­ globin formation, respectively. Hemolytic anemia caused by a drug, such as acetamin­ ophen in cats, is an example of this mechanism. (See also ANEMIA, p 7.) A decreased RBC mass (anemia) may be caused by blood loss, hemolysis, or decreased production. In acute blood loss anemia, RBCs are lost, but mortality is usually related to loss of circulating volume rather than to loss of RBC. Iron is the limiting factor in chronic blood loss. Hemolysis may be caused by toxins, infectious agents, congenital abnormali­ ties, or antibodies directed against RBC membrane antigens. Decreased RBC production may result from primary marrow diseases (eg, aplastic anemia, hematopoietic malignancy, or myelofibro­ sis) or from other causes such as renal failure, drugs, toxins, or antibodies directed against RBC precursors. Malignancy of RBCs or their precursors may be acute (eg, erythroleukemia) or chronic (eg, polycythemia vera). Animals with erythroleukemia are anemic despite having a marrow filled with tubriblasts, whereas those with polycythemia vera have erythrocytosis.

WHITE BLOOD CELLS Phagocytes: The principal function of phagocytes is to defend against invading microorganisms by ingesting and destroying them, thus contributing to cellular inflammatory responses. There are two types of phagocytes: mononuclear phagocytes and granulocytes. Mononuclear phagocytes arise primarily from the marrow and are released into the blood as mono­ cytes. They may circulate for hours to a few days before entering the tissues and differentiating to become macrophages. Granulocytes have a segmented nucleus and are classified according to their staining characteristics as neutrophils, eosinophils, or basophils. Neutrophils circulate for only a few hours before travelling to the tissues. Five distinct stages in the process of phagocytosis have been identified: 1) attraction of phagocytes (chemotaxis) to microorganisms, antigen-antibody complexes, and other mediators of inflammation; 2) attachment to the organism; 3) ingestion; 4) fusion of cell lysosomes with ingested microorganisms and bacterial killing; and 5) digestion. In addition, many phagocytes have other specialized functions. Monocytes form a link to the specific immune system by processing antigen for presentation to lymphocytes and by producing substances such as interleukin-!, which initiates fever and lymphocyte activation and stimulates early hematopoietic progenitors. Eosinophils, while having a role as phagocytes, also have more specific functions that include providing a defense against metazoan parasites and modulating the inflammatory process. They respond chemotactically to histamine, immune complexes, and eosinophil chemotactic factor of anaphylaxis, a substance released by degranulating mast cells. Basophils are not true phagocytes but contain large amounts of histamine and other mediators of inflammation. Eosinophilia and basophilia may be seen in response to systemic allergic reactions and invasion of tissues by parasites. As with the RBCs, the production and circulating numbers of phagocytes are tightly regulated and controlled by various humoral factors, including colony-stimulating factors and interleukins. Unlike the RBCs, which remain circulating in the blood, the phagocytes use this compartment as a pathway to the tissues. Consequently, the number of phagocytes in the blood reflects circumstances in the tissues (eg, inflamma­ tion) as well as the proliferative function of the bone marrow. The sensitivity with

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6

HEMATOPOIETIC SYSTEM INTRODUCTION

which phagocytes reflect these conditions varies from species to species. Abnormal response, such as neutropenia from marrow failure, infections, drugs, or toxins, is likely to result in secondary bacterial infections. Some cases of "idiopathic" neutropenia in dogs may have an immune-mediated cause. Finally, phagocyte precursors may undergo malignant transformation, which results in acute or chronic myelogenous leukemia. Lymphocytes: Lymphocytes are

responsible for both humoral and cellular immunity. Cells of the two branches of the immune system cannot be differentiated morphologically, but they differ in their dynamics of production and circulation. Lymphocyte production in mammals originates in the bone marrow. Some of the lymphocytes destined to be involved in cellular immunity migrate to the thymus and differentiate further under the influence of thymic hormones. These become T cells and are responsible for a variety of helper or cytotoxic immuno­ logic functions. Most circulating lympho­ cytes areT cells, but T cells are also present in the spleen and lymph nodes. The B cells migrate directly to organs without undergoing modification in the thymus and are responsible for humoral immunity (antibody production). Thus, lymphoid organs have populations of both B andT lymphocytes. In the lymph nodes, follicular centers are primarily B cells, and parafollicular zones are primarily T cells. In the spleen, most of the lympho­ cytes of the red pulp are B cells, whereas those of the periarteriolar lymphoid sheaths areT cells. Close association ofT cells and B cells within lymphoid organs is essential • to immune function. Lymphocyte function in the cellular immune system features both afferent (receptor) and efferent (effector) compo­ nents. Long-livedT cells of the peripheral blood are the receptors. In response to antigens to which they have been previously sensitized, they leave the circulation and undergo blast transformation to form activatedT cells, which in turn cause other T cells to undergo blast transformation, both locally and systemically. StimulatedT cells produce lymphokines with a wide range of activities, such as attraction and activation of neutrophils, macrophages, and lymphocytes. The humoral immune system is com­ posed of B cells that produce antibodies of several classes. When sensitized B cells encounter antigen, they divide and differentiate into plasma cells that produce antibody. Therefore, each initially stimu-

lated B cell produces a clone of plasma cells, all producing the same specific antibody. Antibody molecules (immunoglobulins) fall into several classes, each with its own functional characteristics. For example, lgA is the principal antibody of respiratory and intestinal secretions, IgM is the first antibody produced in response to a newly recognized antigen, IgG is the principal antibody of the circulating blood, and IgE is the principal antibody involved in allergic reactions. Antibodies perform their function by combining with the specific antigens that stimulated their production. Antigen­ antibody complexes may be chemotactic for phagocytes, or they may activate complement, a process that produces both cell lysis and substances chemotactic for neutrophils and macrophages. In this manner, the humoral immune system is related to, and interacts with, the nonspe­ cific immune system. The humoral immune system also is related to both the nonspecific immune system and the cellular immune system in other ways. Both "helper" (CD4) and "cytotoxic" (CDS) T-cell classes have been described. HelperT cells recognize processed antigen and activate the humoral immune response. CytotoxicT cells, after sensitization by antigen, are effector cells, which are especially important in antiviral immunity. Natural killer cells, which are a class of lymphocyte distinct fromT cells and B cells, destroy foreign cells (eg, neoplastic cells) even without prior sensitization. Antigen processing by macrophages precedes recognition of an antigen by lymphocytes.These complex processes are involved in routine surveil­ lance against neoplastic cells and recogni­ tion of "self." Lymphocyte response in disease may be appropriate (activation of the immune system) or inappropriate (immune-mediated disease and lymphoproliferative malignan­ cies). (See also THE BIOLOGYOFTilE IMMUNE SYSTEM, p 811.) Immune-mediated disease results from failure of the immune system to recognize host tissues as self. For example, in immune-mediated hemolytic anemia, antibodies are produced against the host's own RBCs. Another inappropriate response of the immune system is allergy. In allergic individuals, IgE antibodies to allergens are bound to the surface of basophils and mast cells. When exposure to the allergen occurs, antigen-antibody complexes are formed, and degranulation of the mast cells and basophils releases vasoactive amines. Reaction to this may be mild ( as in urticaria or atopy) or life-threatening ( as in anaphylaxis ).

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ANEMIA

Lymphocytosis occurs in some species, especially the cat, as a response to epinephrine secretion. Atypical lympho­ cytes may be seen in the blood in response to antigenic stimulation (eg, vaccination). Persistent lymphocytosis in cattle infected with bovine leukemia virus is a benign polyclonal increase in lymphocyte numbers. Lymphoproliferative malignancies include lymphomas and acute lymphoblastic and chronic lymphocytic leukemias. Lymphope­ nia may occur most commonly as a response to glucocorticoid secretion.

PLATELETS

Platelets form the initial hemostatic plug whenever hemorrhage occurs. They also are the source of phospholipid,which is needed for the interaction of coagulation factors to form a fibrin clot. Platelets are produced in the bone marrow from megakaryocytes, under the influence of thrombopoietin. Platelet production begins with invagination of the megakaryocyte cell membrane and the formation of cytoplas­ mic channels and islands. The cytoplasmic islands produce platelets by fragmentation from the megakaryocyte. Mature circulating platelets are packed with dense granules containing ATP, adenosine diphosphate (ADP), and calcium, as well as serotonin, lysosomes,glycogen, mitochondria, and an intracellular canalicu­ lar system. The mitochondria and glycogen are involved in energy production, and the canalicular system serves both as a transport system for granule components and as a source of phospholipid, which is found in high concentration in the membrane lining of the canals. When vessel walls are damaged,collagen and tissue factor are exposed, and circulat­ ing platelets adhere via von Willebrand factor and undergo a change in shape with the accompanying release of ADP. Local platelet aggregation is stimulated by ADP, with the ultimate formation of the primary platelet plug. The local accumulation of fibrin and platelets is known as a hernostatic plug. The fibrin clot that then forms is consolidated by the action of platelet contractile proteins.

7

Platelet disorders are either quantitative (thrornbocytopenia or thrombocytosis) or qualitative (thrombocytopathy). Thrombo­ cytopenia is one of the most common bleeding disorders of animals. In general, platelet counts must fall to 60,000/µL in dogs is considered regenerative. To correct the percent reticulocytes, the formula (see below) can be applied. A corrected reticulocyte percent >1% indicates regeneration in dogs and cats. After acute blood loss or hemolytic crisis, reticulocyto­ sis usually takes 3-4 days to become evident. A serum chemistry panel and urinalysis evaluate organ function. If GI blood loss is suspected, an examination of the feces for occult blood and parasites can be useful. Radiographs can help identify occult disease, such as a penny (zinc toxicity) in the stomach of a puppy with hemolytic anemia. Bruising or bleeding may be signs of a coagulopathy and indicate the need for a coagulation profile. Presence of petechiae or ecchymotic hemorrhage suggest significant thrombocytopenia or thrombocytopathy. If hemolytic disease is suspected, blood can be evaluated for autoagglutination, or a direct Coombs' test might be indicated. A test for autoagglutination can be done by placing a

. PCV of the patient . corrected ret1culocyte % = (observed ret1culocyte %) x - -�-- --- ­ normal PCV for that species

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ANEMIA

lr�:1111

TOXIC CAUSES OF ANEMIA

Pathogenic Mechanism

Drugs

Plants, Foods

Toxins, Chemicals

Heavy Metals

Crude oil, naphthalene

Copper, zinc

Oxidation

Acetaminophen, benzocaine, dapsone, nitrofurans, prirnaquine, propofol, quinacrine

Fava beans, oak, onions, propylene glycol, red maple

Blood loss

Aspirin, naproxen

Bracken fem, Dicoumarol sweet clover

Inununemediated hemolysis

Cephalosporins, levamisole, penicillin, propylthiouracil, sulfonamides

Pirimicarb

Hemolysis

Fenbendazole, heparin

lndole

Lead, selenium

Decreased marrow production

Bracken fem Amphotericin, azidothymidine, cephalosporins, chloramphenicol, estrogen, fenbendazole, griseofulvin, meclofenamic acid, phenobarbital, phenothiazine, phenylbutazone, propylthiouracil, quinidine, recombinant human erythropoietin, sulfonamides, thiacetarsamide

Benzene, trichloro ethylene

Lead

drop of saline on a slide with a fresh drop of the animal's blood; the slide should be gently rotated to mix the drops together, then evaluated grossly and microscopically for macro- and microagglutination. If auto­ agglutination is present, there is no need to perform a Coombs' test. Serology or PCR for infectious agents such as feline leukemia virus, Ehrlichia, equine infectious anemia virus, and Babesia may also help define the cause of anemia (see TABLE 2). Bone marrow evaluation by aspiration and/or biopsy (seep 14) is indicated in any animal with an unexplained, non­ regenerative anemia. If the CBC reveals a decrease in more than one cell line, possibly indicating hypoplastic marrow, a biopsy would be indicated along with an aspirate. Biopsies and aspirates are complementary: biopsies are better to evaluate the architecture and degree of cellularity of the marrow, and aspirates allow for better evaluation of cellular morphology. Aspirates also allow for an evaluation of orderly maturation of the red and white blood cell lines, the ratio of myeloid to erythroid precursors (M:E ratio), and the number of platelet precursors. Iron stores can also be evaluated by Prussian blue staining. An M:E ratio of< 1 indicates that red cell production is greater than white cell production; with an M:E ratio > 1, the opposite is likely. The

M:E ratio is always interpreted in light of a recent CBC, because changes in the ratio could also be due to suppression of one cell line compared with the other.

REGENERATIVE ANEMIAS BLOOD LOSS ANEMIA Acute blood loss can lead to shock and even death if >30%--40% of blood is lost and the hypovolemia that develops is not treated aggressively with IV fluids or compatible blood (seep 17), or both. Causes of acute loss can be known (eg, trauma, surgery) or occult. Coagulopathies, bleeding tumors, gastric ulceration, and external or internal parasites should be excluded as causes. GI parasites, such as Haemonchus in ruminants and hookworms in dogs, can lead to severe blood loss, especially in young animals. Low-grade, chronic blood loss eventually results in iron-deficiency anemia, although some degree of reticulocytosis may persist even after iron stores become depleted. The hallmark of an iron-deficiency anemia is microcytic, hypochromic anemia. This chronic blood loss can be due to some type of parasitism in young animals (eg, fleas, lice, intestinal parasitism), but in older animals, bleeding from GI ulcers or tumors is more common.

10

ANEMIA

l�lllll

INFECTIOUS CAUSES OF ANEMIA

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Infectious Agent

Hemolytic

Species Affected

Marrow Affected

BACTERIA Clostridium perfringens A

Cattle, sheep

Yes

No

Clostridium haemolyticum

Cattle, she�p

Yes

No

Leptospira interrogans

Cattle, pigs, sheep

Yes

No

Mycoplasma spp

Cats

±

Rarely

Haemobartonella spp

Cattle, cats

±

No

VIRUSES Equine infectious anemia virus

Horses

±

Rarely

Feline leukemia virus

Cats

±

Yes

Feline immunodeficiency virus

Cats

No

Yes

No

RICKETISIA Mycoplasma spp

Cattle, goats, llamas, pigs, sheep•

Yes (piglets only)

Anaplasma spp

Cattle, goats, sheep

Yes

No

Ehrlichia spp

Dogs

Yes

Yes

Yes

No

±

No

PROTOZOA Babesiaspp

Cattle, cats, dogs, horses, sheep

Theileria sppb

Cattle, goats, sheep

Cytaua:zoon spp

Cats

No

Yes

Trypanosoma spp

Cattle, horses, pigs

Yes

No

Sarcocystis cruzi

Cattle

Yes

No

a In adults, only clinically relevant in splenectomized or ciitically ill animals. Pathogenic species of Theileria are found in Africa, the Mediterranean, the Middle East, Asia, and Europe. Species found in North America are nonpathogenic.

b

HEMOLYTIC ANEMIA Hemolytic anemias are typically regenera­ tive and result from lysis of RBCs in either the intra- or extravascular space. Intravascu­ lar hemolysis results in hemoglobinemia and hemoglobinuria, whereas extravascular hemolysis does not. Both types of hemolysis can result in icterus. In dogs, the most common cause of hemolytic anemia is

immune mediated (6001-75%), although toxins, RBC trauma, infections, and RBC membrane defects can also cause hemolysis. Immune-mediated Hemolytic Anemia: Immune-mediated hemolytic anemia (IMHA, see p 826) can be primary or secondary to neoplasia, infectious agents, drugs, or vaccinations. In IMHA, the immune system no longer recognizes RBCs

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ANEMIA

as self and develops antibodies to circulat­ ing RBCs, leading to RBC destruction by macrophages and complement. In some cases, antibodies am directed against RBC precmsors in the marrow, resulting in nonregenerative anemia Animals with IMHA are usually icteric, sometimes febrile, and may have splenomegaly. Hematologic hallmarks of IMHA are regenerative anemia, hyperbilirubinemia, spherocytosis, autoagglutination, or a positive Coombs' test. Another methodology to evaluate dogs for anti-RBC antibodies is flow cytometry. Flow cytometry allows for detection and quantitation of red cell surface-bound IgG and IgM. Flow cytometry was found to be 88o/o-1000A, specific for diagnosing dogs with anti-RBC antibodies. One report suggests using flow cytometry to assess response to treatment for dogs, because there is a decrease in surface anti-RBC antibodies before reticulocytosis or increase in RBC count. Flow cytometry may not be readily available to all veterinary hospitals. Animals with IMHA can show mild, indolent signs or be in an acute crisis. It is important to tailor treatment to the anin1al's signs, including treating any underlying infections. Transfusion with packed RBCs is usually required. The goal of therapy is to stop the destruction of RBCs by treating with immunosuppressive drugs; supportive care is also a priority. Prednisone or prednisolone at a dosage of 1-2 mg/kg, bid, is considered first-line therapy, with azathioprine at 2 mg/kg/day (azathioprine is contraindicated in cats and may be replaced by chlorambucil) or cyclosporine at 5-10 mg/kg/day considered as a possible second agent. In one study, low-dose aspirin at 0.5 mg/kg/day improved survival times in dogs treated with azathioprine and prednisone. The veterinary literatme is ambiguous on choice of second agent or when to introduce a second agent. Other immunosuppressive agents that have been used include mycophenolate and leflunomide. In the acute hemolytic crisis, drugs such as cyclosp01ine ( 10 mg/kg/day, initially) or human intravenous immunoglobin (MG, 0.5-1.5 g/kg as a single dose) may also have benefit because of rapid onset of action. Pulmonary thromboembolism is a risk in dogs with IMHA. These dogs are often hypercoagulable, which can be documented with thromboelastography. Dogs docu­ mented to be in a hypercoagulable state should be anticoagulated with heparin, which may be used in combination with antiplatelet therapy (aspirin 0.5 mg/kg/day

with or without clopidogrel 1-2 mg/kg/day) if the platelet count is >40,000/µL. The dosing range for heparin is wide and variable, and dosage also depends on whether frac­ tionated or unfractionated heparin is used. Heparin therapy can be monitored using activated partial thromboplastin time (A.PTT) or antifactor Xa concentrations (low-molecular-weight heparin). Mortality rates for IMHA range from 200/o-75%, depending on the severity of clinical signs. Negative prognostic indicators may include a rapid drop in PCV, high bilirubin concentration, moderate to marked leukocytosis (28,000 to >40,000 cells/µL), increased BUN, petechiae, intravascular hemolysis, autoagglutination, disseminated intravascular coagulation, and thromboembolic complications. Moderate to marked leukocytosis has been reported to be associated with tissue necrosis, most likely secondary to tissue hypoxia or thromboembolic disease. Referral to tertiary care facilities may improve survival. Alloimmune Hemolysis: Neonatal isoerythrolysis (NI) is an immune-mediated hemolytic disease seen in newborn horses, mules, cattle, pigs, cats, and rarely dogs. NI is caused by ingestion of maternal colostrum containing antibodies to one of the neonate's blood group antigens. The maternal antibodies develop to specific foreign blood group antigens dW'ing previous pregnancies, unmatched transfusions, and from Babesia and Anaplasma vaccinations in cattle. Cats are unique in that blood type B cats have natW'ally occurring anti-A antibodies without prior exposme, and their kittens that are type A develop hemolysis after nW"Sing. In horses, the antigens usually involved are A, C, and Q; NI is most commonly seen in Thoroughbreds and mules. Neonates with NI are normal at birth but develop severe hemolytic anemia within 2-3 days and become weak and icteric. Diagnosis is confim1ed by screening maternal serum, plasma, or.colostrun1 against the paternal or neonatal RBCs. Treatment consists of stopping any colostrum while giving supportive care with transfusions. If necessary, neonates can be transfused with triple-washed maternal RBCs. NI can be avoided by withholding maternal colostrum and giving colostrum from a maternal somce free of the antibodies. The newborn's RBCs can be mixed with maternal serum to look for agglutination before the newborn is allowed to receive maternal colostrum.

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ANEMIA Microangiopathic Hemolysis: Micro­

angiopathic hemolysis is caused by RBC damage secondary to turbulent flow through abnormal vessels. In dogs, it can be seen secondary to severe heartworm infection, vascular tumors (hemangiosar ­ coma), splenic torsions, and disseminated intravascular coagulation; in other species, causes include hemolytic uremic syndrome in calves, equine infectious anemia, African swine fever, and chronic classical swine fever. Schistocytes are common in blood smears from these animals. Treatment involves correction of the underlying disease process. Metabolic Causes of Hemolysis:

Hypophosphatemia (see p 1000) causes postparturient hemoglobinuria and hemolysis in cattle, sheep, and goats. It can occur 2-6 wk after parturition. Hypophos­ phatemia with secondary hemolysis is seen in dogs and cats secondary to diabetes mellitus, hepatic lipidosis, and refeeding syndrome. Treatment with either oral or IV phosphorus is indicated, depending on the degree of hypophosphatemia Cattle that drink too much water (water intoxication) are at risk of developing hemolysis secondary to hypotonic plasma This is seen in calves 2-10 mo old and causes respira­ tory distress and hemoglobinuria Clinical signs can progress to convulsions and coma. Hemolytic anemia, hyponatremia and hypochloremia, decreased serum osmolality, and low urine specific gravity in a calf would support the diagnosis of water intoxication. Treatment consists of hypertonic fluids (2.5% saline) and diuretics (eg, mannitol). Toxins: Toxins and drugs can-cause

anemia by many mechanisms. Those implicated most frequently in animals and their pathogenic mechanisms are listed (see TABLE 1). Infections: Many infectious agents­

bacterial, viral, rickettsial, and protozoal­ can cause anemia by direct damage to RBCs, leading to hemolysis, or by direct effects on precursors in the bone marrow (see TABLE 2). Heritable Diseases: Several heritable

RBC disorders cause anemia. Pyruvate kinase deficiencies are seen in Basenjis, Beagles, West Highland White Teniers, Cairn Teniers, and other breeds, as well as Abyssinian and Somali cats. Phosphofruc­ tokinase deficiency occurs in English Springer Spaniels. Deficiencies in these

enzymes lead to shortened RBC life span and regenerative anemia In dogs with phosphofructokinase deficiency, the hemolytic crises are set off by alkalosis secondary to excessive excitement or exercise. If such situations are minimized, these dogs may have a normal life expectancy. There is no treatment for pyruvate kinase deficiency, and affected dogs will have a shortened life span due to myelofibrosis and osteosclerosis of the bone marrow. Affected cats will have chronic intermittent hemolytic anemia, which is sometimes helped by splenectomy and steroids. Unlike dogs, cats have not been reported to develop osteosclerosis. A hereditary hemoglobinopathy, porphyria (seep 986), leads to build-up of porphyrins in the body and has been described in cattle, cats, and pigs. It is most prevalent in Holstein cattle and can lead to a hemolytic crisis. Affected calves fail to thrive and are photosensitive. Diagnosis is made by finding increased levels of porphyrins in bone marrow, urine, or plasma. Teeth of affected animals fluoresce under ultraviolet light.

NONREGENERATIVE ANEMIAS NUTRITIONAL DEFICIENCIES Nutritional deficiency anemias develop when micronutrients needed for RBC formation are not present in adequate amounts. Anemia develops gradually and may initially be regenerative but ultimately becomes nonregenerative. Starvation causes anemia by a combination of vitamin and mineral deficiencies as well as a negative energy and protein balance. Deficiencies most likely to cause anemia are iron, copper, cobalamin (8 12), B6, riboflavin, niacin, vitamin E, and vitamin C (important only in primates and guinea pigs). Iron deficiency is the most common deficiency seen in dogs and piglets but occurs less commonly in horses, cats, and ruminants. Iron deficiency is rarely nutritional in origin-it most commonly occurs secondary to blood loss (seep 9). Young animals have minimal iron stores, and milk contains very little iron. This can be especially important for piglets that grow rapidly and are often raised indoors with no access to iron. Oral iron supple­ mentation is indicated as treatment for iron deficiency; any source of blood loss must be elin1inated. Copper deficiency can develop in ruminants fed forage grown in copper­ deficient soil. Copper is necessary for the

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metabolism of iron. Copper deficiency may occur secondary to high dietary molybde­ num or sulfate in cattle and can develop in pigs fed whey diets. Low blood copper concentrations or low copper concentra­ tions in liver biopsies (more definitive) are diagnostic. Treatment is oral or injectable copper supplementation. B vitamin deficiencies are rare. Certain drugs (anticonvulsants, drugs that inter­ fere with folate metabolism) have been associated with development of folate or cobalamin deficiency, leading to a normocytic, normochromic, nonregenera­ tive anemia. Cobalamin malabsorption has been reported in Giant Schnauzers (their enterocytes are unable to absorb cobala­ min). These dogs respond to parenteral supplementation with cobalamin. Rumi­ nants also develop a secondary cobalamin deficiency when grazing on cobalt-deficient pasture. Treatment with oral cobalt or parenteral cobalamin is indicated.

ANEMIA OF CHRONIC DISEASE Anemia of chronic disease can be characte1° ized as mild to moderate, nonregenerative, normochromic, and normocytic. It is the most common fonn of anemia seen in animals. The anemia can be secondary to chronic inflammation or infection, neoplasia, liver disease, hyper- or hypoad­ renocorticism, or hypothyroidism. The anemia is mediated by cytokines produced by inflammatory cells, which lead to decreases in iron availability, RBC survival, and the marrow's ability to regenerate. Treatment should be directed at the underlying disease and often results in resolution of the anemia The anemia may be reduced by treatment with recombinant human erythropoietin, but the risk of antibody formation to endogenous erythropoietin may outweigh benefit. Darbepoetin appears to have less impact to induce reactive antibodies.

RENAL DISEASE Chronic renal disease is a common cause of nonregenerative anemia in animals. Erythropoietin is normally produced by the peritubular endothelial cells in the renal cortex. Animals with renal disease produce less erythropoietin, leading to anemia Recombinant human erythropoietin (44-132 U/kg, three times/wk, with most animals starting at 88 U/kg) has been used for treatment. PCV is monitored weekly until the desired improvement is reached (this will vary with the initial degree of

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anemia), after which the dosage is decreased. Animals receiving recombinant human erythropoietin require supplemental iron to support RBC production. (See also HEMATINICS, p 2540.) Darbepoeitin also has been found to be valuable in management of anemia associated with chronic kidney disease.

PRIMARY BONE MARROW DISEASES Primary bone marrow disease or failure from any cause can lead to nonregenerative anemia and pancytopenia. With diffuse marrow involvement, granulocytes are affected first, followed by platelets and finally RBCs. Aplastic anemia has been reported in dogs, cats, ruminants, horses, and pigs with pancytopenia and a hypoplastic marrow, replaced by fat. Most cases are idiopathic, but reported causes include infection (feline leukemia virus, Ehrlichia, parvovirus), drug therapy (methimazole, chemothera­ peutic agents, antibiotics [trimethoprim­ sulfa, chloramphemicol], fenbendazole), toxin ingestion (estrogen), and total body irradiation (see TABLES 1 and 2). There may also be an immune-mediated component to this disease. Diagnosis is confirmed by bone marrow aspiration and core biopsy. Treatment consists of eliminating the underlying cause and providing supportive measures such as broad-spectrum antibiotics and transfusions. lmmunosup­ pressive agents such as prednisone, cyclosporine, mycophenolate, or azathi50 yr. An ideal substitute would can-y and deliver oxygen like red cells, be easy to

produce in large quantities, be nonantigenic, and persist in the circulation at least long enough for resuscitation. One hemoglobin-based oxygen carrier of bovine origin is currently licensed for use in dogs. The hemoglobin is collected asepti­ cally, filtered to remove all red cell stromal elements, and polymerized to allow the product to persist in the circulation for a half-life of -36 hr. This product has been shown to carry and deliver oxygen efficiently, can be used in1mediately without need for typing or crossmatching, and has a 3-yr shelf life at room temperature. Because the strncture of the hemoglobin molecule is similar between species, bovine hemoglobin is mininlally antigenic. Although currently licensed for use only in dogs, it has been used in cats, horses, llan1as, birds, and people. Its colloidal effects are especially useful in resuscitation after trauma with acute blood loss. Because t.he cost of hemoglobin solution is often higher, and duration of effect is shorter than that of blood, the main value of hemoglobin is in emergency situations when blood is not inunediately available. Volume overload is a potential risk if hemoglobin is given too rapidly. Another concern with hemoglobin solutions is that nitric oxide is scavenged and removed by the product. This paradoxically might cause vasoconstriction and decrease oxygen delivery to ischemic tissues.

BLOOD PARASITES ANAPLASMOSIS Anaplasmosis, formerly known as gall sickness, traditionally refers to a disease of ruminants caused by obligate intraerythro­ cytic bacteria of the order Rickettsiales, family Anaplasmataceae, genusAna­ plasma. Cattle, sheep, goats, buffalo, and some wild ruminants can be infected with the erythrocyticAnaplasma. Anaplasmosis occurs in tropical and subtropical regions worldwide ( -40 ° N to 32 ° S), including South and Central Anlerica, the USA, southern Europe, Africa, Asia, and Australia. TheAnaplasma genus also includesA plwgocylophilum (compiled from species previously known as Ehrlichia. phagocy­ tophila, E equi, and hw11an granulocytic ehrlichiosis agent, see p 803), A bovis

(fom1erly E bovis), andA platys (fom1erly E platys), all of which invade blood cells

other tllan erythrocytes of tlleir respective manunalian hosts. Bovine anaplasmosis is of economic significance in tile cattle industry.

Etiology and Pathogenesis: Clinical bovine anaplasmosis is usually caused by A mar. ginale. AnA marginale with an appendage has been calledA caudatum, but it is not considered to be a separate species. Cattle are also infected with A centrale, which generally results in mild disease. A ovis may cause mild to severe disease in sheep, deer, and goats. A phagocytophilum has recently been reported to infect cattle; however, natural infection is rare and it does not cause clinical disease.

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Transmission and Epidemiology: Up to 17 different tick vector species (including

Dermacentor, Rhipicephalus, !rodes, Hyalomma, andAigas) have been reported to transmitAnaplasma spp. Not all of these

are likely significant vectors in the field, and it has been shown that strains of A maiginale also coevolve with particular tick strains. Rhipicephalus (Boophilus) spp are major vectors in Australia and Africa, and Dermacento . r spp have been incriminated as the main vectors in the USA. After feeding on an infected animal, intrastadial or trans-stadia! transmission may occur. Transovarial transmission may also occur, although this is rare, even in the single-host Rhipicephalus spp. A replica­ tive cycle occurs in the infected tick. Mechanical transmission via biting dipterans occurs in some regions. Transpla­ cental transmission has been reported and is usually associated with acute infection of the darn in the second or third trimester of gestation. Anaplasmosis may also be spread through the use of contaminated needles or dehoming or other surgical instruments. There is a strong correlation between age of cattle and severity of disease. Calves are much more resistant to disease (although not infection) than older cattle. This resistance is not due to colostral antibody from immune darns. In endemic areas where cattle first become infected with A mar. ginale early in life, losses due to anaplasmosis are minimal. After recovery from the acute phase of infection, cattle remain chronically infected carriers but are generally immune to further clinical disease. However, these chronically infected cattle may relapse to anaplasmosis when immunosuppressed (eg, by cortico­ steroids), when infected with other pathogens, or after splenectomy. Carriers serve as a reservoir for further transmission. Serious losses occur when mature cattle with no previous exposure are moved into endemic areas or under endemically unstable situations when transmission rates are insufficient to ensure that all cattle are infected before reaching the more susceptible adult age. Clinical Findings: In animals < 1 yr old anaplasmosis is usually subclinical, in yearlings and 2-yr-olds it is moderately severe, and in older cattle it is severe and often fatal. Anaplasmosis is characterized by progressive anemia due to extravascular destruction of infected and uninfected erythrocytes. The prepatent period of A maiginale is directly related to the infective

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dose and typically ranges from 15-36 days (although it may be as long as 100 days). After the prepatent period, peracute (most severe but rare), acute, or chronic anaplasmosis may follow. Rickettsemia approximately doubles every 24 hr during the exponential growth phase. Generally, 10%-300!& of erythrocytes are infected at peak rickettsemia, although this figure may be as high as 65%. RBC count, PCV, and hemoglobin values are all severely reduced. Macrocytic anemia with circulating reticulocytes may be present late in the disease. Animals with peracute infections succumb within a few hours of the onset of clinical signs. Acutely infected animals lose condition rapidly. Milk production falls. Inappetence, loss of coordination, breathlessness when exerted, and a rapid bounding pulse are usually evident in the late stages. The urine may be brown but, in contrast to babesiosis, hemoglobinuria does not occur. A transient febrile response, with the body temperature rarely exceeding l06° F (41 °C) occurs at about the tin1e of peak rickettsemia Mucous membranes appear pale and then yellow. Pregnant cows may abort. Surviving cattle convalesce over several weeks, during which hematologic paran1eters gradually return to norn1al. Bos indicus breeds of cattle appear to possess a greater resistance to A marginale infection thanB taunts breeds, but variation of resistance of individuals within breeds of both species occurs. Differences in virulence between Anaplasma strains and the level and duration of the rickett­ semia also play a role in severity of clinical manifestations. Lesions: Lesions are typical of those found in animals with anemia due to erythrophagocytosis. The carcasses of cattle tl1at die from anaplasmosis are generally markedly anemic and jaundiced. Blood is thin and watery. The spleen is characteristi­ cally enlarged and soft, with prominent follicles. The liver may be mottled and yellow-orange. The gallbladder is often distended and contains thick brown or green bile. Hepatic and mediastinal lymph nodes appear brown. There are serous effusions in body cavities, pulmonary edema, petechial hemorrhages in the epi- and endocardium, and often evidence of severe GI stasis. Widespread phagocytosis of erythrocytes is evident on microscopic examination of the reticuloendothelial organs. A significant proportion of erythrocytes are usually found to be parasitized after death due to acute infection.

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Diagnosis: A marginale, together with the hemoprotozoaBabesia bovis and B bigemina, are the causative agents of tick fever in cattle. These three species have similar geographic distributions, except that anaplasmosis occurs in the absence of babe­ siosis in the USA. Microscopic examination of Giemsa-stained thin and thick blood films is critical to distinguish anaplasmosis from babesiosis (see p 21) and other conditions that result in anemia and jaundice, such as leptospirosis (see p 646) and theileriosis (see p 33). Blood in anticoagulant should also be obtained for hematologic testing. In Giemsa-stained thin blood films, Anaplasma spp appear as dense, homoge­ neously staining blue-purple inclusions 0.3-1 µm in diameter. A marginale inclusions are usually located toward the margin of the infected erythrocyte, whereas A centrale inclusion bodies are located more centrally. A caudatum cannot be distinguished from A marginale using Giemsa-stained blood films. Special staining techniques are used to identify this species based on observation of characteristic appendages associated with the bacteria. A caudatum has been reported only in North America and could possibly be a morpho­ logic form of A marginale and not a separate species. Inclusion bodies contain 1-8 initial bodies 0.3-0.4 µm in diameter, which are the individual rickettsiae. The percentage of infected erythrocytes varies with the stage and severity of disease;. maximum rickettsemias in excess of 50% can occur with A marginale. Microscopi­ cally, the infection ·becomes visible 2-6 wk after transmission. During the course of infection, the rickettsemia can double each

Anaplasma marginale in bovine blood, Wright-Giemsa, 1 OOx oil immersion. Intracellular organisms appear as basophilic, spherical inclusions generally located near the margin of erythrocytes. Echinocytes are frequently present. Courtesy of Ms. Sue

Anderson, Tick Fever Centre, Wacol,.Oueensland, Australia.

day for up to 10 days and then decreases. Severe anemia can persist for weeks after parasites cannot be detected in blood smears. Chronically infected carriers may be identified with a fair degree of accuracy by serologic testing using the msp5 ELISA, complement fixation, or card agglutination tests. Nucleic acid-based detection methods are most useful, because species and strain differentiation tests may not detect carrier levels. At necropsy, thin blood films of liver, kidney, spleen, lungs, and peripheral blood should be prepared for microscopic examination. Treatment, Control, and Prevention:

Tetracycline antibiotics and imidocarb are currently used for treatment. Cattle may be sterilized by treatment with these drugs and remain immune to severe anaplasmosis subsequently for at least 8 mo. Prompt administration of tetracycline drugs (tetracycline, chlortetracycline, oxytetracycline, rolitetracycline, doxycy­ cline, minocycline) in the early stages of acute disease (eg, PCV > 15%) usually ensures survival. A commonly used treatment consists of a single IM irtjection of long-acting oxytetracycline at a dosage of 20 mg/kg. Blood transfusion to partially restore the PCV greatly improves the survival rate of more severely affected cattle. The carrier state may be eliminated by administration of a long-acting oxytetracycline preparation (20 mg/kg, IM, at least two irtjections with a 1-wk interval). Withholding periods for tetracyclines apply in most countries. Ir\jection into the neck muscle rather than the rump is preferred. lmidocarb is also highly efficacious against A marginale as a single irtjection (as the d.ihydrochloride salt at 1.5 mg/kg, SC, or as imidocarb dipropionate at 3 mg/kg). Elimination of the carrier state requires the use of higher repeated doses of imidocarb (eg, 5 mg/kg, IM or SC, two irtjections of the d.ihydrochloride salt 2 wk apart). lmidocarb is a suspected carcinogen with long withholding periods and is not approved for use in the USA or Europe. In South Africa, Australia, Israel, and South America, infection with live A centrale (originating from South Africa) is used as a vaccine to provide cattle with partial protection against the disease caused by A marginale. A centrale (single dose) vaccine produces severe reactions in a small proportion of cattle. In the USA, where live vaccines cannot be used,

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vaccines comprising nonliving A marginale purified from infected bovine erythrocytes and adjuvant have been used in the past but may not currently be available. Inununity generated by using multidose killed vaccine protects cattle from severe disease on subsequent infection, but cattle can still be susceptible to challenge with heterologous strains of A marginale. Instances of isoerythrolysis in suckling calves have occurred due to prior vaccination of dams with preparations that contained bovine erythrocytic material. Long-lasting immunity against A marginale is conferred by preimmunization with live rickettsia, combined with the use of chemotherapy to control severe reactions. The use of attenuated strains of A marginale as a live vaccine has been reported, with instances of severe reactions also occurring. A marginale grown in tick cell cultw·es are being investigated as an alternative live vaccine source. Subunit vaccines to con­ trol bovine anaplasmosis are also under investigation. In some areas, sustained strin­ gent control or elimination of the arthropod vectors may be a viable control strategy; however, in other areas immunization is recommended.

BABESIOSIS Babesiosis is caused by intraerythrocytic protozoan parasites of the genus Babesia. Transmitted by ticks, babesiosis affects a wide range of domestic and wild animals and occasionally people. Although the major economic impact of babesiosis is on the cattle industry, infections in other domestic animals, including horses, sheep, goats, pigs, and dogs, assume varying degrees of importance throughout the world. Two important species in cattleB bigemina andB bovis-are widespread in tropical and subtropical areas and are the focus of this discussion. However, because there are many common features of the diseases caused by differentBabesia, much of this information can be applied to other species. Transmission and Epidemiology: The

main vectors of B bigemina and B bovis are l-hostRhipicephalus (Boophilus) spp ticks, in which transmission occurs transovarially. Although the parasites can be readily transmitted experimentally by blood inoculation, mechanical transmission by insects or during surgical procedures has no practical significance. Intrauterine infection has also been reported but is rare.

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InRhipicephalus spp ticks, the blood stages of the parasite are ingested during engorgement and undergo sexual and asexual multiplication in the replete female, infecting eggs and subsequent parasitic stages. Transmission to the host occurs when larvae (in the case of B bovis) or nymphs and adults (in the case of B bigemina) feed. The percentage of larvae infected can vary from 0-500A, or higher, depending mainly on the level of para­ sitemia of the host at the time the female ticks engorge. Under field conditions, the rate of tick transmission is generally higher forB bigemina than forB bovis. In endemic areas, three features are important in detemtlning the risk of clinical disease: 1) calves have a degree of immunity (related both to colostral-derived antibodies and to age-specific factors) that persists for -6 mo, 2) animals that recover from Babesia infections are generally immune for their commercial life (4 yr), and 3) the susceptibility of cattle breeds to ticks and Babesia infections varies; eg, Bos indicus cattle tend to be more resistant to ticks and the effects ofB bovis and B bigemina. infection than Bos taurus--derived breeds. At high levels of tick transmission, virtually all calves become infected withBabesia by 6 mo of age, show few if any clinical signs, and subsequently become immune. This situation can be upset by either a natural (eg, climatic) or artificial (eg, acaricide treatment or changing breed composition of herd) reduction in tick numbers to levels such that tick transmission ofBabe:;ia to calves is insufficient to ensure all are infected during this critical early period. Other circumstances that can lead to clinical outbreaks include the introduction of susceptible cattle to endemic areas and the incursion ofBabesia-infected ticks into previously tick-free areas. Strain variation in immunity has been demonstrated but is probably not of practical significance in the field. Clinical Findings and Pathogenesis:

B bovis is a much more virulent organism thanB bigemina. With most strains of B bigemina, the pathogenic effects relate more directly to erythrocyte destruction. With virulent strains ofB bovis, a hypoten­ sive shock syndrome, combined with generalized nonspecific inflammation, coagulation disturbances, and erythrocytic stasis in capillaries, contribute to the pathogenesis. The acute disease generally runs a course of -1 wk. The first sign is fever (frequently 2!106°F [41°C]), which persists throughout,

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BLOOD PARASITES

and is accompanied later by inappetence, increased respiratory rate, muscle tremors, anemia, jaundice, and weight loss; hemo­ globinemia and hemoglobinuria occur in the final stages. CNS involvement due to adhesion of parasitized erythrocytes in brain capillaries can occur with B bovis infections. Either constipation or diarrhea may be present. Late-term pregnant cows may abort, and temporary infertility due to transient fever may be seen in bulls. Animals that recover from the acute disease remain infected for a number of years with B bovis and for a few months in the case of B bigemina.. No clinical signs are apparent during this carrier state. Lesions: Lesions (particularly with

B bovis) include an enlarged and friable

spleen; a swollen liver with an enlarged gallbladder containing thick granular bile; congested, dark-colored kidneys; and generalized anemia and jaw1dice. Most clinical cases of B bigemina have hemoglobinuria, but this is not invariably the case with B bovis. Other organs, including the brain and heart, may show congestion or petechiae.

Diagnosis: Clinically, babesiosis can be confused with other conditions that cause fever, anemia, hemolysis, jaundice, or red urine. Therefore, confirmation of diagnosis by microscopic examination of Giemsa­ stained blood or organ smears is essenti�. From the live aninlal, thick and thin blood smears should be prepared, preferably from capillaries in the ear or tail tip. Smears of heart muscle, kidney, liver, lung, brain, and from a blood vessel in an extremity (eg, lower leg) should be taken at necropsy. Microscopically, the species of Babesia involved can be determined morphologi­ cally, but expe1tise is required, especially in B bovis infections in which few organisms are present. B bovis is small, with the para­ sites in paired form at an obtuse angle to each other and measuring -1-1.5 x 0.5-1 µm. B bigemina is larger (3-3.5 x 1-1.5 µm), with paired parasites at an acute angle to each other. Single fom1s of both parasites are also commonly seen. A number of serologic tests have been described for detection of antibodies to Babesia in carrier aninlals. The most commonly used are the indirect fluorescent antibody test and ELISA. A commercially produced ELISA for B bigemina is available. PCR and real-time PCR assays capable of detecting extremely low parasitemias, as occur in carrier aninlals,

and differentiating isolates have also been described. A procedure that may occasion­ ally be justified to confirm infection in suspected carrier aninlals is the subino­ culation of blood ( -500 mL) into a fully susceptible aninlal, preferably a splenecto­ mized calf, and subsequent monitoring of the recipient for infection. Treatment and Control: A vaiiety of drugs have been used to treat babesiosis in the past, but only dinlinazene aceturate and inlidocarb dipropionate are still in common use. These drugs are not available in all endemic countries, or their use may be restricted. Manufacturers' recommenda­ tions for use should be followed. For treating cattle, dinlinazene is given lM at 3.5 mg/kg. For treatment, inlidocarb is given SC at 1.2 mg/kg. At a dosage of 3 mg/kg, inlidocarb provides protection from babesiosis for -4 wk and will also eliminateB bov'i.s and B bigemina from carrier ailimals. Suppmtive treatment is advisable, paiticularly in valuable aninlals, and may include the use of anti-infla!llffiatory drugs, cmticosteroids, and fluid therapy. Blood transfusions may be life-saving in very anemic aninlals. Vaccination using live, attenuated strains of the parasites has been used successfully in a number of countries, including Argentina, Australia, Brazil, Israel, South Africa, and Uruguay. The vaccine is provided in either a chilled or frozen form. One vaccination produces adequate immunity for the commercial life of the aninlal; however, vaccine breakdowns have been reported. Several recombinant antigens have been shown experimentally to induce some immunity, but commercial vaccines are not yet available. Although controlling or complete eradi­ cation of the tick vector can break the transmission cycle, this a�proach is rarely feasible in the longte1m and can lead to large, susceptible populations in endemic areas with consequent risk of outbreaks of disease in naive aninlals. Zoonotic Risk: A number of cases of human babesiosis have been reported. The rodent parasite B microti and the cattle parasite B divergens are the most commonly implicated species in North America and Europe, respectively. However, B duncani, B venatorum, B conradae, and some less well-defined species have also been incrinlinated. The reservoir hosts and vectors of some of these species are not necessaiily known with any certainty. Human Babesia infections are

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acquired via bites from infected ticks or through contaminated blood from an infected transfusion donor. Cases reported in splenectomized or otherwise immuno­ compromised individuals are often fatal. Other Important Babesia of Domestic Animals

More than 100 species of Babesia have been isolated from domestic animals and wildlife. The following are indicative of those affecting domestic animals, but the list is far from complete. Cattle: B divergens and B major are two temperate-zone species with features comparable to those of B bovis and B bigemina, respectively. B divergens is a small, pathogenic Babesia of considerable importance in the British Isles and northwest Europe, whereas B major is a large Babesia of lower pathogenicity. B divergens is transmitted by Ixodes ricinus, and B major by Haemaphysalis punctata. Horses: Equine babesiosis is caused by

Theileria (formerly Babesia) equi or B caballi. T equi is a small parasite and is more pathogenic than B caballi. T equi was reclassified as a Theileria (see p 33) in 1998. Equine babesiosis is found in Africa, Europe, Asia, South and Central America, and the southern USA. It is transmitted by ticks of the generaRhipicephalus, Dermacentor, and Hyalomma. Intrauterine infection, particularly with T equi, is also relatively common. Sheep and Goats: Although small ruminants can be infected by several species of Babesia, the two most important species are B ovis and B motasi, transmit­ ted by Rhipicephalus bursa and Haema­ physalis spp, respectively. Infection is of importance in the Middle East, southern Europe, and some African and Asian countries. Pigs: B trautmanni has been recorded as causing severe disease in pigs. This parasite has been reported from Europe and Africa. Another species, B perroncitoi, is of similar pathogenicity but apparently has a limited distribution in the areas mentioned above. The vectors of these Babesia have not been clarified, althoughRhipicephalus spp have been shown to transmit B t:rautmanni. Dogs and Cats: Babesia species have been reported in dogs from most regions.

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These include B canis, B vogeli, and B rossi. B canis is transmitted by Derma­ centor reticularis in Europe, B vogeli by Rhipicephaliis sanguineus in tropical and subtropical countries, andB rossi by Haemaphysalis leachi in South Africa. Consequences of Babesia infection vary from a mild, transient illness to acute disease that rapidly results in death. B gibsoni is the other important Babesia of dogs and is a much smaller parasite. It has a more limited distribution and characteristically causes a chronic disease with progressive, severe anemia that is not readily treated with normal babesiacides. Illness of varying severity due to Bfelis in domestic cats has mostly been reported in southern Africa. Sporadic cases associated with other Babesia species have been reported elsewhere. An unusual feature of Bfelis is its lack of response to the normal babesiacides. However, primaquine phosphate (0.5 mg/kg, IM, twice with a 24-hr interval) is reported to be effective. CYTAUXZOONOSIS

Cytauxzoonosis is an emerging, life-threat­ ening infectious disease of domestic cats (Felis catus) caused by the tick-transmitted protozoan parasite Cytauxzoonfelis. Cytauxzoon spp are apicomplexan parasites within the family Theileriidae along with their closest relatives of Theileria spp. Cfelis is transmitted to domestic cats by the lone star tick (Amblyomma americanum). The natural host for C Jelis is the bobcat (Lynx rujus); reservoir hosts of the parasite include bobcats and domestic cats that survive infection. Since the discovery of feline cytauxzo­ onosis in Missouri in the mid-1970s, the distribution of C Jelis has been expanding. Cfelis has been reported in domestic cats in Missouri, Arkansas, Florida, Georgia, Louisiana, Mississippi, Oklahoma, Texas, Kentucky, Kansas, Tennessee, North Carolina, South Carolina, Nebraska, Iowa, and Virginia. Anecdotal reports of C Jelis infection in domestic cats in additional states include Alabama, southern Illinois, and Ohio. Aberrant and Natural Hosts: The domestic cat has been considered an aberrant or dead-end host of CJelis given the acute and fatal course of disease; however, there are reports of domestic cats surviving natural infection with and without treatment. As a natural host, the bobcat typi­ cally experiences subclinical infection,

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BLOOD PARASITES followed by a chronic parasitemia. Rare cases of fatal cytauxzoonosis in bobcats have been reported. Cytauxzoonosis has been reported in several other wild felids in the USA and other countries, with both fatal and nonfatal outcomes. Infection has been reported in cougars, panthers, and tigers in the USA, in addition to two suspected but unconfirmed cases in cheetahs. Cfelis infections of wild felids reported in other countries include lions, jaguars, pumas, ocelots, and little spotted cats. In the early 1980s, interspecies transmission of Cfelis was investigated to identify additional potential natural and aberrant hosts among 91 wildlife, laboratory, and domestic farm animals. Bobcats and domestic cats were the only anin1als confirmed to be suscepti­ ble to Cfelis. Transmission and Risk Factors: Cfelis is transmitted by the lone star tick, A am.er­ icanum.. Cytauxzoonosis is typically diagnosed during April through September, which correlates with climate-dependent seasonal tick activity. Cats living near heavily wooded, low-density residential areas pa.tticularly close to natural or unmanaged habitats where both ticks and bobcats may be in close proximity are at highest risk of infection. Experimental infections have been induced with parenteral injection of tissue homogenates (SC, IP, and IV) from acutely infected cats. However, infection was not induced when these tissues were administered intragas­ trically or when noninfected cats were housed together with infected cats in the absence of arthropod vectors, suggesting that oral and "cat-to-cat" transmission does not occur. One recent study failed to document perinatal transmissi6n of Cfelis from 2 chronically infected dams to 14 healthy kittens, suggesting that vertical transmission may not occur commonly, if at all. Life Cycle and Pathogenesis: After transmission from the tick into the cat, Cfelis undergoes two major stages: schizogony and merogony. First, sporozo­ ites infect WBCs (mononuclear phago­ cytes) and undergo schizogony (asexual reproduction) to form schizonts. Schizont-infected WBCs have been detected -12 days after experimental infection and increase in size from 15 µm to up to 250 µm in diameter. They are most commonly detected in lymph node, spleen, liver, lung, and bone marrow but have been documented in many organs and are occasionally seen on blood smears.

Schizont-infected WBCs are the principal cause of disease and death; they are found predominantly lining and often occluding blood vessels. These "parasitic thrombi" result in ischemia and tissue necrosis. Schizont-infected WBCs then rupture and release piroplasms ( merozoites), which infect RBCs. The piroplasms in RBCs are fairly innocuous, with parasitemias ranging from 1o/er-4% on average; however, higher parasitemias (ie, >100/o) have been docun1ented. During acute infection, detection of merozoite-infected RBCs is variable and has been correlated with an increase in body temperature and a decrease in leukocytes. Without treatment, survivors typically remain chronically parasitemic, and at least one cat has been shown experimentally to be solidly inlmune to subsequent infections. Chronic para­ sitemia has been established via inoculation with merozoite-infected RBCs. These chronically parasitemic cats clid not develop overt clinical disease but were not immune to subsequent challenge with infection of sporozoites/schizonts, suggesting that the schizogenous tissue phase is required to establish inlmunity in domestic cats. Clinical Findings and Lesions: Onset of clinical signs for cats infected with Cfelis usually occurs 5-14 days ( -10 on average) after infection by tick transmission. Nonspecific signs such as depression, lethargy, and anorexia are the most · common presenting problems. Pyrexia and dehydration are the most conm10n findings on physical examination; body tempera­ ture, which increases gradually, can be as high as 106 ° F (41 ° C). Other findings include icterus, lymphadenomegaly, and hepato­ splenomegaly. In extremis, cats are often hypothermic, dyspneic, and vocalize as if in pain. Without treatment, death typically occurs within 2-3 days after peak in temperature. At necropsy, splehomegaly, hepatomegaly, enlarged lymph nodes, and renal edema are usually seen. The lungs show extensive edema and congestion with petechial hemorrhage on serosal surfaces and throughout the interstitium. There is progressive venous distention, especially of the mesenteric and renal veins and the posterior vena cava. Hydropericardium is often seen with petechial hemorrhage of the epicardium. When first described, mortality of Cfelis infection was reported to be nearly 1000/o. A study of Cfelis in northwestern Arka.tlSas and northeastern Oklahoma indicated survival of natural infection in 18 cats with and without treatment; these cats seemed

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BLOOD PARASITES

"less sick" initially, did not have tempera­ tures > 106°F (41°C), and never became hypo­ thennic. Similar sporadic reports in other areas exist. Some hypotheses for swvival in these cats have included the following: l) an atypical route of infection, 2) innate inununity in certain cats, 3) increased detection of carriers, 4) decreased virulence with strain attenuation or occurrence of a new strain, 5) dose of infectious inoculum, and 6) tinting and type of treatment. Diagnosis: The most common abnor­ malities on the CBC in animals with cytauxzoonosis include leukopenia with toxic neutrophils and thrombocytopenia with a normocytic, normochromic anemia seen at later stages. The most common biochemical abnormalities are hyperbiliru­ binemia and hypoalbuminemia but may vary depending on organ systems affected by parasitic thrombosis and ischemia with tissue necrosis. Other, less consistently detected abnormalities include increased liver enzyme concentrations and azotemia. Rapid diagnosis requires microscopic observation of piroplasms or schizonts. Observation of piroplasms on blood smears is variable; they are seen in association with increasing body temperature and typically become apparent approximately 1-3 days before death. There are anecdotal reports of a higher level of sensitivity when blood is collected from smaller vessels ( eg, ear vein prick) to prepare blood smears. On a well-prepared, well-stained (Wright­ Giemsa, Giemsa, Romanowsky most commonly) blood smear, when detectable, merozoites may be seen ranging from 1o/o-4% on average, with extremely high percentages (ie, > 10%) reported in some cases. They are pleomorphic and may be round, oval, anaplasmoid, bipolar (bi.nucle­ ated), or rod-shaped; however, the round and oval piroplasm fom1s are most commonly seen. The round forms are 1-2.2 µm in dian1eter, whereas oval fom1s are 0.8-1 µm x 1.5-2 µm. They are pale centrally and contain a small, magenta, round to crescent-shaped nucleus on one side. Once the parasitemia is -0.5%, Maltese cross and paired piriforms may be seen. Smears must be examined carefully to exclude Mycoplasma haemofelis, Howell-Jolly bodies, stain precipitate, and water artifact. The schizont tissue stage precedes the formation of the RBC phase. Occasionally, schizonts may be seen in peripheral blood smears, particularly at the feathered edge, and may be ntistaken for large platelet

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clumps at low power. In the absence of detection of RBC piroplasms or schizonts on blood smear, a rapid diagnosis should be pursued by perfomting fine-needle aspiration of a peripheral lymph node, spleen, or liver to identify schizonts cytologically. These phagocytes are 15-250 µm in dian1eter and contain an ovoid nucleus with a distinctive, prominent, large, dark nucleolus. The cytoplasm is often greatly distended, with numerous small deeply basophilic particles representing developing merozoites. ln the absence of these observations, a diagnostic PCR test with greater sensitivity and specificity than nticroscopy can be done. This test is recommended in suspect cases in which the parasite is not observed, as well as to confinn identification of piroplasms or schizonts. Treatment and Control: Historically,

attempts to treat cytauxzoonosis with a variety of anti.parasitic drugs (parvaquone, buparvaquone, trimethoprim/sulfadiazine, sodium thiacetarsan1ide) have been met with little success. ln one study, five of six cats and one additional cat were success­ fully treated with dintinazene aceturate (not approved in the USA) and imidocarb dipropionate (2 mg/kg, lM, two injections 3-7 days apart), respectively. The most consistent successful treatment in a large case se1ies resulted in survival of 64% of cats given a combination of atovaquone (15 mg/kg, PO, ti.ct for 10 days) and azithromycin (10 mg/kg/day, PO, for 10 days) and supportive care. Atovaquone is a ubiquinone analogue that binds cytochrome b. In one study of C felis-i.nfected cats treated with atovaquone and azithromycin, a CJet-is cytochrome b subtype (cytb l) was identified that was associated with increased survival in the cats infected with this subtype compared with other subtypes. Future development of a rapid means to identify the cytb l C felis subtype in infected cats may help better predict the likelihood of survival with treatment. Supportive care, including fluid therapy and heparin (100-200 U/kg, SC, tid) should be instituted in all cases. Nutritional support via an esophageal or nasoesopha­ geal feeding tube is recommended, which also facilitates administration of oral medications (eg, atovaquone and azithro­ mycin). Oxygen therapy and blood transfusions should be administered when necessary. Anti-i.nflanunatory drugs may be warranted in cases with W1relenting fever; however, the use of NSAlDs is contraindi­ cated in cats with azotemia or dehydration.

rv

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BLOOD PARASITES

Once a diagnosis is achieved and treat­ ments have begun, minimal stress and handling are recommended. Recovery, including resolution of fever, is often slow and may take as long as 5---7 days. Cats that survive have a complete clinical recovery, including resolution of hematologic and biochemical abnormalities within 2-3 wk. Some survivors remain persistently infected with piroplasms and may represent a reservoir of infection. In one study, dose-intense diaminazene diaceturate (4 mg/kg/day, IM, for 5 consecutive days) failed to reduce the severity of parasitemia in cats chronically infected with C Jelis and resulted in adverse drug reactions. Prevention: Routine application of a tick preventive is recommended to prevent cytauxzoonosis; however, disease has occurred in cats despite this treatment. In one study, a tick-repellent collar for cats containing imidacloprid 100/70,000/ µL (70 x 1Q9fL) for dogs, >50,000/µL (50 x 1Q9fL) for cats, >30,000/µL (30 x 109/L) for horses, and >20,000/µL (20 x 1Q9fL) for ruminants. Morphologic Abnormalities: Abnor­ malities of morphology may be associated with either acquired or inherited disease. Toxic changes are identified only in neutrophils. The term originates from historical observation that certain cell features were associated with general, usually overwhelming, toxic states, such as systemic bacterial infections and severe, acute inflammatory lesions. The tem1 is misleading in that it implies neutro­ phil injury. The cells are not injured and have normal function. Toxic change is best defined as a set of morphologic changes observed on the blood smear that occur as a result of accelerated marrow production of neutrophils. The accelerated produc­ tion is in response to relatively severe inflammatory states that maximally stimulate the bone marrow. Morphologic changes include (in order of frequency) diffuse cytoplasmic basophilia, Dahle bodies, and fine cytoplasmic vacuolation. More rare changes include increased prominence of cytoplasmic azurophilic granules, cellular gigantism, and binuclea­ tion. Toxic change is almost always associated with the concurrent presence of a left shift. It is graded as mild, I)loderate, or severe by subjective evaluation of the more common changes noted on examination of a blood smear. Dahle bodies, blue-gray cytoplasmic inclusions, are aggregates of endoplasmic reticulum. They are unique in that they may be found in clinically healthy cats and therefore are not interpreted as toxic change in this species unless accompanied by other features. Reactive lymphocytes have increased, distinctly basophilic cytoplasm and may have irregular or clefted nuclei. They may vary considerably in diameter. They have condensed chromatin and therefore are not blasts. They are interpreted as immunologi­ cally stimulated B cells. Granular lymphocytes have condensed chromatin and increased pale blue-gray cytoplasm that contains several small pink or azurophilic granules. The nucleus may be round to clefted. These are large granular lymphocytes and may be either natural killer (NK) lymphocytes or T lymphocytes. Blast cells are usually an indication of hematopoietic cell neoplasia if they are reproducible or present in large numbers.

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LEUKOCYTE DISORDERS

Their lineage may be tentatively identified by morphologic criteria, but flow cytometric analysis is required to definitively identify lineage. Many of the following morphologic changes are uncommon. Chediak-lligashi syndrome (see p 50) described in Persian cats, people, ·mmk, foxes, Hereford and Brangus cattle, mice, and killer whales is an autosomal recessive defect involving lysosomal granules. There is hyperfusion of granules resulting in large, eosinophilic cytoplasmic inclusions. Susceptibility to bacterial infections is increased, as is the tendency to bleed because of both neutrophil and platelet function abnormalities. Partial oculocutaneous albinism due to abnormal melanin granule formation may occur. The mucopolysaccharidoses are a group of lysosomal storage disorders in which there is a defect in degradation of glycosaminoglycans. Both neutrophils and lymphocytes may contain accumulated mucopolysaccharide product in the form of purple or metachromatic intracytoplas­ mic granules. Lymphocytes may also be vacuolated. These disorders are associ­ ated with a variety of systemic clinical abnormalities and are seen in dogs and cats. Another group of lysosomal storage disorders recognized in dogs and cats may result in cytoplasmic vacuoles predomi­ nantly in lymphocytes and occasionally in neutrophils. These disorders include gangliosidoses, cx-mannosidosis, Niemann­ Pick disease variants, acid-lipase deficiency, and fucosidosis. Most of these disorders result in severe, progressive neurologic disorders resulting from accumulated product in neuronal tissue. Locoweed toxicity is regarded as an acquired form of lysosomal storage defect in large animals. It is due to toxic principle from the plant that inhibits one or more enzymes of oligosaccharide metabolism. This may result in vacuolation in lymphocytes. . Pelger-Huet anomaly is a nuclear hyposegmentation defect of granulocytes in people, cats, rabbits, horses, and dogs that are heterozygous for the anomaly. Neutrophils have normal function but a near absence of segmented nuclear morphology. Most or all of the neutrophils appear as bands and metamyelocytes and may appear as a marked left shift in an otherwise normal leukogram. Eosinophils and basophils, if present, also exhibit nuclear hyposegmenta­ tion. Affected heterozygote animals are clinically normal; the homozygous inheritance of the trait is lethal.

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Hypersegmentation is an increased degree of nuclear segmentation resulting in multiple lobes connected by nuclear filaments. It is a nonspecific indication of increased time in circulation and is normal aging of the cell. This may be seen with stress leukograms or corticosteroid administration. Leukocyte agglutination may occur with either neutrophils or lymphocytes. This is seen on low magnification as aggregates of 5-15 tightly clumped leukocytes. Avid agglutination may result in a markedly false low total WBC concentration on some cell counting instruments. This is likely due to the presence of a naturally occurring cold agglutinin that is operative only in vitro at laboratory temperature. There is no known clinical significance. Infectious disease inclusions are occasionally recognized. Canine distemper inclusions may be seen in neutrophils, monocytes, and lymphocytes, as well as in newly produced erythrocytes. The ehrlichioses of various animal species and canine hepatozoonosis may have cytoplas­ mic inclusions of respective organisms of these tickbome diseases.

Specific Interpretative Leukogram Responses The abnormal leukogram is typically interpreted into one of several responses, each of which may consist of one or more abnormalities in the differential. Some may also be associated with concurrent changes in erythrocytes and platelets. Important species differences in leukogram responses are described below.

Corticosteroid-induced or Stress Response: In this very common leukocyte

response, endogenous steroid release from stress or treatment with exogenous corticosteroids results in a leukogram with multiple changes. Lymphopenia is the most consistent change, and mature neutrophilia is usually present. Monocytosis and eosinopenia are expected changes in dogs but are more variable in other species. Neutrophiliais due to decreased adherence to the vascular endothelium, which inhibits margination and increases circulating time. As a result, neutrophils may also become hypersegmented. There may also be increased marrow release of neutrophils. Lymphocytes become redistributed to lymphoid tissues instead of remaining in circulation. This response may be misinter­ preted as inflanlffiation, but a left shift is not usually present.

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LEUKOCYTE DISORDERS

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Excitement or Epinephrine Re­ sponse: Leukocytosis may occur as

a result of exercise or excitement; this response is mediated by increased epinephrine concentration and may be thought of as a transient physiologic response. Epinephrine flushes cells from the marginal to the central pool. The effect may double the total WBC concentration within minutes. In addition, splenic contraction releases WBCs and RBCs into the peripheral circulation. The leukocytosis is usually due to a mature neutrophilia without a left shift. Lyrnphocytosis may be present, especially in young horses or cats. The effect in cats is often recognized as a prominent lyrnphocy­ tosis--as much as two times the upper reference value. The excitement response is relatively uncommon in dogs.

Inflammatory Response: The concentration of neutrophils in blood in response to inflammatory disease is highly variable and dynamic. It is best viewed as a balance between tissue demand and bone marrow production at all phases of the response. There are important species differences in this balance that are related to bone marrow storage reserve and proliferative capacity. At the beginning of an inflammatory process, the bone marrow responds by delivery of its reserve of late-stage maturing neutrophils, including band cells. If consumption exceeds marrow delivery during this acute stage, neutropenia with a prominent left shift will develop. In dogs and cats, this is an indication of severity of the inflammatory lesion. Subsequently, it takes 2-4 days for the marrow to accelerate neutrophil production by increased stem-100,000/µL [100 x 109/L]), lyrnphocytosis, and death ( usually between 2 wk and 8 ino of age) are characteristic. Calves often are stunted and have recurrent pneumonia, ulcerative stomatitis, enteritis, and periodontitis. On examination of tissues, there are few neutrophils, except within vessel lurnens, because they persist in the circulation and have impaired entry into the tissues. Testing is available to detect carriers. A similar defect has also been reported in some Irish Setter dogs. Neutropenia may develop because of excessive tissue demand for neutrophils or reduced granulopoiesis. It may be seen with overwhelming bacterial infections, especially gram-negative septicemia or

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LEUKOCYTE DISORDERS

endotoxemia, in all species. Immune­ mediated destruction of neutrophils is diagnosed by exclusion of other consump­ tive processes. Stem-cell iltjury may occur from many causes such as certain viral infections (see TABLE 7), chemical iltjury, and idiosyncratic drug reactions, eg, sulfona­ mides, penicillins, cephalosporins, and chloramphenicol in cats. These reactions typically affect all bone marrow cell lines but are recognized initially as neutropenia because of the relatively short lifespan of this cell type. Neutropenia is seen in the now rare cyclic hematopoiesis syndrome of gray Collie dogs, also known as canine cyclic neutrope­ nia It is an inherited, autosomal recessive disease characterized by a profound periodic neutropenia, associated overwhelming recurrent bacterial infections, bleeding, and coat color dilution. The defect is due to a mutation in a protein that may regulate neutrophil elastase activity. Neutrophil matu­ ration is arrested at regular intervals of 11-14 days; the peripheral blood neutropenia lasts 3--4 days and is followed by neutrophilia All other hematopoietic cells, including lymphocytes, also have cyclic production that is minimally evident because of the relatively long circulation time of other cell types. Affected puppies often die at birth or during the first week and rarely live> 1 yr. Surviving dogs may be stunted and weak and develop serious recurrent bacterial infections during periods of neutropenia Monocytosis may be seen in the inflammatory pattern at any stage of its progression. Monocytosis is more likely, and tends to be of greater magnitude, when the process becomes chronic. Combined Corticosteroid-induced and Inflammatory Response: Inflam­

matory disease processes commonly induce a concurrent endogenous corticosteroid response, recognized by the presence of

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lymphopenia in cortjunction with an inflammatory neutrophil response (left shift). The neutrophil response to inflamma­ tion overrides and may be additive to the corticosteroid influence on neutrophils. Lymphocytosis: Mild lymphocytosis and reactive lymphocytes may occur after vaccination. Modest lymphocytosis, in the range of 7,000-20,000/µL (7-20 x 109/L), should prompt consideration of a possible physiologic excitement response, particu­ larly in cats. lf that is excluded, then a lymphoproliferative disorder should be considered. lf examination of lymphocyte morphology reveals prolymphocytes and/or blast cells, then lymphocytic leukemia is the working interpretation. lf the cells are all small with normal appearing chromatin, then chronic lymphocytic leukemia is a considera­ tion requiring further evaluation. Chronic ehrlichiosis may result in lymphocytosis of this magnitude in dogs. At higher concentra­ tions, the lymphocytosis may be regarded as conclusive evidence of leukemia Persistent lymphocytosis in cattle is defined by lymphocyte concentrations consistently> 7,500/µL (7.5 x 109/L). It is due to a B-cell proliferation that occurs in a subset of animals infected with bovine leuke­ mia virus (BLV). Affected cattle are usually asymptomatic. The finding of persistent lymphocytosis is regarded as a positive indication of BLV infection in the individual. A smaller subset of BLY-infected cattle, either with or without lymphocytosis, may progress to develop lymphoma or lympho­ cytic leukemia Lymphopenia: Lymphopenia is a

common leukogram abnormality most commonly associated with endogenous (stress) or exogenous corticosteroid administration. The most likely cause is steroid-induced apoptosis of lymphocytes. Lymphopenia also rarely occurs due to

VIRAL INFECTIONS THAT MAY CAUSE TRANSIENT NEUTROPENIA

Species

Infection

Dogs

Parvovirus, canine distemper ( acute phase)

Cats

Panleukopenia (parvovirus), feline leukemia virus

Horses

Equine influenza, equine viral arteritis (acute phase), equine herpesvirus

Cattle

Bovine viral diarrhea virus

Pigs

Classical swine fever virus, African swine fever virus

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LEUKOCYTE DISORDERS

other causes, such as extravasation of lymph (eg, lymphangiectasia, chylous effusion), some viral infections with tropism for rapidly dividing cells (eg, parvoviral infections), and hereditary immunodefi­ ciency disease (eg, combined immunodefi­ ciency disease of Arabian foals). Stem-cell Injury and Pancytopenia:

A number of factors may cause reversible or irreversible stem-cell injury. These injuries may affect erythrocyte, platelet, lymphocyte, and/or granulocyte production. Because of short circulating lifespan, neutropenia is often the first abnormality seen. When chronic or irreversible, these injuries result in decreases in all three major blood cell lines, with the hemogram demonstrating leukopenia, nonregenerative anemia, and thrombocytopenia General causes include 1) overdoses of radiation and antineoplastic drugs, 2) drug or plant toxicities (eg, estrogen toxicity in dogs, bracken fem toxicity in cattle, phenylbutazone toxicity in species other than horses), 3) hematopoietic cell neoplasia involving bone marrow (myelophthisis), and 4) viral infections that irtjure rapidly dividing cells and may cause transient neutropenia (see TABLE 7). Eosinophilia and Basophilia: Eosino­

philia, or the combination of eosinophilia and basophilia, prompts the consideration of the following processes: allergic-based inflammation, parasitic infestation, subepithelial (skin, respiratory, GI) inflammation that is likely allergic in nature, and less cpmmonly, paraneoplastic induction. Eosinophilia is seen in most dogs with heartworm disease and may be seen in dogs and cats with flea infestation.

Leukemia, canine blood smear; note several atypical large cells of hematopoietic origin with convoluted nuclei. Courtesy of Dr. Darren Wood.

Hypereosinophilic syndrome has been reported in cats, dogs, and ferrets. This poorly understood syndrome is character­ ized by consistent marked eosinophilia and eosinophil tissue infiltration with associated organ dysfunction. Decreased concentra­ tion of these cell types in blood has no pathologic relevance. Prominent Metarubricytosis: Although typically absent, metarubricytes occasion­ ally become a major component of the total nucleated cell count. The magnitude may be 10%-50% of the nucleated cell population or more, with absolute numbers reaching 5,000-10,000/µL (5-10 x 109/L). This may occur rarely in early phases of an intense regenerative response to anemia It may also be associated with endothelial injury (eg, heat stroke) resulting in abnormal release rate of nRBCs from marrow. Most nRBCs will be counted as lymphocytes on cell counters with differential capability. This may result in a preliminary result of lymphocytosis being corrected later only by examiI\ation of the blood smear. Hematopoietic Cell Neoplasia and Leukemia: Most cases of hematopoietic

cell neoplasia of either lymphocytic or bone marrow origin will have some abnormal cells in blood. Sometimes, neoplastic cells are present in low numbers and are detected only by scanning the blood smear under low magnification. Finding abnormal hematopoi­ etic precursor cells in blood in small numbers prompts investigation of bone marrow and/ or other hematopoietic tissues (such as the spleen) for possible neoplastic disease. The opposite extreme is marked leukocytosis with a predominance of the abnormal (neoplastic) cell population. In this situation, the blood sample is diagnostic for leukemia. If poorly differentiated, the cells are classified as blasts, with possible cell lineage determined based on morpho­ logic appearance. If well differentiated, the cell lineage is usually more clear, because the cells are mature. Lymphocytic leukemias are more common in domestic animals than are myeloproliferative disorders (ie, leukemias of granulocytes, erythrocytes, or platelets). Myelodysplasia is a term used to describe peripheral blood cytopenias, a hyperplastic response in bone marrow, and dysplastic features in developing cells. This can occur with a toxic insult to the bone marrow but may also indicate a preleukemic phase, and serial hemograms should be monitored. A distinction is often made between an "acute" or "chronic" leukemia The terms

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LYMPHADENITIS AND LYMPHANGITIS

are more in reference to the clinical course of the disease rather than the duration of the tumor. An acute leukemia of leukocytes often causes systemic signs of illness and a poor short-term prognosis. These animals have variable numbers of poorly differenti­ ated blast cells in circulation, as well as cytopenias in other cell lines. In contrast, a chronic leukemia of leukocytes often causes few to no clinical signs,,may be discovered incidentally, and can have a long clinical course. These animals usually have

large numbers of well-differentiated cells in circulation and lack cytopenias. Considerable progress is being made in the use of monoclonal antibody labeling and flow cytometric analysis to better establish cell lineage, particularly when the morphol­ ogy is equivocal. This is particularly useful for poorly differentiated leukemias, in which morphology alone is unreliable. The distinction between well-differentiated or chronic myelogenous leukemia and extreme neutrophilic leukocytosis can be difficult.

• LYMPHADENITIS AND1 LY1MPHANGITIS

CASEOUS LYMPHADENms OF SHEEP AND GOATS Caseous lymphadenitis (CL) is a chronic, contagious disease caused by the bacterium Corynebacterium pseudotuberculosis. Although prevalence of CL varies by region and cpuntry, it is found worldwide and is of major concern for small ruminant prodµcers in North America. The disease is characterized by abscess formation in or near major peripheral lymph.nodes (external form) or within internal organs and lymph nodes (internal form). Although both the external and internal forms of CL occur in sheep and goats, the external forn1 is more common in goats, and the internal form is more common in sheep. Economic losses from CL include death,condemna­ tion and trim of infected carc,isses, hide and wool loss, loss of sales for breeding animals, and premature culling of affected animals from the herd or flock Once established on a farm or region (endemic),it is primarily maintained by contanlination of the environment with active draining lesions, animals with the internal form of the disease that contanlinate the environment through nasal discharge or coughing,the ability of the bacteria to survive harsh environmental conditions, and lack of strict biosecurity necessary to reduce th� number and preyent introduction of new cases. Although CL is typically considere400 bpm) nonsustained ventricular tachycardia. It takes 6--8 sec of no blood flow to the brain to result in unconsciousness, so the tachycardia must last for that long for syncope to occur and then must stop spontaneously for sudden death not to

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occur. The diagnosis is based on the nmnber of premature ventricula.i· complexes(PVCs) on a Holter monitor(>100-300 PVCs in 24 hr is generally considered diagnostic of ARVC in this breed). The QRS complexes of the PVCs are most commonly upright in the leads where the QRS complex is usually upright, meaning they originate from the right ventricle. The hea.it looks nom1al on thoracic radiographs and an echocardio­ gra.in in most Boxers with ARVC, although some will develop a true DCM and go into hea.tt failure. Boxers presented for syncope without DCM are treated with sotalol (1-3 mg/kg, PO, bid) or a combination of mexiletine(5--10 mg/kg, PO, tid) and atenolol(12.5--25 mg/dog, PO, bid). Dogs refractory to sotalol may have mexiletine added. In Boxers with ARVC that do not have DCM, tl1e prognosis is often good, and many live for several years on antia.t-rhytb­ mic therapy. The longtem1 prognosis for dogs with DCM that are in hea.tt failure is poor. Most live only several months. In cats, the disease usually ma.ttifests as right ventricular and atrial enla.i·gement and right hea.tt failure, usually along with some supravent1icular a.i1d ventricular tachyar­ rhythmias. Dyspnea and tachypnea due to pleural effusion, ascites, and nonspecific clinical signs such as a.i1orexia and lethargy a.i·e repo1ted in affected cats. Treatment is sintilar to that of DCM. Longtenn prognosis is generally poor. Hypertrophic Cardiomyopathy: Hypertrophic cardiomyopathy(HCM) is characterized by primary concentric left ventricula.i· hypertrophy (ie, thick wallsJ resulting from an inherent myocardial disorder rather than pressure overload (such as caused by aortic stenosis), hormonal stimulation(such as hyperthy­ roidism or acromegaly), infiltration of the myocardium(eg, lymphoma), or other noncardiac disease. It is primarily seen in domestic cats and rarely in small dogs. It has also been reported in cattle. Papillary muscle enlargement is a consistent feature of the disease in cats. In people, HCM is caused by mutations in a nmnber of sarcomeric genes. Mutations in one sarcomeric gene, the cardiac myosin binding C gene, have been identified in Maine Coon and Ragdoll cats. These mutations are thought to result in the production of dysfunctional sarcomeres within myocytes. The myocardimn then produces new sarcomeres to help the dysfunctional ones, resulting in hypertrophy that may be ntild to severe. Severe hypertrophy is often accompanied by

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HEART DISEASE AND HEARTFAILURE

cellular necrosis and resultant replacement fibrosis (myocardial scarring). Increased fibrosis coupled with severe wall thickening results in a stiffer than normal left ventricle in diastole, which increases diastolic pressure for any given diastolic volume. The increased pressure is transmitted backward into the left atrium in diastole, resulting in left atrial enlargement and, if severe enough, in left heart failure. Left heart failure manifests as pulmonary edema and pleural effusion in cats. Myocardial contractility is nom1al, but left ventricular end-systolic dian1eter is usually less than normal and may become zero (end-systolic cavity obliteration) due to the increased wall thickness resulting in a decrease in systolic wall stress (ie, afterload). Severe left at1ial enlargement can develop, which causes blood flow to stagnate. This can lead to the fon11ation of a left atrial thrombus and the potential for systemic thromboembolism. A cranial displacement of the anterior mitral valve leaflet during ventricular systole, a phenomenon termed systolic anterior motion of the mitral valve, is a common finding in cats with HCM and is due to marked enlargement of the papillary muscles that drag the mitral valve leaflet into the left vent1iculru· outflow tract in systole. This phenomenon produces two turbulent jets-one of dyn8lll.ic subaortic stenosis and the other of mitral regurgita­ tion. Systolic anterior motion is the most common cause of a heart murmur in a cat withHCM. Gross pathology includes increased cardiac weight (>20 g), increased left ventricular wall thickness, papillary muscle hypertrophy, and often left atrial enlargement. The myocardium often contracts after death (ie, unde.cgoes rigor), so the postmortem diagnosis ofHCM often crumot be made based on left ventricular wall thickness alone. HCM is the most common primary heart disease diagnosed in cats, but it is rare in dogs. It is fru11.ilial in many breeds of cats, including Persians, Sphynx, Norwegian Forest Cats, Bengals, Turkish Vans, and American and British Shorthairs. As in Maine Coons and Ragdolls, the mode of inheritance is thought to be autosomal dominant. The disease is seen in cats from 3 mo to 17 yr of age, although most cats are middle aged at presentation. It is not present at birth but develops over time. Penetrance is often -93%) than cats with bilateral hindlimb infarction (15o/e>-36%) regardless of therapy used. Aspirin (25 mglkg, PO, every 48-72 hr; or 5 mg,'cat, PO, every 48-72 hr) has historically been the most widely used preventive therapy for cardioembolic disease in cats. Altl1ough aspirin appears relatively safe in cats (up to 20"A,GI aclve1se effects) and is inexpensive unless compounding is done, the antiplatelet efficacy of aspi.Jin in cats has been called into question, and CUITently there is no evidence that aspirin prevents first-time or recun·ent cardioembolism. Clopidogrel may be a more effective antiplatelet drug in this species. Clopiclogrel (18.75 mg,'cat/clay, PO) inhibits botl1 primary and secondary platelet aggregation. These effects are more potent than tl1ose induced by aspirin. Clopidogrel also inlpai.Js the platelet-release reaction, decreasing the release of pro-aggregating and vasoconstrictive agents. Adve1se effects are rare but can include vomiting in up to l()OA, of cats; this appears to be an1elioratecl by giving the drug witl1 food. A combination protocol of aspi.Jin and clopidogrel has been used previously. Although this protocol has not been studied objectively, it seems to be well tolerated despite a theoretical increased risk of bleeding. A multicenter, randomized, prospective study revealed that clopidogrel was associated witl1 a signifi­ cantly prolonged survival tin1e compared with aspi.J'in in cats tl1at presented with cardiogenic aiterial thromboembolism. The time to recun-ence of arte1ial thromboembo­ lism or deatl1 in the clopidogrel group was >365 days versus 192 days in tl1e aspi.Jin group. Warfai·i..11 (0.25-0.5 mg,'day/cat, PO) has also been used for prevention of primary or secondary cai·dioemboli. Dosing is adjusted to prolong the prothrombin tinle to 1.5-1.7 x the pretreatment value. Because warfarin decreases the anticoagulant proteins C and S before reduction in factors II, VII, IX, and X, joint treatment with heparin is recom­ mended for the first 5-7 clays of warfarin therapy. Problems with wai'farin therapy include large inter- and intra-individual variability, difficult dosing because of tablet size, and bleedmg, i.J1cluding fatal hem01° rhage. Because of these lin1itations and lack of objective clinical data demonstrating efficacy, warfarin is not a fust-line

145

anti thrombotic for carclioembolic prevention in cats. The low-moleculai0weight hepa1ins (LMWHs) are smaller in size than UIUrac­ tionated heparm but maintain the ability to inhibit factor Xa, with a greatly reduced inhibition of Ila. The reduced anti-Ila activity translates into a negligible effect on the activated paitial tliromboplastin time, but measurement of anti-Xa activity can be used to monitor closing efficacy. Enoxaparin (1-1.5 mg/kg, SC, once or tw ice daily) ai1d daltepai'in (150-170 IU/kg, SC, bicl-tid ) have both been used in cats. These drugs have been well tolerated with only rare bleeding repo1ted, but objective clinical studies evaluating their efficacy have not been perfonned. These agents have been frequently combi.J1ecl with clopiclogrel in an attempt to provide a more complete ai1tithrombotic effect. This protocol appears to be well tolerated, altl1ough some minor bleeding has been seen. Reported recurrence rates for cats receivi.J1g some fo1m of antithrombotic prevention ai·e l 7o/e>-75%, with a 1-yr recurrence rate of 25o/e>-50%. Long-tenn median survival times after an initial cardioembolic event have ranged from 51-376 days. Although these nll1llbe1s may seem daunting, many of these cats can do well. lf owners ai·e willing to treat, they should be encouraged to give cats 24-72 hr of supportive care before decidi.J1g on euthanasia, UIUess severe infarction, severe CHF, or reperfusion injury are present. Arterial thrombosis in clogs is most commonly associated with protein-losing nephropathy and neoplasia, though idiopathic thrombosis is also seen. There is very little cli.Jlical experience with aiterial thromboembolism in dogs, but thrombo­ lytic therapy using streptokmase, uroki­ nase, and tPA have been reported in isolated cases with vai"iable success. There are no clinical trials evaluating the efficacy of anti.thrombotic therapy for prevention of arterial thromboembolism in dogs, but dosing protocols for aspi.Jin (0.5-5 mg/kg, PO, once or twice daily), clopidogrel (1-3 mglkg,'day, PO), wai'farin (0.1-0.22 mg/kg,' day, PO), dalteparm (150 IU/kg, SC,bid-tid), enoxaparin (1-1.5 mg/kg, SC, once or twice daily), and rivaroxaban (0.5-1 mglkg,'day, PO) have been reported. Treatment reconunendations for pulrnonaiy embolism in dogs are sinlilai· to those for cardioembolic disease in cats. Aspi.J'in (0.5 mglkg,'clay, PO) has inlproved survival in dogs with in1mtme-mediatcd hemolytic anemia when added to standard inlmunosuppressive therapy.

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DIGESTIVE SYSTEM INTRODUCTION 154

Function 154 Pathophysiology 155 Clinical Findings of GI Disease 156 Examination of the GI Tract 157 Infectious Diseases 158 Noninfectious Diseases 161 Principles of Therapy 161

CONGENITAL AND INHERITED ANOMALIES

Mouth 162 Teeth 164 Cysts and Sinuses of the Head and Neck 165 Esophagus 166 Hernias 166 Stomach 167 Small and Large Intestine 168 Liver 169

162

171 Estimation of Age by Examination of the Teeth 171

DENTAL DEVEL OPMENT DENTIS T RY 175

Large Animals 175 Congenital and Developmental Anomalies 176 Abnormal Tooth Eruption 177 Irregular Wear of the Dentition 177 Periodontal Disease 177 Dental Caries 178 Small Animals 178 Periodontal Disease 178 Endodontic Disease 180 Tooth Resorption 181 Developmental Abnormalities 182 Dentofacial Trauma 185 Dental Caries 185

PHARYNGEAL PARALYSIS

186

DISEASES OF T HE RECTUM AND ANUS

Anal Sac Disease 187 Perianal Fistula 187 Perianal Tumors 188 Perinea! Hernia 188 Rectal and Anorectal Strictures 189

187

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DIGESTIVE SYSTEM

Rectal Neoplasms 189 Rectal Polyps 189 Rectal Prolapse 189 Rectal Tears 190

BACTERIAL DISEASES ENTERIC CAMPYLOBACTERIOSIS 191 SALMONELLOSIS 195 TYZZER DISEASE 199 PROTOZOAL DISEASES AMEBIASIS 202 COCCIDIOSIS 203

Cattle 205 Sheep 206 Goats 207 Pigs 208 Cats and Dogs 208

CRYPTOSPORIDIOSIS 209 GIARDIASIS 211 LARGE ANIMALS DISEASES OF THE MOUTH 213 DISEASES OF THE ESOPHAGUS 215

Obstruction (Choke) 215 Strictures 217 Neoplasia 21 �

GASTROINTESTINAL ULCERS 218 Horses 218 Pigs 219

DISEASES OF THE RUMINANT FORESTOMACH 221 Simple Ind igestion 221 Grain Overload 222 Subacute Ruminal Acid osis 225 Bloat 227 Traumatic Reticuloperitonitis 230 Vagal Indigestion Synd rome 233 Ruminal Drinking 236 Ruminal Parakeratosis 237

DISEASES OF THE ABOMASUM 238 Left or Right Displaced Abomasum and Abomasal Volvulus 238

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DIGESTIVE SYSTEM

Abomasal Ulcers 241 Dietary Abomasal Impaction 244 ACUTE INTESTINAL OBSTRUCTIONS

245

248 Diseases Associated with Colic by Anatomic Location 258 Stomach 258 Small Intestine 258 Cecum and Large Intestine 262

COLIC IN HORSES

INTESTINAL DISEASES IN RUMINANTS 266

Cattle 266 Bovine Viral Diarrhea and Mucosal Disease Complex 267 Jejunal Hemorrhage Syndrome 270 Winter Dysentery 271 Other Intestinal Diseases of Cattle 272 Sheep and Goats 273 Watery Mouth Disease in Lambs 274 Diarrhea in Neonatal Ruminants 275

INTESTINAL DISEASES IN HORSES AND FOALS 281

Diarrheal Disease in Horses 281 Salmonellosis 281 Potomac Horse Fever 283 Clostridia-associated Enterocolitis 285 Colitis-X 286 Coronavirus 287 Parasitism 287 Sand Enterocolopathy 287 Recurrent Diarrhea 288 Infiltrative Colonic Disease 288 Miscellaneous Causes of Diarrhea 288 Diarrheal Disease in Foals 289 Weight Loss and Hypoproteinemia 291 Gastrointestinal Neoplasia 291 Inflammatory Bowel Disease 291 NSAID Toxicosis 292 Small-intestinal Fibrosis 293

293 Clostridium difficile Enteritis 293 Clostridium perfringens Type A Enteritis 295 Clostridium perfringens Type C Enteritis 295 Edema Disease 296 Enteric Colibacillosis 296 Hemorrhagic Bowel Syndrome 296 Intestinal Salmonellosis 296 Intestinal Spirochetosis 297 Parasitism 298 Porcine Epidemic Diarrhea 298

INTESTINAL DISEASES IN PIGS

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DIGESTIVE SYSTEM

Porcine Proliferative Enteritis 299 Rectal Strictures 300 Rotaviral Enteritis 301 Swine Dysentery 301 Transmissible Gastroenteritis 302 Other Intestinal Viruses of Pigs 303 GASTROINTESTINAL PARASITES OF RUMINANTS

Cattle 308

303

Haemonchus, Ostertagia, and Trichostrongylus spp Cooperia spp 310 Bunostomum sp 310 Strongyloides sp 310 Nematodirus spp 310 Toxocara sp 311 Oesophagostomum sp 311 Chabertia sp 311 Trichuris spp 312

308

Haemonchus, Ostertagia, and Trichostrongylus spp

312

Tapeworms 312 Sheep and Goats 312

Intestinal Trichostrongylosis 313 Bunostomum and Gaigeria spp 313 Nematodirus spp 313 Oesophagostomum sp 313 Chabertia sp 314 Strongyloides sp 314 Trichuris spp 314 Tapeworms 314

GASTROINTESTINAL PARASITES OF HORSES Gasterophilus spp 315 Habronema spp 315 Oxyuris sp 316 . Parascaris sp 316

Large Strongyles 316 Small Strongyles 317 Strongyloides sp 319 Tapeworms 319 Trichostrongylus sp 319

GASTROINTESTINAL PARASITES OF P IGS 320 Ascaris suum 320 lv1acracanthorhynchussp 321 Oesophagostomum spp 322

Stomach Worms 322

Strongyloides sp 323 Trichuris sp 323

315

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DIGESTIVE SYSTEM

FLUKE INFECTIONS IN RUMINANTS 324

Fasciola hepatica 324 Fasciola gigantica 326 Fascioloides magna 327 Dicrocoelium dendriticum 327 Eurytrema spp 328 Paramphistomes 328

HEPATIC DISEASE 329

Acute Hepatitis 338 Idiopathic Acute Hepatic Disease 338 Acute Hepatic Necrosis in Cattle 339 Fatty Liver Disease of Cattle 1018 (MET) Infectious Hepatitis and Hepatic Abscesses 340 'Iyzzer Disease 340 Cholangiohepatitis 340 Equine Rhinopneumonitis 341 Infectious Necrotic Hepatitis 341 Bacillary Hemoglobinuria 341 Hepatic Abscesses 341 Hepatotoxins 341 Chemical and Drug-related Causes of Toxic Hepatopathy 342 lVlycotoxicoses 342 Blue-green Algae Intoxication 343 Hepatotoxic Plants 343 Cholelithiasis, Choledocholithiasis, and Hepatolithiasis 344 Chronic Active Hepatitis 345 Hyperlipemia and Hepatic Lipidosis 346 Hepatic Neoplasia 348 lVliscellaneous Hepatic Disorders 349 Cholangitis 349 Hepatic Failure in Foals 349 Biliary Atresia 349 Hemochromatosis 349 Right Hepatic Lobe Atrophy in Horses 350 Hepatic Lobe Torsion 350 Hepatic Amyloidosis 350 Congenital Hepatic Fibrosis 350 Primary Hyperammonemia of Adult Horses 350 Portosystemic Shunts 351 Hyperammonemia oflVlorgan Weanlings 351 Hyperbilirubinemia Syndromes 351 Gilbert Syndrome 351 Dubin-Johnson Syndrome 351 Liver Abscesses in Cattle 352

MALASSIMILATION SYNDROMES ABDOMINAL FAT NECROSIS

360

353

151

152

DIGESTIVE SYSTEM

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SMALL ANIMALS DISEASES OF THE MOUTH 361 Oral Inflammatory and Ulcerative Disease 361 Feline Stomatitis 362 Canine Stomatitis 363 Eosinophilic Granuloma Complex 971 (1TG) Lip Fold Dermatitis and Cheilitis 364 Mycotic Stomatitis 364 Acute Necrotizing Ulcerative Gingivitis 364 Glossitis 365 Soft-tissue Trauma 365 Papillomas 366 Oral Tumors 366 Salivary Disorders 367 Ptyalism 367 Salivary Mucocele 368 Salivary Fistula 368 Salivary Gland Tumors 368 Sialadenitis 369 Sialadenosis 369 Necrotizing Sialometaplasia 369 Xerostomia 369 DISEASES OF THE ESOPHAGUS 370 Cricopharyngeal Achalasia 370 Dilatation of the Esophagus 370 Esophageal Dysmotility 371 Esophageal Strictures 371 Esophagitis 372 Esophageal Foreign Bodies 372 Esophageal Diverticula 373 Bronchoesophageal Fistula 373 DISEASES OF THE STOMACH AND INTESTINES 373 Canine Parvovirus 373 Colitis 377 Constipation and Obstipation 380 Feline Enteric Coronavirus 383 Gastric Dilation and Volvulus 384 Gastritis 386 Gastrointestinal Neoplasia 388 Gastrointestinal Obstruction 390 Gastrointestinal Ulcers 393 Helicobacter Infection 394 Hemorrhagic Gastroenteritis 396 Inflammatory Bowel Disease 397 Malabsorption Syndromes 400

DIGESTIVE SYSTEM

407 Pancreatitis 407 Exocrine Pancreatic Insufficiency 409 Pancreatic Neoplasms 411 Pancreatic Abscesses 412 Pancreatic Pseudocyst 412

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THE EXOCRINE PA NCREAS

GASTROINTESTINAL PARASITES 412 Spirocerca lupi 412 Physaloptera spp 413 Ollulanus sp 413 Strongyloides sp 414

Roundworms 415 Hookworms 416 Whipworms 421 Acanthocephalans 421 Oncicola sp 421

Macracanthorhynchus sp

Tapeworms 421 Flukes 426 Intestinal Flukes 426 Hepatic Flukes 427

421

429 Laboratory Analyses and Imaging 430 Hematology 430 Coagulation Tests 430 Enzyme Activity 430 Other Serum Biochemical Measures 434 Hepatic Function Tests 436 Imaging 437 Cholecystocentesis 438 Liver Cytology 438 Liver Biopsy 438 Pathologic Changes in Bile 439 Nutrition 439 Diseases of the Liver 442 Fulrninant Hepatic Failure 442 Hepatic Encephalopathy 443 Portal Hypertension and Ascites 445 Portosysternic Vascular Malformations 446 Acquired Portosystemic Shunts 450 Other Hepatic Vascular Disorders 450 Hepatic Arteriovenous Malformation 450 Hepatic Vein Outflow Obstruction 451 Hepatotoxins 451 Infectious Diseases of the Liver 453 Feline Hepatic Lipidosis 456

HEPATIC DISEASE

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DIGESTIVE SYSTEM

Biliary Cirrhosis 459 Canine Cholangiohepatitis 459 Canine Chronic Hepatitis 460 Copper-associated Hepatopathy 460 Idiopathic Chronic Hepatitis 462 Breed-specific Chronic Hepatitis 464 Lobular Dissecting Hepatitis 466 Canine Vacuolar Hepatopathy 467 Metabolic Diseases Affecting the Liver 468 Hepatocutaneous Syndrome 468 Nodular Hyperplasia 469 Hepatic Neoplasia 469 Miscellaneous Liver Diseases 472 Glycogen Storage Disease 472 Hepatic Amyloidosis 472 Diseases of the Gallbladder and Extrahepatic Biliary System 473 Cholecystitis 473 Canine Gallbladder Mucocele 475 Other Disorders of the Gallbladder 477 Other Disorders of the Bile Ducts 477 Extrahepatic Bile Duct Obstruction 478 Cholelithiasis 479 Biliary Tree Rupture and Bile Peritonitis 480 Feline Cholangitis/Cholangiohepatitis Syndrome 481 Hepatobiliary Fluke Infection 484

DIGESTIVE SYSTEM INTRODUCTION The digestive tract includes the oral cavity and associated organs (lips, teeth, tongue, and salivary glands), the esophagus, the forestomachs (reticulum, rumen, omasum) of ruminants and the true stomach in all species, the small intestine, the liver, the exocrine pancreas, the large intestine, and the rectum and anus. Gut-associated lymphoid tissue (tonsils, ?eyer's patches, diffuse lymphoid tissue) is distributed along the GI tract. The peritoneum covers the abdominal viscera and is involved in many GI diseases. Fundamental efforts to manage GI disorders should always be directed toward localizing disease to a particular segment and determining a cause. A rational therapeutic plan can then be fom1ulated.

Function The prin1ary functions of the GI tract include prehension of feed and water; mastication, ensalivation, and swallo�g of feed; digestion of feed and ab_sorpt10n of nutrients; maintenance of tlwd and electrolyte balance; and evacuation of waste products. There are four primary functions-digestion, absorption, motility, and evacuation-and, correspondingly, fow· primary modes of dysfunction. Normal GI tract motility involves peristalsis, muscle activity that moves ingesta from the esophagus to the rectum; segmentation movements, which chum and mix the ingesta; and segmental resistance and sphincter tone, which retard aboral

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DIGESTIVE SYSTEM INTRODUCTION

progression of gut contents. In ruminants, these movements are of major importance in normal forestomach function. Pathophysiology Abnormal motor function usually manifests as decreased motility. Segmental resistance is usually reduced, and transit rate increases. Motility depends on stimulation via the sympathetic and parasympathetic nervous systems (and thus on the activity of the central and peripheral parts of these systems) and on the GI musculature and its intrinsic nerve plexuses. Debility, accompa­ nied by weakness of the musculature, acute peritonitis, and hypokalernia, produces atony of the gut wall (paralytic ileus). The intestines distend with fluid and gas, and fecal output is reduced. In addition, chronic stasis of the small intestine may predispose to abnom1al proliferation of microflora. Such bacterial overgrowth may cause malabsorption by injuring mucosal cells, by competing for nut1ients, and by deconjugat­ ing bile salts and hydroxylating fatty acids. Vomiting is a neural reflex act that results in ejection of food and fluid from the stomach through the oral cavity. It is always associated with antecedent events such as premonition, nausea, salivation, or shivering and is accompanied by repeated contractions of the abdominal muscles. Regurgitation is characterized by passive, retrograde reflux of previously swallowed material from the esophagus, stomach, or rumen. In diseases of the esophagus, swallowed material may not reach the stomach. One of the major consequences of subnormal motility is distention with fluid and gas. Much of the accumulated fluid is saliva and gastric and intestinal juices secreted during nonnal digestion. Disten­ tion causes pain and reflex spasm of adjoining gut segments. It also stin1ulates further secretion of fluid into the lwnen of the gut, which exacerbates the condition. When the distention exceeds a critical point, the ability of the musculature of the wall to respond dinlinishes, the initial pain disappears, and paralytic ileus develops in which all GI muscle tone is lost. Dehydration, acid-base and electrolyte imbalance, and circulatory failure are major consequences of GI distention. Accumulation of gut fluids stimulates additional secretion of fluids and electrolytes in the anterior segments of the intestine, which can worsen the abnormalities and lead to shock. Abdominal pain associated with GI disease usually is caused by stretching of

155

the intestinal wall. Contraction of the gut causes pain by direct and reflex distention of neighboring segments. Spasm, an exaggerated segmenting contraction of one section of intestine, results in distention of the immediately anterior segment when a peristaltic wave arrives. Other factors that may cause abdominal pain include edema and failure of local blood supply, eg, in local embolism or twisting of the mesentery. Specific diseases cause diaiThea by varied and characteristic mechanisms, the recognition of which is useful in understand­ ing, diagnosing, and managing GI diseases. The major mechanisms of diaJThea are increased penneability, hypersecretion, and osmosis. Disorders of motility are often secondary. In healthy animals, water and electrolytes continuously tra11Sfer across the intestinal mucosa. Secretions (from blood to gut) and absorptions (from gut to blood) occur simultaneously. In clinically healthy anin1als, absorption exceeds secretion, ie, there is net absorption. Inflan1mation in the intestines can be accompanied by an increase in "pore size" in the mucosa, pe1mitting increased flow through the membrane ("leak") down the pressure gradient from blood to the intestinal lwnen. If the ainount exuded exceeds the absorptive capacity of the intestines, diaJThea results. The size of the material that leaks through the mucosa varies, depending on the magnitude of the increase in pore size. Large increases in pore size permit exudation of plasma protein, resulting in protein-losing enteropathies (eg, lymphangiectasia in dogs, paratuberculosis in cattle, nematode infections). Greater increases in pore size result in the loss of RBCs, producing hemorrhagic diaJThea (eg, hemorrhagic gastroenteritis, parvovirus infection, severe hookwom1 infection). Hypersecretion is a net intestinal loss of fluid and electrolytes that is independent of changes in permeability, absorptive capacity, or exogenously generated osmotic gradients. Enterotoxic colibacillosis is a11 exan1ple of dian·heal disease due to intestinal hypersecretion; enterotoxigenic Escherichia coli produce enterotoxin that stin1ulates the crypt epitheliwn to secrete fluid beyond the absorptive capacity of the intestines. The villi, along with their digestive and absorptive capabilities, remain intact. The fluid secreted is isotonic, alkaline, and free of exudates. The intact villi are beneficial because a fluid (adminis­ tered PO) that contains glucose, ainino acids, and sodium is absorbed, even with hypersecretion.

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DIGESTIVE SYSTEM INTRODUCTION

Osmotic diarrhea is seen when inad­ equate absorption results in a collection of solutes in the gut lumen, which cause water to be retained by their osmotic activity. It develops in any condition that results in nutrient malabsorption or maldigestion or when an animal ingests a large amount of osmotically active substances that are not absorbed, eg, an overeating puppy. Malabsorption (seep 353 and seep 373) is failure of digestion and absorption due to some defect in the villous digestive and absorptive cells, which are mature cells that cover the villi. Several epitheliotropic viruses directly infect and destroy the villous absorptive epithelial cells or their precursors, eg, coronavirus, transmissible gastroenteritis virus of piglets, and rotavirus of calves. Feline panleukopenia virus and canine parvovirus destroy tl1e crypt epithelium, which results in failure of renewal of villous absorptive cells and collapse of the villi; regeneration is a longer process after parvoviral infection than after viral infections of villous tip epithelium (eg, coronavirus, rotavirus ). Intestinal malab­ sorption also may be caused by any defect that impairs absorptive capacity, such as diffuse inflan1rnatory disorders (eg, lymphocytic-plasmacytic enteritis, eosinophilic enteritis) or neoplasia (eg, lymphosarcoma). Other examples of malabsorption include defects of pancreatic secretion that result in maldigestion. Rarely, because of failure to digest lactose (which, in large amounts, has a hyperosmotic effect), neonatal fann animals or pups may have diarrhea while they are being fed milk Reduced secretion of digestive enzymes at the surface of villous tip cells is characteristic of epitheliotropic viral infections recognized • in farm anin1als. The ability of the GI tract to digest food depends on its motor and secretory functions and, in herbivores, on the activity of the microflora of the forestomachs of ruminants, or of the cecum and colon of horses and pigs. The flora of ruminants can digest cellulose; ferment carbohydrates to volatile fatty acids; and convert nitrog­ enous substances to an1monia, amino acids, and protein. In certain circum­ stances, the activity of the flora can be suppressed to the point that digestion becomes abnormal or ceases. Incorrect diet, prolonged starvation or inappetence, and hyperacidity (as occurs in engorge­ ment on grain) all impair microbial digestion. The bacteria, yeast.s, and protozoa also may be adversely affected by the oral administration of drugs that

are antimicrobial or that drastically alter the pH of rumen contents.

Clinical Findings of GI Disease Signs of GI disease include excessive salivation, dian·hea, constipation or scant feces, vomiting, regurgitation, GI tract hemorrhage, abdominal pain and distention, tenesmus, shock and dehydration, and suboptimal performance. The location and nature of the lesions that cause malfunction often can be determined by recognition and analysis of the clinical findings. In addition, abnormalities of prehension, mastication, and swallowing usually are associated with diseases of the oral mucosa, teeth, mandible or other bony structures of the head, pharynx, or esophagus. Vomiting is most common in single-stomached animals and usually is due to gastroente1itis or nonalin1entary disease (eg, uremia, pyometra, endocrine disease). The vomitus in a dog or cat with a bleeding lesion (gast1ic ulcer or neoplasm) may contain frank blood or have the appearance of coffee grounds. Horses and rabbits do not vomit. Regurgita­ tion may signify disease of the oropharynx or esophagus and is not accompanied by the premonitory signs seen with vomiting. Large-volume, fluid diarrhea usually is associated with hypersecretion (eg, in enterotoxigenic colibacillosis in newborn calves) or with malabsorptive (osmotic) effects. Blood and fibrinous casts in the feces indicate a hemorrhagic, fibrino­ necrotic enteritis of the small or large intestine, eg, bovine viral diarrhea, coccidiosis, salmonellosis, or swine dysentery. Black, tarry feces (melena) indicate hemorrhage in the stomach or upper part of the small intestine. Tenesmus of GI origin usually is associ­ ated with inflammatory disease of the rectum and anus. Small amounts of soft feres may indicate a partial obstruction of the intestines. Abdominal distention can result from accumulation of gas, fluid, or ingesta, usually due to hypomotility (functional obstruction, adynamic paralytic ileus) or to a physical obstruction (eg, foreign body or intussuscep­ tion). Distention may, of course, result from something as direct as overeating. A "ping" heard during auscultation and percussion of the abdomen indicates a gas-filled viscus. A sudden onset of severe abdominal distention in an adult run1inant usually is due to ruminal tympany. Ballottement and succussion may reveal fluid-splasl1ing sounds when t11e run1en or bowel is filled with fluid. Varying degrees of dehydration and acid-base and

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DIGESTIVE SYSTEM INTRODUCTION electrolyte imbalance, which may lead to shock, are seen when large quantities of fluid are Jost (eg, in diarrhea or sequestered in intestinal obstruction) or in gastJ.ic or abomasal volvulus. Abdominal pain is due to stretching or inflammation of the serosal surfaces of abdominal viscera or the peritonewn; it may be acute or subacute, and its manifestation varies among species. In horses, acute abdominal pain is conunon (seep 248). Subacute pain is more common in cattle and is characterized by reluctance to move and by grunting with each respiration or deep palpation of the abdomen. Abdominal pain in dogs and cats may be acute or subacute and is characterized by whining, meowing, and abnormal postmes (eg, outstretched forelin1bs, the stemwn on the floor, and the hindlirnbs raised). Abdominal pain may be difficult to localize to a particular viscus or organ within the abdomen. Examination of the GI Tract A complete, accmate history and routine clinical examination can often detem1ine the diagnosis. In outbreaks of GI tract disease in farm animals, the history and epidemiologic findings are of prime importance. In small aninlals, travel history or other details such as recent adoption from a shelter or recent kenneling or exposme to other animals in dog parks might give clinical suspicion to certain infectious diseases. If the history and epidemiologic and clinical findings are consistent with GI disease, the lesion should be localized within the system, and the type of lesion and its cause detennined. The abnom1ality may sometin1es be localized to the large or small intestine by history, physical examination, and fecal characteristics (see TABLE 1). The distinc­ tion is important because it narrows the

157

differential diagnoses and determines the direction of further investigation. However, the clinician should appreciate that in some instances the disorder can involve the entire bowel, with one set of localizing signs overshadowing the other. The clinical and laboratory techniques and their applications include the following: 1) visual inspection of the oral cavity and of the contom of the abdomen for distention or contraction; 2) palpation through the abdominal wall or per rectwn to evaluate shape, size, and position of abdominal viscera; 3) abdominal percussion to detect "pings," which suggest gas-filled viscera; 4) auscultation to deteffiline the intensity, frequency, and dmation of GI movements, as well as fluid-splashing soW1ds associated with fluid-filled stomachs and intestines and fluid-rushing sounds associated with diarrheal disease; 5) succussion to reveal fluid-splashing sounds; 6) ballottement to evaluate density and size of abdominal organs by their movement away from and back to the abdominal wall; and 7) gross examination of feces to assess bulk, con­ sistency, color, and presence of mucus, blood, or undigested food particles. Microscopic studies include exanlination for parasites. Cytology of a rectal or colonic mucosal smear stained with new methylene blue or Wright stain for fecal leukocytes is useful to detect inflanunatory bowel disease or the presence of intracellular fungal organ­ isms in the case of infection with Histo­ plasma capsulatum. The following may be useful (or necessary): 1) bacterial cult.me and virus isolation; 2) endoscopy to visualize the mucosa! surface of the esophagus, stomach, duodenwn, colon, and rectwn; 3) abdominocentesis to collect fluid from distended viscera or from the peritoneal cavity for examination; 4) radiography (contrast) to diagnose obstructive disease; 5) abdominal ultra-

DIFFERENTIATION OF SMALL-INTESTINAL FROM LARGE-INTESTINAL DIARRHEA Clinical Sign

Small Intestine

Large Intestine

Frequency of defecation

Nom1al or slightly increased

Very frequent

Fecal volume

Normal to increased

Decreased

Urgency

Absent

Usually present

Tenesmus

Absent

Usually present

Mucus in feces

Usually absent

Frequent

Blood in feces

Dark black (melena)

Red (fresh)

Weight loss

May be present

Rare

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DIGESTIVE SYSTEM INTRODUCTION

sonography to evaluate the wall thiclmess of the stomach and intestines and to detect abdominal masses, intussusceptions, and mesente1ic lymphadenopathy in small animals, and to investigate abdominal disorders in horses and cows; 6) biopsy (endoscopic, laparoscopic, ultrasound­ guided, surgical) to obtain samples for microscopic examination (samples of intestines and liver are useful to diagnose chronic enteritis and liver disease); and 7) tests for digestion and absorption to estimate and differentiate malabsorption and maldigestion. Common absorption tests include the measurement of the serun1 concentrations of cobalarnin (vitamin B,2) and folate. In addition, in small animals, an increased serun1 folate concentration in coajunction with a decreased cobalanli.n is consistent with antibiotic-responsive diarrhea Exoc1ine pancreatic ftmction can be evaluated by the detem1ination of serun1 trypsin-like immunoreactivity and by measurement of serum canine and feline

pancreas-specific lipase, which are sensitive and specific markers for the diagnosis of pancreatitis; laparotomy and biopsy may be indicated in cases in which the diagnosis is not clear or in which surgical correction may be required.

INFECTIOUS DISEASES The GI tract is subject to infection by many pathogens, which are a major cause of economic loss due to illness, suboptin1al performance, and death (see TABLE 2). These infections spread by direct contact or the fecal-oral route. Many of the pathogens are part of the normal intestinal flora, and disease develops only after a stressful event, eg, salmonellosis in horses after transporta­ tion, extended anesthesia, or surgery. The intestinal flora becomes established within a few hours after birth, which emphasizes the importance of the early ingestion of colostrum to provide protection against septicemia and il1testinal infection.

COMMON PATHOGENS OF THE GASTROINTESTINAL TRACT Pathogen

Cattle, Sheep, and Goats

Pigs

Vil1.1ses

Bovine viral diarrhea, rotavirus, coronavirus, rinderpest, malignant catarrhal fever, bluetongue, foot­ and-rnouth disease

Transmissible gastroenteritis, porcine circovirus type II, porcine epidemic diarrhea virus, rotavirus, foot-and­ mouth disease, vesicular stornatitis, vesicular exan­ thema

Bacteria

Enterotoxigenic Escherichia coli, Scrlmonella spp, Myco­ bacte,ium paratube1·c1.llosis, F'usobacte,-ium necrnphorum, Clost1-idium pe,:f,ingrns (types B, C, and D), Actinoba­ cillus lignieresii, Yersinia rnte,·ocolitica, Campylobacte,· jejuni

Enterotoxigenic E coli, Salmonella spp, Brachyspira hyodysente,iae, Clost1idium pe,:f,ingens types B and C, Lawsonia intracellulmis, Clostridiwn dijficile

Protozoa

Eimeria spp, Cryptosp01-idi­ um spp

Eimeria spp, Isospora s1.tis

Fungi

Candida spp (cattle)

Candidaspp

Algae

Prototheca spp

Prototheca spp

Rickettsiae

Parasites (helminths) See GASTROINTESTINAL PARASITES OF RUMINANTS, p 303.

See GASTROI OF PIGS, p

TESTINAL PARASITES

320.

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Definitive etiologic diagnosis of infectious disease of the GI tract depends on demonstrating the pathogen in the tract or in the feces of the affected animal. In herd epidemics, such as an outbreak of acute undifferentiated diarrhea in newborn calves or piglets, the best opportunity to establish a diagnosis is in the earliest stage of the disease by selecting untreated animals and submit­ ting them for necropsy and detailed microbiologic examination of the intestinal flora. When selective necropsy is not an option, a series of carefully collected daily fecal samples should be submitted to a diagnostic laboratory with a request for special culture techniques, depending on the infectious disease suspected. Molecular technologies, including ELISA and PCR, have been developed to demonstrate the presence of viral, bacterial, or protozoa! proteins or nucleic acids within the feces, which can provide a definitive diagnosis

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(eg, canine parvovirus, salmonellosis, cryptosporidiosis). Overview of Gastrointestinal Parasitism The GI tract may be inhabited by many species of parasites. Their cycles may be direct, in which eggs and larvae are passed in the feces and stadia! development occurs to the infective stage, which is then ingested by the final host. Alternatively, the inrn1ature stages may be ingested by an intern1ediate host (usually an invertebrate) in which further development occurs, and infection is acquired when the intern1ediate host or free-living stage shed by that host is ingested by the final host. Sometimes, there is no development in the intermediate host, in which case it is known as a transp01t or paratenic host, depending on whether the laivae are encapsulated or in the tissues. Clinical parasitism depends on the number and pathogenicity of the pai·asites, which

COMMON PATHOGENS OF THE GASTROINTESTINAL TRACT (continued) Horses

Dogs and Cats

Rotavirus, vesicular stomatitis, coronavirus

Canine parvovirus, canine coronavirus, feline panleukopenia virus, feline enteric coronavirus, canine and feline rotavi­ ruses, canine and feline astroviruses

Neorickettsia risticii (Potomac horse fever

Neorickettsia helminlhoeca (salmon

Enterotoxigenic E coli, Salmonella spp,

Salmonella spp, Yersinia enterocolilica, Campylobacter jejuni, Clostridium spp, Clostridium piliforme, Mycobacter·ium spp, Shigella spp, adherent invasive E coli, Bra.chyspira spp

Eimeria spp, C?-yptosporidium spp

Isospora spp, Sarcocystis spp, Besnoitia spp, Hammondia sp, Toxoplasma sp, Giardia sp, Tritrichomonas spp, Enlamoeba hislolylica, Balanlidium coli, Cryptosporidium spp, Neospora sp

Aspergillus fumigatus

Hisloplasma capsulalum, Aspergillus spp, Candida albicans, phycomycetes

Protolheca spp

Prototheca spp

See GASTROINTESTINAL PARASITES

See GASTROINTESTI

[ equine monocytic ehrlichiosis])

Rhodococcus equi, Aclinobacillus equuli, Clostridium perfringens types Band C, Clostridium difficile, Lawsonia intracel­ lulmis

OF HORSES, p 315.

poisoning in dogs)

OF SMALL ANIMALS, p

AL PARASITES

412.

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depend on the biotic potential of the parasites or, when appropriate, their intem1ediate host and the clin1ate and management practices. In the host, resistance, age, nutrition, and concomitant disease also influence the course of parasitic infection. The economic in1por­ tance of subclinical parasitism in farm animals is also determined by the above factors, and it is well established that lightly parasitized animals that show no clinical evidence of disease perfonn less efficiently in the feedlot, dairy, or finishing house. Feed conversion in light to moderate parasitism is adversely affected and is primarily due to reduced appetite and poor use of absorbed protein and energy. Carcass quality and size also are reduced, which further reduce financial returns. Endopara­ sites of companion animals can cause severe disease or unthrift.iness and are aesthetically undesirable. Furthermore, some of these parasites also infect people. Because parasitism is easily confused with other debilitating conditions, diagnosis depends heavily on the seasonal character of parasitic infection; previous farm history; and exan1ination of feces for evidence of oocysts, worm eggs, or lruvae. Increased serum pepsinogen levels can support the diagnosis of some abomasal infections, as can increased serun1 liver enzymes for liver fluke infection. ELISA are being used, and other serologic (including monoclonal antibody) techniques are under develop­ ment; serodiagnosis will likely be used more frequently as the specificity of the tests improves. These tests should be_patticulru·ly useful in companion animals hru·boring parasites incriminated in zoonoses. Advances in epidemiology (particulru·ly regarding factors affecting seasonal development of the free-living stages and their survival), coupled with the discovery of highly efficient broad-spectrun1 anthelrnintics, have made successful treatment and control of GI pru·asites both possible and practical. Response to therapy is usually rapid, ru1d single treatments usually suffice unless reinfection occurs or the lesions are patticularly severe. Preventive control in large animals is generally achieved by integrating grassland management with the use of anthelmintics. Improved methods of administering anthelmintics (eg, the pour-on method or sustained or pulsed-release devices) have also helped. Strategies to prevent parasitism and related production losses are prut of any modem herd-health, flock, or stud progran1. Similar preventive progrruns are equally important in controlling parasitism

in pet animals. Control by vaccination is limited to lungwonns; vaccine for cattle is available in several European countries, and vaccine for sheep is available in pruts of eastern Europe and in the Middle East. To estimate parasite load, seep 1620. Treatment of Infectious Diseases Antimicrobial agents ru·e used for the treatment of bacterial diseases, and ru1thelmintics for parasitic diseases. There is no specific therapy for treatment of viral diseases. Antin1icrobials are commonly given PO daily for several days until recovery is appru·ent, but tl1ere is little objective evidence of efficacy. There is evidence tlrnt overdosage or prolonged oral treatment may be detrin1ental (eg, bacte1ial overgrowth, villous atrophy). Parenteral administration of antimicrobials is indicated when septicemia is apparent or may occur. The choice of antimicrobial agent depends on the suspected disease, previous results, and cost. In herd epidemics, antimicrobials may be added to the feed or water supplies at tl1erapeutic levels for several days, followed by preventive levels for an extended period, depending on the infection pressure in the population. The feed and water supplies of in-contact animals also may be medicated in ru1 attempt to prevent new cases from developing. (See also SYSl"EMIC PIIARMACO­ TIIERAPEUTICS Of THE DIGESl'IVE SYSl"EM, p 2544.) Control of Infectious Diseases Effective control of the conunon infectious diseases of the GI tract depends on practicing good sat1itation and hygiene, developing and maintaining nonspecific resistance in the anin1al, and in certain cases, providing specific inununity by vaccinating tl1e pregnant dat11 or susceptible animal. Effective sat1itation and hygiene is achieved primarily by providing adequate space for animals and by regular cleaning of pens and efficient removal of manure from tl1e inunediate environment. Development and maintenance of nonspecific resistance depends on the genetic selection of animals that have a reasonable degree of inherent resistance and on the provision of adequate nutrition and housing, which minin1izes stress and allows the animals to grow and behave nom1ally. The development of infected but clinically healthy animals, which can shed patl10gens for weeks or months, is a major problem with some infec­ tious diseases of the GI tract, eg, salrnonel­ losis. Ideally, these canier animals should be identified by n1icrobiologic means and

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DIGESTIVE SYSTEM INTRODUCTION

isolated from the rest of the herd until free of the infection or culled. Certain diseases (eg, enterotoxigenic colibacillosis in calves and piglets) can be controlled by vaccination of the pregnant dam several weeks before parturition. This method depends on achieving a protective level of antibodies in the colostrum. There are exceptions but, in most cases, systemic immunity provides little protection against the infectious enteritides; effective immunity against GI disease depends on stimulation of local intestinal immunity after the neonatal period. During the neona­ tal period, protection can be provided through the local action of maternally derived antibodies. For exan1ple, secretory IgA progressively increases in sow's milk from the time of farrowing until weaning, which provides the piglet with daily protection during the nursing period.

NONINFECTIOUS DISEASES The major causes of noninfectious disease of the GI tract include dietary overload or indigestible feeds, chemical or physical agents, obstruction of the stomach and intestines caused by tl1e ingestion of foreign bodies or by any physical displacement or injury to the GI tract that interferes with the flow of ingesta, enzyme deficiencies, abnormalities of the mucosa tl1at interfere with normal function (eg, gastric ulcers, intlan1matory bowel disease, villous atrophy, neoplasms), and congenital defects. GI manifestations such as vomiting and dianhea may develop secondary to systemic or metabolic diseases such as uremia, liver disease, and hypoadrenocorticism. The causes are uncertain in several diseases, including abomasal ulcers in cattle, gastric ulcers in pigs and foals, gastric torsion in dogs, and acute intestinal obstruction and displacement of the abomasum in cattle. In noninfectious diseases of the GI tract, usually only a single anin1al is affected at one time; exceptions are diseases associated with excessive feed intake or poisons, in which herd outbreaks are common.

PRINCIPLES OF THERAPY See also SYSTEMIC PI-IARMACOTHERAPEUTICS OF THE DIGESTIVE SYSTEM, p 2544, and THE RUMINANT DIGESTIVE SYSTEM, p 2561. Although eliminating the cause of the disease is the primary objective, the major part of treatment is supportive and symptomatic, aimed at relieving pain, correcting abnormalities, and allowing healing to occur.

161

Elimination of tl1e primary cause may involve antinucrobials, coccidiostats, antifungal agents, anthelmintics, antidotes for poisons, or surgical correction of displacements. Correction of excessive or depressed motility appears rational, but often the nature and degree of abnormal motility ai·e uncertain; in addition, available drugs may not give consistent results. There is little clinical evidence to recommend the routine use of anticholinergic or opioid drugs to slow intestinal transit. Slowing intestinal transit may be counterproductive to the defense mechanism of diarrhea, which acts to evacuate harmful organisms and their toxins. In general, anticholinergic drugs probably are justified only for short-term symptomatic relief of pain and tenesmus associated with inflan1matory diseases of the colon and rectum. In some disorders of gastric or colonic motility, prokinetic drugs (eg, metoclopramide, erythromycin) may be useful. Replacement of fluid and electrolytes is necessary when dehydration and electro­ lyte and acid-base imbalance occur as in diarrhea, persistent vomiting, intestinal obstruction, or torsion of the stomach(s), in which large ainou.nts of fluid and electro­ lytes are sequestered. Relief of distention medically by stomach tube (as in bloat in ruminants) or surgically (as in acute intestinal obstruction, or in torsion of the abomasun1 in ruminants or of the stomach in monogastric anin1als) may be required. The GI tract may become distended with gas, fluid, or ingesta at any level due to physical or functional obstruction. Relief of abdominal pain by administra­ tion of analgesics should be done when the pain is reflexly affecting other body systems (eg, cardiovascular collapse) or when it is causing the a11imal to injure itself because of rolling, kicking, or throwing itself. Animals treated with analgesics must be monitored regularly to ensure that the relief of pain does not provide a false sense of security; the lesion may be progressively worsening while the a11imal is under the influence of the analgesic. Reconstitution of ruminal flora should be done in situations in which the ruminal flora may be seriously depleted (eg, in prolonged anorexia or acute indigestion). Transfau.na­ tion (ruminal fluid transfer; see p 2562) involves oral administration of ruminal contents from a healthy anin1al that contains rumen bacteria and protozoa and volatile fatty acids.

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CONGENITAL AND INHERITED ANOMALIES OF THE DIGESTIVE SYSTEM MOUTH Congenital Oronasal Fistulas (Cleft Palate and Cleft Lip): Congenital orona­

sal fistulas are the result of failure of fusion of the palatine shelves during gestation ( which occurs at 25--28 days of gestation in dogs). Clefts can be either of the primary palate (involving the lip and incisive bone) causing cleft lip (harelip), or of the secondary palate (involving the hard and soft palate) causing cleft palate. The conditions can occur singly or together. In dogs, CT studies have shown association of cleft palate with other craniofacial abnom1alities, including hypoplastic tyrnpanic bullae, hypoplastic nasal turbinates, and maxillary malocclusions, mostly of the incisors. Neurologic exanlination should be performed in affected animals, because concurrent hydrocephalus has also been described. Animals are typically diagnosed at, or shortly after, birth by oral examination, by observation of dysphagia or milk from the nares after nursing, and/or by respiratory compromise and aspiration pnewnonia. Many affected neonates are euthanized or die early in life. Cleft palate and cleft lip have been described in most domesticated animal species, including dogs, cats, runlinants, horses, and can1elids. In dogs, brachyce­ phalic breeds are overrepresented, with up to 300Ai risk factor. Other breeds with higher incidence include Beagles, Cocker Spaniels, Dachshunds, German Shepherds, Labrador Retrievers, Schnauzers, Old Spanish Pointers, and Shetland Sheepdogs. The most conunonly affected cat breed is the Sian1ese. Etiologies include genetic, teratogenic, and nutritional causes. Modes of inheritance are monogenic autosomal recessive or incomplete dominant in several breeds. In Btittany Spaniels, Pyrenean Shepherds, Beagles, Old Spanish Pointers, and Boxers, it is believed to be an autoso­ mal recessive trait, whereas in Bulldogs (French and English) and Shill Tzus, an autosomal dominant with incomplete penetrance mode of inheritance is suspected. Autosomal recessive inheritance patterns are seen in Angus cattle with arthrogryposis multiplex, in Charolais cattle with cleft palate and arthrogryposis, and in

Texel sheep with cleft lip. Teratogens and nutritional causes during pregnancy include high levels of vitainin A in the diet, administration of g1iseofulvin, folic acid deficiency, and ingestion of toxic plants. In cattle, ingestion of lupine during days 40-100 of gestation results in arthrygryposis and cleft palate, due to the effects of anagyrine found in Lupinus sericeus and L caudatus. Ingestion of poison hemlock (Conium maculatum), which contains the toxic principle coniine, results in sinlilar signs in both cattle and goats, whereas ingestion of Veratrum californicum in sheep, goats, and cattle all result in cleft lip and/or palate in the fetus. For puppies and kittens in which euthanasia is not elected, medical management is required until surgical options are explored. Animals are fed via orogastric intubation until dry food can be tolerated. Water can be offered by overhead dispenser. A custom-molded palate guard has been described in experimental settings to allow adult dogs to eat and drink nom1ally. Aspiration pneumonia should be quickly identified and treated. Surgical correction is recommended after at least 12 wk of age, although some studies have shown higher success when performed at >20 wk, or as adults. Surgical correction has a high failure rate because of continued growth of puppies or kittens postopera­ tively, the size of the patient, and irritation of the surgery site by the tongue and feed mate1ial. Surgical techniques depend on the location and size of the cleft defect. For secondary palate defects, sliding mucoperi­ osteal flaps or overlapping flaps are most commonly used. Extensive involvement of the soft palate carries a poor prognosis, even with surgical intervention. Surgical repair should be attempted only after ethical questions have been addressed, and the affected animal should be surgically sterilized or removed from breeding stock to prevent reproducing the anomaly in future offsp1ing. Occlusal Anomalies: Occlusal abnor­

malities due to abnom1al lengths of the maxilla and mandible are common in animals. Brachygnathia, also called overbite, overshot, overjet, short lower jaw, or parrot mouth in horses, is manifest when

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CONGENITAL AND INHERITED ANOMALIES OF THE DIGESTIVE SYSTEM

the mandible is shorter than the maxilla. It can be found, with varying severity and incidence, in all species of animals and is diagnosed by oral examination. In Red Angus cattle, it is inherited in a recessive manner through a deletion mutation on chromosome 4, which results in stillborn calves with osteopetrosis (seep 1044), brachygnathism, and impacted molars. In Simrnental cattle, brachygnathlsm can be seen in calves as an autosomal recessive trait, or in combination with trisomy 17, a lethal condition. A lethal, autosomal recessive disorder of Merino sheep results in brachygnathlsm, cardiomegaly, and renal hypoplasia. Brachygnathlsm is conunon in horses, due to either a lengthened maxilla or shortened mandible. Modes of inhe1itance are unknown. It may occur in utero due to treatment of the mare with griseofulvin. Most horses do not experience dysphagia; however, cheek teeth malocclusions are conunon, and regular dental care is required. Correction can be attempted in foals via surgical placement of tension band wires around the maxillary incisors to inhibit maxillary growth. In small animals, mild fonns may be of no clinical significance; however, more severe forms may result in trauma to the hard palate or the restriction of nonnal mandibular growth secondary to erupting adult mandibular canine teeth. Treatment varies from none to various orthodontic or endodontic procedures, depending on severity. The mandibular canine teeth are often removed or a crown reduction procedure performed, with concurrent pulpotomy or root canal. Intervention early in life is reconunended and improves both short- and longtem1 outcomes. Prognathia, also called undershot, underjet, or monkey or sow mouth in horses, is identified when the mandible is longer than the maxilla. It is diagnosed by oral examination. In brachycephalic dogs and Persian cats, it is considered a nonnal breed characteristic. In horses, it is more commonly seen in miniature and Arabian breeds. The degree of severity is variable and may not require treatment. In severe cases in foals, surgical placement of tension band wires can allow for continued maxillary growth. The most severe consequences are the result of malocclu­ sions. Affected foals may have difficulty nursing, and older anin1als may experience difficulty grazing. Cheek teeth malocclu­ sions should be addressed with regular dental care. Chondrodysplasia, a sin1ple dominant trait of Dexter cattle, is a lethal defect that

163

can result in "bulldog calves," with severe skeletal malformation and craniofacial dysplasia that has the appearance of prognathism.

Tongue Anomalies: Ankyloglossia,

also called "tongue-tie," is a disorder of Anatolian Shepherd dogs characterized by a short, thickened lingual frenulum that inhibits nonnal movements of the tongue. By unknown mechanism, the normal fetal apoptosis of the cranial 2/3 of the frenulun1 does not occur. Clinically, the tongue appears notched or with a "W" shape. Animals may experience dysphagia; difficulty suckling, ch-inking, or licking; trouble vocalizing; and impedence of panting and therefore thennoregulation. Frenuloplasty is corrective. Breeding of affected anin1als is not reconunended. Microglossia is a congenital defect characterized by missing or underdevel­ oped lateral and rostral thin portions of the tongue that result in prehensile and motility disturbances. It is often referred to as "bird tongue" in dogs and may be a component of the fading puppy syndrome, because affected puppies have difficulty nursing and swallowing and can aspirate or quickly become dehydrated. In cattle, excessive salivation has been seen. Even with sup­ portive dietary meastu-es, the prognosis is poor. Macroglossia, or large tongue, has been described in association with nasopharyn­ geal dysgenesis in Dachshunds. It has also been seen in double-muscled cattle breeds, such as the Belgian Blue, and can inhibit nursing of calves. Epitheliogenesis imperfecta is a disorder of the skin in which the epithelium is absent, revealing the dermis. Commonly affected areas include the limbs, back, and oral mucosa and tongue. It is inherited by a simple recessive manner and is well described in cattle and horses, particularly Saddlebreds. Euthanasia is typically elected.

Tight-lip Syndrome of Chinese Shar-Pei: A small or absent lower anterior

lip vestibule is a congenital defect of some Shar-Pei dogs. The lower lip covers the mandibular incisors and canines, disrupting normal occlusion, inhibiting mandibular growth, and leading to the dog biting on the lip (which presents welfare issues). In extreme cases, the mandibular incisors become lingually directed. Surgical correction by chelioplasty has been described using several different mucosal flap techniques. Any animals that have

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undergone surgical correction should not be presented for conformation showing and should not be bred.

TEETH

Abnormal Number: Deviation from the

dental formula has been seen in several species. Complete lack of development of teeth, or anodontia, is rare. Hypodontia or oligodontia has been described as inherited by a recessive manner in Kerry Blue Terriers and associated with X -linked hypohidrotic ectodennal dysplasia in other breeds. Most cases appear to affect the premolars. Hyperdontia, also called polyodontia or supernumerary teeth, is seen most often in the permanent teeth and can affect the incisors, premolars, or molars. Presw11ably, these teeth arise from overproliferation of the dental lamina during development. Supernwnerary teeth tend to cause crowding and malocclusions, which can cause dysphagia, dental disease, and discomfort. In horses, supernumerary incisors are typically not extracted and are managed with regular reduction. For supernwnerary cheek teeth, diastema and sinusitis due to oromaxillary sinus fistula forn1ation are possible sequelae. Teeth are either extracted or reduced often to prevent complications. Irregularities of Shedding: Retention of the deciduous teeth in horses is conunon. The incisors tend to retain rostrally to the pennanent incisors; however, radiographs · will help to discern their identity. Incisors retained in other orientations can result in malocclusion and/or displacement of permanent incisors. Retained cheek teeth are called "caps," which are typically shed as the permanent tooth erupts underneath them. Loose caps can cause discomfort to

Retained deciduous incisors in a horse.

Courtesy of Dr. Gordon Baker.

the horse, manifest as headshaking, inappetence, quidding, and training issues. Caps can be extracted if they are loose, if the contralateral cap has al.ready been shed, or if there is space between the cap and the pern1anent tooth below. Retained deciduous teeth are common in dogs and secondary to the failure of the pe1iodontal ligament to detach from the deciduous tooth, with the permanent canine teeth erupting rostrally. One study showed highest incidence in dogs 100,000/g of feces have been reported in 8- to 12-wk-old Jambs that appeared healthy. However, diarrhea with oocyst counts of a pathogenic species of>20,000/g is character­ istic of coccidiosis in sheep. Immune complex glomerulonephritis has also been attributed to coccidiosis. F1y strike and secondary bacterial enteric infections may accompany coccidiosis in lan1bs. Lambs 1-6 mo old in Jan1bing pens, intensive grazing areas, and feedlots are at greatest risk as a result of shipping, ration change, crowding stress, severe weather, and contamination of the environment with oocysts from ewes or other Jambs. Because occurrence of coccidiosis under these management systems often becomes so predictable, coccidiostats should be administered prophylactically for 28 consecu­ tive days beginning a few days after lambs are introduced into the environment. A con­ centrated ration containing monensin at 15 g/tonne can be fed to ewes from 4 wk before lambing until weaning, and to Jambs from 4--20 wk of age. The toxic level of monensin for Jambs is 4 mg/kg. Lasalocid (15-70 mg/head/day, depending on body wt) may be effective. A combination of monensin and lasalocid at 22 and 100 mg/kg of diet, respectively, is an effective prophylactic against naturally occurring coccidiosis in early weaned Jambs under feedlot conditions. Treatment of affected sheep once coccidiosis has been diagnosed is not effective, but seve1ity can be reduced if treatment is begun early. A single treatment of toltrazuril (20 mg/kg) can significantly reduce the oocyst output in naturally infected Jan1bs for-3 wk after administra­ tion. Diclazuril (1 mg/kg) is an effective oral anticoccidial in lambs and is administered

207

•once at-6-8 wk of age (most common) or twice (at 3-4 wk of age and again 3 wk later). Sulfaquinoxaline in drinking water at 0.015% concentration for 3-5 days may be used to treat affected lambs. In groups of lambs at pasture, frequent rotation of pastures for parasite control also helps control coccidial infection. However, when lambs are exposed to infection early in life as a result of infection from the ewe and a contami­ nated lambing ground, a solid inlmunity usually develops and problems are seen only when the stocking density is extremely high.

COCCIDIOSIS OF GOATS Numerous species of Eimeria, are found in goats in No1th America and elsewhere. The Eimeria spp are host specific and are not transmitted from sheep to goats. E arloingi, E christenseni, and E ovinoi­ dalis are highly pathogenic in kids. Clinical signs include diarrhea with or without mucus or blood, dehydration, emaciation, weakness, anorexia, and death. Some goats are actually constipated and die acutely without diarrhea. Usually, stages and lesions are confined to the small intestine, which may appear congested, hemonhagic, or ulcerated, and have scattered pale, yellow to white macroscopic plaques in the mucosa. Histologically, villous epitheliun1 is sloughed, and inflanlffiatory cells are seen in the Jan1ina propria and submucosa. In addition, there have been several reports of hepatobiliary coccidiosis with liver failure in dairy goats. Diagnosis of intestinal coccidiosis is based on finding oocysts of the pathogenic species in diarrheal feces, usually at tens of thousands to millions per gram of feces. It is not unusual to find oocyst counts as high as 70,000/g of feces in kids without overt disease, but weight gain may be affected. Angora and dairy goats, raised under different management practices, may have sinlilar patterns of exposure of kids. Just after parturition, nursery pens and surround­ ing areas may be heavily contanlinated with oocysts from does. Resistance to infection is decreasedjust after shipping, changing rations, introducing new anin1als, or mixing young with older aninlals. Coccidiostats can be administered to a herd immediately after diagnosis or as a preventive in predictable situations such as those mentioned above. Diagnosis and treatment are sinlilar to those for cattle and sheep. Sulfadirnidine at 55 g/tonne is also effective for control of coccidiosis in goats. In nonlactating goats, adding monensin to the feed at 18 g/tonne is preventive.

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COCCIDIOSIS OF PIGS Eight species of Eimeria and one of Isospora infect pigs in Notth America. Piglets 5---15 days old are characteristically infected with only I suis, which produces enteritis and diarrhea. These agents must be differentiated from viruses, bacte1ia, and helminths that also cause scours in neonatal pigs. I suis is prevalent in neonatal pigs. lnfection is charactetized by a watery or greasy diatThea, usually yellowish to white and foul smelling. Piglets may appear weak, dehydrated, and undersized; weight gains are depressed, and sometimes piglets die. A conttibuting factor to mortality is that piglets become covered with diatTheic feces and stay damp. Oocysts at·e usually shed in the feces and can be identified by their size, shape, and sporulation chat·actetistics; however, in peracute infections, diagnosis must be based on finding stages of the pat-a.site in impression smears or histologic sections of the small intestine, because pigs can die before oocysts are formed. In severely affected piglets, histologic lesions confined to thejejunw11 at1d ilewn at·e chat-acte1ized by villous att·ophy, blunting of villi, focal ulceration, at1d fibtinonecrotic entetitis with parasite stages in epithelial cells. Preventive control by feeding anticoccidi­ als to sows from 2 wk before fan·owing through lactation or to neonatal pigs from birth to weaning has been reported; however, effectiveness of the latter has not been confirmed. Although the sow is a logical source of infection for piglets, this· has not been well docwnented. Thorough removal of feces and disinfection of fatTowing facilities between litters greatly decreases infection. Piglets iliat recover from infection at·e highly resistant to reinfection. Aliliough less commonly associated with clinical coccidiosis, E debliecki, E neode­ bliecki, E scabra, and E spinosa have been fom1d in pigs -1-3 mo old with diarrhea. Illness may last 7-10 days, wiili pigs remaining untluifty. Treattnent of coccidiosis may include sulfamethazine in drinking water. The control of coccidiosis in newborn piglets infected with I suis has been mu-eliable. The use of coccidiostats in ilie feed of ilie sow for several days or a few weeks before and after fat-rowing has been recommended at1d used in ilie field, but the results are vat"iable. A.mprolimn at1d monensin are ineffective for prevention of expetirnental coccidiosis in piglets. A control progratn designed to decrease ilie mu-nber of oocysts has been reconunended at1d consists of

proper cleaning, disinfection, at1d steatn cleatling of the fatrnwing housing. A.mprolium (25% feed grade) at the rate of 10 kg/tonne of sows' feed statted 1 wk before fatTowing at1d continued until ilie piglets are 3 wk of age has been recom­ mended, but the results at·e unsatisfactory. A single dose of toltt·azmil (20 mg/kg, PO) decreased oocyst excretion, ilie incidence of diatThea, at1d weight gain impairment in piglets with experimentally induced coccidiosis. Diclazuril (5 mg/kg) is being investigated as at1 oral at1ticoccidial in piglets.

COCCIDIOSIS OF CATS AND DOGS Mat1y species of coccidia infect tl1e intes­ tinal tract of cats at1d dogs. All species appear to be host-specific. Cats have species of Isospora, Besnoitia, Toxo­ plasma, Hammondia, at1d Sa1·coC'lJStis. Dogs have species of Isospora, Hammon­ dia, at1d Sarcocystis. Neiilier dogs nor cats have Eimeria. Hammondia has an obligatory two-host life cycle wiili cats or dogs as final hosts at1d rodents or ruminat1ts as intetmediate hosts, respectively. Hammondia oocysts are indistinguishable from iliose of Toxoplasma at1d Besnoitia but are nonpathogenic in either host. (See also BESNOJTIOSJS, p 597, SARCOCYSTOSI , p 1058, and TOXOPLASMOSJS, p 685.) The most common coccidia of cats at1d dogs at·e Isospora. Some Isospora spp of cats at1d dogs can facultatively infect other mat1u11als and produce in various orgat1S an encysted fom1 iliat is infective for the cat or dog. Two species infect cats: Ifelis at1d I rivolta; both cat1 be identified easily by oocyst size at1d shape. Al.most every cat eventually becomes infected with 1felis. Four species infect dogs: I canis, I ohioen­ sis, I burrowsi, at1d I neorivolta. In dogs, only 1 canis ca11 be identified by tl1e oocyst structure; ilie oilier three Isospora overlap in din1ensions and cat1 be differentiated only by endogenous developmental characteristics. Clinical coccidiosis, although not common, has been repotted in kittens at1d puppies. In kittens, it is seen ptirnarily during weatling stress. The most conunon clinical signs in severe cases at·e diatThea (sometimes bloody), weight loss, at1d dehydration. Usually, coccidiosis is associated with oilier infectious agents, in1munosuppression, or stress. Treattnent may be unnecessary in cats, because they usually spontaneously eliminate the infection. In clinically affected

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CRYPTOSPORIDIOSIS cats, trimethoprim-sulfonamide (30-60 mg/kg/day for 6 days) can be used. In kennel conditions when the need for prophylaxis might be predicted, arnprolium is said to be effective, although it is not approved for use in dogs. In severe cases, in addition to supportive fluid therapy, sulfonamides such as sulfadimethoxine (50 mg/kg the first day and 25 mg/kg/day for

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2--3 wk thereafter) can be used. Sanitation is important, especially in catte1ies and kennels, or where large numbers of animals are housed. Feces should be removed frequently. Fecal contamination of feed and water should be prevented. Runs, cages, and utensils should be disinfected daily. Raw meat should not be fed. Insect control should be established.

CRYPTOSPORIDIOSIS Cryptosporidiosis is recognized worldwide, primarily in neonatal calves but also in lambs, kids, foals, and piglets. Crypto­ sporidia cause varying degrees of natw·ally occw1.ing diarrhea in neonatal farm animals. The parasites commonly act in conceit with otl1er enteropathogens to produce intestinal injury and diarrhea Etiology and Epidemiology: There are cwTently 19 species and 40 genotypes of Clyptosporidium. C hominis (fom1erly C parvum type I) is a specific hwnan pathogen. C parvum (formerly C parvum type II) is zoonotic and infective to many animals, including people and calves. Four cryptosporidial species have been isolated from cattle (C parvum, C andersoni, C bovis, and C ryanae). C andersoni infects the abomaswn of older cattle; C bovis and C ryanae are cattle adapted (cattle are the major host). C parvum is a common cause of calf diarrhea, and cryptosporidial oocysts have been detected in the feces of 7(J'/o of 1- to 3-wk-old dairy calves. Wection can be detected as early as 5 days of age, with the greatest proportion of calves excreting organisms between days 9 and 14. Many reports associate infection in calves with diarrhea occurring at 5--15 days of age. C parirum is also a common enteric infection in young lambs and goats. Diarrhea can result from a monoinfection but more commonly is associated with mixed infections. Wection can be associated with severe outbreaks of diarrhea, with high case fatality rates in lan1bs 4--10 days old and in goat kids 5--21 days old. Cryptosporidial infection in pigs is seen over a wider age range than in ruminants and has been seen in pigs from 1 wk old through market age. Most infections are asymptomatic, and the

organism does not appear to be an in1portant enteric pathogen in pigs, although it may contribute to postweaning malabsorptive diarrhea. Cryptosporidial infection in foals appears less prevalent and is seen at a later age than in rwninants, with excretion rates peaking at 5--8 wk old. Wection is not usually detected in yearlings or adults. Most studies indicate that cryptosporidiosis is not a common disease in foals; infections in immw10competent foals are usually subclini­ cal. Persistent clinical infections are seen in Arabian foals with inherited combined inm1unodeficiency. Cryptosporidiosis is also recorded in young deer and can be a cause of diarrhea in artificially reared orphans. Transmission: The source of crypto­ spo1idial infection is oocysts that are fully sporulated and infective when excreted in the feces. Large numbers are excreted during the patent period, resulting in heavy environmental contamination. Transmis­ sion may occur directly from calf to calf, indirectly via fomite or hwnan transmission, from contamination in the envi.rorunent, or by fecal contamination of tl1e feed or water supply. A periparturient rise in the excretion of oocysts may occur in ewes. C parvwn is not host-specific, and infection from other species (eg, rodents, fann cats) via contamination of feed is also possible. Oocysts are resistant to most disinfec­ tants and can survive for several months in cool and moist conditions. Oocyst infectivity can be destroyed by ammonia, fonnalin, freeze-drying, and exposure to temperatures 149°F (65°C). Ammoniwn hydroxide, hydrogen peroxide, chlorine dioxide, 10% fom1ol saline, and 5% anm1onia are effective in destroying oocyst infectivity. Wectivity in calf feces is reduced after 1-4 days of drying.

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CRYPTOSPORIDIOSIS

Concun·ent infections with other enteric pathogens, especially rotavirus and coronavirus, are common, and epidemiologic studies suggest that dianhea is more severe in mixed infections. Imrnunocompromised animals are more susceptible to clinical disease than itmnunocompetent anit11als, but the relationship between disease and failure of passive transfer of colostral itmnunoglob­ ulins is not clear. Age-related resistance, uru·elated to prior exposure, is seen in lambs but not calves. Wection results in production of parasite-specific antibody, but both cell-mediated and hwnoral antibody are important in protection, as well as local antibody in the gut of the neonate. Case fatality rates ill cryptosporidiosis are generally low unless complicated by other factors (eg, concurrent infections, energy deficits from itiadequate illtake of colostrwn and milk, chilling from adverse weather conditions). Pathogenesis: The life cycle of Crypto­ sporidium consists of six major developmen­

tal events. After ingestion of the oocyst, there is excystation (release of infective sporozo­ ites), merogony (asexual multiplication), gametogony (gan1ete fonnation), fertiliza­ tion, oocyst wall fom1ation, and sporogony (sporozoite formation). Oocysts of Crypto­ sporidium spp can sporulate within host cells and are infective when passed in the feces. Wection persists until the host's inm1une response eliminates the parasite. In natural and experimentally produced cases in calves, cryptosporidia are most numerous in the lower part of the small intestine and less common in the cecwn and colon. Prepatent periods are 2---7 days in calves and 2---5 days in lambs. Oocysts are usually passed in the feces of calves for 3---12 days. Clinical Findings: Calves with crypto­ sporidiosis usually have a mild to moderate diarrhea that persists for several days regardless of treatment. The age at onset is later, and the duration of dian·hea tends to be a few days longer than are seen in the dianheas caused by rotavirus, coronavirus, or enterotoxigenic Escherichia coli. Feces are yellow or pale, watery, and contam mucus. The persistent dian·hea may result in marked weight loss and emaciation. In most cases, the diarrhea is self-limiting after several days. Varying degrees of apathy, anorexia, and dehydration are present. Only rarely do severe dehydration, weakness, and collapse occur, in contrast to findings in other causes of acute diarrhea in neonatal calves. Case fatality rates can be high in herds with cryptosporidiosis when the calf

feeder withholds milk and feeds only electrolyte solutions durmg the episode of diarrhea. The persistent nature of the diarrhea leads to a marked energy deficit in these circwnstances, and the calves die of inanition at 3---4 wk old. Lesions: Calves with persistent diarrhea have villous atrophy in the small intestine. Histologically, large nwnbers of the parasite are embedded in the microvilli of the absorptive enterocytes. ln low-grade itlfections, only a few parasites are present, with no apparent histologic changes in the it1testine. The villi are shorter than nmmal, with crypt hyperplasia and a mixed inflanmiatory cell mfiltrate. Diagnosis: Diagnosis is based on detection of oocysts by examination of fecal smears with Ziehl-Neelsen stams, fecal flotation techniques, ELISA, fluorescent­ labeled antibodies, a rapid inununochromato­ graphic test, and PCR. Sheather's flotation sedimentation stamillg is the most sensitive (830Ai) and specific (99"A,) of these tech­ niques, with a relatively low cost per test. This technique requires centrifuging a fecal sample ill Sheather's solution, aspirating the top layer and dilutillg the fluid in phosphate buffer salille, centrifugillg, and placillg the sediment on the slide and perfonning a modified Ziehl-Neelsen technique to look for cryptosporidial oocysts. It has been suggested that if the dianhea is caused by cryptosporidia, there should be 105-107 oocysts/mL of feces. The oocysts are small (5----6 mm in diameter) and relatively non­ refractile. They are difficult to detect by nonnal light microscopy but are readily detected by phase-contrast microscopy. Treatment: There are no currently licensed therapeutics available in the USA for C parvum infection in food anin1als. Anecdotal reports of success with extra-label use of variC'luS compounds have not been replicated in controlled trials. Experimental treatments have for the most part been toxic or ineffective. Halofugillone is reported to markedly reduce oocyst output in experimentally Wected lambs and natw·ally and experimentally Wected calves; therapy was also reported to prevent diarrhea. Paromomycill sulfate (100 mg/kg/ day, PO, for 11 days from the second day of age) proved successful ill preventing natural disease in a controlled clinical field trial ill goat kids. Affected calves should be suppo1ted with fluids and electrolytes, both orally and parenterally, as necessary until recovery occurs. Cows' whole milk should be given

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GIARDIASIS in small quantities several times daily (tt:> the full level of requirement) to optimize digestion and to minimize weight loss. Several days of intensive care and feeding may be required before recovery is apparent. Parenteral nutrition may be considered for valuable calves. Control: The disease is difficult to control. Reducing the number of oocysts ingested may reduce the severity of infection and allow inummit;y to develop. Calves should be born in a clean environment, and adequate amounts of colostrum should be fed at an early age. Calves should be kept separate without calf-to-calf contact for at least the first 2 wk of life, with strict hygiene at feeding. Diarrheic calves should be isolated from healthy calves during the course of the diarrhea and for several days after recovery. Great ca.re must be taken to avoid mechani­ cal transmission of infection. Calf-rearing houses should be vacated and cleaned out on a regular basis; an "all-in/all-out" manage­ ment system, with thorough cleaning and several weeks of drying between batches of calves, should be used. Rats, mice, and flies should be controlled when possible, and rodents and pets should not have access to calf grain and milk feed storage areas. Hyperimmune bovine colostrum can reduce the severity of diaffhea and the

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period of oocyst excretion in experimentally infected calves. Protection is not related to circulating levels of specific antibody but requires a high titer of C par1YUm antibody in the gut lun1en for prolonged periods. Many research groups have attempted to develop effective vaccines against cryptosporidia. Unfortunately, to date, vaccinations have not been effective. Zoonotic Risk: Infections in domestic animals may be a reservoir for infection of susceptible people. C hominis and C parvum are considered to be relatively common nonviral causes of self-limiting diarrhea in immunocompetent people, particularly children. In immunocompro­ mised people, clinical disease may be severe. The infection is transmitted predominantly from person to person, but direct infection from animals and waterborne infection from contamination of surface water and drinking water by domestic or wild animal feces can also be important. Animal handlers on a calf farm can be at high risk of diarrhea due to cryptosporidiosis transmitted from infected calves. Immunocompromised people should be restricted from access to young animals and possibly from access to fam1s.

GIARDIASIS (Giardosis, Lambliasis, Lambliosis) Giardiasis is a chronic, intestinal protozoal infection seen worldwide in most domestic and wild mammals, many birds, and people. Infection is common in dogs, cats, ruminants, and pigs. Giardia spp have been reported in 0.44%--39% of fecal samples from pet and shelter dogs and cats, 1 %--53% in small ruminants, 9%--73% in cattle, 1 %--38% in pigs, and 0.5%--20% in horses, with higher rates of infection in younger animals. Farm prevalences in production animals vary between ()OA, and l 00%, with the highest prevalence in younger animals. The cumulative inci­ dence on a farm where Giardia has been diagnosed is lOOOA, in cattle and goats and nearly lOOOA, in sheep. Three major morphologic groups have been described: G muris from mice, G agilis from amphibians, and a third

group from various warm-blooded animals. There are at least four species in this third group, including G ardeae and G psittaci from birds, G microti from muskrats and voles, and G duodenalis (also known as G intestinalis and G lamblia), a species complex with a wide mammalian host range infecting people and domestic animals. Molecular char­ acterization has shown that G duodenalis is in fact a species complex, comprising seven assemblages (A to G), some of which have distinct host preferences (eg, assemblage CID in dogs, assemblage F in cats) or a limited host range (eg, assem­ blage E in hoofed livestock), whereas others infect a wide range of anin1als, including people (assemblage A and B). There is increasing evidence that some assemblages (A and B) that infect domestic

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GIARDIASIS

animals can also infect people, although transmission patterns are not totally understood. Dogs have mainly assem­ blages C and D, cats have assemblages Al and F, and people are infected with assemblages A2 and B; however, some studies have identified human assemblages of Giardia in canine fecal samples. Cycle and Transmission: Flagellate protozoa (trophozoites) of the genus Giardia inhabit the mucosa! surfaces of the small intestine, where they attach to the brush border, absorb nutrients, and multiply by binary fission. They usually live in the proximal portion of the small intestine. 'Irophozoites encyst in the small or large intestine, and the newly fonned cysts pass in the feces. There are no intracellular stages. The prepatent period is generally 3-10 days. Cyst shedding may be continual over several days and weeks but is often intermittent, especially in the chronic phase of infection. The cyst is the infective stage and can survive for several weeks in the environment, whereas trophozoites cannot. 'Iransrnission occms by the fecal-oral route, either by direct contact with an infected host or through a contaminated environment. Characteristics that facilitate infection include the high excretion of cysts by infected animals and the low dose needed for infection. Giardia cysts are infectious immediately after excretion and are very resistant, resulting in a gradual increase u:i environmental infection pressme. High humidity facilitates survival of cysts in the environment, and ovei·crowding favors transmission. Pathogenesis: Giardia infections cause an increase in epithelial permeability, increased numbers of intraepithelial lymphocytes, and activation ofT lympho­ cytes. 'Irophozoite toxins and T-cell activation initiate a diffuse shortening of brush border microvilli and decreased activity of the small-intestinal brush border enzymes, especially lipase, some proteases, and dissachaiidases. The diffuse rnicrovillus shortening leads to a decrease in overall absorptive area in the small intestine and an impaired intake of water, electrolytes, and nutrients. The combined effect of this decreased resorption ai1d the brush border enzyme deficiencies results in malabsorptive diarrhea and lower weight gain. The reduced activity of lipase and the increased produc­ tion of mucin by goblet cells may explain the steatorrhea and mucous diarrhea that has been described in Giardia-infected hosts.

Clinical Findings and Lesions:

Giardia infections in dogs and cats may

be inapparent or may produce weight loss and chronic diarrhea or steato1Thea, which can be continual or intermittent, particu­ larly in puppies and kittens. Feces usually are soft, poorly formed, pale, malodorous, contain mucus, and appear fatty. Watery diarrhea is unusual in uncomplicated cases, and blood is usually not present in feces. Occasionally, vomiting occurs. Giardiasis must be differentiated from other causes of nutrient malassimilation (eg, exocrine pancreatic insufficiency [see p 409) and intestinal malabsorption [see p 400)). Clinical laboratory findings usually are normal. In calves, and to a lesser extent in other production animals, giardiasis cai1 result in diarrhea that does not respond to antibiotic or coccidiostatic treabnent. The excretion of pasty to fluid feces with a mucoid appearance may indicate giardiasis, especially when the diarrhea occurs in young aninlals (1-6 mo old). Experimental infection of goat kids, lainbs, and calves resulted in a decreased feed efficiency and subsequently a decreased weight gain. Gross intestinal lesions are seldom evident, although microscopic lesions, consisting of villous atrophy and cuboidal enterocytes, may be present. Diagnosis: The motile, piriform trophozoites (12-18 x 7-10 µm) are occasionally seen in saline smears of loose or watery feces.They should not be confused with yeast or with trichomo­ nads, which have a single rather than double nucleus, an undulating membrane, and no concave ventral surface. The oval cysts (9-15 x 7-10 µm) can be detected in feces concentrated by the centrifugation­ flotation technique using zinc sulfate (specific gravity 1.18). S9diun1 chloride, sucrose, or sodium nitrate flotation media may be too hypertonic and distort the cysts. Staining cysts with iodine aids identification. Because Giardia cysts are excreted intermittently, several fecal exaininations should be performed if giardiasis is suspected (eg, three samples collected throughout 3-5 days). Giardia may be underdiagnosed, because the cysts are intermittently shed. For the detection of parasite antigen, immunofluorescence assays and ELISA are commercially available. An in-house ELISA available for use in dogs and cats is a useful tool for clinical diagnosis, particularly when coupled with a centrifugal flotation

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DISEASES OF THE MOUTH IN LARGE ANIMALS examination of feces. It is best to test symptomatic animals with a combination of a direct saline smear of feces, fecal flotation with centrifugation, and a sensitive, specific ELISA optimized for use in the animal being tested (eg, ELISA for dogs and cats).

Treatment: No drugs are approved for

treatment of gia.rdiasis in dogs and cats in the USA Fenbendazole (50 mg/kg/day for 5-10 days) effectively .removes Giardia cysts from the feces of dogs; no adverse effects are .reported, and it is safe for pregnant and lactating animals. This dosage is approved to treat. Giardia infections in dogs in Europe. Fenbendazole is not approved in cats but may reduce clinical signs and cyst shedding at 50 mg/kg/day for 5 days. Albendazole is effective at 25 mg/kg, bid for 4 days in dogs and for 5 days in cats but should not be used in these species, because it has Jed to bone mar.row suppression and is not approved for use in these species. A combination of praziquantel (5.4-7 mg/kg), pyranlel (26.8-35.2 mg/kg), and febantel (26.8--35.2 mg/kg) also effectively decreases cyst excretion in infected dogs when adminis­ tered for 3 days. A synergistic effect. between pyrantel and febantel was demonstrated in an animal model, suggesting that the combination product may be preferred over febantel alone. Metronidazole (extra-label at 25 mg/kg, bid for 5 days) is -65% effective in eliminat­ ing Giardia spp from infected dogs but may be associated with acute development of anorexia and vomiting, which may occasionally progress to pronounced generalized ataxia and vertical positional nystag.mus. Metronidazole may be ad.minis­ tered to cats at 10--25 mg/kg, bid for 5 days. Metronidazole benzoate is perhaps better tolerated by cats. Safety concerns limit the use of metronidazole in dogs and cats. A possible treatment strategy for dogs would

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be to treat first with fenbendazole for 5-10 days or to administer both fenbendazole and metronidazole together for 5 days, being sure to bathe the dogs to remove cysts. lf clinical disease still persists and cyst shedding continues, the combination therapy should be extended for another 10 days. Currently, no drug is licensed for the treatment of giardiasis in ruminants. Fenbendazole and albendazole (5-20 mg/kg/day for 3 days) significantly reduce the peak and duration of cyst excretion and result in a clinical benefit in treated calves. Paromomycin (50-75 mg/kg, PO, for 5 days) was found to be highly efficacious in calves. Oral fenbendazole may be an option for treatment in some birds.

Control: Giardia cysts are immediately infective when passed in the feces and swvive in the environment. Cysts are a source of infection and reinfection for animals, particularly those in crowded conditions (eg, kennels, catteries, or intensive rearing systems for production ani­ mals). Feces should be removed as soon as possible (at least daily) and disposed of with municipal waste. Wected dogs and cats should be bathed to remove cysts from the hair coat. Prompt and frequent removal of feces limits environ.mental contamination, as does subsequent disinfection. Cysts are inactivated by most quaternary ammonium compounds, steam, and boiling water. To increase the efficacy of disinfectants, solutions should be left for 5-20 min before being rinsed off contaminated surfaces. Disinfection of grass yards or runs is impossible, and these areas should be considered contan1ina.ted for at least a month after infected dogs last had access. Cysts are susceptible to desiccation, and areas should be allowed to ·dry thoroughly after cleaning.

DISEASES OF THE MOUTH IN LARGE ANIMALS LIP LACERATIONS Wounds of the lips and cheeks occur frequently in horses. The most common ca.use is external trauma or secondary to the use of inappropriate bits or restraint devices. Lip lacerations may be accornpa-

nied by mandibular or incisive bone fractures with or without dental fractures and tooth a.vulsions. These occur when a horse grasps objects with its mouth and then pulls back when startled. Lip lacerations witl1out bone or teetl1 involve­ ment can be sutw·ed, usually witl1 a good

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DISEASES OF THE MOUTH IN LARGE ANIMALS

result. Healing is rapid because of the good blood supply to the head. Lacerations left to heal by second intention can result in orocutaneous fistula, which may require resection and primaty wound closure. Rarely, skin grafts or mucosa! flaps are required to manage orocutaneous fistula.

GLOSSOPLEGIA G lossoplegia, or paralysis of the tongue, is uncommon. Causes in horses include incorrect placement of obstetric snares in neonates during forced extraction, strangles, upper respiratory tract infections, meningitis, botulism, encephalomyelitis, leukoencephalomalacia, equine protozoa! encephalomyelitis, and cerebral abscessa­ tion. Any condition that damages the hypoglossal nerve (cranial nerve XII), which is the major motor nerve to the muscles of the tongue, can result in glossoplegia. Neonates with glossoplegia must be monitored carefully to ensure they are able to eat. If necessaiy in affected foals, a nasogastric tube should be placed for administration of colostrum or IV plasma administered to prevent failure of passive transfer. Foals unable to maintain hydration may require IV fluid therapy and anti-inflatn­ matory medication (eg, phenylbutazone, flunixin meglumine, or dexan1ethasone). Prophylaxis against gastric ulceration is also indicated. If the condition persists for > 10 days after birth, the prognosis for regaining normal function is guarded. Inflammatory diseases and trawna may also result in transient glossoplegia. Occasion­ ally, horses undergoing prolonged dental procedures involving excessive traction on the tongue can develop temporaiy glossoplegia. The prognosis gf glosso­ plegia depends on the horse's response to treatment for the primaiy condition. In cattle, glossoplegia may accompany severe actinobacillosis (seep 589). There may be complete paralysis of the tongue accompanied by necrosis of the tip. Such conditions are occasionally seen in out­ breaks in feedlot cattle and may follow a bout of viral stomatitis.

the mouth and cause hard, thickened, tumorous plaques that may not be detected until well advanced. Verrucose, fibroblastic, and sessile or flat forms of equine sarcoid can involve the mouth and lips. Carbon dioxide laser removal of oral and lip melanomas should be considered. Complete removal of oral and lip melano­ mas is not necessaiy for a successful outcome. In addition, some horses may respond to oral cin1etidine therapy. Surgical resection of sai·coids can be performed successfully with the carbon dioxide laser. Along with laser resection, intratumoral administration of cisplatin can be consid­ ered to lessen the chances for recurrence. Cryosurgery is another acceptable method of treatment. Squamous cell carcinoma can be difficult to treat because of its invasive nature. Surgical debulking with the carbon dioxide laser followed by intratwnoral injection of cisplatin can be effective in select cases. Regardless of treatment, the prognosis for complete resolution of oral squamous cell carcinoma is guarded to poor. (See also TUMORS OF THE SKIN AND son TISSUES, p 942.)

SLAFRAMINE TOXICOSIS Causes of slaframine toxicosis include the ingestion of forages, particularly clovers, infected with the fungusRhizoctonia leguminicola, which produces the toxic alkaloid slafran1ine. Profuse ptyalism is often the only clinical sign. Affected animals have no evidence of oral ulceration or other oral lesions. Ptyalism resolves once the animal is removed from the affected forage. The differential diagnoses for large animals (particularly ruminants) include blue­ tongue, vesiculat· stomatitis, vesicular exanthema, and foot-and-mouth disease.

NEOPLASIA Neoplasia of the mouth and lips other than viral papillomas are uncommon and include melanomas, sarcoids, and squatnous cell carcinoma. In gray horses, melanomas may develop and infiltrate the commissures of

An extensive sarcoid involving the lower lip of a horse. Courtesy of Dr. Jan Hawkins.

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DISEASES OF THE ESOPHAGUS IN LARGE ANIMALS

STOMATITIS Stomatitis is a clinical sign of many diseases in large animals. Oral trauma or contact with chemical irritants (eg, horses that lick at their legs after having been blistered with caustic agents) may result in transient stomatitis. Traumatic irtjury from the ingestion of the awns of barley, foxtail, porcupine grass, and spear grass, as well as feeding on plants infested with hairy caterpillars, also will result in stomatitis in horses and cattle. Clinical signs commonly associated with acute active stomatitis include ptyalism, dysphagia, or resistance to oral examina­ tion. Oral examination is facilitated by sedation, after which the mouth can be examined carefully with the aid of a mouth speculum and a light source. Ulcers should be visually and digitally evaluated to determine whether embedded foreign material (eg, grass awns) is present. If the etiology is ingestion of foreign material, changing the quality and quantity of the hay or removing the anin1al from a pasture with grass awns may effect recovery. Differential diagnoses include actinobac­ illosis, foot-and -mouth disease, malignant

215

catarrhal fever, and bovine viral diarrhea. Epidemic diseases such as bluetongue in ruminants, swine vesicular disease, and vesicular stomatitis in horses must be differentiated from other forms of acute noninfectious or contagious stomatitis.

PAPILLA R STOMATITIS Viral papillomas are found around the lips and mouths of young animals, particularly in cattle from 1 mo to 2 yr old. In some herds, the rate of occurrence may be lOOOA,. The lesions are characteristically white to pink, raised, and appear proliferative. Most papillomas resolve spontaneously. However, in some cases, the lesions may coalesce to form cosmetically unacceptable masses, and owners may request therapy. Surgical removal of larger masses can be cosmetically acceptable and lessen recovery tin1e. Small masses can also be manually debrided or crushed to stin1ulate the in1mune system. Other therapies, including cryosurgery and the use of autologous vaccines, may also be effective. Most papillomas eventually disappear if given tin1e.

DISEASES OF THE ESOPHAGUS IN LARGE ANIMALS ESOPHAGEAL OBSTRUCTION (Choke)

Esophageal obstruction (choke) occurs when the esophagus is obstructed by food or foreign objects. It is the most common esophageal disease in large animals. Horses most commonly obstruct on grain, beet pulp, or hay. Esophageal obstruction can also occur after recovery from standing chemical restraint or general anesthesia. Cattle tend to obstruct on a single solid object, eg, apples, beets, potatoes, turnips, com stalks, or ears of com. Clinical Findings: In horses, clinical

signs associated with esophageal obstruc­ tion include nasal discharge of feed material or saliva, dysphagia, coughing, or ptyalism. The horse may appear anxious and/or appear to "retch" by stretching and arching

the neck. Affected horses may continue to eat or drink, worsening the clinical signs. In cattle, clinical signs include free-gas bloat, ptyalism, or nasal discharge of food and water. Ruminants may be bloated and in distress or recumbent, or there may be protrusion of the tongue, extension of the head, bruxism, and ptyalism. Acute and complete esophageal obstruction is an emergency because it prohibits eructation of rurninal gases, and free-gas bloat develops. Severe free-gas bloat may result in asphyxia, because the expanding rumen puts pressure on the diaphragm and reduces venous return of blood to the heart. Diagnosis: The clinical signs of esopha­

geal obstruction are usually diagnostic. Physical examination findings compatible with esophageal obstruction include nasal

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discharge of feed material and water, bruxism, ptyalism, and palpable enlarge­ ment of the esophagus; in some instances, foreign objects lodged in the cervical esophagus may be located via palpation. Subcutaneous emphysema, cervical cellulitis, and fever may be associated with esophageal rupture. The inability to pass a stomach (ruminants) or nasogastric tube (horses) can also confinn the diagnosis. An endoscopic examination helps localize the site of esophageal obstruction, type of obstructing material, and extent of esophageal ulceration. Because of the risk of aspiration pneumonia, the respiratory tract should be evaluated carefulJy, including auscultation of the heart and lungs and thoracic radiography. In complicated or chronic cases, a CBC and serum biochemistry profile should be perfonned. CBC abno1malities include leukocytosis, left shift, toxic neutrophils, and hyperfibrinogenemia. Biochemical abno1malities include hyponatremia, hypochloremia, and hypokalemia second­ ary to excessive loss of saliva. Treatment: In horses, many cases of

esophageal obstruction may resolve spontaneously if feed and water are withheld. Spontaneous resolution can be aided by rv administration of sedatives (such as xylazine and detomidine). Oxytocin (0.11-0.22 mg/kg, fV) has proved useful to relax esophageal smooth muscle. To ensure that the esophageal obstruction has resolved completely, all horses with suspected obstruction should have a nasogastric tube passed into the stomach or an endoscopic examination. Waiting >4-6 hr before passing a nasogastric tube is not reco1111�ended because of the risk of esophageal mucosa! ulceration and aspiration pneumonia. Horses that do not respond to conservative management (withdrawal of feed and water, rv sedation or oxytocin) should be initially treated with esophageal lavage as follows: After rv sedation, a nasogastric tube is inserted to the level of the obstruction. Water is delivered to the obstruction site with a stomach pump, and the tube is slowly inserted and withdrawn to lavage the esophagus. The head must be lower than the torso to minimize aspiration of water into the lungs. Lavage via nasogastric tube is successful in at least 900/o of cases. For horses unresponsive to standing esophageal lavage, general anesthesia should be considered, with the horse

positioned in lateral recumbency and orotracheally intubated. Again, the head must be positioned lower than the torso to prevent water passing into the lungs. A cuffed endotracheal tube (18-22111111) is inserted into the esophagus as far as possible or to the level of the esophageal obstruction, and the cuff inflated. A nasogastric tube is inserted through the endotracheal tube, and the esophagus is lavaged as previously described. Again, resolution of obstruction should be con­ firmed with endoscopy or passage of the nasogastric tube into the stomach. An esophagotomy to resolve esophageal obstruction is rarely required. Aii clu-onic cases of esophageal obstruction should be evaluated endoscopi­ cally after successful resolution. These horses frequently have esophageal ulceration that can be circunlferential. Severe mucosa! ulceration can result in esophageal stricture and repeat obstruction. Endoscopy is also useful to exclude esophageal diverticula, which can predispose to esophageal obstruction. Esophageal diverticula can also be diagnosed with contrast esophagograms. Horses without mucosa! ulceration should be fed water-soaked, complete pelleted feed for at least 7 1-4 days to minimize the likelihood of repeat esopha­ geal obstruction. Horses with mucosa! ulceration should be fed this diet for 60 days, after which follow-up endoscopy should be performed to evaluate whether mucosa! ulceration has resolved and esophageal stricture has occurred. Horses with chronic mucosa! ulceration with strictw·e may require surgical management. Aspiration pneumonia should be managed with rv or oral antimicrobials and anti­ inflan1IT1atory drugs. Con1IT1only used antimicrobials include potassium or procaine penicillin G (22,000 U/kg, rv [potassium] or IM [procaine], bid-qid), trimethoprim sulfamethoxazole (30 mg/kg, PO, bid), and gentamicin sulfate (6.6 mg/kg/day, rv or IM). Metronidazole (15 mg/kg, PO, qid) is useful for management of anaerobic infections. The most common anti-inflan1IT1atory drugs used are phenyl­ butazone (2.2-4.4 mg/kg, PO or rv, bid) and flunixin meglwnine (l.l mg/kg, rv, bid). In cattle, esophageal obstruction accompanied by ruminal tyrnpany is an emergency, and if clinical signs of distress indicate, the bloat (seep 227) must be relieved by trocarization tlu-ough the left sublumbar fossa. Once tyrnpany has been relieved, solid objects (eg, potatoes) may

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often be massaged free or spontaneously dislodge as their outer surfaces are softened by saliva. Caution should be used if any attempt is made to push an offending object down the esophagus using a probang; esophageal rupture and fatal septic mediastinitis may result. Esophageal obstruction in ruminants can be managed with standing esophageal lavage via orogastric tube or while under general anesthesia (seep 215). Large foreign bodies can often be pushed into the rumen without further problems. Rare cases of esophageal obstruction with foreign bodies may be treated with esophagotomy.

Complications of Esophageal Obstruction ln horses and cattle, aspiration pnewnonia (seep 1417) and septic pleuropneun10nia may be complications of esophageal obstruction, especially in chronic cases. Chronic esophageal obstruction (>24 hr) may be associated with pressure necrosis of the esophageal mucosa due to prolonged contact with the foreign body. Circwnferen­ tial mucosa! dan1age may contribute to esophageal stricture. An often fatal complication of chronic esophageal obstruction is esophageal rupture. Cervical esophageal rupture can lead to localized cervical cellulitis or septic mediastinitis or pleuropneumonia. Intrathoracic esophageal rupture is typically fatal. Cervical esophageal rupture can be managed by local drainage, wound lavage, and insertion of a nasogastric tube into the rupture site. A traction diverticulwn is allowed to form, and the nasogastric tube is removed. Esophageal rupture managed with extraoral alimentation rarely results in esophageal stricture. ln cases of septic mediastinitis or pleuropneumonia, euthanasia should be considered because of the difficulty in successfully resolving the bacterial infection.

Esophageal Obstruction Secondary to Extraesophageal Disease Cervical and prethoracic trauma may result in periesophageal or esophageal fibrosis involving the muscular layer. This can result in esophageal stiicture and intemlittent or recurrent esophageal obstruction. ln some cases, there is no external evidence of cervical or prethoracic trauma ln cases of suspected extraesophageal trauma, endoscopic exanlination of the esophagus

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and a contrast esophagogram can be useful diagnostic tools. Once the site of esophageal stricture is identified, some cases of muscular stricture can be resolved with esophageal myotomy or removal of fibrous connective tissue surrounding the esophagus.

ESOPHAGEAL STRICTURES Idiopathic esophageal strictures can occur in foals. Initial diagnosis based on clinical signs may be delayed because of other more frequent causes of dysphagia, including idiopathic dorsal displacement of the soft palate or nasal reflux of milk, cleft palate, or pharyngeal cysts. All cases of nasal discharge of milk in foals should be evaluated with endoscopy. Esophageal stricture in older horses or ruminants typically results from mucosa! ulceration secondary to esophageal obstruction. Appropriate treatment depends on whether the stricture is mucosal or mural (involving the muscular wall). Mucosa! stJictures can be treated conservatively with dietary management (seep 215), bougienage with a cuffed endotracheal tube, or surgery. Mural st1ictures are best managed with esophageal myotomy. Surgical treatinent of mucosal strictures may involve esophagot­ omy through the strictured area with insertion of a nasogastric tube, resulting in a traction diverticulum, mucosal resection and anastomosis, or full-thickness esophageal resection and anastomosis.

ESOPHAGEAL NEOPLASIA The most common neoplasia of the esophagus in horses is squamous cell carcinoma, which carries a guarded prognosis. Focal neoplastic masses can be managed with esophageal resection and anastomosis. Unfortunately, most cases of squamous cell carcinoma are not amenable to surgery, and euthanasia should be considered. In ruminants, bovine viral papillomas (ie, warts) occasionally develop in the cranial esophagus and pharynx and, in the presence of other agents, may result in development of esophageal carcinoma. ln some areas of the world (eg, Scotland and South America), such disease may follow ingestion of natural bracken fem toxins. There is also a causal relationship between such bracken fem tun1ors and bladder cancers in cattle. (See also BRACKEN FERN POISONING, p 3089.)

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GASTROINTESTINAL ULCERS IN LARGE ANIMALS

GASTROINTESTINAL ULCERS IN LARGE ANIMALS Gastric ulcers are important in adult horses, foals, and pigs. Abomasal ulcers (seep 241) in mature cattle and calves appear to be increasing in in1portance.

GASTRIC ULCERS IN HORSES (Equine gastric ulcer syndrome)

Gastric ulcers (equine gastric ulcer syndrome [EGUS]) are conunon in horses and foals. This syndrome is most closely associated with horses involved in performance disciplines; changes in housing or social interaction; and illness. Prevalence in urunedicated racehorses in active training is at least 900Ai, whereas that in non-racing performance disciplines exceeds 600A Neonatal foals are at significant risk for development of perforating peptic ulcers until they are several weeks old, because their gastric mucosa is not developed to full thickness at birth. Although spontaneous healing of peptic ulcer lesions has been noted, if the horse is maintained in the circumstances inciting EGUS, the lesions are unlikely to heal without medical intervention. EGUS describes a spectrum of inflanuna­ tory and disruptive mucosal pathophysiol- . ogy affecting tissues of the distal esophagus, stomach, and entrance µito the duodenum. Endoscopic surveys indicate that -800Ai of these lesions are found in the nonglandular squamous mucosa of the stomach, especially on the lesser curvature just proxin1al to the margo plicatus. However, significant portions of the squamous mucosa along the greater curvature and up into the fundus may also be involved, along with lesions in the antrum or pylorus. Duodenal ulceration in adult horses and foals is considered part of EGUS and, hence, a peptic (acid-induced) disorder. Duodenal ulceration, perforation, and stricture can occur, and it is not known whether these problems develop solely as a result of enteritis (duodenitis) or whether peptic factors have a role. However, once a stricture occurs, gastric and esophageal ulcers are often present and severe, secondary to delayed gastric emptying. Etiology: Ulcers in the nonglandular squamous mucosa are associated with

repeated direct insult from ultra-low pH fluid normally found in the glandular region of the stomach. Pressure increases inside the abdomen (associated with exercise), collapsing the stomach and forcing the acid gastric contents upward. The more fluid (and highly acidic) contents of the lower stomach come in contact with the nonglandular squamous mucosa, causing inflanm1ation and, potentially, erosions to varying degrees. The causes of ulcers in the glandular mucosa of the stomach are less well defined. Use of nonselective NSAIDs are known to reduce blood flow to the GI tract, causing decreased production of the mucobica.rbonate matrix by the gastric glandular mucosa and resulting in ulceration. This is not a consistent finding, however. Additionally, attempts have been made to isolate and/or correlate evidence of Helicobacter spp organisms from the stomach of horses with and without gastritis and ulcers. Results of these studies have been equivocal or negative, and the role of this organism in glandular equine gastric ulcers has not been determined. Clinical Findings: Most foals with gastric ulcers do not exhibit clinical signs. Clinical signs become apparent when the ulceration is widespread or severe. The classic clinical signs for gastric ulcers in foals include diarrhea, bruxism, poor nursing, dorsal recumbency, and ptyalism. These signs are vague and not specific for gastric ulcers. In fact, ptyalism is a sign of esophagitis, which in most foals is secondary to gastric outflow obstruction and gastroesophageal reflux. Other causes, including esophageal obstruction and Candida infection, should be considered. Importantly, when a foal exhibits clinical signs, the ulcers are severe and should be diagnosed and treated immediately. Sudden gastric perforation without prior signs occurs sporadically in foals. Adult horses with ulcers display nonspecific signs, including abdominal discomfort (colic), poor appetite, mild weight loss, poor body condition, and attitude changes. Horses with severe abdominal pain or colic may have gastric ulcers, but they are unlikely to be the primary cause of the abdominal pain. No

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GASTROINTESTINAL ULCERS IN LARGE ANIMALS strong correlation between the extent of ulceration and the severity of clinical signs has been seen. Complications related to gastric ulcers are most frequent and severe in foals and include perforation, delayed gastric emptying, gastroesophageal reflux and esophagitis, and megaesophagus secondary to chronic gastroesophageal reflux. Ulcers in the proximal duodenum or at the pylorus can cause fibrosis and st1icture. Duodenal and pyloric stricture can lead to delayed gastric emptying in foals and adult horses. In rare cases, severe gastric ulceration causes fibrosis and contracture of the stomach. Diagnosis: Neither clinical signs nor clinicopathologic laboratory tests are specific for gastric ulcers, and an abnormal­ ity in a laboratory test does not preclude the possibility that another disorder may be present. Gastric ulcers can develop secondary to stress due to problems in many organ systems or as a result of hospitalization or stall confinement. Endoscopy and visualization of the ulcers in an empty stomach is the only definitive method of diagnosis. Endoscopes with light sources that can be varied in wavelength may be used to more easily visualize inflammatory stages of this disease before breaching of the epithelium by outright ulceration. A presumptive diagnosis can be reasonably made from significant reduction in clinical signs after several days of treatment with a medication known to be effective in raising gastric pH and allowing healing of gastric mucosa. Treatment: Suppression of gastric acidity and maintenance of a pH between 4 and 5

Gastric ulcers on endoscopy in a foal. Courtesy of Dr. Thomas Lane.

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are the primary treatment objectives. Studies have examined the use of surface­ coating agents, antacids, histamine type-2 receptor antagonists (ranitidine and cin1etidine), and the proton pwnp inhibitor omeprazole in a carrier designed to aid passage through the acid stomach into the small intestine for absorption. Sucralfate binds to the gastric glandular mucosa and may promote healing there, although studies using sucralfate have not shown it to be efficacious in the treatment of gastric ulcers in horses or foals. Thus, its use in horses is questionable. Antacids have yet to be proved effective in either healing or preventing gastric ulcers. They must be administered in relatively high volumes every 2 hr to neutralize stomach acid. Ranitidine (6.6 mg/kg, PO, tid) has been shown to be effective in healing gastric ulcers when horses were removed from training. Studies have not shown cimetidine to be effective. Omeprazole is the only medication approved by the FDA for treatment (4 mg/kg/day, PO) or prevention ( 1 mg/kg/day, PO) of gastric ulcers in horses, and it has been shown to allow gastiic ulcers to heal in horses that continue their nonnal training.

GASTRIC ULCERS IN PIGS Ulcers affect the pars esophagea in pigs and cause sporadic cases of acute gastric hemorrhage, resulting in death or slow growth due to chronic ulceration. Etiology: Ulcers result when the unprotected stratified squamous epithe­ lium of the pars esophagea is subjected to insult from the mixtw-e of acid, bile, and digestive enzymes present in the distal region of the stomach. The mucosa that surrounds the esophageal opening is not protected by mucus and therefore relies on maintenance of a pH gradient between the proximal and distal regions of the pig stomach. Many risk factors are associated with the development of ulcers, most of which are associated with an increa5e in fluidity of the stomach contents. The most irnpo1tant of these factors relate to feed, particularly the use of finely ground feed (25% of the animals tested have a run1inal pH 250 mEq/kg of diet dry matter, using the fonnula (Na+ K)- (CI+ S) to calculate DCAD. Supplementing the diet with direct-fed microbials that enhance lactate utilization in the rumen may reduce the risk of subacute rwninal acidosis. Yeasts, propionobacteria, lactobacilli, and enterococci have been used for this purpose. Ionophore (eg, monensin sodium) supplementation may also reduce the risk by selectively inhibiting run1inal lactate producers and by reducing meal size.

BLOAT (Ruminal tympany)

Bloat is an overdistention of the rwneno­ reticulwn with the gases of fermentati,,on, either in the form of a persistent foan1 mixed with the rwninal contents, called prin1ary or frothy bloat, or in the form of free gas separated from the ingesta, called secondary or free-gas bloat. It is predomi­ nantly a disorder of cattle but may also be seen in sheep. The susceptibility of individual cattle to bloat varies and is genetically determined. Death rates as high as 200Ai are recorded in cattle grazing bloat-prone pasture, and in pastoral areas, the annual mortality rate from bloat in dairy cows may approach l%. There is also economic loss from depressed milk production in nonfatal cases and from suboptimal use of bloat-prone pastures. Bloat can be a significant cause of mortality in feedlot cattle.

Etiology and Pathogenesis: In

primary ruminal tympany, or frothy bloat, the cause is entrapment of the nom1al gases of fennentation in a stable

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foam. Coalescence of the small gas bubbles is inhibited, and intraruminal pressure increases because ernctation cannot occur. Several factors, both animal and plant, influence the formation of a stable foam. Soluble leaf proteins, saponins, and hemicelluloses are believed to be the primary foanting agents and to form a monomolecular layer around gas run1en bubbles that has its greatest stability at about pH 6. Salivary mucin is antifoan1ing, but saliva production is reduced with succulent forages. Bloat-producing pastures are more rapidly digested and may release a greater amount of small chloroplast particles that trap gas bubbles and prevent their coalescence. The inunediate effect of feeding is probably to supply nutrients for a burst of microbial fennentation. However, the major factor that determines whether bloat will occur is the nature of the nnninal contents. Protein content and rates of digestion and nuninal passage reflect the forage's potential for causing bloat. Over a 24-hr period, the bloat-causing forage and unknown animal factors combine to maintain an increased concentration of small feed pa.iticles and enhance the susceptibility to bloat. Bloat is most common in animals grazing legun1e or legume-dontinant pastures, particula.i·ly alfalfa, ladino, and red and white clovers, but also is seen with grazing of young green cereal crops, rape, kale, turnips, and legume vegetable crops. Legmne forages such as alfalfa and clover have a higher percentage of protein and a.i·e digested more quickly. Other legumes, such as sainfoin, crown vetch, milk vetch, fenugreek, and birdsfoot trefoil, a.i·e high in protein but do not cause bloat, probably because they contain condensed tannins, which precipitate proteip and are digested more slowly than alfalfa or clover. Legmninous bloat is most common when cattle are placed on lush pastures, particularly those dominated by rapidly growing leguminous plants in the vegetative and early bud stages, but can also be seen when high-quality hay is fed. Frothy bloat also is seen in feedlot cattle, and less commonly in dairy cattle, on high-grain diets. The cause of the foa.in in feedlot bloat is uncertain but is thought to be either the production of insoluble slin1e by certain species of rnmen bacteria in cattle fed high-carbohydrate diets or the entrapment of the gases of fennentation by the fine pa.iticle size of ground feed. Fine particulate matter, such as in finely ground grain, can markedly affect foam stability, as

can a low roughage intake. Feedlot bloat is most common in cattle that have been on a grain diet for 1-2 mo. This timing may be due to the increase in the level of grain feeding or to the time it takes for the slime-producing lllll1en bacteria to proliferate to la.i·ge enough numbers. In secondary ruminal tympany, or free-gas bloat, physical obstrnction of ernctation is caused by esophageal obstrnction due to a foreign body (eg, potatoes, apples, turnips, kiwifruit), stenosis, or pressure from enJa.i·gement outside the esophagus (as from lyrnphad­ enopathy or sporadic juvenile thymic lymphoma). Inteiference with esophageal groove function in vagal indigestion and diaphragmatic hernia may cause chronic lllll1inal tyrnpany. This also occurs in tetanus. Tun1ors and other lesions, such as those caused by infection with Actinomy­ ces bovis, of the esophageal groove or the reticular wall are less common causes of obstrnctive bloat. There also may be inteiference with the nerve pathways involved in the ernctation reflex. Lesions of the wall of the reticulum (which contains tension receptors and receptors that discriminate between gas, foam, and liquid) may interrupt the normal reflex essential for escape of gas from the lllll1en. Ruminal tyrnpany also can be seconda.iy to the acute onset of run1inal atony that occurs in anaphylaxis and in grain overload; this causes a decrease in =en pH and possibly an esophagitis and nunenitis that can inteifere with ernctation. Runtinal tyrnpany also develops with hypocalcernia. Chronic runtinal tyrnpany is relatively frequent in calves up to 6 mo old without appa.i·ent cause; this fonn usually resolves spontaneously. Unusual postures, particularly lateral reclU11bency, are conrn10nly associated with secondary tympany. Rlll11inants may die of bloat if they become accidentally cast in dorsal recumbency Qr other restrictive positions in handling facilities, crowded tra.t1Sportation vehicles, or irrigation ditches.

Clinical Findings: Bloat is a common

cause of sudden death. Cattle not observed closely, such as pastured and feedlot cattle and dry dairy cattle, usually are found dead. In lactating dairy cattle, which are observed regularly, bloat conunonly begins within 1 hr after being turned onto a bloat-produc­ ing pasture. Bloat may develop on the first day after being placed on the pasture but more co11U110nly develops on the second or third day.

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In primary pasture bloat, the rumen becomes obviously distended suddenly, and the left flank may be so distended that the contour of the paralumbar fossa protrudes above the vertebral column; the entire abdomen is enlarged. As the bloat pro­ gresses, the skin over the left flank becomes progressively more taut and, in severe cases, cannot be "tented." Dyspnea and grunting are marked and are accompanied by mouth breathing, protrusion of the tongue, extension of the head, and frequent urination. Rumen motility does not decrease until bloat is severe. If the tympany continues to worsen, the animal will collapse and die. Death may occur within 1 hr after grazing began but is more common -3-4 hr after onset of clinical signs. In a group of affected cattle, there are usually several with clinical bloat and some with mild to moderate abdominal distention. In secondary bloat, the excess gas is usually free on top of the solid and fluid mminal contents, although frothy bloat may be seen in vagal indigestion when there is increased rwninal activity. Secondary bloat is seen sporadically. There is tympanic resonance over the dorsal abdomen left of the midline. Free gas produces a higher pitched ping on percussion than frothy bloat. The distention of the rumen can be detected on rectal examination. In free-gas bloat, the passage of a stomach tube or trocarization releases large quantities of gas and alleviates distention. Lesions: Necropsy findings are charac­ teristic. Congestion and hemorrhage of the lymph nodes of the head and neck, epicardium, and upper respiratory tract are marked. The lungs are compressed, and intrabronchial hemorrhage may be present. The ce1vical esophagus is congested and hemorrhagic, but the thoracic portion of the esopha..,"lls is pale and blanched-the demarcation known as the "bloat line" of the esophagus. The rumen is distended, but the contents usually are much less frothy than before death. The liver is pale because of expulsion of blood from the organ.

for the cow. Recovery is usually uneventful, with only occasional minor complications. A trocar and cannula may be used for emergency relief, although the standard­ sized instrument is not large enough to allow the viscous, stable foam in peracute cases to escape quickly enough. A larger bore instmment (2.5 cm in diameter) is necessary, but an incision through the skin must be made before it can be inserted through the muscle layers and into the rumen. If the cannula fails to reduce the bloat and the anin1al's life is threatened, an emergency run1enotomy should be perfom1ed. If the cannula provides some relief, an antifoarning agent can be administered through the cannula, which can remain in place until the animal has returned to normal, usually within several hours. When the anin1al's life is not immediately threatened, passing a stomach tube of the largest bore possible is recommended. A few attempts should be made to clear the tube by blowing at1d moving it back and forth in an attempt to find large pockets of run1en gas that can be released. In frothy bloat, it may be in1possible to reduce the pressure with the tube, and an antifoaming agent should be administered while the tube is in place. If the bloat is not relieved quickly by the antifoaming agent, the animal must be observed cai·efully for the next hour to determine whether the treatment has been successful or whether at1 alternative therapy is necessaiy. A variety of antifoa111ing agents are effective, including vegetable oils (eg, peanut, com, soybean) and mineral oils (paraffins), at doses of 250-500 mL. Dioctyl sodium sulfosuccinate, a surfactant, is commonly incorporated into one of the above oils and sold as a proprietary antibloat remedy, which is effective if administered early. Poloxalene (25--50 g, PO) is effective in treating legume bloat but not feedlot bloat. Placement of a rumen fistula provides short-term relief for cases of free-gas bloat associated with external obstruction of the esophagus.

Diagnosis: Usually, the clinical diagnosis of frothy bloat is obvious. The causes of secondary bloat must be ascertained by clinical examination to dete1mine the cause of the failure of emctation.

Control and Prevention: Prevention of pasture bloat can be difficult. Management practices used to reduce the risk of bloat include feeding hay, particularly orchard grass, before turning cattle on pasture, maintaining grass dominance in the sward, or using sttip grazing to restrict intake, with movement of anin1als to a new strip in the afternoon, not the early morning. Hay must constitute at least one-third of the diet to

Treatment: In life-threatening cases, an

emergency rumenotomy may be necessaiy; it is accompanied by an explosive release of rwninal contents and, thus, marked relief

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effectively reduce risk of bloat. Feeding hay or strip grazing may be reliable when the pasture is only moderately dangerous, but these methods are less reliable when the pasture is in the pre-bloom stage and the bloat potential is high. Mature pastures are less likely to cause bloat than immature or rapidly growing pastures. The only satisfactory method available to prevent pasture bloating is continual administration of an antifoarning agent during the risk petiod. This is widely practiced in grassland countries such as Australia and New Zealand. The most reliable method is drenching twice daily (eg, at milking times) with an antifoaming agent. Spraying the agent onto the pasture is equally effective, provided the animals have access only to treated pasture. This method is ideal for strip grazing but not when grazing is uncontrolled. The antifoan1ing agent can be added to the feed or water or incorporated into feed blocks, but success with this meU10d depends on adequate individual intake. The agent can be "painted" on the flanks of the animals, from which it is licked during the day, but anin1als that do not lick will be unprotected. Available anti.foaming agents include oils and fats and synthetic nonionic surfactants. Oils and fats are given at 60--120 mllhead/ day; doses up to 240 mL are indicated during dangerous periods. Poloxalene, a synthetic polymer, is a highly effective non.ionic surfactant that can be given at 10--20 glhead/ day and up to 40 glhead/day in high-risk situations. It is safe and economical to use and is administered daily through the susceptible period by adding to water, feed grain mixtures, or molasses. Pluronic agents facilitate the solubilization of wate1°insolu­ blc factors that contribute to formation of a.stable foam. A pluronic detergent.(Alfa­ sure®) and a water-soluble mixture of alcohol ethoxylate and pluronic detergents (Blocare 4511) also are effective but are not approved by the FDA. Ionophores effectively prevent bloat, and a sustained­ release capsule administered into the nm1en and releasing 300 mg of monensin daily for a 100-day period protects against pasture bloat and improves milk production on bloat-prone pastures. The ultinlate aim in control is develop­ ment of a pasture that permits high production, while keeping incidence of bloat low. The use of pastures of clover and grasses in equal amounts comes closest to achieving this goal. Bloat potential varies between cultivars of alfalfa, and low-risk LIRD (low initial rate of digestion) cultivars

are available commerciaJJy. The addition of legun1es with high condensed tannins to the pasture seeding mix ( lOOAisain.foin) can reduce the 1isk of bloat where there is sttip grazing, as can the feeding of sain.foin pellets. To prevent feedlot bloat, rations should contain �10-15% cut or chopped roughage mixed into the complete feed. Preferably, the roughage should be a cereal, grain straw, grass hay, or equivalent. Grains should be rolled or cracked, not finely ground. Pelleted rations made from finely ground grain should be avoided. The addition of tallow (3%--5% of the total ration) may be successful occasionaJJy, but it was not effective in contt·olled ttials. The nonionic swfactants, such as poloxalene, have been ineffective in preventing feedlot bloat, but the ionophore lasalocid is effective in control.

TRAUMATIC RETICULOPERITONITIS (Hardware disease, Traumatic gastritis) Traw11atic reticuloperitonitis develops as a consequence of perforation of the reticulwn. It is important as a differential diagnosis of other diseases marked by stasis of the GI tract, because it causes similar signs. Trawnatic reticuloperitonitis is most common in mature dairy cattle, occasion­ ally seen in beef cattle, and rarely reported in other flU11i.nants. Cattle commonly ingest foreign objects, because they do not disc1iminate against metal mate1ials in feed and do not completely masticate feed before swaJJow­ ing. The disease is common when green chop, silage, and hay are made from fields that contain old rusting fences or baling wire, or when pastures are on areas or sites where buildings have recently been constructed, burned, or tom down. The grain ration may also be a source because of accidental addition of metal·. Etiology: Swallowed metallic objects, such as nails or pieces of wire, faJJ directly into the reticulwn or pass into the nunen and are subsequently carried over the ruminoreticular fold into the cranioventral part of the reticulwn by rwninal contrac­ tions. The reticulo-omasal orifice is elevated above the floor, which tends to retain heavy objects in the reticulum, and tl1e honey­ comb-like reticular mucosa traps sharp objects. Contractions of tl1e reticultm1 promote penett·ation of U1e waJJ by the

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DISEASES OF THE RUMINANT FORESTOMACH foreign object. Compression of the 1wninoreticulum by the uterns in late pregnancy and straining during parturition increase the likelihood of an initial penetration of the reticulum and may also disrnpt adhesions caused by an earlier penetration. Pe1foration of the wall of the reticulum allows leakage of ingesta and bacteria, which contaminates the peritoneal cavity. The resulting peritonitis is generally localized and frequently results in adhesions. Less conm1only, a more severe diffuse peritonitis develops. The object can penetrate the diaphragm and enter the thoracic cavity (causing pleuritis and sometimes pulmonary abscessation) and the pe1icardial sac (causing pericarditis, sometimes followed by myocarditis ). Occasionally, tl1e liver or spleen may be pierced and become infected, resulting in abscessation, or septicemia can develop.

Clinical Findings: The initial penetration

of the reticulwn is characterized by the sudden onset of nuninoreticular atony and a sharp fall in milk production. Fecal output is decreased. The rectal temperature is often mildly increased. The heart rate is nom1al or slightly increased, and respiration is usually shallow and rapid. Initially, tl1e

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cow exhibits an arched back; an anxious expression; a reluctance to move; and an uneasy, careful gait. Forced sudden movements as well as defecating, urinating, lying down, getting up, ai1d stepping over batTiers may be accompanied by groaning. A grw1t may be elicited by applying pressure to the xiphoid or by finnJy pinching the withers, which causes extension of the tl1orax and lower abdomen. The grunt can be detected by placing a stethoscope over the trachea and applying pressure or pinching the withers at the end of an inspiration. Tremor of the triceps and abduction of the elbow may be seen. In chronic cases, feed intake and fecal output a.re reduced, and milk production remains low. Signs of cranial abdominal pain become less a.ppai·ent, and the rectal temperature usually retwns to nonnal as the a.cute inflan1mation subsides and pe1itoneal contatnina.tion is walled off. Some cattle develop vagal indigestion syndrome (seep 233) because of the adhesions that fom1 after foreign body perforation, particularly those on the ventromedial reticulum. Cows wit.11 plewitis or pericarditis due to foreign body perforation usually ai·e depressed, tachycardic (>90 bpm), and pyrexic (104° F [40° C]). Pleuritis is manifest

reticulai· groove atJium ruminis

heait reticulum

dorsal sac

of the rumen

ventJ"al sac

of the rnmen

The relationship between the reticulum, diaphragm, and heart and pericardium in large ruminants. Illustration by Dr. Gheorghe Constantinescu.

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DISEASES OF THE RUMINANT FORESTOMACH

by fast, shallow respiration; muffled lung sounds; and possibly pleuritic friction rubs. Thoracentesis may yield several liters of septic fluid. Traumatic pericarditis is most commonly characterized by muffled heart sounds; however, early in the disease process pericardia! fiiction rubs or gas and fluid splashing sounds (washing machine murmur) can be heard on auscultation. Jugular vein distention and congestive heart failure with marked submandibular and brisket edema is a frequent sequela of traw11atic reticuloperica.rditis. Prognosis is grave with these complications. Penetration th.rough the pericardium into the myocat0 dium usually results in extensive hemo1° rhage into the pericardia! sac or ventricular arrhythmias and sudden death. Diagnosis: This can be based on history

(when available) and clinical findings if the cow is exatnined when signs initially appear. Without an accurate history and when the condition has been present for several days or longer, diagnosis is more difficult. Other causes of peritonitis, par­ ticularly perforated abomasal ulcers, can be difficult to distinguish from traumatic reticuloperitonitis. Differential diagnoses should include conditions that can produce variable or nonspecific GI signs, eg, indigestion, lymphosarcoma, or intestinal obstruction. Abomasal displacement or volvulus should be excluded by simultane­ ous auscultation and percussion. Pleuritis or pericarditis of nontrawnatic origin produces signs similar to those associated with foreign body pe1foration. Although not always necessary, laborato1y tests may be helpful. In many cases, there is a neutrophilia with a left shift. Plasrna fibrinogen concentrations may be increased, and serun1 haptoglobin, runyloid A, and total plasma protein concentrations may be markedly increased. Severely affected cattle may have coagulation abnormalities, as evidenced by prolonged prothrombin time, th.rombin time, and activated partial th.romboplastin time. The acid-base status at1d serum electrolyte levels are typically normal, because abomasal and small-intestinal absorption can remain normal. However, mru·ked hypokalemic, hypochloremic metabolic alkalosis can be seen, presumably because adynrunic ileus from peritonitis can affect abomasal and GI motility and resorption of abomasal secretions. The metabolic alkalosis can be created or exacerbated by treatment with alkalinizing agents such as magnesiun1 hydroxide used as a laxative. Peritoneal fluid analysis can help dete1mine

whether peritonitis is present, particularly the concentration of o-dimer and the neutrophil percentage in the peritoneal fluid. However, the peritonitis frequently becomes walled off, and in these cases peritoneal fluid may be within the reference range unless obtained from within the lesion. The presence of a magnet in the reticulun1 can be determined by movement of a magnetic compass in the region of the cranioventral abdomen; the presence of a magnet in the reticulum makes traumatic reticuloperitonitis very unlikely unless the penetrating object is not magnetic. Ultrasonography of the ventral abdomen using a 3-MHz transducer is the most accurate way to diagnose localized pe1itonitis near the reticulum and character­ ize the reticulru· contraction frequency. It rru·ely identifies the presence of a penetrat­ ing object. Ultrasonography of the heart and thorax is ve1y useful in the diagnosis of pleuritis and pericarditis as a sequelae of traumatic reticuloperitonitis and has replaced radiography in the diagnosis of reticuloperitonitis. Lateral radiographs of the cranioventral abdomen can detect metallic material in the reticulun1 but should be taken only after oral administration of a magnet. To detennine whether the reticulwn is currently perforated, the foreign body must be visible beyond tl1e border of the reticulum, unattached to the magnet in the reticulum, or positioned off the floor of the reticulum. A depression in the cranioventral aspect of the reticulum or identification of an abscess (by gas accumulation outside a viscus), soft-tissue masses, or a fluid line in the cranial abdomen are also reliable radiographic findings of penetration. Portable radiographic units cannot penetrate the reticulru· area of standing adult cattle, and the cow may need to be transported to where there is equipment with sufficient power. The cow should not be placed in dorsal recurnbency to obtain radiographs, because such manipulation places stress on adhesions and may lead to a localized peritonitis becoming a diffuse peritonitis due to gravitational spread of infection. Electronic metal detectors Catl identify metal in the reticulun1 but do not distinguish between perforating and non perforating foreign bodies. Treatment: Treatment of the typical case

seen early in its course may be surgical or medical. Eitl1er approach improves the chances of recove1y from -600A, in untreated cases to 800/2 mm long) into the abomasum. The abomasum has difficulty in emptying the larger particles of food because of the increased viscosity, and they accumulate in the abomasum, resulting in abomasal impaction. Type IV vagal indigestion, or partial forestomach obstruction, is poorly defined. It typically develops in cattle during gestation and is more appropriately tennecl indigestion of late gestation. The condition is thought to be related to the enlarging uterus shifting the abomasum to a more cranial position, which inhibits normal abomasal emptying.

Clinical Findings: The clinical signs vary to some extent with the location of the obstruction. In all cases, there Is a gradual development (over days to weeks) of abdominal distention secondary to ruminoreticular distention. Distention of the dorsal and ventral sacs of the rumen results in an "L-shaped" rumen on rectal exanlination. Left dorsal and left and right ventral distention of the abdomen causes a "papple" (pear plus apple) shape as viewed from behind. Cattle with vagal indigestion syndrome have a diminished appetite, which typically improves temporarily if distention is relieved. Milk production gradually decreases, fecal output is reduced, and the rumen develops a "splashy" fluid consis­ tency. The feces are characteristically very scant and sticky and may contain longer than nonnal particles. The strength of rumen contractions is decreased; however, rumen motility is often increased (3-4 contractions/min). It is commonly possible to see movements of the left abdominal wall

that mirror the movements of the hyperac­ tive rumen. However, rumen contraction sounds are not audible because the contents have become frothy due to the prolonged contractions and failw-e of the rumen to empty. Temperature and respiratory rate are usually normal; however, these can be increased depending on the cause. Braclycardia is present in 25%-40% of cases and is clue to decreased feed intake rather than a direct stimulation of the vagus nerve. Tachycardia develops as the disease progresses and cattle become dehydrated. Over tin1e, the animal develops a rough hair coat, loses condition, and becomes weak (in some cases to the point of recumbency), with marked clinical signs of dehydration. On rectal palpation, the rumen is distended with gas or froth that occupies the entire left abdomen, pushing the left kidney to the right of the midline. The ventral sac of the rumen is enlarged and palpable to the right of the midline (the characteristic "L-shaped" rrunen). It is impo1tant to recognize that diagnosis of vagal indigestion syndrome requires the presence of a markedly increased rumino­ reticular volume. Palpation of the lower half of the right side of the abdomen below the costochondraljunction may detect an in1pactecl abomasum that feels doughy. Hematologic findings vary. The PCV can be increased because of dehydration or decreased because of bone marrow depression ( anemia of chronic disease). The WBC may be normal, increased, or decreased. If an inflan1lllatory condition such as peritonitis is present, the neutrophil to lyn1phocyte ratio is typically reversed, and a neutrophilia may be present. Lyrnphocytosis can be seen with vagal indigestion due to lyrnphosarcoma. Leukopenia may be present with diffuse peritonitis. Increased serum globulin and total protein can be seen with abscesses. Metabolic status is normal, or metabolic alkalosis may be present. The serum chloride concentration varies with the site of the obstruction. It is usually normal if the lesion is proxin1al to the abomasum. A low serum chloride concentration is consistent with reflux of chloride from the abomasum into the nU11en (internal vomiting) and obstruction at the level of the abomasum (type III). Metabolic alkalosis is typically present if serum chloride is decreased. Rwnen chloride concentration is increased in type III vagal indigestion and provides a useful method to differentiate type II from type III vagal indigestion. The serum

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DISEASES OF THE RUMINANT FORESTOMACH potassium concentration is usually low due to decreased potassium intake in the feed. Serum calcium concentration is often moderately decreased because of ongoing mHk production, but it is rarely low enough to cause recumbency. Serum urea and creatinine concentrations increase with dehydration due to prerenal azotemia.

Diagnosis: Diagnosis is based on the presence of subacute to clu·onic ruminore­ ticular and abdominal distention. Because vagal indigestion is by definition a subacute to chronic disease, this diagnosis should not be made in cattle that have not been sick for at least several days, which excludes acute rumen tympany and acute frothy bloat. Other causes of abdominal distention, such as ascites and uterine enlargement, are included in the differential diagnosis and can almost invariably be excluded by rectal palpation because of the absence of ruminoreticular distention. Occasional cases of longstanding obstruction of the cecum or small intestine can cause severe ruminoreticular and abdominal distention; however, palpable cecal or small-intestinal distention is also palpable rectally. In addition, the rumen is distended but not L-shaped, and a characteristic ping is present in the case of cecocolic volvulus. Diagnosing the specific cause of vagal indigestion is more difficult but is important because of differences in treatment and prognosis. Physical examination, rectal examination, CBC, blood acid-base detem1ination, and serum biochemical values are often useful. Peritoneal fluid analysis can support the diagnosis of peritonitis if total protein or nucleated cells are increased. Lateral radiographs of the reticulum should be taken to identify an opaque linear .foreign body (eg, wire) or reticular abscess. Ultrasonography of the cranioventral abdomen can indicate the presence of focal peritonitis and the reticular contraction rate. Definitive diagnosis often requires exploratory surgery (left paralumbar fossa laparotomy and rumenotomy). Treatment and Prognosis: If the value of the anin1aljustifies treatment, surgery is almost always needed to identify and potentially correct the underlying cause. Medical management alone is usually ineffective. A left paralun1bar fossa laparotomy and rumenotomy provides the opportunity for definitive treatment in some cases. Emptying the rumen at the time of surge1y may help restore nom1al rumen

235

motility. Stin1ulation of low-threshold tension receptors in the reticulw11 occurs under normal circumstances and causes reflex reticuloruminal contractions. However, severe distention causes stimulation of high-threshold receptors that have the opposite effect and inhibit contractions. Suppo1tive or symptomatic therapy should be provided in all cases, which typically involves correcting dehydration as well as calciwn and electrolyte deficits, commonly with oral fluids and electrolytes. Severely dehydrated animals and those with longstanding disease require IV fluids. Fresh water and nom1al feed should be avaHable. Transfaunation at surgery or via oroesopha­ geal intubation may help reestablish nom1al nunen flora in cattle with chronic anorexia. Antimicrobials (procaine penicillin or oxytetracycline) should be given if the underlying cause is infectious or if a rumen fistula is created. Treatment of type I vagal indigestion (failure of eructation) also typically involves creating a rwnen fistula to allow free gas to escape. If surgery is not economically feasible and the underlying cause of vagal indigestion has been identified and treated, a rumen trocar can be placed temporarily. Such trocars are commercially avaHable and must be secure and self-retaining to prevent potentially fatal leakage of rumen contents into the peritoneal cavity. The trocar should not be removed for at least 2 wk to allow fim1 adhesions to fom1 between the rumen and body wall. The prognosis for animals with type I vagal indigestion is usually favorable. After creation of a rumen fistula, the signs of vagal indigestion resolve in nearly all cases. However, anin1als with chronic respiratory disease or pharyngeal trauma may not recover from the underlying condition. Leakage of ingesta from fistulas can cause off-flavored milk. Peritonitis can develop from leakage around the fistula or after rumenotomy; however, this should not happen with good surgical teclutique. Type II vagal indigestion (faHure of omasal transport) rarely responds to sup­ portive or symptomatic therapy without surgical intervention. Left paralumbar fossa laparotomy and rwnenotomy can be used to identify adhesions in the vicinity of the reticulum, reticular or hepatic abscesses, or obstrnction of the omasal canal. Removal of foreign bodies, wires, and some masses at surgery and lancing of perireticular abscesses into the reticulum affords a fair to good prognosis. A diagnosis of lymphosar-

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DISEASES OF THE RUMINANT FORESTOMACH

coma at surgery wan·ants a grave prognosis. Reticular abscesses identified at surgery should be cautiously drained into the reticulum, and antibiotics given for 10-14 days. Reportedly, 83% of cattle with reticular abscesses respond favorably to treatment. Identification of adhesions in the vicinity of the reticulum warrants a fair to good prognosis witl1 surgery, antibiotic therapy, and appropriate supportive treatment. Hepatic abscesses must be drained by a second surgery. Large-bore carumlas placed through the body wall, through the adhesions, and into the abscess will drain the purulent material. However, recurrence is more of a problem with hepatic abscesses than with reticular abscesses. Animals witl1 type III vagal indigestion (secondary abomasal impaction) diagnosed without surgery usually do not receive fwther treatment because of the poor prognosis, particularly if there is a history of traumatic reticuloperitonitis or abomasal volvulus. If the diagnosis is made at surgery or if the abomasal impaction is thought to be dietary, dioctyl sodium sulfosuccinate can be infused directly into the abomasum via the reticulo-omasal orifice after emptying the rumen. A nasogastric tube can be passed into tl1e abomasum via the reticulo-omasal orifice at surgery and left in place for continued treatment (3---4 L of mineral oil daily for 3-5 days). If possible, impacted material should be removed manually tl1rough the reticulo-omasal mifice. Other lesions, such as abscesses in the medial wall of the reticulwn, should be identified and drained. Abomasotomy and removal of abomasal contents, using a right paracostal approach with the cow in left lateral recumbency, can be performed as a last resort. However, recurrence of the in1paction is common. Pyloric oj:Jstruction in cattle is rare and is most often due to a foreign body obstructing the lumen. Pyloromyotomy is almost never effective in resolving abomasal impactions. Type III vagal indigestion has a poor prognosis regardless of the cause or the treatment. However, cattle with mild to moderate primary abomasal impactions will respond to therapy, although severely affected anin1als will not (seep 244). Cattle with secondary impactions due to traumatic reticuloperitonitis or as a sequela of abomasal volvulus seldom recover. Animals with foreign bodies (eg, trichobezoars) obstructing the pylorus have a good prognosis if the obstruction is removed. Therapeutic induction of parturition has been recommended for treatment of cattle with type IV vagal indigestion (indigestion

of late gestation), and some cows have in1proved with this treatment; however, because type IV vagal indigestion is a poorly defined condition, the prognosis is always guarded. A more specific prognosis is based on response to therapy and identification of a specific lesion at exploratory celiotomy and nunenotomy.

Prevention: The most common cause of vagal indigestion syndrome is traumatic reticuloperitonitis, which causes adhesions and abscesses that interfere with both reticular motility and the appropriate stratification of feed particles for passage through the abomasum. Therefore, prevention of traumatic reticuloperitonitis is important. Good management practices may prevent some cases of vagal indigestion associated with chronic pneumonia. Early diagnosis of abomasal volvulus, with same-day surgical correction, may prevent some cases.

RUMINAL DRINKING "Rwninal drinking" is caused by failure of the reticular groove reflex, and it results in nuninal acidosis in calves on a liquid diet. The disorder presents as primary chronic disease (rurninal drinking syndrome) in veal calves, and in its acute fonn as a complica­ tion secondary to different neonatal diseases, most con11110nly neonatal diarrhea It has also been described in artificially fed lambs. The reticular groove is a muscular structure extending from the cardia to the reticulo-omasal orifice. Its correct closure is a precondition for the direct passage of ingested milk or milk replacer into the abomasum. When the reticular groove partially or completely fails to close, milk spills into the reticulorumen and is fennented to short-chain fatty acids and/or lactic acid. The subsequent drop in the pH of the ruminal contents to values that occasionally fall below 4 leads to variable degrees of inflanunation of the mucosa of the forestomachs and the abomasum. In chronic cases, hyperkeratosis or parakera­ tosis of the ruminal mucosa can lead to impaim1ent of nuninal motility with chronic or recurrent tympany. Additionally, atrophy of the intestinal villi and a decrease in brush border enzyme activity with maldigestion and malabsorption have been seen. Systemic consequences of acute ruminal drinking are mainly due to absorption of organic acids from the digestive tract. In particular, the L- and D-isomers of lactic acid may lead to metabolic acidosis with the

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DISEASES OF THE RUMINANT FORESTOMACH accumulation of o-lactate because of an absence of a specific enzyme for its metabolism in mammals. This accumulation of o-lactate has recently been found to be responsible for clinical signs such as depression, ataxia, and general weakness. Primary dysfunction of the reticular groove occurs as a result of stressful situations (prolonged transpott, grouping, change in feeding techniques), especially in bucket-fed veal calves. Clinical signs usually appear some weeks after the anival of the calves at the fattening units and are cha.racte1ized by inappetence, depression, poor growth, hair loss, recurrent tympany, ventral abdominal clistention, and passing of clay-like feces. Fluid-splashing sounds can be heard on succussion of the left flank. Recovery of fennented mminal contents via stomach tube is diagnostic. In these advanced, chronic cases the prognosis is poor. If the disease is detected early enough, feeding small vohunes of milk from a nipple-bottle or bucket may be successful. Additionally, the closure of the reticular groove can be triggered by allowing the calf to suck a finger before the milk feed is offered. Acute mminal acidosis secondary to other disorders is most commonly seen in calves with neonatal diarrhea but occurs also in other painful or weakening diseases. In these cases, the clinical picture is usually dominated by the underlying disease. In cases of severe mmenitis, calves may exhibit teeth grinding, arching of the back, and slight abdominal distention. Force­ feeding of inappetent or primarily anorectic calves can also cause rwninal acidosis or worsen the situation by providing substrate for fwther fermentation. The prognosis for secondary mminal drinking depends mainly on the success of treatment of the underlying disease. Calves with metabolic acidosis and dehydration due to neonatal diarrhea usually recover

Severe rumenitis in a 10-day-old calf after a prolonged course of ruminal drinking. Courtesy of Dr. Ingrid Lorenz.

237

spontaneously from mminal drinking after adequate treatment, and the condition will in general remain unrecognized. In calves that were force-fed or that do not respond to treatment as expected, mminal drinking should be considered, and an exainination of the nuninal fluid perfonned. Removal of the contents and lavage witl1 warm water via stomach tube may be beneficial, especially after prolonged force-feeding. Prophylaxis ofmminal &inking consists of early treatment of diseased calves, adequate feeding techniques, and minimizing stress in pmchased calves.

RUMINAL PARAKERATOSIS Run1inal parakeratosis is a disease of cattle and sheep characterized by hardening and enlargement of the papillae of the mmen. It is most conunon in anin1als fed a high­ concentrate ration dming the finishing period. It also is seen in cattle fed rations of hea t -treated alfalfa pellets, as well as in calves with prolonged mminal acidosis due to mminal drinking. It does not appear to be related to the feeding of antibiotics or protein concentrates. Incidence in a group may be as high as 400,1,. The lesions are tl1ought to be caused by the lowered pH and the increased concentration of volatile fatty acids (VFAs) in the rum.i.nal fluid, and do not usually develop in cattle fed unprocessed whole grain (on which anin1als gain weight as readily). This may be related to the higher · pH ai1d higher concentration of acetic acid than tl1ose of the longer chain VFAs in the mminal contents. Many of the papillae are enlai·ged ai1d hai·de.ned, and several may adhere together to form bunclles. The papillae of the anterior ventral sac are conunonly affected. In cattle, the roof of tl1e dorsal sac may show multiple foci (each 2-3 cm2) of parakeratosis. In sheep, abnom1al papillae may be visible and palpable through the wall of tl1e intact nunen. Affected papillae contain excessive layers of keratinized epithelial cells, particles of food, and bacteria. The mmens of affected cattle are difficult to clean in tl1e preparation of tripe. The abnormal epithelium, by interfering with absorption, may reduce efficiency of feed utilization and rate of gain, although there is little evidence to support this theory. Run1inal parakeratosis may be prevented by finishing animals on rations that contain unground ingredients in the proportion of 1 pa.it roughage to 3 parts concentrate. The necessity ai1d economics of prevention are not well defined.

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DISEASES OF THE ABOMAS UM

DISEASES OF THE ABOMASUM Abomasal disorders include left displaced abomasum (LDA), 1ight displaced aboma­ sum (RDA), abomasal volvulus (AV), abomasal ulceration, and impaction. Displacement or volvulus is seen most commonly in dairy cows but can also be seen in dairy bulls and calves. Except for AV, abomasal displacement is rare in beef cattle and essentially undiagnosed in small ruminants. Abomasal ulcers are seen in dairy and beef cattle and in calves and lambs; they are rarely diagnosed in small ruminants. Impactions can be primary, which. is most frequent in beef cattle, or secondary, which develop most often in dairy cows as a forn1 of vagal indigestion. Impactions may have a hereditary basis in some black-faced sheep.

LEFT OR RIGHT DISPLACED ABOMASUM AND ABOMASAL VOLVULUS Because the abomasum is suspended loosely by the greater omentum and lesser omentum, it can be moved from its normal position on the right ventral part of the abdomen to the left or right side (LDA, RDA), or it can rotate on its mesenteric axis while displaced to the right and lateral to the liver (AV). The abomasum can shift from its normal position to left displace­ ment or to right displacement over a relatively short period. AV can develop rapidly or slowly from an uncorrected RDA.

Etiology: Although LDA, RDA, and AV (previously incorrectly referred to as right torsion of the abomasum) are often considered separately, there is evidence of a common underlying etiology; they may be different manifestations of the same or a similar disease process. The etiology is multifactmial, although abomasal hypomotility and dysfunction of the intrinsic nervous system are thought to play an important role in development of displacement or volvulus. Important contributing factors include abomasal hypomotility associated with hypocalcemia and possibly hypokalemia, as well as concurrent diseases (mastitis, metritis) associated wilh endoloxernia and decreased rumen fill, periparturient changes in the position of intra-abdominal organs, and genetic predisposition, particularly in deep-bodied cows. Genetic

predisposition is correlated with milk yield, indicating that current selection practices for milk production are increasing the incidence of abomasal displacement. Hypomotility is also related to ingestion of high-concentrate, low-roughage diets, which reduce abomasal motility through a poorly defined mechanism that may involve hyperinsulinemia or increased concentra­ tions of volatile fatty acids. One of the mechanisms of excessive gas accun1ulation in cattle with abomasal displacement is reticulum-mediated inflow of ruminal gas into the abomasum that is hypomotile. In addition, high-concentrate diets result in increased gas production in the abomasum (mostly carbon dioxide, methane, and nitrogen). Finally, subclinical and clinical ketosis increase the risk of abomasal displacement through an unknown mechanism that may be associated with decreased rumen fill. Approximately 800/o of displacements are seen within 1 mo of parturition; however, they can be seen at any time. LDA is much more common than RDA (30 LDA to 1 RDA); cases of AV are also more common than RDA (10 LDA to 1 AV). AV is preceded by RDA.

Pathogenesis: In LDA, as a result of abomasal hypomotility and gas production, the partially gas-distended abomasun1 becomes displaced upward along the left abdominal wall lateral to the rumen. The fundus and greater curvature of tl1e abomasum are primarily displaced, which in turn causes displacement of the pylorus and duodenum. The omasun1, reticulum, and liver are also rotated to varying degrees. The abornasal obstruction is pa.itial, and although the segment contains some gas and fluid, a certain a.J11ount can still escape, and the distention rarely becomes severe. Because there is rnininlal interference with blood supply unless the gas distention is marked, the effects of displacement are entirely due to interference with digestion and passage of ingesta, which lead to decreased appetite and dehydration. A mild metabolic alkalosis with hypoch.lorernia and hypokalemia are common. The hypoch.lorernic metabolic alkalosis is due to abomasal hypomotility, continued secretion of hydrochloric acid into the abomasum, and the partial abomasal outflow obstruction, with sequestration of chloride in the abomasum

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DISEASES OF THE ABOMASUM and reflux into the rumen. Hypokalemia is due to decreased intake of feeds high in potassium, sequestration of potassium in the abomasum, and dehydration. Secondary ketosis is common and may be complicated by development of hepatic lipidosis (fatty liver disease; seep 1018). In RDA, hypomotility, gas production, and displacement of the partially gas-filled abomasum occur as in LDA. Mild hypoka­ lemic, hypochloremic, metabolic alkalosis develops as well. After this dilatation phase, rotation of the abomasum on its mesenteric axis leads to volvulus and local circulatory in1painnent and ischemia (hemorrhagic strangulating obstruction). The volvulus is usually in a counterclock­ wise direction when viewed from the rear and the right side of the animal. The omasum is displaced medially and can be involved in the volvulus with occlusion of its blood supply (called an omasal­ abomasal volvulus) and displacement of the liver and reticulun1. In rare cases, the reticulum can be involved (called a reticular-omasal-abomasal volvulus). A large quantity of chloride-rich fluid (up to 50 L) accun1ulates in the abomasum, and hypochloremic, hypokalemic metabolic alkalosis develops. The blood supply to the abomasun1, and often the omasw11 and proximal duodenum, is compromised, eventually resulting in ischemic necrosis of the abomasum and proximal duodenum as well as dehydration and circulatory failure. As circulatory failure progresses, a metabolic acidosis due to hyper-L-lacta ­ temia and azotemia can become super­ imposed on the preexisting metabolic alkalosis. Clinical Findings: The typical history of abomasal displacement includes anorexia (most commonly a lack of appetite for grain with a decreased or normal appetite for roughage) and decreased milk production (usually significant but not as dramatic as with traumatic reticuloperitonitis or other causes of peritonitis). In AV, anorexia is complete, milk production is more markedly and progressively reduced, and clinical deterioration is rapid. In abomasal displacement, temperature, heart rate, and respiratory rate are usually nonnal. The caudal part of the rib cage on the side of the displacement may appear "sprung." Hydration appears subjectively normal with displacements except in some chronic cases. Rumen motility may be normal but often is reduced in frequency and strength of contraction. Feces are usually reduced in quantity and more fluid than normal.

239

The most important diagnostic physical finding is a ping on simultaneous ausculta­ tion and percussion of the abdomen, which should be performed in the area marked by a line from the tuber coxae to the point of the elbow, and from the elbow toward the stifle. The ping ( detected dmi.ng sin1ultaneous percussion and auscultation) characteristic of an LDA is most commonly located in an area between ribs 9 and 13 in the middle to upper third of the left abdomen; however, the ping can be more ventral or more caudal, or both. Pings associated with a nunen gas cap are usually more dorsal, less resonant, and extend more caudally through the left paralun1ba.r fossa. Rectal examination can confirm a gas-filled rumen or an extremely empty rumen that con-elates with the rumen ping in these cases. Pings associated with pnewnoperitoneum typically are less resonant, present on both sides of the abdomen, and are inconsistent in location on repeated evaluation. Frequently, secondary ketosis develops, and ketones are present in the Uli.ne or milk. Ketosis that develops in association with abomasal displacement responds only transiently to treatment and recurs (versus in primary ketosis, which develops early in lactation in high-producing cows and responds to therapy permanently if instituted early). (See also KETOSIS IN CA11'LE, p 1024.) The ping associated with RDA also is most commonly located in the area between ribs 10 and 13 on the right abdomen. Dif­ ferentiation between various causes of a right-side ping can be difficult in some cases, although a ping cranial to rib 10 usually indicates the presence of AV because tl1e liver is displaced medially by the distended viscus. A small, right-side ping underlying ribs 12 or 13 and extending as far fo1ward as rib 10 is common in cows with fw1ctional ileus from a number of causes. This ping is most often associated with gas in the ascending colon and resolves with correction of the underlying condition. Cecal dilatation and rotation are character­ ized by a right-side ping. The ping extends through the dorsal paralumbar fossa in cecal dilatation and usually is located more caudally (well into the paralun1bar fossa) in cecal rotation than the ping of RDA. Palpation per rectum is helpful in different­ iating an RDA from cecal dilatation or rotation. Other right-side pings are produced by pneumoperitonewn or gas in the rectun1, descending colon, duodenum, or uterus. Spontaneous fluid splashing or gas tinkling sounds may be heard on ausculta­ tion of the area of the ping or on simultane­ ous ballottement and auscultation of the

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DISEASES OF THE ABOMASUM

rumen

----:-8:1-;JHH---superficial wall of greater omentum ' reticulum -------/ abomasum

1

A

I

abomasum

reticulum

lesser omenttm1 �r---�'{--llr-l.--greater omentwn

A) Normal topography of left abdominal viscera, cow. B) Left displacement of abomasum. Illustration by Dr. Gheorghe Constantinescu. Adapted, with permission, from Delahunta and Habel, Applied

Veterinary Anatomy, W.B. Saunders, 1986.

abdomen (succussion). The characteristic rectal examination findings with LDA include a medially displaced rumen and left kidney. The abomasurn is rarely palpable in LDA and only occasionally in RDA. The clinical signs associated with abomasal volvulus are more severe than with simple displacements because of the vascular compromise. However, an early abomasal volvulus can be difficult to distinguish from an RDA except by the presence of a right-side ping cranial to rib 10 (indicating medial displacement of the liver by the abomasal volvulus) and the anatomic position identified at surgery. In contrast to cases of displacement, an anin1al with AV has tachycardia propor­ tional to the severity of the condition. The area of the ping is usually larger (extending as far forward as rib 8), and the amount of succussible fluid is greater. The anin1al is more depressed, and signs of weakness, toxemia, and dehydration develop as the disease progresses. The caudal extent of

the abomasurn is usually palpable per rectwn. Without therapy, the animal often becomes recumbent within 48-72 hr after developing volvulus. Death occurs from shock and dehydration and is sudden if the ischemic abomasurn ruptures. Diagnosis: For displacement or

volvulus, diagnosis is based on the presence of the characteristic ping on simultaneous auscultation and percussion and exclusion of other causes of left- or right-side pings. Ultrasonography may be helpful in confirming a diagnosis of LDA, RDA, or AV, but it cannot reliably differentiate RDA from AV. Recent parturition, partial anorexia, and decreased milk production suggest displacement. A ketosis that is only temporarily responsive to treatment is consistent with abomasal displacement, which may be intermittent. The typical signs on physical examination (in addition to the ping), rectal examination, and laboratory evaluation also support the

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DISEASESOFTHE ABOMASUM diagnosis. Melena or signs of peritonitis (eg, fever, tachycardia, localized abdomi­ nal pain, pneumoperitoneum) with anLDA may indicate a bleeding or perforated abomasal ulcer, respectively. In cattle with AV, blood L-lactate concentrations �2 mmol/L indicate a positive outcome with surgical correction, whereas cattle with blood L-lactate concentrations �6 mmol/L have a high probability of a negative outcome.

Treatment: Open (surgical) and closed (percutaneous) techniques can be used to correct abomasal displacements. Rolling a cow through a 180° arc after casting her on her right side corrects most LDAs; however, recurrence is very likely.LDA can be corrected surgically using right flank pyloric omentopexy, right paramed­ ian abomasopexy, left paralumbar abomasopexy, combined left flank and right paramedian laparoscopy (two-step procedure), or left flank laparoscopy (one-step procedure). Blind suture techniques (toggle-pin fixation or the "big needle" [blind-stitch] method), performed in the right paramedian area, are percutaneous methods for correction of LDA; however, the exact location of the suture is not known. Potentially fatal complications can develop after blind suture techniques, and the reported success rate is less than that of surgical correction by right flank pyloric omen­ topexy. With toggle-pin fixation, the pH can be checked to confirm that the pin is in the abomasum, which reduces the likeli­ hood of attaching rumen, small intestine, or omentum to the body wall rather than the abomasum. RDA and AV are corrected surgically (using right paralumbar fossa omentopexy) when economically feasible. The right paran1edian abomasopexy should be used only to correct RDA and AV in cattle unable to stand. Ancillary treatment of animals witl1 abomasal displacement include treating any concurrent disease (eg, metritis, mastitis, ketosis). Calcium borogluconate or calcium gluconate SC or calcium gels PO help restore nom1al abomasal motility in many cases. Administration of erytiu·omycin ( 10 mg/kg, IM) at tl1e time of surgery increases abomasal emptying rate and milk production in the in1mediate postoperative period. Because surgical con-ection of abomasal displacement or volvulus is frequently done on the farm, tl1e prokinetic effect of erythromycin suggests that it might be prefen-ed if antimicrobials are administered to control intraoperative

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infection. However, administration of an antin'licrobial for a nonantimicrobial effect should not be promoted. In simple displacement, fluid and electrolyte abnom1alities correct spontane­ ously with access to water and a salt block. Providing electrolyte water (60 g sodium chloride and 30 g potassium chloride in 19L of water) via stomach tube is helpful in cases of longer duration. Anin1als witl1 significant dehydration and metabolic derangement require IV tl1erapy, typically administered as hype1tonic saline (7.2% NaCl, 5 mUkg, IV over 5 min). Occasionally, animals with abomasal displacement or volvulus have at1ial fibrillation, tl1ought to be of metabolic origin and primarily due to concunent hypoka­ len'lia and metabolic alkalosis. Correction of the displacement or volvulus almost always results in correction of the atrial fibrillation withrn 5 days. Aggressive treatment of ketosis plays an impo1tant role in successful treatment of abomasal displacement, because most of tl1e cattle tl1at die after surgical correction ofLDA and RDA do so from the metabolic consequences of prolonged anorexia. The prognosis after correction of simple LDA or RDA is good, witl1 survival rates of 95%. AV has a variable and less favorable prognosis (average survival rate of 700A,); a high heart rate, moderate to severe dehydration, a longer period of illness, a large quantity of fluid in the abomastm1, increased blood or plasma L-lactate concentration, and the presence of omasal-abomasal or reticulo-omasal­ abomasal volvulus are associated with a poorer prognosis.

Prevention: The incidence of abomasal displacements can be decreased by ensuring a rapid increase in rumen volume after calving, feeding a total mixed ration ratl1er than feeding grain twice daily ("slug feeding"), avoiding rapid dietary changes, maintaining adequate roughage in the diet, avoiding postpartmient hypocalcemia, and minrntizing and promptly treating concur­ rent disease and ketosis.

ABOMASAL ULCERS Abomasal ulcers affect mature cattle and calves and have several different manifestations.

Etiology and Pathogenesis: Except for lymphosarcoma of the abomasum and tl1e erosions of the abomasal mucosa that develop in viral diseases such as bovine

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viral diarrhea and bovine malignant catarrhal fever, the causes of abomasal ulceration are not well understood. Many different causes have been suggested. Although abomasal ulcers can be seen any time during lactation, they are common in high-producing, mature dairy cows within the first 6 wk after parturition. The most likely cause is prolonged inappetence, which results in sustained periods of low abomasal pH; hence, the adage "no acid, no ulcer." Abomasal ulcers may also arise in associ­ ation with lymphosarcoma, abomasal disorders (displacement or volvulus), or increased luminal pressure causing ischemia of abomasal mucosa; they may also appear to be unrelated to other disease. Abomasal ulcers are very conunon in mil k f- ed calves after they have consumed milk or milk replacer for 4--12 wk. Most of these ulcers are subclinical and nonhemor­ rhagic. Occasionally, milk-fed calves 4 L of fluid reflux from the stomach; no borborygmi on auscultation; peritoneal fluid with increased protein, erythrocytes, and toxic neutrophils; and a tightly distended intestine, displaced colon, or enterolith or foreign body identified on rectal exan1ination. Perfonning surgery (if indicated) early is critical to success and improves the prognosis for survival. Therefore, it is more in1portant to decide whether the horse should be referred to a clinic where surgery could be perfom1ed if needed than to determine whether emergency surgery is definitively required. It is generally prudent to refer the following types of cases: 1) a horse that responds initially to an analgesic but requires additional analgesic tl1erapy a few hours later, 2) a horse tlmt continues to exhibit signs of pain despite administration of analgesics, 3) a horse that remains painful but has normal pe1itoneal fluid, 4) a horse with distended loops of small intestine on rectal exan1ination, or 5) a horse with large quantities of fluid removed from the stomach but no distended small intestine palpable on rectal examination. When surgery is required, in most instances, the horse is anesthetized and positioned in dorsal recwnbency, and the surgical incision is made on the ventral midline. Once the peritoneal cavity is entered, portions of the intestine should be examined to detennine the definitive cause of the colic. Correction may involve repositioning a displaced po1tion of intestine, removing an obstruction, or resecting devitalized intestine. When devitalized segments of intestine must be removed or an enterotomy perfom1ed, postoperative care may include antibiotics, IV fluids, polymyxin B, anti.bodies directed against endotoxin, and NSAIDs to combat endotoxemia. When a displaced segment of intestine is simply returned to its normal location, the postoperative care is much less intense. Each horse must be handled individually, and its treatment needs are based on the response to surgery and development of complications.

Prognosis A large retrospective study in the USA docw11ented an overall swvival rate of 600A, for horses with colic and a survival rate of 500Ai for those horses undergoing abdominal surgery, including those euthanized dw·ing

257

surgery for inoperative conditions. Swvival rates for horses with strangulating obstruction and inflanm1atory diseases were only 24% and 42%, respectively. In contrast, horses with an w1defmcd cause for the colic episode had a survival rate of 94%. When the segment of the GI tract was considered, the swvival rates for conditions affecting the small intestine and stomach were poorer than for those affecting the large colon. In addition, conditions that interfered with both tl1e passage of ingesta and the intestinal blood supply dramatically decreased the chances of smvival. The results of more recent studies are far more promising, with survival rates for horses tmdergoing emergency abdominal surgery often >800A,. Fw.thermore, there have been reports docwnenting survival rates of 700A, for horses requiring resection of strangu­ lated small intestine or correction of large-colon volvulus. In earlier retrospective studies, these conditions were associated with survival rates �30%. Although data on longtem1 survival (ie, the horse returning to its intended use) are more difficult to obtain, recent findings indicate that most horses that die or are euthanized because of serious problems do so within 3 mo after surgery. Values obtained from several variables are often combined to predict smvival in horses with colic. Prognostic indicators include pain assessment, intestinal distention, mucous membrane color, and cardiovascular system function. Smvival rates are highest for horses with mild abdominal pain and are lowest for horses with severe pain. Horses with palpable intestinal distention have lower survival rates than horses lacking evidence of intestinal distention, and survival rates are even lower if no intestinal sounds are audible on auscultation of the abdomen. Red mucous membranes are frequently associated with endotoxemia, which decreases the survival rate. Cardiovascular system function reflects the degree of shock and, therefore, correlates with the prognosis for survival. For instance, horses with low systolic blood pressure or a high heait rate have a decreased chance of survival. Of the laboratory analyses used to predict survival, blood lactate concentration and the anion gap are used most often. Measurement of blood lactate has been used as an indicator of tissue perfusion, with increasing concentrations of lactic acid corresponding with poor tissue perfusion. In recent studies, changes in blood lactate concentration over tin1e have been

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particularly useful to detennine the prognosis for swvival, with increasing concentrations being associated with a poor prognosis. Furthermore, changes in peritoneal fluid lactate concentrations over time have been used to help identify horses that require emergency abdominal surgery. Similarly, the anion gap (the calculated difference between the measured cations and the measured anions) reflects the generation of organic anions, most notably lactic acid, due to reduced tissue perfusion. The concentration of protein in the peritoneal fluid also has been used to predict swvival, with higher concentrations associated with a poorer prognosis.

DISEASES ASSOCIATED WITH COUC BY A! :rOM C lOCATIO Stomach Gastric Dilatation and Gastric Rupture: The most common cause of

gastric dilatation in horses is excessive gas or intestinal obstruction. Gastric dilatation may be associated with overeating fermentable feedstuffs such as grains, lush grass, and beet pulp. Presumably, the large increase in production of volatile fatty acids inhibits gastric emptying. If untreated, gastric dilatation associated with overeating can rapidly lead to gastric rupture. If intestinal obstruction is the cause, the obstruction most often involves the small intestine. The fluid from the obstructed small intestine accumulates in the lumen of the stomach, causing dilatation of the stomach and retrieval of gastric reflux on passage of the nasogastric tube. Gastric dilatation also may develop in some horses with certain colonic displacements, most notably right dorsal displacement of the colon around the cecum (see p 265). It is presumed that the displaced colon obstructs duodenal outflow. Gastric dilatation with fluid and gastric reflux also are characteristic findings in horses with proximal enteritis-jejunitis. Rupture of the stomach is a fatal complication of gastric dilatation. The stomach generally tears along its greater curvature. Approximately two-thirds of all gastric ruptures occur secondary to mechanical obstruction, ileus, and trauma; the remaining cases are due to overload or to idiopathic causes. Clinical signs associated with gastric dilatation include severe abdominal pain, tachycardia, and retching. The mucous membranes may be pale. Classically, these acute signs are replaced by relief, depres-

sion, and toxemia after the stomach has ruptured. The prognosis for swvival may be excellent in most cases of gastric dilatation, but gastric rupture is fatal. Gastric Impaction: Impaction of the stomach is an uncommon cause of colic. Although it may be associated with ingestion of certain feedstuffs (eg, beet pulp, pelleted feeds, persimmon seeds, straw, barley), contributing factors (eg, diseased teeth, inadequate intake of water, and rapid eating) should also be considered. Because the incidence of this condition is low, it is difficult to detennine which factors may be most important. The most striking clinical sign associated with gastric impaction is severe abdominal pain. Because of the lack of other characteristic findings, the diagnosis most often is made at surgery, and the decision for surgery is based on unrelenting pain. Use of a 3-m endoscope has made it possible to identify this problem without surgery. Treatment usually involves repeated intragastric administration of saline carbonated drinks ("soft drinks") if the condition has been identified without surgery. If the gastric impaction has been identified at surgery, saline or water can be infused into the mass through a needle passed through the wall of the stomach. After the fluid has been injected into the mass, the stomach then is massaged and the obstruction is broken down. If a nasogastric tube is in place at the time of surgery, water · may be pumped into the stomach and the mass massaged. Gavage is continued after surgery with the hopes of removing some of the impacted material, and this can be followed by feeding slurries and pasture grazing once the in1paction begins to resolve. The prognosis is favorable if the diagnosis has been made without surgery or if decision to perform exploratory surgery is made early and the impaction can be broken down manually at surgery.

Intestine Clinical signs of colic may arise due to obstruction, inflammation, or strangulating obstruction of the small intestine. The prognosis for conditions affecting the small intestine is often guarded. Hence, rapid diag­ nosis and appropriate treatment are critical. lleal Impaction: The most common condition producing sin1ple obstruction of the lumen of the small intestine is ileal impaction. It is most common in the

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COLIC IN HORSES

southeastern USA, Germany, and the Netherlands. The results of clinical studies in the UK indicate that infection with the intestinal tapewmm Anoplocephala perfoliala and ileal impaction are strongly associated. In a similar study performed in the USA, two risk factors for ileal impaction were identified: 1) the feeding of Coastal Bermuda hay, and 2) the lack of administra­ tion of pyrantel pamoate, an anthelrnintic with some efficacy against A per.foliata, within the 3 mo preceding development of the impaction. Further, it has been suggested that the impaction develops secondary to spastic contractions of the ileal musculature against ingesta. Clinical signs include the onset of mild to severe abdominal pain followed by reduced intestinal sounds, gastric reflux, and tachycardia. Although early rectal exan1ination may permit identification of the impaction in the ileum low in the right caudal abdominal quadrant, subsequent distention of the jejunum may make this identification difficult or impossible. The most common differential diagnosis is proximal enteritis-jejunitis, and distinguish­ ing the two conditions can often be difficult. Because the horse's condition initially may remain stable and the degree of abdominal pain may be mild, many horses with this condition are not referred for intensive care or surgery for> 18 hr. The protein concentration of the peritoneal fluid may increase if the impaction has persisted for this long. Horses with ileal in1paction respond to treatment with fluids and mineral oil if the impaction has been identified early (ie, before gastric reflux has developed). If surgery is indicated, the impacted mass may be mixed with saline or carboxymethylcel­ lulose and massaged into the cecum, or an enterotomy may be performed in the distal jejunum and the ingesta removed through the incision. Ileus may develop after surgery. Depending on the degree of damage to the serosal surface of the small intestine at the tin1e of surgery, complica­ tions may develop several weeks after surgery due to intra-abdominal adhesions (see below). Adhesions: Intra-abdominal adhesions generally affect the small intestine and usually cause obstruction of the intestinal lumen, although they may cause strangu­ lating obstruction. These adhesions develop in response to peritoneal injury and, most often, are the result of previous small-intestinal surgery, chronic small-

259

intestinal distention, peritonitis, or larval parasite migration. The tissue response to ischemia, traumatic tissue handling, foreign material, hemorrhage, or dehydra­ tion results in the formation of fibrinous (and subsequently fibrous) adhesions. Clinical signs are seen if the adhesion causes kinking, compression, or stricture of the intestine. Adhesions should be considered if the horse has had prior abdominal surgery and a more recent history of recurrent abdominal pain. Clinical signs associated with intra-abdominal adhesions range from mild, recurrent colic to severe unrelenting pain. Most conunonly, intra-abdominal adhesions cause clinical signs within 60 days of the initial surgery if they are going to be a significant problem for the horse. Surgical treatment involves transection of the adhesion, resection of the affected intestine, and anastomosis to achieve normal flow of ingesta. Therapeutic agents purported to reduce the subsequent formation of additional adhesions then are used. These include the systemic adminis­ tration of antinlicrobials, NSAIDs, and instil­ lation of sterile carboxymethylcellulose into tl1e abdomen at the time of closure. The owner should be informed that adhesions are likely to recur and that the longten11 prognosis for horses with extensive adhesions is poor. Ascarid Impaction: Young horses,

particularly those on farms with inad­ equate parasite control programs, may develop ascarid impactions of the small intestine. These impactions are seen after administration of an anthelmintic with high efficacy againstParascaris equorum. The anthelmintics most conu11only associated with this condition are iven11ectin, pipera­ zine, and organophosphates. These drugs paralyze the ascarids, resulting in accumu­ lation of masses of the wom1s in the small­ intestinal lumen. It has been suggested that disruption of the surface of the ascarid releases antigenic fluids that inhibit intestinal muscular activity, thereby increasing the likelihood of intestinal obstruction. Clinical signs range from mild to severe abdominal pain, evidence of toxemia, and gastric reflux that may contain ascarids. Ascarid impaction should be suspected if the affected horse is a weanling or yearling, in poor condition, and has a recent history of deworming. Medical treatment with fluids and intestinal lubricants may be successful in some cases. Other horses may

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require surgical inteivention and removal of the ascarids through multiple enterotomies. The prognosis is guarded if surgery has to be performed. The owner should be advised that other young horses on the premises should be treated with anthelmintics that have lower efficacy against ascarids, such as fenbendazole. These initial treatments can then be followed with more efficacious compounds. Proximal Enteritis-Jejunitis: This poorly understood disease affects the proximal portion of the small intestine and has vaiious names, including proximal enteritis-jejunitis, anterior enteritis, and duodenitis-jejunitis. TI1e condition has been recognized in the southeastern and nmtheastem USA, England, and on the European continent. The cause is unlrnown. The affected intestine contains lesions varying from hyperemia to necrosis and infiltration of the submucosa with inflanm1atory cells. Often, there is edema and hemorrhage in the vaiious layers of the intestinal wall. Varying degrees of abdominal pain, ranging from mild to severe, are characteris­ tic. When U1e prevalence of the condition peaked in the 1980s, it was characterized by vol wninous amounts of gastric reflux, progression from pain to depression, and moderate to severe distention of the small intestine on rectal examination. In addition, the distended duodenwn often was palpated as it coursed around the base of the cecwn. The peritoneal fluid often contained an increased concentration of protein (>3 g/dL) with a normal nwnber of WBCs, but fuis finding did not consistently distinguish the condition from otl1er causes of small-intestinal disease. Based on a11ecclotal reports, the prevalence and clinical seve1ity of the condition have decreased, at least in regions of the USA where the condition characteiistically had a more severe course and was accompanied by a high incidence of laminitis. Treatment may be either medical or surgical. Medical treatment includes continued gastric decompression until the gastiic reflux abates, IV fluids, and analgesics, as required. Many cliniciai15 administer penicillin and low doses of flunixin meglumine; some also administer neostigmine, lidocaine, or metocloprainide to stimulate small-intestinal motility. Some surgeons, particularly in the UK, believe exploratory laparotomy and intestinal decompression result in a more rapid recovery. The survival rate associated with proximal enteiitis-jejunitis is reported to

be 44%. The horse's feet should receive particulai· attention because acute lanlinitis has been repmtecl as a common complica­ tion, with a prevalence of -25%. lntussusception: Most intussusceptions that develop in horses are jejuno-jejunal, ileal-ileal, or ileocecal. The length of intestine that has become invaginated (the intussusceptun1) into the more clistal segment of intestine (the intussuscipiens) may range from a few centimeters to as much as a meter. Although the precise cause of most intussusceptions remains specula­ tive, alterations in peristalsis due to enteritis, surgical trawna, pai·asite damage, anU1elmintics, andAnoplocephala pe,foliala infection have been suggested. Horses 180°. As the degree of the rotation increases, the vascular supply to

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COLIC IN HORSES the intestine is lost. Presumably because of its attachment to the cecum, the distal aspect of the volvulus is the ileum in most cases. Horses with small-intestinal volvulus have acute pain and an increased heart rate, a prolonged capillaty refill time, and gastric reflux. Because of the loss of fluid into the intestine and stomach, these horses rapidly become dehydrated and have increased PCV and plasma protein concentrations. The horse's status may dete1iorate rapidly because of hypovolemia at1d endotoxemia. Rectal exainination generally reveals turgid distended loops of small intestine, and the peritoneal fluid contains increased numbers ofWBCs and protein. Treatment involves surgical correction of the volvulus via a ventral midline celiotomy. lf the intestine is nonviable, it must be resected and an anastomosis performed. The prognosis for survival depends on the duration of illness and atnount of intestine that must be resected. Prognosis is good with early detection and surgery. Horses with a longer period of illness preopera­ tively, or those that develop postoperative ileus and peritonitis, are at increased risk of adhesion formation. It has been suggested that euthanasia is warranted if >500/o of the length of the small intestine must be removed. However, results of an experimen­ tal study in ponies indicated that removal of 700/o of the small intestine did not result in malabsorption provided the ponies were fed several (8) small pelleted meals each day. Pedunculated Lipomas: Colic due to pedunculated lipomas is seen in horses > 10 yr old. Pedunculated lipomas are suspended from the mesentery by a stalk or pedicle, which wraps around a segment of intestine, occluding the lumen of the intestine and interfering with its blood supply. The lipoma frequently forms a knot with the pedicle. Clinical signs range from depression to severe abdominal pain, gastric reflux, and rapid deterioration in metabolic status. Distended loops of small intestine ai·e palpable on rectal exan1ination and can be identified with abdominal ultrasonography; the lipoma can be felt per rectum in rare cases. The peritoneal fluid contains an increased munber ofWBCs and RBCs and an increased protein content. Treatment requires transection of the pedicle and, if necessaiy, resection of the devitalized intestine. The prognosis depends on the time between onset of clinical signs and surgery. If surgery is performed early, the prognosis is good; however, if surgery is not perfonned until

261

signs of cai·diovascular deterioration are present, the prognosis for survival is fair to poor. Internal Incarceration: The most conm1on sites for internal incai·cerations are mesenteric rents and the epiploic foratnen. Mesenteric rents are defects in the small-intestinal mesentery. Problems develop when a segment of small intestine passes through the mesenteric defect, and the intestine becomes incai·cerated. Because the intestine distends with fluid and blood, volvulus of the affected segment frequently occurs. Mesenteric rents causing intestinal incarceration occur in horses of all ages. The epiploic foramen is a natural opening bounded by the caudate lobe of tl1e liver, the portal vein, and the caudal vena cava. The distaljejunun1 and ileum ai·e the most common portions of the intestine that become incai·cerated through the epiploic foratnen. Although generally the intestine passes through the epiploic foran1en from left to right, tearing the omentwn in the process, it also may pass in the opposite direction to enter the omental bursa. It has been reported that horses > 7 yr old are affected most frequently by epiploic foratnen entrapment. However, tl1e condition also often develops in horses 15 yr old because of the increased risk of fatal hemotThage in aged horses given this drug. If left dorsal displacement of the colon recurs, the renosplenic space may be sutured closed laparoscopicaUy. Overall, the prognosis is good, with most studies rep01ting survival rates >800Ai. Right Dorsal Displacement: The left

colons move laterally around the base of the cecwn to lie between the cecum and the right body wall. With the most common form of this displacement, the pelvic flexure ends up positioned near the diaphragm. In many instances, the displacement may be complicated by twisting of the colon near the base of the cecwn. Although there may be some interference with venous drainage from the affected colon, usually the arterial supply remains intact. Most horses with right dorsal displace­ ments exhibit moderate degrees of pain, and there is slow development of systemic deterioration. In some cases, however, the pain may be severe. Rectal examination may reveal the taenia of the colon running transversely across the pelvic inlet. It may not be possible to palpate the ventral cecal band on rectal examination. Some horses with this condition have gastric reflux, preswnably due to occlusion of the lumen of the duodenun1. Some horses with this condition appear to be stable and may show intennittent signs consistent with mild abdominal pain. Treatment may be conservative, involving attention to fluid needs and administration of mild analgesics. For painful horses, however, surgery must be performed to locate the pelvic flexure, to exteriorize and decompress the left po1tion of the colon, if possible, and then to relocate the colon to its normal position by rotating it around the cecal base. The twisting of the colon must be identified and coITected. The prognosis for survival is good, provided that the colonic wall is not damaged during surgery.

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Right Dorsal Colitis: Right dorsal

colitis has been recognized with increasing regularity in recent years, particularly in, but not limited to, horses receiving excessive amounts of NSAIDs. Because the condition has been identified in horses receiving recommended doses of these drugs, it appears that some horses ar·e particularly sensitive to their toxic effects. The drug most commonly associated with right dorsal colitis is phenylbutazone, but this may reflect the common a11d often chronic use of this drug. The most common lesions reported in horses with right dorsal colitis are ulceration a11d thickening a11d/or fibrosis of the wall of the right dorsal colon. Horses commonly present with abdominal pain, a11orexia, a11d lethargy. In ma11y cases, the signs are consistent with severe abdominal pain, fever, endotoxemia, a11d dianhea. Horses with the more chronic form of the disease present with intermit­ tent abdominal pain, weight Joss, lethargy, a11d a11orexia. In most cases, hypoproteine­ mia is a common finding on hematology a11d may account for ventral edema in some horses with the chronic form of the disease. The diagnosis is usually based on the history, clinical signs, and hematologic findings. In some cases, ultrasonographic evaluation of the colon via the twelfth to fifteenth intercostal spaces may provide evidence of marked thickening of the colonic wall. Treatment of affected horses includes discontinuation of NSAIDs, rest, a11d a cha11ge in diet to a complete pelleted feed that contains 360°, there is

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strangulating obstruction of the entire left colon. The onset of colic is sudden, and the degree of pain may be mild to moderate if the volvulus results only in obstruction of the intestinal lumen. When the twist is more extensive, the pain is severe and the horse may not respond to analgesics. The colon is extremely enlarged, and the mesentery between the dorsal and ventral colons is edematous on rectal examination. The heart rate is rapid, the horse's condition deteriorates rapidly, and there is poor peripheral perfusion. Distention of tl1e abdomen usually is marked. Generally, results of peritoneal fluid analysis and the degree of colonic involvement are poorly correlated. Although the cause of colonic volvulus remains unknown, it is presumed to be associated with a disproportionate amount of gas in the colon. On brood­ mare farms, the condition frequently is associated with recent (within 90 days) or impending parturition, a grass diet, or highly fermentable feeds. The presence of a foal at the mare's side (recent history of parturition) is an additional risk factor. Treatment of colonic volvulus requires surgery to correct the volvulus and remove affected bowel, if necessary. Although the technique for removal of90% of the colon has been perfected in healthy horses, extreme difficulty can be encountered if the colon is edematous. Because the recurrence rate has been estimated to be as high as 20% in some clinical studies, colopexy pr0cedures have been devised to reduce the recurrence of the condition in broodmares. Although the results of a study involving several university hospitals reported a 27% survival rate, survival rates >85% are common for practices situated near broodmare farms.

Impaction and Foreign Body Obstruction of the Descending Colon: Abnom1alities involving tl1e

descending (small) colon are infrequent, accounting for 4-fold increase in antibody titer in paired serum san1ples obtained 2:2 wk

269

apart is necessary to verify recent infection. Isolation of BVDV from blood, nasal swab specimens, or tissues confirms active infection. Identification of persistent infection requires detection of virns in clinical specin1ens obtained at least 3 wk apart. Colostral antibody can impair the sensitivity of virns isolation in blood during the first weeks of life. At necropsy, tissues of choice for viral isolation include spleen, lymph node, and ulcerated segments of the GI tract. Alternatives to viral isolation include antigen-capture ELISA to detect virus in blood, serum, or tissue biopsies; immuno­ histochemistry to detect viral protein in frozen or fixed tissues; PCR to detect viral RNA in clinical specimens; and PCR or in situ hybridization to detect viral RNA in fresh or fixed tissues. Differentiation of viral genotypes and subgenotypes may be accomplished by PCR assays alone, or by PCR assays followed by analysis of nucleotide sequence, restriction frag­ ment analysis, or palindromic nucleotide substitution analysis. Monoclonal antibody binding assays and viral neutralization assays also differentiate viral genotypes. Treatment and Control: Treatment

of BVD remains limited primarily to suppo1tive therapy. Control is based on sound management practices that include use of biosecurity measures, elimination of persistently infected cattle, and vaccina­ tion. Replacement cattle should be tested for persistent infection before entry into the herd. Quarantine or physical separa­ tion of replacement cattle from the resident herd for 2-4 wk should be considered, and vaccination of replace­ ment cattle for BVD should be done before commingling with the resident herd. Embryo donors and recipients also should be tested for persistent infection. If vaccination of embryo donors or recipients is warranted, it should be done at least one estrous cycle before embryo transfer is performed. Because BVDV is shed into semen, breeding bulls should be tested for persistent infection before use. Artificial insemination should be done only with semen obtained from bulls free of persistent infection. Screening cattle herds for persistent infection can be done by PCR assays using skin biopsies, blood, or milk; by classical virus isolation metl10ds using serum or buffy coat cells; by antigen-capture ELISA using serum, buffy coat, milk, or skin biopsies; or by antigen detection using

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immunochemical methods on tissue or skin biopsies. Several strategies, based on herd size, type of herd being screened, financial limitations of the herd owner, and testing ability of the diagnostic laboratory being used, are available to screen herds for persistent infection. When identified, persistently infected cattle should be removed from the herd as soon as possible, and direct or indirect contact with pregnant cattle should be prevented. Inactivated and modified-live virus vaccines are available. They contain a variety of strains of BVDV representing both viral biotypes and viral genotypes 1 and 2. Antigenic diversity among BVDV may affect the efficacy of a given vaccine if the vaccine virus or viruses differ significantly from the challenge virus. Proper and safe immunization of cattle with either inactivated or modified-live virus vaccines requires adherence to the manufacturer's instructions. Because BVDV is fetotropic and irnmunosuppres­ sive, use of modified-live virus vaccines is not recommended in cattle that are pregnant or showing signs of disease. Inactivated viral vaccines may be used in pregnant cattle. Protection conferred by inactivated vaccines may be of short dw·ation, and frequent vaccination may be necessary to prevent disease or reproduc­ tive failure. Colostral antibody confers partial to complete protection against disease in most calves for 3-6 mo after birth. Vaccination of neonatal cattle tnat have acquired colostral antibody may not stimulate a protective in1mune response, and revaccination at 5-9 mo of age may be necessary. A booster dose of vaccine is often administered before first breeding, and additional booster doses of vaccine may be administered in sllbsequent years before breeding.

Jejuna! Hemorrhage Syndrome (Hemorrhagic bowel syndrome of cattle) Jejuna! hemorrhage syndrome is a sporadic disease of uncertain etiology that is observed with increasing frequency in cattle. It is manifest by sudden onset of abdominal pain, progressing to sternal recumbency, shock, and death.

Etiology and Pathogenesis: The etiology of jejuna! hemorrhage syndrome is uncertain but is believed to be multifacto­ rial. Clostridium peifringens type A, a normal inhabitant of the bovine digestive tract, has been incrinlinated as an important

causative agent, because this organism is isolated from the intestines of naturally occurring cases at a higher frequency and in higher numbers than from cattle with other intestinal diseases. Another proposed potential causative agent isAspergillus Jumigatus, a common fungus in feed and forages. The primary lesion is sin1ilar to that caused by C peifringe,is in young, rapidly growing animals and consists of an acute, localized, necrotizing, hemorrhagic enteritis of the small intestine that leads to develop­ ment of an intralunlinal blood clot. The clot causes a physical obstruction, with proximal accw11ulation of intestinal fluid and gas and development of hypochloremia, hypokalemia, dehydration, and varying degrees of anemia. The hemorrhagic enteritis is progressive. Ischemia and necrosis extends through tl1e intestinal wall, and within 24--48 hr, there is a fib1inous peritonitis, continued electrolyte imbal­ ance, profound toxemia, and death.

Epidemiology: Jejuna! hemorrhage syndrome occurs sporadically, primarily in mature lactating dairy cows in Nortl1 America and Europe, but it has also been recorded in beef cattle. Most cases occur in mature dairy cattle in tl1e first 3 mo of lactation, with highest incidence rates during the cold months of the year. Possible risk factors for disease are those associated with management practices aimed at achieving high milk production, such as high ferment­ able carbohydrate content of the diet and feeding a total mixed ration. The animal-level disease incidence rate is estimated to be 1o/c,-2"A,, but outbreaks in a herd can be associated with morbidity rates of;,,10%. Mortality in general is high, with 8(1>/c,--100% of affected animals dying within 48 hr. Clinical Findings: Cattle affected by jejuna! hemorrhage syndrome have a history of sudden anorexia and depression, a pronounced reduction in milk produc­ tion, abdominal distention and pain with kicking at the abdomen, and weakness progressing to recwnbency. Clinical findings include depression, dehydration, increased heart and respiratory rates, and pale mucous membranes. The abdomen may be moderately distended on the right side, the rwnen is atonic, and fluid sounds may be elicited by succussion over the right abdomen. Dark red blood clots may be fotmd in the feces and rectum. Distended and finn loops of intestine may be palpable on deep rectal examination. On laparot­ omy, a segment of the small intestine is dark red and distended, with a serosal

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INTESTINAL DISEASES IN RUMINANTS surface covered by tags of fibrin. The small intestine proximal to the affected segment and the abomasum are distended with gas and fluid. Ultrasonography may aid in diagnosis. Most affected cattle die witltin 2-4 days despite intensive fluid and electrolyte therapy. Sudden death without prior clinical findings may occur. The hemogran1 is variable; serum biochemistry reflects obstruction of the upper small intestine and sequestration of abomasal secretions with resultant hypokalemia and hypochlo­ remia. Lesions: Necrohemorrhagic jejunitis with intraluminal hemorrhage is severe. The affected segment of intestine is dark red and dilated, with tags of fibrin on the serosal surface. The lumen contains a firm blood clot adherent to the mucosa, and the affected segment of intestine is necrotic.

Diagnosis: Diagnosis of jejuna! hemor­

rhage syndrome can be made either during an exploratory laparotomy or at necropsy and is based on the presence of a character­ istic focal necrohemorrhagic enteritis of the distal small intestine. Differential diagnoses include other causes of physical or functional obstruction of the small intestine such as intussusception (seep 245), cecal dilatation and volvulus, and diffuse peritonitis (seep 670), from right-sided torsion of the abomasum (seep 238) and torsion at the root of the mesentery, and from diseases with melena such as abomasal ulcer (seep 241). Treatment and Control: Fluid and

electrolyte therapy and laparotomy with massage of affected bowel loops to break down obstructing blood clots and, in advanced stages, resection of the affected segment of the intestine are treatment options for jejuna! hemorrhage syndrome. Even with such treatment, the fatality rate is very ltigh, and the prognosis is grave. No preventive strategies have been identified. A short-term protective effect of a C perfringens type C and D vaccine against hemorrhagic bowel syndrome in some herds has been reported anecdotally, but there is currently no corroborating scientific evidence.

Winter Dysentery Winter dysentery is an acute, highly contagious GI disorder that affects housed adult dairy cattle, primarily during winter. Clinical features include explosive diarrhea

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(sometimes accompanied by dysentery), a profound drop in milk production, variable anorexia and depression, and mild respiratory signs such as couglting. The disease has a ltigh morbidity but low mortality, and spontaneous recovery witltin a few days is typical. Etiology: Although the precise etiology of

winter dysentery has not been conclusively confirmed, an increasing body of evidence implicates a bovine coronavirus (BCoV), closely related to the virus that causes diarrhea in neonatal calves. Evidence for BCoV as the cause of winter dysentery includes the following: 1) clinical signs and pathologic findings are consistent with disease induced by BCoV, 2) seroconversion to BCoV has been demonstrated in affected cattle, 3) the virus is frequently isolated from diarrheic feces of cattle that exhibit clinical signs of winter dysentery, and 4) the disease has been reproduced by briefly exposing BCoV seronegative, lactating cows to a calf experimentally infected with feces from cows with winter dysentery. Notwithstanding, it has not been possible to consistently reproduce winter dysentery through oral inoculation of adult cattle witll BCoV. Concun·ent risk factors, such as changes in diet, cold temperatures, closed confinement with ltigh anin1al density, poor ventilation, and presence of other microo1° ganisrns, may be required before BCoV causes clinical disease in adult cattle. Transmission, Epidemiology, and Pathogenesis: BCoV is transmitted via

tile fecal-oral route through ingestion of feed or water contanlinated witll feces from clinical cases or clinically healthy carrier animals. Viral particles present in respira­ tory secretions of affected aninlals may furtller enhance transmission. Transmission of disease is promoted by close confine­ ment. Winter dysentery is highly contagious and easily introduced to barns by visitors, carrier animals, and fornites. Winter dysentery is common in northern climates where animals are housed indoors for extended periods during tile winter months. It is seen frequently in the northern USA, Canada, the UK, Europe, Australia, New Zealand, Israel, and Japan. Coronaviruses survive best at low temperatures and at low ultraviolet light intensities, which can lead to a buildup of virus in the environment during tile colder montlls. Adult lactating cows tllat have recently calved are most severely affected, but tile disease can affect younger or older aninlals and males. Mortality rates associated with winter

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dysentery are generally low (1%-2%), but morbidity in affected herds is high, with 20%---500Ai of the animals in a herd exhibiting clinical signs within a few days, and close to lOQOA, of animals in the herd exhibiting signs within a week. Some degree of immunity to winter dysentery appears to develop, because recurrences, if seen in the san1e herd, are noted at 1- to 5-yr intervals. Inflan1111atory mediators that cause hypersecretion in the small intestine and colon are thought to contribute to the volmninous dianhea seen in cattle with winter dysentery. In addition, destruction of epithelial cells in the colonic crypts results in transudation of extracellular fluid and blood, explaining the hemorrhagic nature of the diarrhea in some cases. Clinical Findings: Winter dysentery is

characterized clinically by an acute onset of fluid diarrhea and a profolll1d decrease in milk production (25o/e>-95%production loss). Feces are liquid and homogenous with little odor, dark green to black, and may contain blood (typically in first-lactation heifers) or mucus. A sweet, musty, lll1pleasant odor is reported in bams with large nmnbers of affected cattle. Nasolacrin1al discharge or cough may accompany or precede the diarrhea Other signs include mild colic, dehydration, depression, a brief period of anorexia, and some decrease in body condition. Occasionally, animals exhibit more severe signs such as passage of feces with variable amolll1ts of blood, severe dehydration, and weakness. Fatalities are rare. Diarrhea in individual anin1als has a short course, and feces return to normal in 2-3 days in most animals. Disease in the herd typically subsides in 1-2 wk, but milk production may take weeks to months to return to nom1al. Lesions: The small intestine may be dilated and flaccid. Lesions are p1imarily seen in the large intestine and consist of cecal and colonic mucosa! hyperemia, linear streaks or pinpoint-sized hemor­ rhages mostly along the colonic mucosa! ridges, and blood in the Iumen of the large intestine. Histologic findings may include widespread degeneration and necrosis of colonic glandular epithelimn. Diagnosis: A diagnosis of winter dysentery can be confirmed by demonstrat­ ing coronaviral particles in fecal san1ples via ELISA or electron microscopy. Seroconver­ sion to coronavi.tus in acute and convales­ cent seflll11 samples, taken 8 wk apart, also helps confirm the diagnosis.

Differential diagnoses for acute diarrhea in adult cattle include bovine viral diarrhea (BVD), enteric salrnonellosis, and coccidio­ sis. These diseases can be excluded by absence of mucosa! lesions (BVD), negative fecal cultures (Salmonella spp), and negative fecal flotation (coccidiosis), as well as by the characteristic clinical presentation of winter dysentery (rapid onset of diarrheal disease of short duration in a herd with high morbidity but low mortality). Treatment and Control: Most cattle affected by winter dysentery recover spontaneously. Fresh water, palatable feed, and free-choice salt should be available at all tin1es. The use of astringents, protect­ ants, and adsorbents is controversial. IV fluid therapy or blood transfusions may be required in severely affected cattle. There is no vaccine for winter dysentery. Isolation of newly introduced cattle for 2 wk and isolation of any adult cow with diarrhea is advised to decrease the likelihood of disease introduction into a herd. In an outbreak, access to the premises should be restricted, and all persons in contact with affected cattle should ensure that their footwear and clothing are clean before leaving an affected faim. Other Intestinal Diseases of Cattle

Infection with Salmonella spp (see p 195) can produce diarrhea in animals of all ages, especially those that ai·e stressed, closely stocked, or exposed to a heavily containi­ nated feed or water supply. In older animals, the disease is manifest by dysentery and toxemia, and mortality can be significant. Rotavirus and coronavirus occasionally cause outbreaks of dianhea in suckling calves up to 2-3 mo old. The feces are vollll11inous and may contain mucus. Toxemia is not evident and mortality is negligible, but growtl1 is decreased. (See also D!ARRIIEA IN NEONATAL RUM[NANTS, p 275.) Necrotic enteritis of lll1known etiology is seen in beef cattle 5-12 wk old, commonly affecting several calves within the herd. There is sudden onset of fever, depression, and profuse diarrhea. The feces are initially dai·k green, contain blood, and frequently stain the perinelll11. Circulai· erosions may be present in the oral mucosa. A proportion of calves recover after a clinical course of 3-5 days. The clinical course is longer in fatal cases; animals have scant mucohemor­ rhagic feces that are passed with tenesmus and develop a severe non.regenerative leukopenia. A secondary fibrinous broncho-

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INTESTINAL DISEASES IN RUMINANTS

pneumonia may develop. Mortality is high despite intensive antibiotic treatment. At necropsy, there is ulcerative necrosis of the terminal small intestine and the large intestine. Coccidiosis (see p 205) usually is seen in calves >2 mo old but< 1 yr old, especially in situations of heavy stocking density and overgrazing. It is characterized by dysentery and tenesmus and may be accompanied by nervous signs. Intestinal helminthiasis, particularly ostertagiosis (seep 308), is seen in cattle of the same age group. Type I ostertagiosis is seen in cattle on pasture, but Type II ostertagiosis may be seen in housed animals. Explosive outbreaks of diarrhea in mature cattle are associated most commonly with winter dysentery (seep 271) but also with salmonellosis when there is heavy contamination of feed or water. Chronic diarrhea and wasting often in combination with good appetite, occun·ing as a sporadic disease in adult catUe is typical for paratuberculosis (seep 762). Chronic diarrhea and wasting also occurring in younger animals may be caused by chronic salmonellosis and chronic BVD infection. Other possible causes of chronic diarrhea include congestive heart failure, uremia, and chronic peritonitis. Persistent diarrhea with unthriftiness, and occasionally wasting in yearling and mature cattle, can be associ­ ated with a secondary copper deficiency due to excess molybdenum in the pastures. Diarrhea may also accompany selenium­ responsive ill-tluift syndromes in growing cattle. Individual cases or outbreaks of diarrhea may be associated with dietary indiscre­ tions. Diarrhea may follow cases of simple indigestion and is common in grain overload (seep 222). It also follows ingestion of toxic amow1ts of chemicals (eg, arsenic, copper, zinc, and molybdenum) or certain poisonous plants and mycotoxicoses; dipyridyl and organophosphate poisoning can also cause diarrhea. Cattle may also harbor organisms such as Escherichia coli 0157:H7, Yersinia enterocolilica, and Campylobacterjejuni in the intestine; although these are rarely associated with clinical disease in cows, fecal contamination of milk may lead to outbreaks of gastroenteritis in people who consume unpasteurized milk or cheese products. Retail meat products can also be infected if there has been fecal contamina­ tion of the carcass at slaughter. Intestinal adenocarcinoma, commonly seen in association with bovine enzootic hematuria, is believed to result from the

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interaction of a carcinogen (ptaquiloside) in bracken fem (Pt.eridium spp, seep 3089) and papilloma virus. Intestinal obstructions are seen sporadically (seep 245). Cecal dilatation and volvulus are seen predominantly in adult cattle in the postparturient period. Intussusception occurring at the distal jejunum or proximal ilew11 is the most common cause of complete obstruction in both adult cattle and calves. Ileocecocolic, cecocolic, and colonic intussusceptions are seen less frequently in calves and not at all in adult cattle because of the greater strengtl1 of tlle ileocecal ligan1ent and the presence of mesenteric fat, which stabilize this region of the bowel in older cattle. Intestinal volvulus and volvulus around the mesenteric root are seen sporadically at all ages. Rarely, intestinal obstruction is caused by incarceration and entrapment of the small intestine by persistent urachal or wnbilical remnants, by obstruction of the small intestine or descending colon by phytobezoars and enteroliths, or by compression from fat necrosis or lipoma. Intestinal obstruction can also be caused by congenital disease (seep 168), most commonly by atresia coli (which is seen botll sporadically and in clusters on a farm and may be caused by rectal palpation of tlle anlniotic vesicle at 35 and 41 days of pregnancy) but also by atresia ani (which may be accompanied by urogenital defects and defects of the tail).

INTESTINAL DISEASES IN SHEEP AND GOATS The causes and circw11stances of diarrhea in neonatal lambs and kids are sinillar to tllose in newborn calves. Intensive lambing practices and shed-lambing increase the potential for disease and buildup of infectious agents and can be associated with serious outbreaks of diarrhea. The serotypes of enteropathogenic Escherichia coli tllat cause secretory diarrhea in calves also do so in lan1bs, and the approach to diagnosis, treatment, and control is sinlilar. Sinlilarly, rotavirus, coronavirus, and cryptosporidia (see p 209) also cause outbreaks of diarrhea in lambs. (See also DIARRHEA IN NEONATAL RUMINANTS, p 275.) Lamb dysentery caused by Clostridium perfringens type B (see p 609) is a distinct intestinal disease of lambs in the first week of life. It is seen principally in hill breeds of sheep in the UK and is characterized by sudden death or diarrhea, dysentery, and toxemia. In tlle USA, C pe,jringens type C causes a similar

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syndrome. Watery mouth or rattle belly (see below), a disease of uncertain etiology associated with failme of transfer of passive immunity, is seen predominantly in the UK. Coccidiosis (seep 206) and GI helminthia­ sis (seep 312), except for haemonchosis, are in1portant causes of diarrhea in older nmsing and weaned sheep. Terminal ileitis and villous atrophy, both of unknown etiology, are often present in the intestine of lambs culled because of poor growth. GI helminthiasis is the most conunon cause of diarrhea in pastmed sheep. Coccidiosis develops in association with overstocking or intensive indoor housing and poor sanitation. Salmonellosis (see p 195) can cause diarrhea in all ages; the circumstances in y0tmg lan1bs are similar to those in calves. It also can cause outbreaks of diarrhea late in pregnancy and is frequently accompanied by abortion. Salmonellosis is more conunon when sheep or goats are congregated intensively or stressed, particularly by shipping. Yersinia pseudotuberculosis and Y enterocolitica have both been associated with enterocoli­ tis and diarrhea in young sheep at pastme that are debilitated from factors such as starvation and cold weather. Diarrhea may be present in bluetongue in sheep (see p 738) and is accompanied by typical mucosa! lesions. In goats, diarrhea is often prominent in enterotoxemia associated with C perfringens type D (seep 610). This is not a feature of the clinical disease in sheep but may be present in flockn1ates of affected sheep. In feedlot sheep, diarrhea most conunonly is associated with grain overload, salmonellosis, 0r coccidiosis. Other intestinal diseases of adult sheep may manifest with diarrhea. Infection with C perfringens type C (strnck, seep 609) manifests with abdominal pain, J;enesmus, and rapid death. Intestinal obstruction due to intestinal accidents occms sporadically but is usually not seen clinically. Sheep with paratuberculosis (seep 762) usually show progressive emaciation without diarrhea Progressive emaciation also is the primary sign in adult sheep with intestinal adenocar­ cinoma, which can be prevalent in certain areas, associated with ingestion of bracken fem (seep 3089).

Watery Mouth Disease in Lambs (Slavery mouth, Slavers, Rattle belly)

Watery moutl1 disease is a condition of intensively reared lambs occmring dming the first days of life. Morbidity in a flock can be as high as 30"Ai, and the mortality rate may exceed 80"Ai.

Etiology and Pathogenesis: Watery mouth disease has been associated with ingestion of gram-negative bacteria, particularly E coli, that smvive in the neonatal GI tract and translocate from the gut to the bloodstrean1. The strains involved are K99 antigen negative and regarded normally as nonenteropathogenic and nonenterotoxigenic. The resultant bacteremia may be tolerated by the lamb, but > 104 colony-forming units/mL are associated with release of free endotoxin, and endotoxic shock develops rapidly. Lambs 12-72 hr old with inadequate or delayed access to colostrum are at greatest risk Otl1er risk factors that have a negative effect on colostrum intake include being born in larger litters, being born to a dan1 with poor body condition, and stressors such as early castration. Clinical Findings: Lambs affected with watery mouth disease are hypothermic, dull, stop feeding, and, classically, have long strings of saliva drooling from the mouth. Less obvious cases may have a wet muzzle; others may show no external signs of excess salivation, but the mouth may be cold to the touch and contain frothy saliva. Lacrimation may also be seen. The abomaswn may become distended with gas and liquid, giving the deceptive appearance of a well-fed Jamb, but if these lan1bs are lifted and shaken gently, a noise associated with the alternative nan1e of "rattle belly" may be heard. Although scoms occasionally occm, this is not a characteristic featme of the condition. Lesions: Necropsy may reveal a bloated and inflamed GI tract, retained meconiun1, pale kidneys and muscle, dehydration, and enlarged and reactive mesenteric lymph nodes.

Diagnosis: Biochemical and hematologic changes and necropsy findings in lambs affected with watery mouth disease are consistent with endotoxemia and the clinical diagnosis of endotoxic shock Terminally, lambs develop endotoxemia, leukopenia, severe hypoglycemia, lactic acidemia, and metabolic acidosis. Differential diagnoses include joint ill or navel ill, hypothern1ia, primary starvation, and infectious enteritis. Treatment: There is no specific treatment for watery mouth disease. Parenteral antin1icrobial and anti-inflan1matory therapy combined with oral rehydration are essential; 50-200 mL of an

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INTESTINAL DISEASES IN RUMINANTS electrolyte and 5o/e>--l0% glucose solution containing a water-soluble antibiotic (neomycin and/or streptomycin) given tid by stomach tube will help maintain hydration and provide energy. Systemic antimicrobial therapy with a gram-negative spectrum and anti-inflan1matory therapy with NSAIDs or c01ticosteroids to counteract the effects of endotoxemia should also be administered. Purgatives or enemas may help overcome gut stasis and expel the infecting bacteria. Treatment should be continued until signs resolve and the lamb is sucking again. Boosting body temperature by external warming may also be required. However, such ca.re is time­ consuming and expensive and carries no guarantee of success. Prevention: Ewes should be well nourished to ensure a plentiful supply of colostrum. Yards, pens, ewes, and equipment should be kept as clean as possible throughout lambing to help control the buildup of E coli and keep the incidence of disease low. Supplementary feeding of lambs using stored colostrun1 (ewe, cow, or goat) or commercial colostrum substitute should provide a minin1Um of 50 mUkg within 6 hr of birth. Lambs should not be castrated in the first 24 hr because this depresses colostrum intake. In controlled experiments, a single dose of oral antibiotic given within 2 hr of birth to colostrum-deprived lambs delivered into a contan1inated indoor environment was as effective as ewe colostrum in preventing neonatal disease and death in all lambs up to 3 days old, despite the absence of maternal antibodies. Thus, antibiotic treatment can provide simple, quick, and inexpensive protection against watery mouth disease and is an attractive option for the busy sheep farmer. However, it is important that such treatment be targeted to lambs in the high-risk categories specified above, because indiscriminate dosing may encourage antibiotic resistance.

DI ARRHEA IN NEONATAL RUMINANTS (Scours) Diarrhea. is common in newborn calves, lambs, and kids. The clinical presentation can range from mild diarrhea without systemic disease to profuse, acute diarrhea associated with rapid dehydration, severe disturbance of acid-base and electrolyte balance, and death, sometimes in as few as

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12 hr. This discussion emphasizes the disease in calves, but the principles of pa.thophysiology and treatment apply to lambs and kids as well. Etiology: Several enteropathogens a.re associated with diarrhea. in neonates. Their relative prevalence varies geographically, but the most prevalent infections in most areas are Escherichia coli, rotavirus, corona.virus, and Cryptosporidium parvum. Cases of neonatal diarrhea. are commonly associated with more than one of these a.gents, and the cause of most outbreaks is multifa.ctorial. Determining the particular a.gents associated with an outbreak of diarrhea. can be important, because specific therapy and prophylaxis are available for some. Also, some a.gents have zoonotic risk. Diarrhea. is also present in septicemic colibacillosis. Bacteria: E coli is the most important bacterial cause of diarrhea in calves during the first week of life; at least two distinct types of diarrheal disease are produced by different strains of this organism. One type is associated with enterotoxigenic E coli, which has two virulence factors associated with production of diarrhea. Fimbrial antigens enable them to attach to and colonize the villi of the small intestine of neonatal calves in the first days of life. Strains in calves most commonly possess K99 (F5) or F41 fimbrial antigens, or both. These antigens are the focus of immuno­ logic protection. Enterotoxigenic E coli also elaborate a thermostable, nonanti­ genic enterotoxin (Sta) that influences intestinal ion and fluid secretion to produce a noninflammatory secretory diarrhea.. Diarrhea. in calves and lambs also has been associated with enteropathogenic E coli that adhere to the intestine to produce so-called attaching and effacing lesions, with dissolution of the bmsh border and loss of microvillous structure at the site of attachment, a decrease in enzyme activity, and changes in ion transport in the intestine. These entero­ pa.thogens are also called "attaching and effacing E coli." Some produce verotoxin, which may be associated with a more severe hemorrhagic diarrhea.. The infection most frequently is in the cecum and colon, but the distal small intestine can also be affected. The dan1age in severe infections can result in edema and mucosa! erosions and ulceration, leading to hemorrhage into the intestinal lumen. Salmonella spp, especially S Typhimu­ rium and S Dublin, but occasionally other serova.rs, cause diarrhea. in calves 2-12 wk

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Enterotoxigenic Escherichia coli adhering to the intestine of a 2-day-old calf. Courtesy of Dr.

J. J. Hadad and Dr. Carlton Gyles.

Corona.virus is also conunonly associated with diarrhea in calves. It replicates in the epitheliun1 of the upper respiratory tract and in the enterocytes of the intestine, where it produces similar lesions to rota.virus but also infects the epithelial cells of the large intestine to produce atrophy of the colonic ridges. Other viruses, including Breda virus (torovirus), a calici-like virus, astrovirus, and parvovirus, have been demonstrated in the feces of calves with diarrhea and can produce diarrhea in calves experimentally. However, these agents have also been found in the feces of healthy calves. The impor­ tance of these agents in the syndrome of diarrhea in neonates has yet to be deter­ mined. The viruses of bovine virus diarrhea and infectious bovine rhinotracheitis are reported to cause calf diarrhea, but this is not a conunon manifestation of these infections. Protozoa:

Oryplosporidium parzrnm

old. Salmonellae produce enterotoxins but are also invasive and produce inflammatory change within the intestine. In calves, infection commonly progresses to a bacteremia. (See also SALMONELLOSIS, p 195.) Clostridium pe1fringens types A, B, C, and E produce a variety of necrotizing toxins and cause a rapidly fatal hemorrhagic enteritis in calves. The disease in calves is rare and usually sporadic. Infection with type B or C is a common cause of enteritis. and dysentery in lambs (seep 609). Campylobacte1-jejuni and Ye1·sinia ente1-ocolitica may be present in the feces of calves and lambs with diarrhea but also may be found in the feces of healthy animals.

(see p 209) is a common cause of diarrhea in calves and lambs. The parasite does not invade but adheres to the apical surface of enterocytes in the distal small intestine and the colon. This results in loss of microvilli, decreased mucosa.I enzyme activity with villous blunting and fusion Oeading to a reduced villous surface absorptive area), and inflanm1atory changes in the submu­ cosa. Mammalian cryptosporidia lack host specificity. Giardia duodenalis is a common asymptomatic infection in the intestine of young calves and lambs. It has been found in the feces of poorly growing calves that have a chronic mucoid diarrhea, but there is little evidence for a causative association of this organism with diarrhea in calves or lambs.

Viruses: Rota.virus is the most common viral cause of diarrhea in calves and lambs. Groups A and B rota.virus are involved, but group A is most prevalent and clinically important and contains several serotypes of differing virulence. Rota.virus replicates in the mature absorptive and enzym e -produc­ ing enterocytes on the villi of the small intestine, leading to rupture and sloughing of the enterocytes with release of virus to infect adjacent cells. Rota.virus does not infect the inlITlature cells of the crypts. With virulent strains of rota.virus, the loss of enterocytes exceeds the ability of the intestinal crypts to replace them; hence, villous height is reduced, with a consequent decrease in intestinal absorptive surface area and intestinal digestive enzyme activity.

Other Causes: Calves fed large amounts of milk or inappropriately formulated milk replacers produce a large volume of feces with a greater than normal fluid content but do not have a fluid diarrhea with weight loss. Similarly, calves sucking high-producing beef cows grazing lush pasture may have loose feces. Milk replacers with poor quality, heat-denatured proteins or with excessive amounts of soybean or fish protein or carbohydrates of nonrnilk origin have a higher risl5 of producing diarrhea. There is some evidence that oral administration of chloramphenicol, neomycin, or tetracycline to young calves for 3-5 days can result in villous change with resultant malabsorption and mild diarrhea. Prolonged and high-dose antibiotic

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INTESTINAL DISEASES IN RUMINANTS

treatment of calves can lead to diarrhea associated with bacterial superinfection of the intestine. Colisepticemia (see p 749) and rnminal drinking (see p 236) can also be accompanied by diarrhea Epidemiology and Transmission:

Enteropathogens associated with diarrhea are conunonly found in the feces of healthy calves; whether intestinal infection leads to diatThea depends on a number of determi­ nants, including differences in virulence of different strains of a pathogen and the presence of more than one pathogen. The resistance of the calf is of major importance ai1d is lai·gely determined by successful passive transfer of colostral inununoglobu­ lins. Colostturn-deprived calves are highly susceptible to infection with enteropatho­ gens and develop severe and often fatal disease. The progression of infection, the severity of lesions produced, and the severity of the diarrhea can be modulated by immuno­ globulins received via colostrum. Immuno­ globulins act directly on pathogens in the intestinal lumen during the period of colostrum ingestion as well as after, because significant an10unts of circulating inununoglobulins are re-secreted into the intestine, especially when the concentra­ tion of circulating irnmunoglobulin is high. The lack of specific antibodies in dains that have not been exposed to specific pathogens, and the use of specific vaccines, further modulate this influence. Stress caused by a poor environment, inadequate protection from the weather, or an insufficient or inappropriate diet also increases the risk of disease. With all of the enteropathogens, healthy adult cattle may be carriers and periodically excrete the organism in feces. Excretion may increase around parturition and be more frequent in prinuparous cows. This can lead to conta.tninated calving areas and infection of the udder and perineum of the da.tn. Other sources of infection include the feces of healthy calves and the feces of diarrheic calves, which contain large numbers of organisms early in the course of infection. A few scouring calves can result in severe contamination of the calf-rearing ai·ea. Transmission is by fecal-oral contact, fecal aerosol, and, in the case of coronavi­ rns, by respiratory aerosol. Pathogenesis: Diarrhea in neonatal tuminants is usually associated with disease of the small intestine and can be caused by hypersecretion or malabsorption. Hyper­ secretory diarrhea develops when an

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abnormal ainount of fluid is secreted into the gut, exceeding the resorptive capacity of the mucosa. In malabsorptive diarrhea, the capacity of the mucosa to absorb fluid and nutrients is impaired to the extent that it carmot keep up with the normal influx of ingested and secreted fluids. This is usually the result of villous atrophy, in which the loss of mature enterocytes at the tips of the villi results both in a decrease in villous height (with a consequent decrease in the swface ai·ea for absorption) and in loss of the brush border digestive enzymes. The extent and distribution of villous atrophy varies with different pathogens and can explain variation in the severity of clinical disease. Malabsorptive diarrhea may be aggravated by the colonic fermentation of nutrients that nom1ally would have been absorbed in the small intestine. Fermenta­ tion products, especially lactic acid, appear to draw water into the colon osmotically, which contributes to the severity of diarrhea. Inflammation contributes to the pathophysiology of diarrhea in most intestinal infections, and mediators of inflanunation can affect ion flux within the intestine. Inflammation also leads to vascular and lymphatic dainage and to structural dan1age of the crypt-villus unit. Most infectious forms of dian·hea have hypersecretory, inflanunatory, and malabsorptive components, although one usually predominates. These lead to a net loss of water, sodium, potassium, and bicarbonate; if severe, the calf develops hypovolemia, hyponatremia, acidemia, and prerenal azotemia. Enterotoxigenic E coli produce the enterotoxin Sta, which stimulates marked hypersecretion by activating guanylate cyclase and by inducing a net secretion of sodiwn and chlorine. The membrane-bound sodiwn-glucose cotransport system remains functional but carmot compensate for the increased secretory activity. Salmonellae also elaborate enterotoxins. Inflanunation, leading to necrosis of the enterocyte, submucosal inflanunatory infiltration, and villous atrophy, is also a major component of the pathophysiology of diarrhea produced by salmonellae, as well as of diarrhea produced by enteropathogenic E coli and by toxigenic C perfringens. Infections with verotoxin-producing enteropathogenic E coli result in accumula­ tion of fluid within the large intestine ai1d extensive dainage to the large intestinal mucosa, with edema, hemorrhage, and erosion and ulceration of the mucosa, which results in blood and mucus in the lumen.

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Viruses usually produce a malabsorptive diarrhea by destroying the absorptive cells of the mucosa, thus shortening the intestinal villi. The mechanism by which crypto­ sporidia produce diarrhea is not completely understood, but it appears to have both malabsorptive and inflammatory compo­ nents. Inappropriately formulated milk replacers produce diarrhea by two mechanisms, both associated with malabsorption. Vegetable (especially soybean) products are commonly used as protein sources in the manufacture of milk replacers. Depending on the degree of refinement, these products may contain carbohydrates that are indigestible in young calves. Such carbohydrates are not absorbed in the small intestine and may cont1ibute to diarrhea via colonic fennent a ­ tion. In addition, most calves 2 in. (5 cm) are favorable for development of the free-living stages of H placei, but where wide fluctuations occur, a mean minimum temperature of 50°F ( 10°C) may effectively limit development. The preparasitic forms of O ostertagi and T axei develop and survive better in cooler conditions, and their upper limits for sur­ vival are lower than those for H placei. If the ten:iperature is unfavorable or drought conditions eXIst, infective larvae may remain dormant in the feces for weeks until conditions become favorable again eg after heavy rainfall, when large numbers' of infective larvae emerge onto the surround­ ing grass. The prepatent period of O ostertagi is normally -3 wk. Ingested larvae enter the lumen of the abomasal glands and molt by the fourth day; they remain there during the prepatent period, growing and undergoing a final molt before emerging as young adult

Abomasal lesions due to Ostertagia. Courtesy of Or. Sameeh M. Abutarbush.

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GASTROINTESTINAL PARASITES OF RUMINANTS worms from the gastric glands onto the abomasal mucosa. During this time, the specialized cells (pepsinogen-producing zymogen cells, acid-producing parietal cells) lining parasitized glands are lost and replaced by hyperplastic, undifferentiated cuboidal cells, resulting in nodules that may be discrete or confluent. Around the time of worm emergence, the changes seen in parasitized glands also appear in neighbor­ ing nonparasitized glands, rapidly extending the effects of the parasite burden. As a result, in heavy infections, abomasal pH may rise from 2 to >6; from a clinical viewpoint, when pH rises above 4.5, digestion in the abomasum ceases. A protein-losing gastropathy results and, together with anorexia and impaired protein digestion, leads to hypoproteinemia and weight loss. Diarrhea is persistent. In Type I ostertagiosis, which results from recent infection, most worms present are adults, and the response to anthelmintic treatment is good. Type I disease is seen primarily in calves 7-15 mo old. It is most common from time of weaning and ensuing months in warm temperate regions and in young cattle during summer and early fall in cool temperate regions. In Type II ostertagiosis, large numbers of larvae, which had become dormant or inhibited in development at the early fomth larval stage, emerge from the glands weeks or months later. This is seen primarily in cattle 12-20 mo old. In warm temperate regions, inhibition-prone larvae are acquired in spring, and disease may result when large numbers of larvae resume development to the adult stage in late summer or fall. In cold temperate regions, inhibition-prone larvae are acquired during late autumn and mature during late winter or early spring. Larval inhibition in O ostertagi and other nematodes is thought to be analogous to diapause in insects. It has been interpreted as a survival mechanism in which the preparasitic stages on pasture avoid the adverse conditions of winter in cool regions and of hot and dry (or hot and alternately wet and dry) conditions of many warm regions. The factors that cause and later "switch off'' inhibition are not completely known, but prolonged experimental cold conditioning of infective larvae was found to be in1portant in a cool temperate region. In warm regions of both northern and southern hemispheres, conditioning of preparasitic stages to inhibition develops principally during spring before the hot and dry conditions of sun1mer. The resumed development or maturation of the parasites is likely to be genetically predetemiined and may be influenced by

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parturition, nutrition, concurrent infection, and host immune response. H placei may also become inhibited over winter; they then resume development in the spring and infect the pastures with eggs at a time suitable for their development. Both the larval and adult stages are patho­ genic because of their blood-sucking ability. T axei causes gastritis with superficial erosion of the mucosa, hyperemia, and diarrhea. Protein loss from the damaged mucosa and anorexia cause hypoproteine­ mia and weight loss. Inhibition does not occur to the same degree.

Clinical Findings: Yom1g animals are more often affected, but adults not previously exposed to infection frequently show signs and succumb. Ostertagia and Trichostrongylus infections are character­ ized by profuse, watery diarrhea that usually is persistent. In haemonchosis and Mecistocirrus infection, there may be little or no diarrhea but possibly intermittent periods of constipation. Anemia of variable degree is a characteristic sign of both these infections. Concurrent with the diarrhea of O oste rtagi and T axei infections, and with the anemia of heavy Haemonchus infection, there is often hypoproteinemia and edema (rare in O ostertagi infections), particularly under the lower jaw (bottle jaw) and sometimes along the ventral abdomen. Heavy infections can result in death before clinical signs appear. Other variable signs include progressive weight loss, wealrness, rough coat, and anorexia. Lesions: WomlS can readily be seen and identified in the abomasum, and small petechiae may be visible where the wornlS have been feeding. The most characteristic lesions of Ostertagia infection are small, umbilicated nodules 1-2 mm in dian1eter. These may be discrete, but in heavy infections they tend to coalesce and give rise to a "cobblestone" or "morocco leather" appearance. Nodules are most marked in the fundic region but may cover the entire abomasal mucosa and may be accompanied by a rise in gastric pH to 6---7. As a result, pepsinogen will no longer be converted to pepsin and may leak across the damaged epithelium, leading to high plasma levels. TI1ere is also evidence that adult Ostertagia can cause direct hypersecretion of pepsino­ gen. The increased abomasal pH may also stin1ulate production of gastrin and thus hypergastrinemia, which is closely associated with the inappetence that may accompany infection. Tilis parasite-associated drop in

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intake has been shown to be largely responsible for impaired weight gain. Edema is often marked and, in severe cases, may extend over the abomasum and into the small intestine and omentW11. In T axei infections, the mucosa of the abomasum may show congestion and super­ ficial erosions, which are sometimes covered with a fibrinonecrotic exudate. Diagnosis, Treatment, and Control:

Seep303 et seq.

Cooperiaspp

Several species of Cooperia are found in the small intestine of cattle; C punclala, C oncophora, and C peclinata are the most common. The red, coiled adults are5-8 mm long, and the male has a large bmsa. They may be difficult to observe grossly. Their life cycle is essentially the same as that of other trichostrongylids. These worms apparently do not suck blood. Most of them are found in tl1e first10---20 ft (3----6 m) of the small intestine. The prepatent period is12-15 days. The eggs usually can be differentiated from those of the common GI nematodes by their practically parallel sides, but a larval cultme of the feces is necessary to definitively diagnose Cooperia infection in the living animal. ln heavy infections with C punclala and C peclinala, there is profuse diatThea, anorexia, and emaciation, but no anemia; the upper small intestine shows marked congestion of the mucosa with small hemorrhages. The mucosa may show a fine lace-like superficial necrosis. C oncophora produces a milder disease but can be responsible for weight loss and poor productivity. It is usually necessary to make scrapings of the mucosa to demonstrate Cooperia spp, which must be differentiated from Trichoslrongylus spp, Strongyloides papillosus, and in1matme Nemalodirus spp. For diagnosis, treatment, and control, see p303 et seq. Bunostomum sp

The adult male Bunoslomum phlebolo­ mum is -15 mm long and the female -25 mm. Hookwom1s have well-developed buccal capsules into which the mucosa is drawn; cutting plates at the anterior edge of the buccal capsule are used to abrade the mucosa dming feeding. The prepatent period is -2 mo. Infection is by ingestion or skin penetration; the latter is more common in animals kept in poor conditions. Larval penetration of the lower limbs may cause uneasiness and statnping, particularly in stabled cattle. Adult wom1s cause anemia

and rapid weight loss. Diarrhea and constipation may alternate. Hypoproteine­ mic edema may be present, but bottlejaw is rarely as severe as in haemonchosis. Dming tl1e patent period, a diagnosis may be made by demonstrating the characteristic eggs in the feces. On necropsy, the mucosa may appear congested and swollen, with numerous small hemorrhagic points where the worms were attached. The worms are readily seen in the first few feet of the small intestine, and the contents are often blood-stained. As few as 2,000 worms may cause death in calves. Local lesions, edema, and scab fom1ation may result from penetration of larvae into the skin of resistant calves. For diagnosis, treatment, and control, see p303 et seq.

Strongyloides sp

The intestinal threadworm Strongyloides papillosus has an wmsual life cycle. Only the female worms are found in the intestine. They are3 .5-6 mm long and are embedded in the mucosa of the upper small intestine. Small, embryonated eggs are passed in the feces, hatch rapidly, and develop directly into infective larvae or free-living adults. The offspring of these free-living adults may develop into another generation of infective larvae or free-living adults. The host is infected by penetration of the skin or by ingestion; infective larvae can be transmit­ ted in colostrun1 as in other species of the genus. The prepatent period is -10 days. Infections are most common in yoWlg calves, particularly dairy stock. Although signs are rare, they may include intermittent diarrhea, loss of appetite and weight, and sometimes blood and mucus in the feces. Large numbers of worms in the intestine produce catarrhal entetitis with petechiae and ecchymoses, especially in the duodenw11 andjejunum. For diagnosis, treatment, and control, see p303 et seq. Nematodirusspp

Nemalodirus helvelianus is generally

recognized as the most common bovine species, although other species, eg, N spathiger and N ba.ttus, can also infect cattle. The adult males ofN helvetianus are -12 mm long and the females18--25 mm. The eggs develop slowly; the infective third stage is reached within the egg in2 -4 wk and may remain within the egg for several months. Eggs may accwnulate on pastme and hatch in lai·ge numbers after rain to produce heavy infections over a short petiod. The eggs are

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GASTROINTESTINAL PARASITES OF RUMINANTS

highly resistant, and those passed by calves in one season may remain viable and infect calves the next season. After ingestion of infective larvae, the adult stage is reached in -3 wk. Wonns are most nwnerous 10--20 ft (3--6 m) from the pylorus. Signs, which include diarrhea and anorexia, usually develop during the third week of infection before the worms are sexually mature; clinical infections may be seen in dairy calves from 6 wk onward. Diagnosis is difficult during the prepatent period, but during the patent period it is easily made on the basis of the character­ istic eggs. Relatively small numbers of eggs are produced. Fecal sampling of both healthy and sick calves in an affected group will increase the chance of making a diagnosis. Immunity to reinfection develops rapidly. Necropsy may show only a thickened, edematous mucosa. For diagnosis, treatment, and control, see p303 et seq. Toxocarasp The ascarid Toxocara vitul01um is a stout, whitish wonn (males 20--25 cm, females 25--30 cm) found in the small intestine of calves 100--200 eggs per gran1 of feces.

STRONGYLOIDES SP Strongyloides westeri is found in the small

intestine in foals. Adult horses rarely harbor patent infections, but mares often have laival stages within their tissues that are activated by parturition to move into the manunary tissue and, subsequently, are transmitted to foals in the milk. However, the relationship of S westeri infection with diarrhea in foals from 10 days of age has not been clearly established. The life cycle of the wom1 in horses is not known to differ significantly from that of Strongyloides in pigs (seep 323). Diagnosis can be made based on observation of eggs somewhat more oval and about one-third the length of strongyle eggs that contain laivae. Ivermectin and oxibendazole effectively remove S westeri. Transmission of laivae to foals via mare's milk may be prevented by routine treatment of mares with ivem1ectin within 24 hr after foaling.

TAPEWORMS Three species of tapeworms ai·e found in horses: Anoplocephala magna, A pm:fo­ liata, and Paranoplocephala mamillana. They are 8-25 cm long (the first usually being tl1e longest, and the last the shortest). A magnaandP mamillana usually are in the small intestine; A perfoliata is found mostly at the ileocecal junction, in the cecum, and in the ileum. The life cycle is sinlilai· to that of Moniezia spp in run1inants (seep 312) and involves free-living oribatid mites as intennediate hosts. Diagnosis is by demonstration of tl1e chai·acteristic eggs in the feces, but because the discharge of proglottids is sporadic, a single fecal exainination may not be diagnostic. ln light infections, no signs of disease are present; in heavy infections, GI disturbances may be seen. Untluiftiness and anemia have been reported. Ulceration of the mucosa is quite conunon in the ai·ea of attaclunent of A perjolia.t a and has been suggested as one cause of intussusception. lntestinal perforation, peritonitis, and subsequent colic have been associated witl1Anoplo-

319

cephala infections. Colic from disturbances of the ileocecal area is more likely in horses with tapeworm infections than in those not infected. Colic associated with tapewonn infections often recurs. The site of attachment of tapeworms frequently becomes secondarily infected or abscessed. Anoplocephala spp can be effectively treated with pyrai1tel salts; normal dosages (6.6 mg/kg) of pyrantel painoate are 87% effective, while double the normal dosage is >93"A, effective. Daily administration of pyrantel tartrate (2.65 mg/kg) removes Anoplocephala spp. Praziquantel (0.75-1 mg/kg) is 89"/er-100% effective in the removal ofA pm:foliata. Praziquantel (at 1 mg/kg) appears to effectively remove P rna.millana; pyrantel salts do not. Mixtures of tl1e macrocyclic lactones ivermectin or mox.idectin with praziquantel are available and are highly effective against A perfoliata. On facilities where tapewom1s are prevalent, clinical signs of tapeworm infections can be prevented by pyrantel salts administered daily dwing the grazing season, or by administration of effective oral anthelmintics within an inte1val deworming prograin. Treatment of horses according to the latter prograi11 immediately before tum out and at the end of the grazing season is likely to be most beneficial.

TRICHOSTRONGYLUS SP The small stomach wonn (hairworm) of horses, Trichostrongylus atcei, is also found in nuninants (seep 308) and, consequently, is generally a clinical problem only in horses commingled or rotated on pasture with ruminants. Adult T axei are slender and measure up to 8 nun long. Details of the life cycle in Equidae have not been carefully studied, but it is known that the laivae penetrate the mucosa. These worms produce a chronic catarrhal gastritis, which may result in weight loss. The lesions comprise nodular areas of thickened mucosa surrounded by a zone of congestion and covered with a variable amount of mucus. The lesions may be rather small and irregularly circmnscribed, or they may coalesce and involve most or all of the glandular portion of the stomach, and erosions and ulcerations may be seen. Definitive diagnosis based on fecal ex3.111ination is difficult, because the eggs ai·e sinlilar to strongyle eggs. The feces can be cultmed ai1d, in -7 days, the infective laivae identified. Some of the benzinlida­ zoles and ivem1ectin are effective against

Taxei.

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GASTROINTESTINAL PARASITES OF PIGS

GASTROINTESTINAL PARASITES OF PIGS See also COCCIDIOSIS OF PIGS, p 208.

In pigs, GI helminths a.re almost always present; their main effects are loss of appetite, reduction in daily gain, poor feed utilization, and potentiation of other pathogens. Only rarely do they cause death. Adequate nutrition helps reduce the adverse effects of parasitism on feed efficiency and average daily gain. Management and control of GI helminths depends entirely on the production system in place, with individual programs developed for the circumstances of the specific farm, including the knowledge of which parasites a.re present. Maintaining pigs on concrete or entirely on slatted floors, as on intensive farms, can success­ fully control those parasites that have intermediate hosts or that require pasture conditions for transmission. Stearn cleaning is highly effective in killing eggs and larvae. The management approach for outdoor situations and nonconcrete floors is aimed at avoiding a buildup of eggs and larvae within the area. Good sanitation is critical because fecal-oral transmission, through the contamination of food, soil, or bedding, is the primary route by which pigs become infected. Direct sunlight or dry conditions shorten the survival of some eggs and larvae because moisture and warmth a.re needed for their development and survival, which probably accounts for decreased transmis­ sion during hot and cold months. Thermo­ philic composting of feces and/or bedding before use as fertilizer inactivates Ascaris suum and Trichuris suis eggs: Both can survive for a few hours at 50° C but only a few minutes at 55° C. Most disinfectants in use on farms, unfortunately, a.re not effective against parasite eggs, especially those of A suum and T suis. Moving "clean" animals to safe pastures will help reduce parasite buildup, but it must be remem­ bered that eggs of A suum and T suis a.re capable of surviving 6-9 and 5--11 yr, respectively, in the environment, and reinfection wi!J occur even with 2 3- yr of pasture rest. If it is not possible to rotate pastures, pigs may occupy uncleanable ground for many years. In these situations, parasites can build up quickly, and control may be in1possible without the regular use of anthelrnintics. Anthelmintic treatments can be incorporated into any broader

progran1 as needed but should not be the sole basis of a control program. Various anthelmintics a.re available, although not all a.re available in every country. Benzimidazoles, including fenbendazole and flubendazole, a.re available for in-feed administration. Flubendazole is available for in-water and top dressing use, whereas fenbendazole has an oral fonnulation. Two avermectin compounds, iverrnectin and dorarnectin, a.re available as i.ajectables, whereas only ivem1ectin can be used in-feed. Both pyrantel tartrate and leva.misole a.re available as in-feed formulations, but only levantisole can be used in water. Dichlorvos, an organophosphate compound, was the first broad-spectrum deworrner available for pigs and is still in use as an in-feed fom1ulation. Piperazine salts are an older generation of anthelntintic. Despite its narrow spectrun1 of activity, it is sti!J widely used, available as an in-feed or in-water formulation. Although anthelrnintic-resistant populations of Oesophagostomum sp were identified as early as 1987, resistance does not appear to be a widespread problem. In addition, there is nojustification for routinely rotating classes of dewormers; rather, choice of product should be made on the expected efficacy against the parasites present (including ectopa.rasites).

ASCARIS SUUM Adults of the large roundworm, Ascaris suum, a.re found in the small intestine and transitorily in the large intestine during expulsion of the worms. Males a.re up to 25 cm and females up to 40 cm.long, whitish, and quite thick. Large numbers of eggs a.re produced (as many as 200,000 to 1 million/ day/female) although shed intermittently; they can develop to the infective stage (eggs containing L3 Jarva) in 3---4 wk under optimal conditions. In temperate regions, the eggs stay dormant in winter ( d5° C) and resume development when temperature rises in the spring. The eggs a.re highly resistant to chemical agents, but conditions with low humidity, heat, or direct sunlight reduce their survival significantly. Under optimal conditions, eggs may survive for 5--11 yr. When the eggs a.re ingested, the larvae hatch

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GASTROINTESTINAL PARASITES OF PIGS in the intestine, penetrate the wall, and enter the portal circulation. After a short period in the liver, they are canied by the circulation to the lungs, where they pass through the capillaries into the alveolar spaces. Approximately 9-10 days after ingestion, the larvae pass up the bronchial tree, are swallowed, and return to the small intestine by -10-15 days after infection, where they mature into adult worms. The first eggs are passed -6-7 wk after infection. Lifespan is -6-9 mo. Earthworms and dung beetles can serve as paratenic hosts. Distribution and Host Range: A suum

is found in pigs worldwide. Occasionally, nematodes may establish in sheep; how­ ever, ingestion of infective eggs while grazing generally results in pneumonia and liver lesions in sheep. Infections can also be seen in cattle and manifest as an acute, atypical interstitial pneumonia. Whether the human nematode Ascaris lumbricoides a.nd A suum of pigs are the same is still debated. Current evidence indicates there is a single interbreedi..ng population of Ascaiis, and the populations occurring in pigs or people have only slight phenotypical and genotypical adaptive changes. Regardless, it is clear the pig ascarid is zoonotic, havi.ng been found in people from various areas of the world, particularly those in close contact with pigs. Visceral larva migrans due to migrating larvae has been described. Clinical Findings: Adult worms may

significantly reduce the growth rate of you.ng pigs; in rare cases, they may cause mechanical obstruction of the intestine. Migration of larvae through the liver causes hemorrhage, fibrosis, and accumulation of lymphocytes seen as white spots (called "milk spots") under the capsule and leadi..ng to condenmation of the liver at slaughter. These lesions become visible 7 1-0 days after infection and will regress within 1-4 wk; therefore, their presence indicates recent infection/reinfection. In resistant pigs, only a few larvae will reach the liver and the nwnber of white spots will be low, despite continual reinfection. Therefore, the number of white spots and the liver condemnation rate are both poor measures of herd infection level. In heavy infections, the larvae can cause pulmonary edema and consolidation, as well as exacerbate swine influenza and endemic pneumonia. Heavily exposed susceptible pigs show abdominal breathing, conm10nly referred to as "thumps." In addition to the respiratory

321

signs, marked unthriftiness and weight loss may be seen. Infection generally induces development of acquired resistance to reinfection, and prevalence is highest in young growing pigs. If the treatment rate is very low and the level of herd immunity is also low, prevalence may be highest in breedi..ng animals. Diagnosis: During the patent pe1iod,

diagnosis can be made by demonstrating the typical eggs (golden brown, thick pitted outer wall, 50-70 x 40-60 im1) by fecal analysis or by observation of large worms in feces. Pigs are coprophagic; thus, low egg counts ( 90A,) are oxyclozanide (two doses 3 days apai.t) and the combina­ tion of bithional and levai.nisole.

HEPATIC DISEASE IN LARGE ANIMALS

329

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HEPATIC DISEASE IN LARGE ANIMALS Hepatic disease is common in large anin1als. Increases in serum hepatic enzymes and total bile acid concentration may indicate hepatic dysfunction, insult, disease, or failure. Although liver disease is especially common in horses and foals, progression to liver failure is not. Diseases tl1at frequently result in hepatic failure in horses include Theiler disease, 'Iyzzer disease (foals), pyrrolizidine alkaloid toxicosis, hepatic lipidosis, suppurative cholangitis or cholangiohepatitis, cholelitlli­ asis, and chronic active hepatitis. Obstruc­ tive disorders (biliary stones, right dorsal colon displacement, neoplasia, duodenal ulceration and stricture, hepatic torsion, portal vein tlirombosis), aflatoxicosis, leukoencephalomalacia, pancreatic disease, kleingrass or alsike clover poisoning, portal caval shunts, hepatic abscess, and perinatal he1pesvirus 1 infections sporadically result in hepatic failure. Less frequently, hepatic failure is associated wiili endotoxemia, steroid administration, inhalant anesiliesia, systemic granulomatous disease, drug­ induced amyloidosis, hyperan1monemia in Morgan foals, parasite dan1age, iron toxicity, or after neonatal isoeryilirolysis. In nuninants, hepatobiliary disease is associated with hepatic lipidosis, hepatic abscesses, endotoxemia, pyrrolizidine alkaloid and oilier plant toxicoses, certain clostridial diseases, liver flukes, mycotoxi­ cosis, and mineral toxicosis (copper, iron, zinc) or deficiency (cobalt). Vitamin E or seleniwn deficiency (hepatosis dietetica), aflatoxicosis, ascarid migration, bacterial hepatitis, and ingestion of toxic substances (eg, coal tar, cyanamide, blue-green algae, plants, gossypol) are associated wiili hepatic injury in swine. Altllough ilie exact incidence of hepatic disease in camelids (llan1as, alpacas) is unknown, it appears to be common in Nortll America. Hepatic lipidosis (secondruy more often ilian primary) is reportedly the most common liver disease in llan1as and alpacas, occurring in botl1 crias and adults. Bacte1;al (Salmonella spp, Escherichia coli, Listeria spp, Clostridium spp) cholangiohepatitis, adenoviral hepatitis and pnewnonia, fungal hepatitis (coccidioidomycosis), toxic hepatopatlly (copper), haloiliane-induced hepatic necrosis, hepatic neoplasia (lymphosarcoma, hemangiosarcoma,

adenoma), and liver fluke infestation have also been reported in ca.melids. The liver can respond to insult in only a limited nwnber of ways. Fat droplets in ilie liver may be an early and often reversible change. Biliruy hyperplasia is also reversible if the insult is removed early. Necrosis of hepatocytes indicates more recent drunage. The dead cells are removed by an inflamma­ tory process and replaced with eiilier new hepatocytes or fibrosis. Unless ilie dysfunc­ tion is acute and hepatocellular regeneration is evident, prognosis for aninlals wiili liver failure is usually unfavorable. Early hepatic :fibrosis may be reversible wiili prompt recognition and intervention. Chronic disease wiili extensive loss of hepatic parenchyma and fibrosis, especially wiili portal bridging, wruTants a poor prognosis.

Clinical Findings: Clinical signs of

hepatic disease may not be evident until >60"Ar-80% of ilie liver parenchyrna is nonfunctional or when hepatic dysfunction is secondary to disease in another organ system. Clinical signs may vruy witl1 ilie course of tile disease (acute or chronic), primary site of injury (hepatocellular, biliruy), and specific cause. Onset of signs of hepatic encephalopatlly and liver failw·e is often acute regardless of whetller tile hepatic disease process is acute or chronic. Clinical signs and seve1ity of hepatic pathology reflect tl1e degree of compromise of one or more of ilie liver's vital functions, including blood glucose regulation; fat metabolism; production of clotting factors, albwnin, :fibrinogen, nonessential aniino acids, and plasma proteins; bile formation and excretion; bilirubin and cholesterol metabolism; conversion of runmonia to urea; polypeptide and steroid hom1one metabolism; syniliesis of25-hydroxychole­ calciferol; and metabolism and/or detoxification of many drugs and toxins. Icterus, weight loss, or abnom1al behavior are common in horses witl1 liver disease and hepatic failure. CNS signs are often the initial and predominant sign in horses with acute hepatic failure, whereas weight loss is a prominent sign in most but not all horses witll chronic liver disease and failure. Photosensitization and, less commonly, bilateral pharyngeal paralysis, causing inspiratory striclor, diarrhea, or

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constipation, may be present. Affected cattle usually show inappetence, decreased milk production, and weight loss. Tenesmus and ascites are seen in cattle but are not common in affected horses. Weight loss may be the only sign associated with liver abscesses. lcterus, which is most pro­ nounced when the biliary system is diseased, is also common in horses with acute liver failure. It is more variably present in horses with chronic liver failw·e or in ruminants. Fasting hyperbilirubinemia is a more common cause of icterus in horses and is not associated with hepatic disease. Occasionally, persistent hyperbilirubinemia (p1imarily indirect or unconjugated bilirubin) may be seen in healthy horses (especially Thoroughbreds) without evidence of hemolysis or hepatic disease. In ruminants, icterus is more commonly due to hemolysis and primarily involves increases in indirect bilirubin. Hyperbilirubinemia caused by obstructive biliary conditions is rare in goats and sheep. Hepatic encephalopathy is associated with behavioral changes in horses, nuninants, and swine. The severity of hepatic encephalopathy often reflects the degree of hepatic failure but does not differentiate between acute or chronic liver failure. Signs of hepatic encephalopathy range from nonspecific depression and lethargy to head pressing, circling, aimless walking, dysphagia, ataxia, dysmetria, persistent yawning, pica, increased friendliness, aggressiveness, stupor, seizures, or coma. Pharyngeal or laryngeal collapse with loud, stertorous inspiratory noises and dyspnea occurs in some cases of hepatic failure, especially in ponies. The pathogenesis of hepatic encephalopathy is unknown, but proposed theories include anm1onia as a neurotoxin, alterations in monoarnine neurotransmission (serotonin, tryptophan) or catecholamine neurotrans­ mitters, in1balance between aromatic and short branch chain amino acids resulting in increased inhibitory neurotransmitters (-y-aminobutyric acid, L-glutarnate), neuroinllibition due to increased cerebral levels of endogenous benzodiazepine-like substances, increased pern1eability of the blood-brain barrier, and impaired CNS energy metabolism. Although the signs can be dramatic, hepatic encephalopathy is potentially reversible if the w1derlying hepatic disease can be resolved. Photosensitization, which may be seen secondary to acute or chronic liver failw·e, must be differentiated from primary photosensitization (seep 976). Hepatog­ enous photosensitization develops when

compromised hepatic function results in phylloerythrin, a photodynarnic metabolite of chlorophyll, entering the ski.ti. Phyllo­ erythrin in the skin reacts with ultraviolet light and releases energy, causing inflan1ma­ tion and skin damage. Signs of photosensiti­ zation are v3.1.ied but include uneasiness, pain, pnuitus, mild to severe dermatitis with erythema, extensive subcutaneous edema, skin ulceration, sloughing of skin and ophthalmia with lacrimation, photopho­ bia, and corneal cloudiness. Dern1atitis and edema are p3.1.ticul3.1.·ly evident on nonpig­ mented, light-colored or hairless 3.1.·eas of the body and areas exposed to sun. Mucocutaneousjw1ctions and patches of white hair are the most conunon sites of photosensitization in cattle. Occasionally, the underside of the tongue may be affected. Blindness, pyoderma, loss of condition, and occasionally death are possible sequelae. Pru1itus may result from photosensitization or from deposition of bile salts in the skin second3.1.y to alterations in hepatic excretion. Diarrhea or constipation may be seen in animals with hepatic disease. Di3.1.Thea is more commonly seen in cattle tl1an in horses with chronic liver disease or in animals with clu·onic fascioliasis and hepatotoxic plant poisonings. Ponies and horses witl1 hyperlipemia and hepatic failure may develop di3.I.Thea, l3.111initis, and ventral edema. Some 3.1.li.mals with liver disease have alternating di3.1.Thea 3.11d constipation. Horses with liver failure and hepatic encephalopathy frequently develop · colonic impaction due to decreased water intake. Constipation is characteristic of Lantana poisoning in goats and other mminants. RecWTent colic, intermittent fever, ictems, weight loss, and hepatic encepha­ lopathy may be seen in horses with choleliths that obstruct the conm1on bile duct. Infectious or inflarnmatmy hepatic disease or failure of the liver to prevent endotoxin from gaining access to t11e systemic circulation may also result in intem1ittent fever and colic. Abdominal pain, due to pressure on the liver capsule from parenchymal swelling, often is seen in animals with acute diffuse hepatitis or trauma to the capsule itself. Affected animals stand with an arched back, are reluctant to move, or show signs of colic·. In nuninants, pain may be localized to the liver by palpation over the anterior ventrolateral aspect of the abdomen or the last few ribs on tl1e right side. Tenesmus followed by rectal prolapse is seen in some ruminants with liver disease. It may be associated with

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HEPATIC DISEASE IN LARGE ANIMALS diarrhea, hepatic encephalopathy, or edema of the bowel from portal hypertension. Hypoalburninemia is not as frequently associated with liver disease in horses as previously thought. Due to the Jong half-life (-19-20 days in horses, -16 days in cows) and liver reserve for albumin production, hypoalbuminemia is usually a very late event in the disease process. Serum total protein concentrations may be normal or increased because of an increase in !3-globulins in horses with liver disease. Hypoalbuminemia and hypoproteinemia most commonly develop in chronic liver disease, and they are common findings in Ila.mas with liver disease. Generalized ascites or dependent edema may result. Ascites is related to portal hypertension caused by venous blockage and increased hydrostatic pressme and to protein leakage into the peritoneal cavity. The abdominal fluid present with liver disease usually is a modified transudate. Hypoalbuminemia can aggravate tl1e ascites, but if it is seen alone, it more likely will cause intem1andibular, brisket, or ventral edema. Ascites is difficult to appreciate in horses and adult cattle unless it is extensive. Ascites is a common finding in calves with liver cirrhosis. Anemia may be seen in animals with liver dysfunction due to parasitic diseases, chronic copper toxicity (in rnrninants), some plant poisonings, or chronic inflammatory disease. Anemia in acute fasciolosis results from severe hemorrhage into the peritoneal cavity as the larvae penetrate the liver capsule. Trauma and feeding activity of adult flukes within the bile ducts cause anemia and hypoproteine­ mia in animals with chronic fasciolosis. Chronic inflammatory disease (eg, hepatic abscesses, neoplasia) may cause anemia without accompanying hypoproteinemia. Clinical signs of severe or terminal hepatic failme include coagulopathies and hemorrhage due to decreased production of clotting factors by the liver and possibly increased utilization in septic or inflamma­ tory processes. A prolonged prothrombin time is usually seen first because factor VIl has the shortest plasma half-life. Horses may develop a tel111inal hemolytic crisis ca.used by increased RBC fragility. This has not been repmted in rnminants. Fecal color rarely changes in adult herbivores with liver disease. In young rwni­ nants and monogastric aninlals, cholestasis may result in lighter color feces being passed because of loss of stercobilin, a metabolite of bilirubin. Liver disease should always be consid­ ered when nonspecific clinical signs, such

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as depression, weight loss, intermittent fever, and recurrent colic, a.re present without an apparent cause. Differentiation between acute and chronic hepatitis or fail me based on the dw·ation of clinical signs before presentation may be mislead­ ing, because the disease process is often advanced before clinical signs are evident. Early vague signs of depression and decreased appetite may be overlooked. Liver biopsy to detemline the type of pathology, degree of hepatic fibrosis present, and the regenerative capabilities of the liver parenchyma is necessary to develop a treatment plan and give an accmate prognosis. Diagnostic Testing: Laboratory tests often detect liver disease or dysfunction before hepatic fail me occms. Routine biochemical tests such as serum enzyme concentrations are sensitive indicators of liver disease, but they do not assess hepatic function. Dynamic biochemical tests that assess hepatic clearance provide quantita­ tive info1111ation regarding hepatic function. Tests of hepatic function a.re useful diagnostic and prognostic tools and provide a guide for the modification of drug-dosing regimens.

Serum Enzyme Concentrations: Serw11 concentrations of liver-specific enzymes are generally higher in acute liver disease than in chronic liver disease. They may be within normal lin1its in the later stages of subacute or chronic hepatic disease. The magnitude of increases in hepatic enzymes (especially -y-glutamyl transpeptidase) should not be used to dete1111ine prognosis. Hepatic enzymes are used to determine the presence of disease but not necessarily the degree of hepatic dysfunction. Careful interpretation of laboratory values in conjunction with clinical findings is essential. Sequential measmements of serum -y-glutamyl transpeptidase or transferase (GGT), sorbitol dehydrogenase (SDH; also called iditol dehydrogenase [IDH]), AST, bilirubin, and bile acids are commonly used to assess hepatic dysfunction and disease in large animals. Serum GGT, bilirubin and total bile acid concentrations, and sulfo­ bromophthalein (BSP®) clearance are not sensitive indicators of liver disease in young calves. Although GGT is primarily associated with microsomal membranes in the biliary epitheliun1, it is also present in the canalicular surfaces of ilie hepatocytes, pancreas, kidneys, and udder. Because of minary and milk excreLion of GGT and ilie rarity of pancreatitis in large anin1als,

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increased serum GGT concentrations most commonly indicate bile duct or liver disease. Some consider GGT to be the single test of highest sensitivity for liver disease in adult large anin1als. Increase of GGT is most pronounced with obstructive biliary disease. In acute hepatic disease in horses, GGT may continue to increase for 7-14 days despite clinical improvement and retmn toward normal of other laboratory tests. Reportedly, sernm GGT concentrations become increased within a few days of liver damage and remain increased until the tenninal phase. Chronic hepatic fibrosis is the only liver disease in which an abnormal increase in GGT might not be seen. Neonatal foals have higher GGT concentra­ tions due to GGT present in colostrmn and milk. Younger adult horses, especially those in active training, may show a nonspecific increase in GGT that is not associated with liver disease or other increases in liver enzymes or se1U1n bile acid concentration. GGT is of little value in diagnosing liver disease in neonatal calves or lambs, because it is present in colostrun1 and milk. GGT activity may also be increased with colonic displacement or administration of drngs (eg, corticosteroids, rifampin, benzimida­ zoles, anthelmintics). Some liver-derived enzymes are higher in young calves (GGT, alkaline phosphatase [AP], glutamate dehydrogenase, lactate dehydrogenase) and foals (AP, GGT, SDH, AST), because they are transiently increased or come from sources other than the liver. Se1U1n levels of hepatic enzymes also vary in goats with age, breed, and sex. Reference ranges must be appropriate for the species and age group being evaluated. SDH, arginase, omithine carban10yltrans­ ferase (OCT), AST, isoenzyme 5 lactate dehydrogenase (LDH-5), glutamate dehydrogenase (GLDH), and AP are also used to assess hepatic dysfunction and disease. Arginase, SDH, and OCT are liver-specific enzymes in horses, most run1inants, and swine. SDH is most predictive for active hepatocellular disease, with marked increases in enzyme activity after hepatocellular dan1age. Mild increases in SDH can also occur with obstrnctive GI lesions, endotoxemia, anoxia from shock, acute anemia, hyperthermia, and anestl1e­ sia. Because of their short half-lives, SDH and LDH-5 are useful in assessing resolution or progression of liver insult. Both enzymes usually retmn to near-normal values 4 days after liver insult, and neither is usually increased in chronic liver disease. Rarely, in severe cases of hepatic failure, SDH may retmn to normal in spite of a fatal outcome.

Arginase and GLDH are considered specific for acute liver disease, because both have high tissue concentrations in the liver and short half-lives in the blood. AST is highly sensitive for liver disease but lacks specificity, because high concentrations come from both liver and skeletal muscle. Other AST sources include cardiac muscle, erythrocytes, intestinal cells, and the kidneys. When CK is sinmltaneously measured to exclude muscle disease and the se1U1n is not hemolyzed, increases in AST and LDH-5 are caused by hepatocellu­ lar disease. AST may remain increased 10-14 days or longer after an acute, transient insult to the liver. AST values are often normal in chronic hepatic disease. SDH and AST may be markedly increased with intral1epatic cholestasis and mildly increased with extral1epatic cholestasis. Increases in AP and GGT are associated with i.J.Titation or destmction of biliary epitheliun1 and biliary obstruction. AP comes from the placenta, bone, mac­ rophages, intestinal epithelimn, and liver. AP is increased in very young calves and foals, probably because of the placental or bone source. In young calves, AP concentra­ tions up to 1,000 IU/L at birth and 500 IU/L at several weeks of age are considered nonnal. AP concentrations of 152-2,835 IU/L are reported in foals ( < 12 hr old), and AP activity may remain high compared with adult levels for 1-2 mo. In calves ( 500 mg/dL confirm the diagnosis. Cholesterol may be increased, indicating an increase in lipoprotein. Nonesterified fatty acids, very-low-density lipoproteins, and 13-hydroxybutyrate (camelids) may also be increased. Laboratory evidence ofhepatic dysfunction is supportive. Treatment: Correction ofthe underlying disease, IV fluids, and nutritional suppo1t a.re the most essential factors in treatment ofhyperlipemia. Nutritional suppo1t reverses the negative energy balance, increases serwn glucose concentrations, promotes endogenous insulin release, and inhibits mobilization ofpe1ipheral adipose tissue. A polyionic electrolyte solution containing supplemental dextrose (50 g/hr/450 kg) and potassiwn (potassiun1 chlmide at 20-40 mEq/L) should be given IV to hypoglycemic, hypokalemic horses. Glucose adnlinistration may cause refractory hyperglycemia in animals with insulin resistance. Glucose concentrations, renal function, urine output, and semm electrolyte concentrations should be monitored closely. IV fluids and glucose must be adn1inistered cautiously in can1elids with hepatic lipidosis, because many are already hypoproteinemic, and glucose regulation in camelids is often challenging. Intermittent bolus administra­ tion ofpolyionic IV fluids rather than continuous infusion may more effectively maintain hydration without exacerbating existing hypoproteinemia. Voluntary enteral nutrition is preferred if the affected aninlal will conswne adequate quantities ofnutritionally valuable feeds; however, most will not. Frequent feedings

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HEPATIC DISEASE IN LARGE ANIMALS

of a high-carbohydrate, low-fat diet are preferred. In animals with inadequate oral intake, supplemental tube feeding is necessary. Commercially available high-calorie enteral fo1mulations provide adequate short-term nutritional support. Recipes for home-prepared, liquid tube-feeding diets for horses are also available. Small frequent feedings are required to meet caloric needs without overloading the GI tract. Anin1als should be observed after each feeding for signs of abdominal discomfort. Body weight, total fluid intake, and fecal consistency should be monitored daily. In a.nin1als that sUIVive, hyperlipemia. usually resolves in 5-10 days, but enteral feeding should be continued until voluntary feed intake is adequate. Enteral nutritional supplementation and treatment of the primary disease often reverses hyperlipemia. in miniature horses and donkeys but less frequently in ponies. For totally anorectic horses, pa.itial parenteral nutrition may be used. The lipid portion of the solution is omitted. Blood glucose concentration should be monitored at lea.st twice daily to ensw-e that euglyce­ mia. is maintained and that substantial hyperglycemia. (�180 mg/dL) is a.voided. In ca.t11elids, pa.itial parenteral nutrition with enteral supplementation Ca.Il be used to maintain adequate energy intake a.t1d mininlize fw-ther fat mobilization. Because of tl1e distinct metabolism of ca.inelids, parenteral nutrition products must contain higher a.inounts of a.inino acids (relative to nonprotein calories) than traditional fonnula.tions used in other species. Glucose concentrations must be carefully moni­ tored, because ca.inelids do not a.ssinlila.te exogenous glucose well. Exogenous insulin administration is recommended for treatment of ia.twgenic hyperglycemia. and hyperlipemia, especially when these conditions are resistant to more conventional therapies. Insulin decreases mobilization of peripheral adipose tissue by stimulating lipoprotein lipase activity a.t1d by inhibiting adipocyte hom10ne--sensitive lipase activity. The appropriate dosage of insulin to be used in horses has not been well established. When insulin is used, response to therapy, including blood glucose concentrations, must be closely monitored a.t1d the insulin dosage adjusted accordingly. Insulin administration may fail to lower serum triglyceride or glucose concentrations in hyperlipemic a.t1iinals when a.t1 insulin-resistant state is present. lnsulin treatment in ca.inelids has report­ edly been effective in treatment of hepatic lipidosis.

Heparin is used in treatment of hyper­ lipemia because it promotes peripheral utilization of triglyce1ides a.t1d enha.t1ces lipogenesis via stimulation of lipoprotein lipase activity. Heparin may be given IV or SC, witl1 recommended dosages of 40--100 JU/kg, bid. Use of heparin is questionable in affected a.Illl11als with increased hepatic production ofbiglycerides a.t1d without inlpaired peripheral removal of triglycer­ ides. HepariI1 administration may potentiate bleeding complications a.t1d is contra.iI1di­ cated in animals with coagulopathies from liver dysfunction. Nubitional supplementation to prevent hyperlipemia. is indicated in minia.tw-e horses a.t1d donkeys, ponies, horses, a.i1d ca.inelids with systemic disease associated witl1 hypophagia a.t1d high metabolic dema.i1ds. Prognosis: Cliilical biochemical variables are not useful prognostic indicators of smvival in ponies with hyperlipemia. In most instances, sUIVival depends on the ability to successfully treat the priI11a.iy disease. Prognosis is often poor in ponies, sta.Ildard-size horses, and ca.inelids.

HEPATIC NEOPLASIA Prima.iy hepatic tmnors are uncommon in horses a.t1d rmnina.t1ts. They include hepatocellular carcinoma., chola.t1giocarci­ noma, a.i1d rarely lymphoma, hepatobla.s­ toma (foals, young horses, alpaca cria.s), · a.t1d nlixed ha.ina.itoma Chola.t1giocarci­ noma. is the most common a.t1d is prin1a.iily found in nliddle-aged or older horses. Hepatic carcinomas a.rise from hepatocytes, bile ducts, or meta.stasis. Hepa.tocellular ca.i·ciI1oma.s generally are found in yearlings to young adult horses and have also been reported in lla.ina.s a.t1d goats. Adenoma.s or adenocarcinoma.s of the liver have been reported in cattle. Hepatic fibrosarcoma a.t1d bile duct carciI10ma. with meta.stasis to the lungs have been reported in goats. E1ythrocytosis, large areas of extra.i11edul­ lary hematopoiesis, a.t1d meta.stasis to the thoracic cavity have been reported in horses with hepatobla.stoma.. Lymphosarcoma is the most common neopla.sia of the hematopoietic system in horses. As ma.t1y as 37% of horses with lymphosarcoma have neoplastic involve­ ment of the spleen, a.t1d 41% have neoplastic involvement of the liver. Meta.stasis of lymphosa.i·coma. of the liver has been reported in cattle, lla.t11a.s, alpacas, a.t1d goats. The predominant clinical findings with hepatic carcinoma. are lethargy a.i1d weight

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HEPATIC DISEASE IN LARGE ANIMALS

loss. A progressively enlarging abdomen, erythrocytosis, persistent hypoglycemia, icterus, and hepatic failure may also be seen. Cholangiocarcinoma causes pronounced weight loss before the onset of hepatic failure. Liver hepatocellular and biliary enzymes may be increased with hepatic carcinoma or cholangiocarcinoma. Serum 'Y-glutamyl transpeptidase or transferase (GGT) activity in affected horses is usually very high. Hepatocellular carcinomas are characteristically uniform in appearance on ultrasonographic examination. Clinical manifestations of lymphosar­ coma in horses are variable. Early in the disease, nonspecific signs such as weight loss, anorexia, and lethargy are seen. Lymphoma occasionally may diffusely infiltrate the liver and produce signs of hepatic failure, jaundice, and severe depression. Laboratory findings include hypoglycemia, mild to moderate increases in liver enzymes, hyperbilirubinemia, and abnormally low levels of IgM. Ultrasono­ graphic examination helps to detect splenic and hepatic neoplasia. In ruminants, signs produced by tumor growth in other organs (lymph nodes, abomasun1, heart, uterus, spinal cord) are often most predominant. The presence and character of the hepatic neoplasia can be con.firmed by liver biopsy and microscopic exanlination of the tissue. Atypical lymphocytes or lympho­ blasts may be seen in peritoneal fluids and peripheral blood of some affected aninlals. Increased serum cx-fetoprotein concentra­ tion may support hepatoblastoma; however, this is not conclusive because concentra­ tions may also be increased with hepatocel­ lular carcinoma.

MISCELLANEOUS HEPATIC DISORDERS Cholangitis Diseases of the gallbladder are rare in ruminants. Obstruction may be associated with liver fluke infestation, foreign bodies, abscesses, neoplasia, suppurative cholecystitis, or abdominal fat necrosis. Rupture of the gallbladder has been reported in a cow. Cholangitis (inflamma­ tion of the biliary system) has been reported in horses with chronic active liver disease. Mild behavior changes, weight loss, variable colic, icterus, and alterations in hepatic enzyme activity may be seen in affected horses. Treatment consists of longterm antimicrobial and supportive therapy as indicated.

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Hepatic Failure in Foals Hepatic failure in neonatal foals may follow septicemia (especially Actinobacillus equuli), endotoxemia, perinatal asphyxia, Leptospira Pomona infection, equine herpesvirus 1, hepatic duct obstruction secondary to gastroduodenal obstruction, biliary atresia, and iron toxicity. Gastric ulcers and duodenitis in foals can cause strictures of the duodenun1 and subsequent cholangiohepatitis due to bile stasis. Neonatal isoerythrolysis and hemolysis may cause hypoxic and cholestatic hepatic disease. Administration of total parenteral nutrition may cause cholestasis and concurrent hepatic disease.

Biliary Atresia Biliary atresia (extrallepatic) has been reported in foals and in a neonatal lamb. Affected foals presented for anorexia, depression, lethargy, poor growth, colic, polydipsia, polyuria, pyrexia, and icterus at l mo of age. Markedly increased serum 'Y-glutamyl transpeptidase or transferase (GGT) and bilirubin with mildly increased sorbitol dehydrogenase (SDH) suppo1ted a diagnosis of biliary obstruction. Diagnosis of biliary atresia was confirmed at necropsy.

Hemochromatosis Hemochromatosis is an iron storage disease in which hemosiderin is deposited in the parenchymal cells, causing damage and dysfunction of the liver and other tissues. The disease is either primary (idiopathic) or secondary. It is reported in people, Mynal1 birds, Salers cattle, and horses.

Etiology: In Salers cattle, the condition appears to be a homozygous recessive condition with inappropriate intestinal absorption of iron, excessive hepatic storage, and eventual loss of hepatic function. In horses, there is no evidence of a familial tendency or of excessive iron being consumed in the diet. Rather, it appears there is cirrhosis of the liver with secondary iron overload. In horses and cattle, increased iron is deposited in the liver. Clinical Findings and Lesions: In horses, primary clinical signs are weight loss, lethargy, and intermittent anorexia. In cattle, signs include decreased weight gain, poor body condition, dull hair coat, and diarrhea. In both species, serum liver enzyme concentrations, including GGT, alkaline phosphatase, AST, and SDH, are increased. Serum total bile acid concentra-

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tions are increased in horses, and serum iron, total iron binding capacity (TIBC), and percent saturation of the TIBC are usually normal. In some cases, serum iron and ferritin may be increased, but TIBC is not saturated. In cattle, total serum iron, TIBC, and saturation of transferrin are increased. Iron content of the liver tissue is greatly increased in horses (no1mal 100-300 ppm) and cattle (normal 84-100 ppm). Hepato­ megaly and hemosiderin accumulation in the liver, lymph nodes, pancreas, spleen, thyroid, kidney, brain, and glandular tissue are typically present. Diagnosis: Diagnosis is based on history,

clinical signs, and laboratory findings. Finding abundant hemosiderin in tl1e hepatocytes on histopathologic exanlina­ tion of a liver biopsy supports the diagnosis. High liver iron concentrations in animals with no history of excess iron intake help confum tl1e diagnosis. Differential diagnoses include iron toxicosis from exogenous sources and diseases causing chronic weight loss and hepatic dysfunction or disease. Treatment: Phlebotomies to remove blood and reduce the iron stores have been used in treatment of people with hemochro­ matosis. Similar treatment in horses and cattle has been unsuccessful. Deferoxamine is also used in people to induce a negative ion balance and reduce the rate at which iron accwnulates. The effect in cattle and horses has not been evaluated. Right Hepatic Lobe Atrophy in Horses

The tight lobe of the liver is the largest lobe in young horses but frequently atrophies in older animals and becomes fibrous. Right hepatic lobe atrophy was previously considered an incidental postmortem finding, but some consider it to be a pathologic condition. Right hepatic lobe atrophy has been proposed to result from chronic compres­ sion of this pmtion of the liver by the right dorsal colon and base of the cecun1. Feeding horses high-concentrate, low-fiber diets may contribute to a.tony of the right dorsal colon with resultant distention; this compresses the right hepatic lobe against the visceral surface of the diaphragm. Altl10ugh there is no morphologic evidence of direct vascular inlpaim1ent to the right hepatic lobe, vascular compromise may result secondary to compression. With chronicity, the portal circulation to the right

lobe is inlpaired, resulting in hepatic anoxia, deprivation of nutrients, and gradual atrophy of the right lobe of the liver. No evidence of biliary tract disease has been noted. Colic may be seen. Some horses may have signs not related to the GI tract. Hepatic Lobe Torsion

Hepatic lobe torsion can cause colic in horses. Liver enzymes and fibrinogen are increased, but abdominal fluid analysis is vaiiable. Bacteria, including Clostridium spp, may be fow1d in the necrotic portion of liver. Exploratory celiotomy may be required for diagnosis. Hepatic Amyloidosis

Amyloidosis refers to disease characterized by the extracellular deposition of amyloid, a proteinaceous fib1iJ substance, in the tissue. Deposition of an1yloid within an organ distmts normal tissue ai·chitectw·e and possibly function. In horses, the liver and spleen are the most common orgatlS affected by systemic amyloidosis. Reactive or secondary systemic amyloidosis with deposition of amyloid A (AA) fibrils in the liver has been associated with severe parasitism and chronic infection or inflainrnation in horses. (See also AMYLOIDOSES, p 592.) Congenital Hepatic Fibrosis

In a retrospective study of the records from the University of Berne, Institute of Animal Pathology, 30 Swiss Freiberger foals with pathologic lesions compatible with congenital hepatic fibrosis were identified. Affected foals were 1-12 mo old (average 3. 7 mo). Most showed signs and had clinicopathologic changes reflecting severe liver damage. Pedigree analysis traced the disease back to one stallion. Results suggest that congenital hepatic fibrosis in Swiss Freiberger horses is a recessively inherited autosomal genetic defect. A sinli.lar condition has been reported in a calf. Primary Hyperammonemia of Adult Horses

In this syndrome of hyperamrnonemia, blindness and severe neurologic signs are seen in adult horses. The etiology is unknown, but a prinlaiy intestinal problem with overgrowth of urease-producing bacteria within the intestine is suspected. The syndrome is neai·ly always associated with enteric disease, diarrhea, or colic. Diarrhea and, in some cases, protein-losing

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HEPATIC DISEASE IN LARGE ANIMALS enteropathy may persist for several days. In most cases, diarrhea or colic precedes the neurologic signs by 24--48 hr. Laboratory abnormalities include increased blood ammonia concentrations (200-400 µm/1), severe metabolic acidosis, low plasma bicarbonate (�12 mEq/1) concentration, and profound hyperglycemia (250-400 mgtdL). Serun1 concentrations of liver enzymes, total bile acids, and bilirubin are nom1al. In most horses, neurologic signs resolve within 2-3 days with supportive treatment (IV fluids, potassium chloride, glucose, sodiwn bicarbonate) and administration of drngs to reduce =onia absorption (lactulose, neomycin).

Portosystemic Shunts Portosystemic shunts are seen in foals and calves. Hyperanm10nemia and neurologic signs result from liver dysfunction with little laboratory or microscopic evidence of liver disease.

Clinical Findings and Lesions: Clinical signs are first seen when affected foals are -2 mo old and sta.It to ingest larger amounts of grain and forage. N eurologic signs include staggering, wandering, blindness, circling, and seizures. Poor growth and intennittent neurologic signs ( ataxia, wealmess, depression, brnxism, tenesmus) have been reported in affected 2- to 3-mo-old calves. Sernm concentrations of hepatic enzymes are often nonnal. Blood ammonia and total bile acid concentration are increased, and BSP® clearance is prolonged. The liver is often small, with a smooth swface, and nonnal in color and texture. Microscopically, the hepatocytes are small. Portal veins in the triads may be small or absent. Hepatic arteries are often prominent and multiple. Diagnosis: A portosystemic shunt should be suspected in foals or calves exhibiting repeated episodes of cerebral signs without obvious reasons. Signs may be most pronounced and associated with feedings. Catheterizing the mesenteric vein and performing a portogram or nuclear scintigraphy can confirm and locate the shunt. In some cases, the shunt may be seen on ultrasonographic examination of the liver. Treatment: Surgical repair may be attempted in aninlals in which the site of the shunt can be identified, but the prognosis is guarded. Clinical signs in some foals may be

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controlled by resb.icting protein intake and by careful dietary management. Neomycin or lactulose are given orally to decrease ammonia production within the bowel. Supportive care with polyionic fluids, potassiun1, and dextrose may be needed to help decrease neurologic signs.

Hyperammonemia of Morgan Foals A syndrome of depression, ill thrift, and hyperanm10nemia with a variable degree of hepatic involvement is seen in Morgan foals. Affected foals have been related, but the cause of the syndrome is undetermined. Clinical signs are usually first seen around weaning time. Encephalopathy may temporarily in1prove with aggressive supportive therapy but recurs after withdrawal of treab.nent. Liver enzymes and blood anm1onia concentrations a.re increased. Bilirubin concentration is often nom1al. Pathologic hepatic lesions include portal and bridging fibrosis, bile duct hyperplasia, karyomegaly, and cyto1negaly. The disease is fatal.

HYPERBILIRUBINEMIA SYNDROMES Gilbert Syndrome Gilbert syndrome is a congenital hyperbilirn­ binemia seen in people (inherited as an autosomal dominant trait) and in South­ down sheep. It is an unconjugated hyperbili­ rubinemia in the presence of normal erythro­ cyte life span. A defect in carrier proteins or conjugating enzyme is suspected. Affected Southdown sheep have increased conju­ gated and unconjugated plasma bilirnbin concentrations. Hepatic bilirnbin clearance is defective, and affected sheep cannot excrete BSP® into the bile. Icterus is variable. Hi.stopathologic lesions are absent except for pign1ent in the hepatocytes.

Dubin-Johnson Syndrome Dubin-Johnson syndrome is seen sporadi­ cally in people and Coniedale sheep. It is a failure of conjugated bilirubin to enter the bile canaliculi. Excretion of bilirubin and other cor\juga.ted organic anions may be impaired. Affected sheep may be icteric or hyperbilirnbinemic. Sernm conjugated and unconjugated bilirnbin concentrations are increased, and BSP® clearance and bile acid excretion may be delayed in affected Coniedale sheep. HistologicaJJy, the hepatocytes contain a black, melanin-like pigment.

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LIVER ABSCESSES IN CATTLE Liver abscesses are seen in all ages and breeds of cattle wherever cattle are raised. They are most conunon in feedlot and dairy cattle fed rations tl1at predispose to rumenitis. Cattle with liver abscesses have reduced production efficiency. Affected livers are condenmed at slaughter, and adhesions to surrounding organs or the diaphragm may necessitate carcass trimming. Liver abscesses can also lead to disease syndromes associated with posterior vena caval thrombosis.

Etiology and Pathogenesis: Fusobac­ terium necrophorum, a gram-negative,

obligate anaerobic bacteriun1, and a component of normal rumen microflora, is the prinlary etiologic agent. Infection in the liver usually originates from a necrobacil­ lary rumenitis. Two biovars have been inlplicated. Biovar A (F necrophorum necrophorum), the more virulent, is the predominant biovar in the rumen microflora and is isolated, usually in pure culture, from most cases of liver abscessation. Biovar B (F necrophorumfunduliforme) is com­ monly isolated from microabscesses in tl1e rumen wall but is less commonly isolated from liver abscesses, in which it is always found in mixed culture with biovar A or other bacterial species. Trueperella pyogenes, streptococci, staphylococci, and Bacteroides spp are most frequently recovered from mixed cultures. Rumenitis is usually the result of rapid intraruminal fem1entation of dietary carbohydrate with subsequent production of lactic acid and increased acidity of the ruminal fluid ("grain overload"). Rations with high levels of carbohydrate are the principal cause in both da..iry and feedlot cattle, but the texture of the feed and method of feeding can be modifying factors. The incidence of rurnenitis in feedlot cattle is significantly higher when the cattle are transferred directly from a roughage ration to a finishing ration, and when there is poor feed bunk management. F necropho1um, alone or with other bacteria, colonizes through tl1e area of superficial necrosis produced by tl1e acid rumen contents. Leukotoxin may facilitate resistance to phagocytosis. Bacterial emboli from the lesions invade the hepatic portal venous system and are transported to the liver, where they can establish infectious foci of necrobacillosis that eventually develop into abscesses. Other sources of infection in liver abscesses include foreign body penetration

from the reticulum, direct extension of infection from omphalophlebitis in neonatal calves, and bacteremic diseases.

Clinical Findings, Lesions, and Diagnosis: Cattle with liver abscesses

seldom exhibit clinical signs. Detailed clinical examination may show periodic fever, inappetence, and evidence of pain when pressure is applied to the xiphister­ num and posterior rib cage on the right side. Grunting and other signs of pain may occur with movement or when the animal lies down. An episodic drop in milk production occurs in dairy cattle. Clinical signs of omphalophlebitis are commonly present when there is liver abscessation resulting from extension of omphalophle­ bitis. Acute-phase proteins are increased early in the course of the disease, and serum sialic acid concentrations have been used for antemortem diagnosis. When there are several abscesses or a large abscess, leukocytosis with neutro­ philia and increased fibrinogen levels develop, and serum globulin concentra­ tions may increase. Ultrasonography is an aid to diagnosis, but abscesses in the left side of the liver may not be visualized. Feedlot cattle with abscessed livers have reduced feed efficiency, and those with severely abscessed livers gain 5%-15% less per day than cattle without abscesses. Most liver abscesses a.re occult lesions that regress to a sterile scar. Untoward sequelae include peritonitis after abscess rupture into the peritoneal cavity, and sudden death from an anaphylactic or toxic reaction when there is rupture of an abscess into hepatic blood vessels. Rupture into hepatic veins can also lead to thrombophlebitis of the posterior vena cava with thromboembolic disease, endocarditis, pulmonary thromboernbo­ lisrn, multiple pulmonary abscesses, and chronic suppurative pneun10nia. Aneurysms of the pulmonary artery consequent to pulmonary thromboembo­ lism may rupture into airways to result in hemoptysis, epista.xis, and death. Caudal vena caval thrombosis may also lead to portal hypertension with a resulting syndrome of hepatornegaly, ascites, and diarrhea. The rurninal lesions are characterized by a marked inflanunatory reaction and necrosis. Occasionally, abscesses are found in the deeper layers of the rwnen wall. Hepatic necrobacillosis lesions of 6 mmol/L) is associated witl1 an increased likelihood of gastric necrosis and the need for partial gastric resection. Treatment: In1mediate goals in treatment

of GDV include restoring circulating volume and gastric decompression. Rapid surgical con-ection of the volvulus follows initial patient stabilization. Because duration of clinical signs is one of the risk factors of GOV-associated death, it is imperative to recognize and con-ect this condition immediately.

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Correction of hypovolemia is the first treatment priority and is achieved by rapid fluid replacement with one or more large bore (16-to 18-gauge) IV catheters placed in cranial Qugular, cephalic) veins. Shock rate (90 mllkg/hr) fluid therapy with crystalloids should begin immediately. Fluid therapy witl1 combinations of crystalloids, colloids (eg, hetastarch at a rate of 10-20 mUkg, IV), or hypertonic saline (eg, 7% hypertonic saline solution with dextran 70 at a rate of 5 mUkg over 15 min) can be considered for animals in severe shock, ai1d tl1c rate of crystalloid fluid infusion reduced by as much as 40% if iliese products are used. These fluid rates ai·e guidelines only, and fluid resuscitation choices must be tailored to the individual patient's needs. Flow-by oxygen should be provided during stabilization. Electrolyte and acid-base disturbances ai·e usually corrected by adequate fluid therapy and gastric decompression. Because of the potential risk of endotoxemia ai1d GI trai1slocation of bacteria, antibiotics (eg, ai11picillin 22 mg/kg, tid-qid, and continued for 2-3 days after surgery) ai·e often given. Gastric decompression occurs concurrently with fluid resuscitation. Initial decompression attempts should be made with an orogastric tube, which can be performed after sedation with fentanyl (2-5 mcg/kg, IV) or hydro morphone (0.05-0.1 mg/kg, IV), with or without diazepain (0.25-0.5 mg/kg, IV). Agents that cause vasodilation (eg, phenothiazines) should be avoided. A stomach tube is measured from the incisors to the last rib and marked. The tube must not be placed beyond this marking. The lubricated tube is introduced into the mouth (often held open with a roll of tape or bandage material) while the dog is in a sitting position. Some resistance is typically encountered at the esophageal-gastric sphincter. Gentle manipulation and counterclockwise movement of the tube may be necessary to allow passage of the tube into the stomach, but caution must be exercised because it is possible to perforate the esophagus with the tube. Once the tube enters the stomach, gastric gas rapidly escapes. Successful passage of a stomach tube does not exclude the presence of volvulus. After gas and stomach contents ai·e released from the stomach via the tube, the stomach should be lavaged with warm water to decrease the rate of redilation with gas. If an orogastric tube caimot be readily passed, percutaneous gastrocentesis may be performed to release excess gastric gas.

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An area (10 cm x 10 cm) over the right abdominal wall caudal to the last rib and ventral to the transverse vertebral process is clipped and aseptically prepared. Percussion of the area should reveal tympany; this helps avoid accidental puncture of an overlying spleen. If a tympanic structure is not appreciated, the left paracostal region should be assessed. A large-bore needle or over-the-needle catheter is introduced ttu·ough the skin and body wall into the stomach at the site of greatest tympany. Decompression usually allows for subsequent passage of an orogastric tube and lavage of the stomach. Surgical correction of GOV rapidly follows the initial stabilization. Aseptic preparation of the abdomen is perfom1ed before surgery, and a cranioventral midline approach is performed. Before correcting the gastric torsion, the stomach should be decompressed with the help of an assistant placing an orogastric tube or via gastrocen­ tesis intraoperatively. The stomach is then returned to its normal position, and the stomach and spleen are evaluated for ischemia. Any areas of ischemic gastric wall are removed, and a splenectomy is perfom1ed if necessary. Extensive gastric necrosis and necrosis of the gastric cardia are considered poor prognostic indicators. The stomach is emptied of contents, and a gastropexy is perfom1ed to decrease risk of recurrence. Several gastropexy tectuuques have been described and include a simple incisional pexy, a circumcostal (belt-loop) pexy, and a tube g:1$trotomy and pexy. Pre-, intra-, and postoperative monitoring should include continuous ECG, intennit­ tent blood pressure measurement, and frequent assessment of vital parameters, PCV, total solids, electrolytes, blood glucose, and serum lactate. Postoperative medical management includes IV fluid therapy and analgesia. Food should be withheld for 48 hr after surgery. Antiemetic agents (metoclopra­ mide at 0.2-0.5 mg/kg, SC, or 1-2 mg/kg/day, constant-rate IV infusion; ma.ropitant at 1 mg/kg/day, SC) may be administered in cases of continued vomiting. Postoperative cardiac arrhythmias are common, but treatment is often not indicated. Criteria to initiate antiarrhythmic therapy include signs of persistent tachycardia (>140 bpm), hypotension (systolic blood pressure 6 hr before exan1ination, perfom1ing splenectomy and a partial gastrectomy, hypotension at any time during hospitalization, peritonitis, sepsis, and disseminated intravascular coagulation. Preoperative plasma lactate concentration has been shown to be a good predictor of gastric necrosis and a negative prognostic indicator for outcome for dogs with GOV. Prophylactic gastropexy is CWTently being recommended by many veterinary surgeons for breeds at risk or for dogs with relatives that have been affected by GOV. Prophylactic gastropexy can be performed at fue time of sterilization surgeries (spay/neuter). Minimally invasive tectuuques such as laparoscopic-assisted gastropexy are gaining favor. Prophylactic gastropexy has not been shown to prevent development of GOV if petformed at the tin1e of neuter but has been shown to help prevent recurrence if perfom1ed at the time of the first GOV correction. However, in one study of five large dog breeds predisposed to GOV, mortality was reduced (versus no gastro­ pexy) ranging from 2.2:fold (Rottweiler) to 29.6-fold (Great Dane). A prospective study reported a median survival time of 547 days in dogs that undezwent gastropexy versus 188 days for dogs that did not. Owners of breeds at high risk of GOV should be educated about the risk factors for and signs of GDV, and advised to seek inunediate veterinary care if clinical signs are apparent. Additional precautions include avoiding stress, feeding multiple rather than single daily meals, avoiding exercise immediately after feeding, and not using elevated food dishes.

GASTRITIS Gastritis is a general term used to describe a syndrome of acute or chronic vomiting

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DISEASES OF THE STOMACH AND INTESTINES IN SMALL ANIMALS secondary to inflammation of the gast1ic mucosa. Irritation, infection, antigenic stimulation, or injury (eg, chemical, erosion, ulceration) of the gastric mucosa stin1ulates the release of inflammatory and vasoactive mediators with subsequent disruption of gastric epithelial cells, increased gastric acid secretion, and impaired gastric barrier function. Visceral receptors sensitive to gastric distention, gastric inflammation, and tonicity of gastiic contents send impulses via vagal and sympathetic nerves to the vomiting center of the medulla oblongata, thereby stimulating the vomiting reflex. Acute Gastritis: In acute gastritis,

vomiting of sudden onset is presumed or confim1ed to be secondary to inilanunation of the gastric mucosa. Causes include dietary indiscretion or intolerance (eg, ingestion of novel, spoiled, or contaminated foods, or of foreign material), drug or toxin ingestion (eg, antibiotics, NSAIDs, corticosteroids, plants, chemicals), systemic illness (eg, pancreatitis, uremic gastropathy, hypoadrenocorticism), endoparasitism (eg, Physaloplera sp [dog], OUulanus sp [cat]), or bacterial (eg, Helicobacter-associated disease) or viral (eg, canine parvovirus gastroenteritis, feline panleukopenia) infection. Vomiting of sudden onset is characteristic. The vomitus may contain bile, food, froth, blood (frank or digested), or evidence of an ingested substance (eg, grass, bones, foreign material, etc). Additional clinical signs depend on the severity and frequency of vomiting as well as on the underlying cause. Diagnosis is usually based on a thorough history, clinical findings, and response to symptomatic treatJnent. A specific diag­ nosis should be sought if the animal has had access to foreign objects or toxins, if clinical signs do not resolve within 2 days of symptomatic therapy, if hematemesis or melena are present, if the animal is systemically unwell, or if abnormalities are noted on abdominal palpation. Dogs may signal the presence of cranial abdominal discomfort by adopting a "praying" posture (hindquarters raised and chest and forelegs held close to floor), which seems to provide some sense of relief. A CBC, serun1 biochemical profile, and urinalysis may be followed by more specific clinicopathologic testing (eg, basal serum cortisol concentra­ tion, adrenocorticotropic hormone [ACTH] stimulation test, evaluation of vomitus for specific toxins). Diagnostic imaging, including plain and/or barium contrast abdominal radiographs and abdominal ultrasound, may be indicated.

387

Treatment of acute gastritis is generally symptomatic and supportive. Small amounts of oral fluids can be given frequently, with the volun1e increasing as vomiting subsides. lee (crushed or cubes) can be provided as the only source of water initially. Subcutaneous administration of an isotonic balanced electrolyte solution may be sufficient to coffect mild fluid deficits ( 7 days and that cannot be attributed to dietary indiscretion or intolerance; drug, toxin, or foreign body ingestion; systemic illness; endoparasitisrn; infection (bacterial or viral); or neoplasia. The most corru11on clinical sign is intermittent vomiting of fobd or bile. Systemic illness, weight loss, and GI ulceration are infrequent and should raise suspicion of a more se1ious condition or diffuse GI inflammation (eg, inflan1matory bowel disease, pythiosis, etc). Histologic evaluation of endoscopic or surgical gastric biopsies is required for

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definitive diagnosis and classification of chronic gastritis. A CBC, serum biochemical profile, urinalysis, total thyroid hormone concentration (cats), basal serum cortisol concentration possibly with anACTH-stim­ ulation test (to exclude canine hypoadreno­ corticism), and fecal evaluation for endoparasitism are indicated but are frequently unremarkable in animals with chronic gastritis. Diagnostic imaging (plain and/or barium contrast abdominal radiographs, abdominal ultrasound) can identify foreign objects, neoplasia, pylo1ic stenosis, gastric antral mucosal hypertro­ phy, discrete or multifocal mucosal or mural abnormalities, intra-abdominal lymphad­ enomegaly, or other intra-abdominal pathology, and is indicated before gastric biopsy. �phocytic-plasmacytic gastritis and eosinophilic gastritis are characte1'­ ized by diffuse infiltration of the gastric mucosa and lamina propria with lympho­ cytes and plasma cells, or eosinophils, respectively. Similar cellular infiltrates may be seen in the small intestine. Concomitant lymphoid hyperplasia., mucosal a.trophy, or mucosal fibrosis is infrequently seen. Dietary allergy or intolerance, occult parasitism, or hyperimmune response to normal antigens have been proposed as possible ca.uses. Eosinophilic gastritis with eosinophilia. and/or skin lesions should raise suspicion for dietary sensitivity or hypereosinophilic syndrome (ca.ts). Animals with mild clinical signs and mild histologic lesions may respond to syn1pto­ ma.tic care (see p 387 )', empirical deworm­ ing, and exclusive feeding of a hypoaller­ genic or novel protein diet (eg, balanced homemade diet or many conm1ercially available options). In addition to sympto­ matic care, empirical deworming, and dietary modification, animals with moderate to severe, histologica.lly confirmed disease generally require inununosuppressive therapy. Prednisone (or prednisolone in ca.ts) is sta.ited at 2 mg/kg/day, PO (dogs), or2-4 mg/kg/day, PO (ca.ts), and tapered to the lowest dosage that controls clinical signs. Assuming continued clinical remission, prednisone therapy is ultimately discontinued and strict adherence to dietary therapy maintained. If clinical signs persist despite ga.stroprotec­ tant therapy, dieta.iy modification, and prednisone therapy, treatment with an additional inununosuppressive a.gent (dogs: a.za.thioprine2 mg/kg, PO, every24--48 hr; ca.ts >4 kg: chlorambucil2 mg [ total dose], PO, every 48 hr for2-4 wk then tapered to 2 mg every 72-96 hr; ca.ts l 00-fold nonnal, peaking • during the first 5 days of injury. If the ir\jurious event resolves, ALT activity gradually declines to norn1al over 2-3 wk. Altl10ugh this pattern is considered classic, some severe hepatotoxins are not associated with increased ALT activity, because they inllibit gene ti·anscription or inte1fere with ALT biosynthesis (eg, aflatoxin B l hepatotoxicity, microcystin hepatotoxicity). A declining ALT also may represent a paucity of viable hepatocytes in end-stage chronic hepatitis or severe acute liver disease. Examples of classic necrotizing hepatotoxins are carbon tetrachloride, acetaminophen, and nitrosamine. A single exposure to carbon tetrachloride causes an acute sharp increase in ALT that resolves over the ensuing week. Hepatotoxicity induced by acetaminophen causes a marked increase in ALT and AST within 24 hr that may decline within 72 hr to near normal values. This toxin is highly dose dependent in dogs and cats. Cats are exceedingly susceptible, with hematologic signs

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dominating after ingestion of as little as 125 mg. However, in clogs, a dosage of 200 mg/kg may be life-threatening, with susceptibility heightened by antecedent exposure to phenobarbital. Hepatocellular necrosis induced by nitrosamines increases plasma ALT activity, but not significantly, until after 1 wk of inte1mittent chronic exposure. The ALT activity persists for weeks until necrosis resolves. Low-grade hepatocellular degeneration, observed in some clogs with congenital portosystemic shunts, reflects delayed enzyme clearance and low-grade hepatocyte dropout; most of these dogs have small lipogranulomas reflecting single hepatocyte dropout/necrosis in the absence of an inflanm1atory response. Acute hepatic necrosis caused by infectious canine hepatitis increases plasma ALT activity by 30-fold, peaking within 4 days. Thereafter, chronic sustained ALT activity persists as chronic hepatitis develops in dogs unable to clear the virus. Hepatic injury induced by toxins usually causes plasma ALT activity to increase, peak, and return to normal sooner than it does in infectious viral hepatitis. Chronic hepatitis, an idiopathic or coppe1�associated persistent or cyclic necroinfla.nunatory liver ir\jmy in dogs is associated with vaiying severities of necrosis and fibrosis. Cyclic disease activity is reflected by plasma enzyme "flares." At times, plasma ALT activity is>JO-fold normal. Enzyme fluctuations contrast with profiles associated with single injurious events. In dogs with hepatitis, semm ALT activity declines as ir\jury resolves, but serum ALP activity may increase as a result of regenerative responses (progenitor cell proliferation, ductal or ovalcell response). Dogs treated with glucocorticoids may develop mildly increased ALT activity that resolves within several weeks of glucocorti­ coid withdrawal. Despite high sensitivity of ALT to identify liver disorders, its lack of specificity to differentiate clinically significant liver disease, specific histologic abnormalities, or hepatic dysfunction requires that it be interpreted in conjunction with other diagnostic tests. Aspartate Aminotransferase: AST is present in substantial concentrations in a wide variety of tissues, especially muscle. Increased AST activity can reflect reversible or i.JTeversible changes in hepatocellular membrane pe1meability, cell necrosis, hepatic inflanmiation, and in dogs, microsomal enzyme induction. After acute diffu e severe hepatic necrosis, serun1 AST

sharply increases during the first 3 days to values 10- to 30-fold above normal in dogs and up to 50-fold above nom1al in cats. U necrosis resolves, AST activity gradually declines over 2-3 wk. In most cases, AST pai·allels changes in ALT activity. Although increased AST activity in the absence of abnonnal ALT activity impli­ cates an extrahepatic enzyme source (notably in muscle injmy), there ai·e clinical exceptions that may relate to severity and zonal location of hepatic daniage. In some cats with liver disease, AST is a more sensitive marker of liver injury than ALT (eg, hepatic necrosis, cholangiohepatitis, myeloproliferative disease, hepatic infiltrative lymphoma, and EHBDO). A sinlilar trend is evident in some dogs. Because AST is located within the mito­ chondria and free within the cytosol of hepatocytes, AST in fold increases greater than those of ALT may reflect mitochron­ drial injury. Dogs treated with glucocorti­ coids may develop mildly increased AST activity that resolves within several weeks of glucocorticoid withdrawal.

Alkaline Phosphatase: Increased

ALP activity in dogs is the most conunon abnormality on routine biochemical testing; its high sensitivity and low specificity can defy cliagnostic interpretation without a liver biopsy. ALP activity in dogs has the lowest specificity of routinely used liver enzymes as a result of its complexity associated with induction of different isozymes. In dogs at1d cats, tissues containing highest ALP activity (in descending order) are intestine, kidney (cortex), placenta ( dogs only), liver, and bone. Distinct serum ALP isozyrnes can be extracted from some of these tissues in each species; eg, bone CB-ALP), liver (L-ALP), and glucocorticoid­ induced (G-ALP) isoenzyrnes in canine serum. In dogs, L-ALP and G-ALP are primarily responsible for high serum ALP activity, whereas L-ALP is primarily responsible in cats. Increased ALP activity develops in up to 75% of hyperthyroid cats, depending on the chronicity of the condition, with B-ALP substantially contributing. The comparably small magnitudes of ALP activity in cats with liver disease (2- to 3-fold normal) relative to dogs (usually>4- to 5-fold) reflect the lower specific activity of ALP in feline liver and its shorter half-life. Nevertheless, ALP activity remains clinically useful in the diagnosis of feline liver disease when the species-appropriate perspective is maintained.

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HEPATIC DISEASE IN SMALL ANIMALS

The utility of sernrn ALP activity as a diagnostic indicator in dogs is complicated by the conunon accumulation of L-ALP and G-ALP isozyrnes, which can both be induced by steroidogenic hormones. Because the B-ALP isozyrne increases secondary to osteoblast activity, it is detected in young growing animals and in animals with bone tumors, secondary renal hyperparathyroidism, and osteomyelitis. However, the minor contribution of B A - LP to total sernrn ALP activity usually does not lead to an erroneous diagnosis of choles­ tatic liver disease. Bone remodeling secondary to neoplasia may not substan­ tially affect sernrn ALP activity or may cause only a trivial increase (2- to 3-fold) in dogs. In young growing cats, increased B-ALP activity may simulate enzyme activity seen in hepatobiliary disease. Although ALT is inunediately released from the hepatocellular cytosol in acute hepatic necrosis, the small quantities of membrane-bound ALP are not. It takes several days for induction of membrane­ associated enzyme to "gear up" and spill into the systemic circulation. Increased sernrn ALP reflects enhanced de novo hepatic synthesis, canalicular injury, cholestasis, and solubilization of its membrane anchor (by bile salts). The largest increases in serum ALP activity (L-ALP and/or G-ALP 2>100-fold normal) develop in dogs with diffuse or focal cholestatic disorders, massive hepatocel­ lular carcinoma, bile duct carcinoma, and those exposed to steroidogenic hom1ones. Although sernrn activity of ALP may be normal or only modestly increased in dogs with metastatic neoplasia involving the liver, it may also increase dranmtically in dogs with mammary neoplasia. High sernrn ALP activity develops in -55% of dogs with malignant and 47% with benign mammary tumors, with highest ALP activity seen in dogs with malignant mixed tumors. Nevertheless, serum ALP has no value as a diagnostic or prognostic marker in mammary cancer; it remains unclear whether disease remission (surgical, chemotherapy) is followed by a regression in serum ALP activity or whether serum ALP activity functions as a paraneoplastic marker. After acute severe hepatic necrosis, ALP activity increases 2- to 5-fold in dogs and cats, stabilizes, and then gradually declines over 2-3 wk. Sustained ALP activity usually correlates witl1 a reparative ductal response (progenitor or oval cell hyperplasia). In cats, EHBDO results in a 2-fold increase in ALP within 2 days, as much as a 4-fold

433

increase within 1 wk, and up to a 9-fold increase within 2-3 wk. Thereafter, activity stabilizes and gradually declines but usually not into the nonnal range; the declining enzyme activity coordinates with develop­ ing biliary cirrhosis csee EXTRAHEPATIC BILE DUCT OIJSTRUCTION, p 478). Inflammatory disorders involving biliary or canalicular structures or disorders compromising bile flow increase serun1 ALP activity secondary to membrane inflammation/disruption and local bile acid accumulation. In both dogs and cats, sin'lilar increases in serum ALP activity develop in intral1epatic (metabolic, biochemical, sepsis) associated cholestasis or obstruction involving the extral1epatic biliary structures. Consequently, ALP activity cannot differentiate between intra- and extral1epatic cholestatic disorders. Many extral1epatic and primary hepatic conditions are associated with increased L-ALP. In cats, HL (seep 456) is associated with marked increase in ALP activity and jaundice. The increased ALP seemingly reflects canalicular dysfunction or compression. Although ALP in cats is rarely affected by anticonvulsants or glucocorti­ coids, it can increase with diabetes mellitus, hyperthyrnidism, and pancreatitis. In dogs, prin1ary hepatic inflanunation as well as systemic infection or inflanunation and exposure to steroidogenic hormones may induce a glycogen-associated vacuolar hepatopathy (VH). When severe, VH has a cholestatic effect that seemingly causes canalicular compression. Although glycogen-associated VH was initially characterized as a glucocorticoid-initiated lesion, it is now established that nearly 500/o of dogs with glycogen-associated VH lack overt exposure to steroidogenic substances. Chronically ill dogs may produce the G-ALP isozyrnes secondary to stress-induced glucocmticoid release. Such dogs with glycogen-associated VH (lacking exogenous glucocorticoid exposure) may demonstrate normal dexamethasone suppression and adrenocorticotropic hormone (ACTH) response tests. However, in some dogs, high ALP with a glycogen-associated VH signals the presence of atypical adrenal hyperplasia associated with abnonnal sex hormone production. There is no consistent relationship between the magnitude of sernrn ALP activity, the presence of high G-ALP activity, or histologic lesions. Unfortunately, G-ALP is not useful for syndrome characterization because it can become the predominant ALP isoenzyrne in dogs treated with glucocorticoids and in dogs with spontaneous or iatrogenic

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hyperadrenocorticism, hepatic or nonhe­ patic neoplasia, hepatic inflammation, or numerous diverse chronic illnesses, including primary liver disease. The magnitude of ALP activity induced by glucocorticoid administration depends on the type of drug and dose given, as well as the individual's response. The production of G-ALP does not in1ply that a dog treated with cortisone has iatrogenic hyperadreno­ corticism, a suppressed pituitary-adrenal axis, or a clinically important glycogen­ associated VI-I. By comparison, the feline liver is relatively insensitive to glucocorti­ coids, with rare development of a glycogen­ associated VI-I or acceleration of hepatocyte lipid vacuole accumulation. In dogs, semm total ALP activity and I.rALP isozyme also may be induced by administration of certain anticonvulsants (phenobarbital, prirnidone, and phenytoin) and other drugs; in th.is ci.rcwnstance, the ALP activity usually increases 2- to 6-fold normal. In contrast, semm ALP and l.rALP did not increase in cats after administration of phenobarbital (0.25 grain, bid) for 30 days.

Gamma-Glutamyl Transferase:

Garnma-gluta.myl transferase (GGT) is a membrane-bound glycoprotein that plays a critical role in cellular detoxification (involved with glutathione availability), conferring resistance against a number of toxins and drugs. Tissue concentrations of GGT in dogs and cats are highest in the kidney and pancreas, with lesser amounts in the liver, gallbladder, intestines, spleen, heart, lungs, skeletal muscle, and erythro­ cytes. However, serwn GGT activity is largely derived from the liver, altfwugh there is considerable species variation in its localization with.in this organ. Acute, severe, diffuse necrosis is associated with either no change or only mild increases (1- to 3-fold normal) in GGT activity that resolve in -10 days. In dogs with EHBDO, seru.n1 GGT activity increases 1-to 4-fold above normal within 4 days, and 10- to 50-fold within 1-2 wk. Thereafter, values may plateau or continue to increase as high as 100-fold. In cats with EHBDO, semm GGT activity may increase up to 2-fold within 3 days, 2- to 6-fold within 5 days, 3- to 12-fold within l wk, and 4- to 16-fold within 2 wk. Glucocorticoids and certain other microsomal enzyme inducers may stinrnlate GGT production in dogs, sinillar to their influence on ALP. Adnlinis­ tration of dexa.methasone (3 mg/kg/day)

or prednisone (4.4 mg/kg/day, IM) may increase GGT activity within l wk to 4-to 7-fold above nonnal and up to 10-fold within 2 wk Dogs treated with phenytoin or primidone develop only a modest increase in serum GGT activity (up to 2-to 3-fold), unless they develop anticonvulsant hepatotox:icosis that is often associated with marked enzyme activity. Cats with advanced necroinfla.mmatory liver disease, EHBDO, or inflammatory intral1epatic cholestasis can develop a larger increase in GGT activity relative to ALP Glucocorticoids and other enzyme inducers in dogs do not clinically influence semm GGT in cats. The normal range for semm GGT activity in cats is much narrower and lower than that in dogs; therefore, assays must be sensitive enough to detect low GGT activity. GGT values can be markec!Jy increased in dogs and cats with primary hepatic or pancreatic neoplasia. However, GGT does not appear to be suitable for SUJveilJance of hepatic metastasis in either species. Like ALP, GGT lacks specificity in clifferentiating between parenchymal hepatic disease and obstructive biliary disease. It is not as sensitive in dogs as ALP but does have higher specificity. In cats with inflammatory liver disease, it is more sensitive but less specific than ALP; these two enzymes should be interpreted sinrnltaneously. The likelihood that HL has developed secondary to necroinflammatory liver disease, EHBDO, or pancreatic disease can be predicted by examining the relative increases in GGT and ALP Necroinflan1111a­ tory disorders involving biliary structures, the portal triad, or pa.i1creas are often associated with a greater fold increase in GGT tl1an in ALP With the exclusion of these underlying disorders, cats with HL usually have a higher fold increase in ALP relative to GGT; tlus has impo1tant diagnostic utility in disceming the U11derlying cause of I-IL. Neonatal a.iumals of several species, including dogs but not cats, develop high se1um GGT activity secondary to colostrum ingestion.

OTHER SERUM BIOCHEMICAL MEASURES

Albumin: Albumin is produced exclu­

sively by the liver and has a half-life in healthy dogs estin1ated at -8 days. Because the healthy liver is estin1ated to maintain albU111i.n synthesis at 33"A, maximal capacity, it has a large reserve capability for albumin

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synthesis. Albumin functions as an essential transport molecule, maintaining nonnal drug-receptor interactions. In liver disease, decline in albumin concentration compro­ mises its transport functions, increasing risk of adverse drug reactions (more free or unbound drug). Albumin's large role in maintaining colloid osmotic pressure reflects its lower molecular weight compared with other plasma proteins and its higher intravascular concentration. In inflarnmatory disease or during malnutri­ tion, albLUnin may increase its transcapillary escape rate, augmenting distiibution into the interstitial space. Th.is phenomenon hastens onset of hypoalbuminemia in anin1als with necroinflanllllatory liver disease, long before development of ascites. Concurrent hypoalbun1inemia and development of hepatic presinusoidal, sinusoidal, or postsinusoidal portal hypertension is commonly associated with ascites in aninlals with chronic severe liver disease. Albunlin also ftmctions as a scavenger of oxygen radicals and other oxidizing agents. These antioxidant effects may be compro­ mised in necroinflammatory liver disease and fulminant hepatic failure. Any disease processes promoting an oxidative environment (eg, diabetes mellitus, renal disease, hepatic insufficiency, hyperthyroid­ ism) can irreparably damage the albumin molecule, accelerating its turnover (synthesis and catabolism). In many anin1als with liver disease, an early trend toward hypoalbuminernia often reflects systemic inflanllllation (negative acute phase effect). Only in severe hepatic insufficiency (eg, chronic progressive hepatitis) is synthetic failure a dtiving cause of hypoalbuminemia. Protein-losing nephropathy (glomerular disease) or protein-losing enteropathy must be excluded as underlying causes of hypoalbu­ minemia. Glomerular causes are associated with a urine protein:creatinine ratio >3 and hypercholesterolemia, whereas protein­ losing enteropathy is associated with panhy­ poproteinemia and hypocholesterolemia. Bilirubin: Total bilirubin >2.5-3 mg/dL results in clinical icterus. Hyperbilirubin­ emia can reflect prehepatic (eg, hemolysis), hepatic (impaired uptake, intracellular transport, glucuronide cortjugation, or canalicular elinlination), or posthepatid extrallepatic causes (EHBDO, biliary tree rnpture). Total bilirubin concentrations vary markedly with different disease processes. Concentrations are highest in dogs with hemolytic disorders and in cats with HL and

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EHBDO. BilirubinLUia can be detected in healthy dogs because of their ability to conjugate bilirubin in renal tubules (low renal threshold). However, bilirubinuria in cats is always abnormal and should be investigated. Fractionation of total bilirubin into direct (cortjugated) and indirect (uncortjugated) moieties offers little diagnostic utility. Bilirubin covalently bound to albLUnin (biliprotein complexes) remains in the circulation and is not excreted in urine. Chronic retention can impart tissue jaLU1dice in t11e absence of bilirubinuria long after a cholestatic disorder has resolved. Common causes of hyperbilirubinemia include increased hemoprotein liberation (eg, hemolytic anemia, ineffective erythropoiesis, body cavity hemorrhage), bile duct occlusion, ruptured biliary tract, intrallepatic cholestasis, impaired hepatobiliary bilirnbin processing, and sepsis. Jaundiced dogs and cats presenting with regenerative anemia should be tested for hemolytic disorders, including immune-mediated hemolytic anemia, Heinz body hemolysis, zinc toxicity, and erythro­ parasites (including hemotropic Myco­ plasma [cats, dogs] andBabesia [dogs]). BUN and Creatinine: There are no characteristic changes in BUN or creatinine concentrations with liver disorders except that low values are associated witl1 pmtosystemic shunting and feeding of a restiicted protein diet (only BUN, not creati­ nine) formulated to reduce signs of HE. The concentration of BUN reflects nlll11erous variables, including hydration status, nutritional support, enteric bleeding, tissue catabolism, and the hepatic capacity to detoxify ammonia. Anorexia, feeding a low-protein diet, or hepatic insufficiency can result in low normal to subnormal concenti·ation of BUN, whereas increased values relative to creatinine (discordant BUN:creatinine ratio) may reflect dehydra­ tion, enteric bleeding, or consun1ption of a hig h p - rotein diet. Compared with BUN, serum creatinine concentrations are less affected by dietary protein intake. The low BUN and low nom1al or low creatinine concentration often seen in animals with portosystemic shunting reflect increased water tLU11over tl1at increases glomerular filtration rate ( up to 2-fold), contiibuting to PU/PD. Reduced hepatic synthesis of creatinine also contributes to low creatinine concentrations in animals with hepatic insufficiency, considering that creatinine depends on hepatic synthesis of creatine in the transmethylation pathway.

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Glucose: Hypoglycemia is uncommon in acquired liver disease except end-stage cirrhosis or fulrninant liver failure. The inability to store hepatic glycogen or convert glycogen to glucose is more common in neonates and juvenile small­ breed dogs with congenital portosystemic shunts. Other causes of hypoglycemia, including sepsis, insulinoma, iatrogenic insulin overdose, rare glycogen storage disorders, or paraneoplastic effects of large primary hepatic neoplasia (canine hepatocellular carcinoma or adenoma) or other tumors should be considered in an animal with suspected liver disease. Cholesterol: All cells in the body except RBCs synthesize cholesterol for intracellu­ lar use. Cholesterol incorporated in plasma lipoproteins is synthesized only in the liver and distal small intestine. Bile provides the major excretory pathway for cholesterol. Hypocholesterolemia may reflect endo­ crine, metabolic, and nutritional factors as well as hepatic insufficiency and portosys­ temic shunting. Nonhepatic disorders associated with hypocholesterolemia include hypoadrenocorticism, maldiges­ tion/malabsorption, pancreatic exocrine insufficiency, severe starvation, cachexia, sepsis, and hyperthyroidism (cats); hepatic causes include portosystemic shunting (congenital or acquired) and severe hepatic insufficiency (eg, end-stage cirrhosis, fulrninant hepatic failure). Hypercholester­ olemia is more common in ill animals and requires careful consideration of potential nonhepatic disorders, including hypothy­ roidism, diabetes mellitus, pancreatitis, nephrotic syndrome, hyperadrenocorticism or treatment with glucocorticoic:16, idiopathic dyslipidemias, and rarely a postprandial effect. Hypercholesterolemia is usually seen in EHBDO and in some animals with diffuse intrahepatic cholesta­ sis, destructive cholangitis, and marked hepatic regeneration. HEPATIC FUNCTION TESTS Total Serum Bile Acids: TSBA concentrations sensitively detect chole­ static disorders and conditions associated with portosystemic shunting. TSBA concentration should be measured before and 2 hr after meal ingestion; fasting is not required. Insufficient hepalic mass or deviated portal circulation to the systemic circulation via extrahepatic portosystemic shunts (congenital or acquired) or

microscopic shunts within the liver (congenital microvascular dysplasia) cause highTSBA concentrations, particularly in postprandial samples. TSBA concentrations are usually lower before a meal than 2 hr after a meal. However, --15%--200Ai of dogs and 5% of cats have higherTSBA concentrations before a meal than after, likely reflecting physiologic variables influencing the enterohepatic circulation of bile acids (ie, the rate of gallbladder contraction, gastric emptying, and intestinal transit of bile acids to the ileum where they are actively resorbed). TSBA concentra­ tions in dogs >25 µMIL or in cats >20 itMIL are abnormal either before or after a meal (fasting ranges should not be applied because of the variables influencing the TSBA enterohepatic circulation). Collecting a single sample forTSBA measurement (random fasting or a single postprandial sample) can miss detection of abno1n1al values. BecauseTSBA concentrations are a more sensitive indicator of cholestasis than total bilirubin, measuringTSBA concentra­ tion is redundant in anin1als with nonhemo­ lyticjaundice. Use ofTSBAs as a liver function test can indicate need for a liver biopsy.TSBA concentrations should be routinely measured in all young (6 mo), small, "terrier-like breeds" to detect dogs with microvascular dysplasia (MVD). Finding increasedTSBA concentrations in apparently healthy, young, terrier-like breeds, including but not restricted to YorkshireTerriers, Maltese, ShihTzus, Miniature Schnauzers, CairnTerriers, NorfolkTerriers, Havanese, Papillons, Tibetan Spaniels, and Pugs, allows detection of dogs in whichTSBA concentra­ tion will be misleading if discovered in later life during evaluation of illness. Ammonia: Measurement of blood an1monia can detect hepatic disorders associated with HE. Ammonia is derived predominantly from protein degradation, with most generated in the intestines from consumed food and enteric bacterial ureases that catabolize urea into an1111onia and carbon dioxide. Portal transport of an1monia from the intestines to the liver results in a direct 85% detoxification to urea. Ammonia intolerance (in1paired clearance) occurs in any disorder associated with portosystemic shunting and in acute fulminant hepatic failure. Ammonia is not influenced by cholestasis or liver disorders that do not deviate the portosystemic circulation or extensively reduce hepatic parenchyrnal mass.

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HEPATIC DISEASE IN SMALL ANIMALS Although ammonia is regarded as a pivotal cause of HE, animals with overt HE may have normal blood ammonia concen­ Lrations owing to complicated pathologic mechanisms driving HE. A single normal ammonia value cannot discount HE in an animal with suspected chronic liver disease, and serial ammonia measurements may not correlate with an evolving clinical scenario of HE. Thus, ammonia measurements cannot reliably diagnose HE. Measurement of blood ammonia is complicated. Spurious hyperammonemia can reflect slow blood collection, tight tourniquet technique, conditions promoting ammonia liberation from muscle (seizures, crush injuries), sample contamination (human sweat, cigarette smoke, open urine vials), and spontaneous generation in san1ples not in1rnediately cooled on collection or not promptly analyzed. Ammonia is highly volatile, and samples cannot be mailed for analyses. Blood san1ples should be collected into pre-cooled tubes and transported on melting ice to the laboratory for analysis within 20 min. Enzymatic-based methodologies are difficult to standardize. Nonhepatic causes of hyperammonemia also exist, with the most common disorders involving bacterial infection of the urinary tract with a urease-producing organism associated either with uroabdomen or obstructive uropathy. If a random blood ammonia concentra­ tion is within nonnal limits but hepatic insufficiency and portosystemic shtmting suspected, an ammonia tolerance test can be conducted. Ammonium chloride is given at 100 mg/kg in a 5% solutfon orally (can induce vomiting) or at 2 mUkg of a 5% solution administered rectally (instilled 30 cm deep) after a cleansing enema, with blood ammonia measured at baseline and then at 20, 30, 40, or 60 min later. Unfortu­ nately, an ammonia tolerance test may induce iatrogenic HE in susceptible animals. The presence of ammonium biurate crystalluria in an animal with high TSBA.s is pathognomonic for hyperammonemia and portosystemic shunting. A minimum of three urine samples collected at separate daily intervals should be inspected to optimize surveillance for crystal discovery. In animals on restricted protein intake using diets specifically formulated for hepatic insufficiency, finding ammonium biurates may be difficult because of the high efficacy of such diets to control hyperammonemia.

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IMAGING Radiography: Routine abdominal radiographs are useful to detemline liver size and may detect irregular liver borders. Mineralized densities that involve paren­ chyma or the biliary tree can reflect stasis of bile flow, dystrophic mineralization associated with congenital malformations, acquired duct "sacculation," chronic duct inflammation, or choleliths. Choleliths that contain enough calcium bilirubinate or calciun1 carbonate are radiographically visible. A mass effect in the right cranial quadrant in suspected EHBDO may represent an engorged gallbladder, pancreatitis, neoplasia, or focal bile peritonitis. Radiographic suspicion of abdominal effusion (poor abdominal detail) may prompt diagnosis of bile peritonitis and ascitic effusion. Gas within hepatic parenchyma or biliary structures indicates an emphysematous process (eg, cholecysti­ tis, choledochitis, infected biliary cyst, hepatic abscess, necrotic tumor mass) and warrants prompt antimicrobial therapy and either surgical intervention or percutane­ ous, ultrasound-guided aspiration/lavage. Thoracic radiography can indicate signs of systemic disease (eg, metastatic lesions, pleural fluid). Finding sternal lymphadenop­ athy is conunon in cats witll the cholangitis/ cholangiohepatitis syndrome, in which it reflects hepatic infla.nunation. Altllough cholecystography can be accomplished with iodinated contrast given PO or IV, contrast radiographic imaging of the biliary system is rarely pursued. Distribution and concentration of contrast agents within biliary structures is influenced by nun1erous variables, including hyperbili­ rubinemia and major duct occlusion. At best, these agents may disclose cholelitlls, polyps, or sludged bile but are insufficient to confinn bile peritonitis or to localize the site of leakage. Multisector CT and/or hepatic ultrasonography are more useful to discern tllese processes. Contrast studies of the portal vasculature are tile gold standard for confinnation of a congenital portosystemic shunt. Radio­ graphs should be taken in right and left lateral and ventrodorsal positions for best test sensitivity. Multisector CT imaging produces exceptional in1ages and has replaced radiographic portography for diagnosis of congenital portosystemic shtmts because it allows contrast ir\jection into a peripheral vessel, can capture numerous images per second, and allows wee-dimensional anatomic reconstruction.

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Ultrasonography: There are many diagnostic applications of hepatic ultrasonography: 1) identify distention and determine thickness of biliary structures; 2) verify conunon bile duct obstruction; 3) detect gallbladder mucoceles and cholelithiasis; 4) differentiate between diffuse and focal hepatic abnormalities; 5) identify and detemline dimensions of "mass lesions"; 6) identify pancreatic, mesenteric, and perihepatic lymphadeno­ megaly; 7) in coajunction with vascular studies, identify congenital intrahepatic and extrahepatic portosystemic vascular anomalies (PSVAs), APSSs, arteriovenous malformations, and hepatic venule distention reflecting passive congestion; and 8) detect small volume abdominal effusion and small volume of fluid sun-ounding the gallbladder. However, although abdominal ultrasonography has become an indispensable diagnostic tool to assess the liver and biliary system, its use is highly operator dependent, and findings must always be reconciled with the history, physical examination findings, and clinicopathologic data. Reconciliation of data is best done by the principal clinician managing the case, who has the most knowledge of the animal's management and prognosis. Computed Tomography: Multisector

CT imaging, available in specialty referral practices and university teaching hospitals, can distinguish mass lesions, detect changes in structure of hepatic parenchyma and the biliary system, identify choleliths, detect abnonnal hepatic perfusion (involving the portal vein, hepatic artery, or hepatic vein), and portal thrombi, and can detail the extent of traumatic hepatobiliary iajuries.

CHOLECYSTOCENTESIS Cholecystocentesis is the aspiration sampling of gallbladder bile; this can be completed using a percutaneous trans­ hepatic ultrasound-guided approach, by laparoscopic assistance, or during exploratory abdominal surgery. Samples of bile are collected for cytologic investigation and culture of aerobic and anaerobic bacteria and fungi; collection of bile that contains particulate debris or sedin1ent has the highest yield to find microorganisms (cytologically, by culture). Complications of cholecystocentesis may include intrape1;to­ neal bile leakage (reduced by using a transhepatic approach), hemorrhage,

hemobilia, bacteremia, and vasovagal reaction, especially in cats, that may result in ventilatory arrest, severe bradycardia, and death. If a gallbladder mucocele or EHBDO is suspected, cholecystocentesis is contraindicated. It is better to perfo1m a cholecystectomy for gallbladder mucocele and surgically decompress EHBDO (relieve or bypass the obstruction).

LIVER CYTOLOGY Ultrasonographic-guided fine-needle aspirates are routinely used to confum a diagnosis of HL in cats and to identify suppurative septic inflammation, neoplasia, and glycogen-like VH. However, definitive diagnosis of hepatic disease is otherwise impossible with liver aspirates because the absence of acinar architecture compro­ mises anatomic orientation and correct interpretation. Cytologic interpretation of liver aspirates are notoriously discordant with histologic fmdings on biopsy specimens. Neither neoplasia nor sepsis can be definitively excluded using cytology, and inflan1matory disease is too often sus­ pected. Cytology should not be the basis to recommend inununomodulatory or antifibrotic medications or longterm chelation therapy for copper-associated hepatopathy. Rather, liver biopsy remains the standard for diagnoses of most hepatic disorders.

LIVER BIOPSY Hepatic needle true-cut biopsies (especially 18-gauge) collected under uJtrasonographic guidance may yield samples too small and fragmented for accurate diagnosis because of a lack of representative acinar units (at least 15 portal triads should be sampled). Furthem1ore, needle biopsies are usually only collected from the mqre safely sampled left-side lobes, which may miss lesions differentially affecting liver lobes (eg, cholangiohepatitis in cats). Blind-needle biopsies done without ultrasonographic guidance are hazardous and ill advised in animals with suspected hepatic hilar or mesenteric lymphadenomegaly; involve­ ment of the common bi.le duct, gallbladder, intestines (eg, inflanllllatory bowel disease, infiltrative disease), or pancreas; or multiple organ abnom1alities. An exploratory laparotomy is more appropriate. When possible, wedge biopsies or laparoscopic cup forcep biopsies are preferred, because samples of adequate size can be easily and safely acquired from multiple liver lobes, ensuring accurate disease representation.

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These methods also permit assessment of the gross appearance of the liver. Notably, laparoscopic methods are not recom­ mended when disease of the common bile duct or gallbladder is suspected that may necessitate a decompressive biliary procedure, cholecystectomy, or cholestot­ omy. Liver biopsy should always be done even if an obvious biliary abnormality is the predominant disease process, because underlying histologic liver lesions may indicate another primary disease process. It is also important to biopsy grossly normal liver when focal lesions are identified. This practice ensures 1) characterization of "normal" liver histology, 2) determines whether an underlying liver disease coexists, 3) investigates histology of liver distant to the gallbladder in animals undergoing cholecystectomy, and 4) provides multiple liver lobe samples needed to confinn suspected MVD (because this lesion is variable among liver lobes). Routine biopsy evaluation should include examination of a cytologic imprint, Gram stain (if suppurative or pyogranulomatous inflanunation is cytologically detected), routine H&E staining and interpretation, as well as staining with a reticulin stain (discloses sinusoidal collapse of the supporting scaffolding of the liver), Masson's trichrome (to confirm presence and severity of fibrillar connective tissue deposition), Prussian blue to identify iron retention in Kupffer cells (fixed macrophages) and hepatocytes (helps confmn lobular involvement in inflanunation, Kupffer cell activation, presence of rare hemochromato­ sis), rhodanine stain for copper (confirms and can be used to quantify copper with digital scanning of the rhodanine-stained section), aerobic and anaerobic bacterial cultures of liver and bile, and quantification of liver metals (copper, iron, and zinc concen­ trations because these values can help evaluate risk of oxidative i.rtjury and need for zinc supplementation). A tissue sample (formalin fixed) should also be reserved for other special case-specific studies such as special inununohi.stochemical stains or for PCR testing for infectious agents. Before biopsy, bleeding tendencies should be evaluated by careful review of the history, physical examination, blood smear (to confirm platelets d00,000/µL), routine coagulation profile (prothrombin time [PT], activated partial thromboplastin time [APTT]), von Willebrand factor (vWF) activity in high-risk breeds, and a buccal mucosa] bleeding time. Routine coagulation assessments have low reliability to detect bleeding risk. The buccal mucosa! bleeding

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time is more relevant when performed inunediately before the procedure. Animals suspected to have bleeding tendencies should be treated with vitanlin K 1 (0.5-1 mg/kg, SC or IM) at 0, 12, and24 hr before tissue sampling. lf buccal mucosa! bleeding tin1e is >5 nlin, a fresh frozen plasma transfusion is indicated, as is administration of desmopressin acetate (DDAVP, 0.3-1 mcg/kg diluted in saline), which increases plasma vWF 2 f- old over baseline within 1 hr as well as plasma activity of Factor vm. DDAVP can initiate a hemostatic effect in dogs with type 1 vWF (partial quantitative deficiency) but not in dogs with qualitative defects or complete vWF deficiency. In many people with liver disease, DDAVP has improved coagulation ability, although the exact mechanisms remain incompletely clarified.

PATHOLOGIC CHANGES IN BILE (White bile syndrome, lnspissated bile syndrome, Bilirubin deconjugation) In anin1als with bile stasis, nonabsorbable bile constituents (bile salts, phospholipids, glycoprotei.ns, and cholesterol) are subject to concentration or di.I ution when water and inorganic electrolytes (sodium, chloride, bicarbonate) are resorbed or added by the biliary epithelium. EHBDO can produce a "white bile" syndrome reflecting the absence of bilirubin pigments; this usually is found in aninlals with an obstructed gallbladder at the level of the cystic duct or in animals with obstruction of the hepatic ducts. Stasis of bile flow also may cause bile dehydration, promoting a pathologically thickened or sludged bile typically dark green to black in color. Formation of a gallbladder mucocele involves the entrapment, retention, dehydration, and local overproduction of mucin that lends a rubbery viscosity to bile. Bile stasis in obstructed ducts can lead to bilirubin deconjugation, which reduces bilirubin solubility and favors cholelith precipitation. Choleresis (enhanced bile flow) produces "watery," dilute bile and is a therapeutic goal in disorders associated with bile stasis.

NUTRITION Nutritional support has a pivotal influence in cats with HL and is an important component of at-home treatment in aninlals with slowly progressive hepatobiliary disorders. Proper nutritional support improves quality of life in anin1als with hepatic insufficiency prone to HE. Diets for

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animals with hepatobiliary disease should be easily digestible, highly palatable, calorically dense, easy for the owner to prepare and feed, and fed frequently as small meals. Objectives are to optimize food digestion and assimilation and to achieve voluntary food consumption. If animals are anorectic, tube feeding should be considered. Nasogastric tubes are inexpensive, easily placed, and recom­ mended as a short-term solution. Esopha­ gostomy tubes are preferred in cats with HL for longer dietary support. Use of appetite stimulants remains controversial, because they may delay institution of regimented nutJ.itional support. In addition, some commonly used drugs are metabolized in the liver. Diazepam and oxazepam may rarely lead to idiopathic fulrninant hepatic failure in cats. Dietary modification for animals with liver disease depends on tl1eir clinical status, tl1e definitive diagnosis, and assessment of liver function. Diets should be balanced and supplemented with water-soluble vitamins. In severe choles­ tatic disorders that impede enteric access of bile(eg, EHBDO, advanced sclerosing cholangitis in cats), fat-soluble vitamins may become depleted. Vitamin K 1 can be supplemented via parenteral injection of 0.5-1.5 mg/kg every week(titrated against a thrombotest [PIVKA assay] or PT). If vitan1in K1 depletion is confinned, vitanlin E also likely needs supplementation. Because vitanlin E is a fat-soluble vitan1in, a unique, water-soluble form may be necessary for ora.J administration: polyethylene glycol ac-tocopherol succinate(10 IU/kg/day, PO). It is important to follow dosing recommen­ dations, because excessive vitamin K can lead to hemolytic anemia(in cats), and excessive vitanlin E can interfere with vitanlin K function. Liver function also has considerable influence on glucose homeostasis(glycogen­ olysis or gluconeogenesis from aniino acids and lactate), detoxification of nitrogen(urea cycle), and ketogenesis(from fatty acids). In rare circumstances, in animals prone to hypoglycemia, low-dose IV glucose may be transiently needed. Protein modification and restriction is used to address insufficient nitrogen detoxification (see below). Energy Allowance: Energy allocation should be estimated based on ideal body weight, with modified diets gradually introduced. Initial intake should be no greater tllan 500.Ai of tile calculated daily energy requirement on day 1, increased to 75% on day2, and then to 100% by day 3-5.

Energy allowances may require adjustment after the diet is accepted, the animal is stable, and weight and body condition reassessments confirm a need for higher or lower intake. Estimation of initial energy intake is calculated using fom1ulas that predict resting energy requirements in healthy animals. Formulas for estimation of initial energy allocations for dogs are 30 x body wt(kg) + 70(for dogs 2-16 kg); 70 x body wt(kg}°-75(for dogs 16 kg); or 99 x body wt(kg)0.67(safe initial intake for a healthy dog). For cats, 60 x body wt(kg) is often used, unless the cat is markedly overconditioned or has a subnormal metabolic rate or activity level. Frequent reassessment is necessary with energy allowances tailored to response. Dietary Protein Allowance: A diagnosis of liver disease should not automatically dictate a need for protein restriction. In fact, protein restriction can be detJ.imental in some animals, eg, cats with HL or animals with chronic but stable necroinflanllllatory liver disease that do not have APSSs or HE. Unfortunately, altering nutritional support can be difficult and challenging in anin1als that reject novel diet modifications. Protein restriction is appropriate when HE is suspected, an1lllonimn biurate crystalluria is observed in an animal with suspected hepatic insufficiency, or portosystemic shunting(congenital or acquired) is either confinned by imaging studies or suggested by protein C assessments. The protein allowance for an animal with HE should maintain a positive nitrogen balance, avoiding tissue catabolism. Because maintenance of lean body mass(muscle) provides a temporary respite from ammonia toxicity, body condition should be monitored regularly for comparative estin1ates, with tl1e goal being to maintain muscle mass. When protein restriction is deemed necessary, initial restriction to 2.5 g protein/ kg body wt( l mo), acid-fast organisms may not be found in tissue sections, and PCR from forn1alin-fixed tissue may be falsely negative. However, Mycobacteiium sp have also been detected by both histologic staining and by PCR from fonnalin-fixed liver specin1ens from dogs with pyograulomatous hepatitis.

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HEPATIC DISEASE IN SMALL ANIMALS Extrahepatic and lntrahepatic Bacterial Infections and Sepsis: Extrahepatic infection and sepsis can cause cholestasis and hyperbilirubinemia. Increases in semm bilimbin may range from moderate to marked, while increases in liver enzyme activity remain modest. This type of jaundice has been seen in dogs with leptospirosis and in dogs and cats with ill-rlefined sepsis syndromes. Approp1iate treatment targets the underlying organism causing infection. Increased liver enzyme activity in septicemia/sepsis also can reflect bacterial invasion of the liver or hepatocel­ lular damage by associated cytokine release or hypoxia. Animals with acute hepatic failure, chronic hepatobiliary disease, and choles­ tatic disorders are predisposed to systemic bacterial infection and endotoxemia clue to diminished function of hepatic reticuloen­ dotl1elial cells (hepatic Kupffer cells comprise the largest fixed macrophage popu­ lation in tl1e body) and reduced biliary elimination of bacteria cle1ived from the enterohepatic circulation in bile. In acute fulminant hepatic failure, sepsis or septicemia may be masked by fever, hypoglycemia, and leukocytosis that might also represent clinical manifestations of hepatic injury. Animals with chronic disorders causing stasis of bile flow or with chronic hepatic neoplasia are more likely to develop intrahepatic infections. Risk factors associated with biliary tract infection include advanced age, recent episodes of cholangitis, acute cholecystitis, choledo­ cholithiasis, and obstructive jaundice. Treatments tl1at reduce susceptibility to infection and liver injury during fulminant hepatic failure and extra.hepatic bile duct occlusion include administration of N-acetylcysteine, a-tocopherol, glutamine, oral bile acids, and enteric and systemic antibiotics. These strategies increase microvascular perfusion, reduce ente1ic bacte1ial translocation, augment irmate immunity, and protect against oxidant injury. While awaiting results of culture and sensitivity (tissue, abdominal effusion, bile), antibiotics against entelic opportunists should be administered empirically, avoiding dmgs extensively metabolized in the liver. Combination of a [3-lactarnase-­ resistant penicillin, metronidazole (7.5 mg/kg, PO, bid), and enrofloxacin (2.5---5 mg/kg, PO, IM, or IV, bid), may be beneficial duling initial treatment when the underlying infectious cause remains unclear.

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Mycotic Diseases The most common mycotic infections associated witl1 liver dysftmction are coccidioiclomycosis (seep 637) and histoplasmosis (seep 639). In severely affected animals, clinical signs include ascites, jaundice, and hepatornegaly, in addition to signs associated with otl1er involved organ systems. Anti.fungal treatment is variable, determined by the sevelity of infection, organ involvement, and individual clinical response. Because liver involvement in histoplasmosis is seen with disseminated disease, aggressive chemotherapy (including combinations of eitl1er itraconazole or ketoconazole and amphotericin B) are recommended. Debilitated anin1als have a poor prognosis. Coccidioiclomycosis can be treated successfully with several antiI1.mgal medications (itraconazole and tluconazole are preferred to ketoconazole ). Clu-onic treatment (6--12 mo) is required, and relapses may occur. Treatment efficacy is determined based on resolution of clinical signs and radiographic lesions and reduction in serologic titers. Termination of treatment should not be based on serologic titers alone, because tl1ese stabilize and persist in many dogs after clinical recovery. Owners must be infonned that discontinu­ ing medication may result in relapse. Animals recove1ing from CNS infection should receive lifelong treatment. Similarly, animals with disseminated disease suffering infection relapse after treatment discontinu­ ation should continue on longtem1 or lifetime treatment with an azole antifimgal. For chronic treatment, drug doses that effectively maintain remission may be lower than those needed to induce remission. Protozoa! Diseases Toxoplasmosis: Toxoplasmosis (see p 685) can cause acute hepatic failure associated witl1 hepatic necrosis. Toxo­ plasma gondii is more commonly seen in cats positive for feline irnmw1.odeficiency vims and feline leukemia virus. Icterus, abdominal effusion, fever, lethargy, vomiting, and dianhea are seen in addition to clinical signs consistent witl1 CNS, ocular, or pulmonary involvement. Liver disease in dogs is rare but when seen is either in an immunocompromised host or in young dogs and also involves systemic infection. Young dogs may be concurrently infected with canine distemper virus; in these, illness is acute in onset and rapidly fatal. Diagnosis of toxoplasmosis can be difficult; while a

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positive IgM titer indicates active clinical disease, IgG titers may be found in chronic infections and in animals lacking clinical disease. Clindamycin (12.5 mg/kg, PO or IM, bid for 4 wk) is the drug of choice. Because clindan1ycin is metabolized in the liver, dosage reduction may be necessary in severe hepatic insufficiency. Oral clindamy­ cin should be followed by a bolus of water or food to prevent esophageal irritation. In some cases, initial treatment is combined with anti-inflan1matory glucocorticoids to protect against tissue injmy caused by inflanm1atory responses initiated by protozoa] death. Prognosis depends on the degree of debilitation and stage of disease at initial diagnosis and the associated disorder causing inmrnnosuppression. Despite improvement with treatment, animals should be considered chronicaJJy infected and thus must undergo srnveillance for recrndescent disease.

Leishmaniosis: Canine leishmaniosis (see p 589) is a multisysternic disease caused by protozoan parasites of the genus Leish­ mania, most conm1only encountered in animals that have lived in Mediterranean countries, Portugal, the Middle East, and some parts of Africa, India, and Central and South America. It also is occasionaJly encorn1Lered in dogs in Lhe USA (especiaJly Foxhounds). A serosurvey of> 12,000 dogs (Foxhounds, other breeds, wild canids) and 185 people in 35 states and 4 Canadian provinces was done to assess geographic distribution prevalence, host range, and modes of transmission within North America and to assess possible infection in people. Findings identified Leishmania spp-infected Foxhounds in 18 states and 2 Canadian provinces but no evidence of hUlllan infection. North America leishmani­ osis appears widespread in Foxhorn1ds and is limited to dog-to-dog transmission. However, if the organism becomes adapted for vector transmission by indigenous phlebotomines, the probability of hU111an exposure may greatly increase. Clinical features in dogs with naturaJly occrnTing leishmaniosis include nonregen­ erative anemia, increased enzyme (ALP, ALT, and AST) activity, hypoaJbunlinemia, and variable bilirubinernia. Histologic response is characterized by a multifocaJ pyogranulomatous hepatitis associated with hepatocyte vacuolar degeneration with phagocytized organisms seen within macrophages. Severity ofliver lesions represents sequential stages of hepatic infection in chronic visceral leishmaniosis.

However, no correlation has been shown between histologic features and breed, sex, age, clinical features, or hepatic parasite load. Treatment is rarely curative, and prognosis for debilitated animals is poor. Owing to the zoonotic potential of the organism, owners must be informed that their pet will never be completely free of the disease and that relapses may require repeated treatment. This is particularly important if an owner is immunocompro1nised. In the absence of renal insufficiency, a high-protein diet is reconunended. The most conunon specific treatment recom­ mended in the USA is allopurinol (7-20 mg/kg, PO, once to three times daily) given for 3-24 mo or indefinitely lifelong; other first-line treatments include meglu­ mine antimony (100 mg/kg/day, IV or SC), sodiun1 stibogluconate (30-50 mg/kg/day, IV or SC), or liposomaJ amphotericin B (0.25-0.5 mg/kg, IV, every other day until a total dose of 5-10 mg/kg is achieved). Numerous other second-line drugs have also helped control infections.

FELINE HEPATIC LIPIDOSIS Hepatic lipidosis (HL), the most conunon acquired and potentiaJJy lethal feline liver disease, is a multifactmiaJ syndrome. In most cases, a primary disease process causing anorexia sets the stage for HL in overconditioned cats. Peripheral fat mobilization exceeding the hepatic capacity to either redistribute or use fat for 13-oxidation (producing energy) leads to profound hepatocyte cytosolic expansion with triglyceride (fat) stores. In fewer cases, inappetence is caused by environmental stresses (eg, forced weight loss with unacceptable food substitutions, moving to a new household, newly introduced or loss of pets or fantily members, boarding, accidental confinement [ eg, locked in a garage, basement, or attic], or an inside­ only cat being lost outside). The tem1 "idiopathic HL" is appropriate only when an underlying disease condition or event leading to inappetence carmot be identified. HL has no necroinflanunatory compo­ nent, and the severe cholestasis is caused by canaJicular compression secondary to hepatocyte triglyceride vacuolar distention. The syndrome is associated with a nun1ber of metabolic deficits, including low hepatic and RBC glutathione, low plasma tarn"ine, low vitamin K, causing coagulopathies in some cats, thiamine and/or cobaJanlin deficiency and likely other B vitanlin depletions, and electrolyte aberrations

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HEPATIC DISEASE IN SMALL ANIMALS

(especially low potassium and low phosphorns). Clinical signs vary but usually include dramatic weight loss (>25%, may include dehydration deficits), lethargy, vomiting, ptyalism, pallor, neck ventroflexion, hepatomegaly, jaundice, gastroparesis and intestinal ileus (due to electrolyte aberra­ tions), and retention of omental and falciform fat despite diminished peripheral fat stores. Diarrhea is common in HL cats with inflammatory bowel disease or enteric lymphoma as primary disease processes. Classic signs ofHE are not seen, and arnmonium biurate crystalluria is unusual, although bleeding tendencies may develop. Vitamin K, deficiency has been confirmed in numerousHL cats by observation that bleeding tendencies and coagulation test abnormalities resolve with vitamin K, therapy. Laboratory results reflect theHL syndrome as well as the primary underlying disease. A nonregenerative anemia, poikilocytosis, increased RBCHeinz bodies, variable WBC count, hyperbilirnbinemia and bilirnbinmia, mild to marked increases in ALT and AST, and marked increases in ALP are common. In cats with a prin1ary necroinflanllllatory process involving the pancreas, liver, bile ducts, or gallbladder, GGT activity will be increased, usually exceeding the fold increase in ALP. In all other conditions causingHL, GGT activity is normal or only modestly increased. The GGT:ALP relationship is useful in discerning underlying cholangitis/cholangiohepatitis and other diseases involving biliary strnctm·es (including pancreatitis). Finding a high GGT also predicts whether a liver or pancreatic biopsy is indicated. Depending on underlying disorders, hypoalbUlllinemia and hyperglobulinemia may be found. Prolonged PT or APTT may develop; the PIVKA clotting time is more sensitive for detection of vitaniin K, sufficiency. In t11e earliest stages of theHL syndrome, TSBAs are abnormal before onset of jaundice (this circumstance is rarely encountered). Peritoneal effusion is rare but when found represents the prin1ary disease process or iatrogenic fluid overload. Ultrasonographic evaluation reveals homogeneous hyperechoic hepatic parenchyma and subjective hepatomegaly. Hyperechogenicity is determined by comparing hepatic parenchyrna to falciform fat and the spleen (liver is normally hypoechoic vs spleen). Kidneys also may appear hyperechoic because of increased renal tubular fatty vacuolation. Ultrasono­ graphic exan1ination should carefully assess

457

the entire abdomen for evidence of an underlying disease process and include evaluation of the biliary tree, gallbladder, pancreas, intestinal wall thickness, hepatic and mesenteric lymph nodes, kidneys, and urinary bladder, and scrutiny for uroliths in the kidneys, ureters, or bladder. Definitive diagnosis is based on the history, physical examination findings, laboratory features, ultrasonographic appearance of the liver, and ultrasound­ guided hepatic aspiration cytology. Liver biopsy is not necessary to diagnoseHL; however, underlying cholangitis/ cholangiohepatitis or hepatic lymphoma may eventually require biopsy for definitive diagnosis. Cytology preparations show profound vacuolar distention of hepato­ cytes involving >800,1, of hepatocytes aspirated. Canalicular cholestasis is conunonly seen. Mistaken aspiration of omental fat rather than liver is easily deduced by the absence of hepatocytes. Treatment ofHL is aimed at correcting fluid, electrolyte, and metabolic deficits and initiating food intake. Because cats withHL may have high lactate concentrations and may not be able to metabolize acetate, 0.9% NaCl is the fluid of choice. Fluids should not be supplemented with dextrose, because this will reduce utilization of intraliepatic fatty acids for (3-oxidation. Because affected cats are usually overconditioned, fluid tl1erapy must be based on ideal body weight. Overhydration is common when fluid dosage is based on total overconditioned body weight and can lead to pleural and abdominal effusion and pulmonary edema. Fluids should be appropriately supple­ mented with potassim11 (using the sliding scale) based on electrolyte status. If initial serum phosphate concentration is low (l hr) constant-rate infusion, because it may induce hyperanm10nemia by deviating substrates from the urea cycle. Vitamin K, is given with a small needle (0.5--1.5 mg/kg, SC or IM, three doses given at 12-hr intervals) before procedures that might provoke bleeding (eg, insertion of a jugular catheter, esophageal feeding tube, cystocen­ tesis, or hepatic aspiration sampling). Some cats may develop renal potassium wasting as a result of underlying renal disease or lipid accwnulation in their renal tubules. The fractional excretion of potassium can be estimated by measming potassium and creatinine in sin1ultaneously collected baseline sernrn and urine san1ples: fi·actional potassiun1 excretion= ([urine potassium/urine creatinine] x [ serun1 creatinine/serun1 potassiwn]) x lOOOA,. In a hypokalemic cat, a value 200A,represent marked renal potassium wasting and indicate the need for aggressive potassium supplementation. Cats with prodigious potassium needs should have potassium gluconate added to their food as soon as oral intake is established. This will reduce the concentrations of potassiw11 needed in the IV fluids and associ­ ated risk of iatrogenic hyperkalemia Nutritional support is tl1e cornerstone of recovery (seep 439). Feeding is initiated after the cat is rehydrated and has reasonable electrolyte balance, because these are requisite factors enabling nom1al enteric motility. Because cats with HL are in metabolic liver failure, appetite stimulants are inappropriate; diazepam, oxazepam, cyproheptidine, and mirtazepine should not be used and will not recover an affected cat .

Occasionally, an appetite stin1ulant may help initiate feeding early in syndrome development. A palatable odiferous food should be offered initially. If the cat salivates or objects, all food should be removed because of the 1isk of inducing a "food aversion syndrome." If oral feeding is not tolerated, feeding a liquid diet (eg, CliniCare®) with supplements via a nasoesophageal tube is cautiously initiated as a first step. A 5--10 mL volun1e of tepid water is administered first to assess the cat's tolerance and response. If no vomiting or signs of discomfort are noted, the process is repeated with liquefied food. After a few days of nasoesophageal feeding, if the cat is judged to be a reason­ able anesthetic risk, an esophagostomy tube CE-tube) is placed with the distal tip 2-4 cm craniad to the esophageal-gastric junction. This should be docwnented with a lateral thoracic radiograph. A high-protein, calorie-dense, balanced feline diet is recommended for E-tube feeding. Only rarely should a protein­ restricted diet be used, because protein restriction can aggravate hepatic lipid accunmlation. Rather, use of lactulose and oral amoxicillin or low-dose metronidazole (7.5 mg/kg, bid) can optimize nitrogen tolerance to allow feeding of a nonnal feline diet (these measures modify enteric flora, substrate utilization, and increase colonic catharsis or cleansing). A munber of metabolic supplements have improved recovery of affected cats: taurine (250-500 mg/cat/day), medical grade liquid oral L-carnitine (250-500 mg/cat/day), vitamin E (10 IU/kg/day), and potassiun1 gluconate (if hypokalernia is persistent). Initial feedings are small and given frequently or by constant-rate infusion. On the first day, one-third to one-half of the cat's energy requirements are fed; the amount fed is then gradually increased over the next 2-4 days to the ideal intake. If vomiting occurs, electrolytes must be rechecked, feeding tube position verified, and factors relevant to the underlying disease process considered. Metoclopramide (0.05--0.1 mg/ kg, IM, up to tic!, or 0.25--0.5 mg/kg divided per day as a constant-rate infusion), ondansetron (0.025 mg/kg, IV, up to bid), or maropitant (1 mg/kg/day, no more than 5 days) may be used as antiemetics. Enteric motility may be stimulated by exercise during owner visits. To ave1t development of hypophos­ phatemia induced by re-feeding, which can cause weakness, hemolysis, encephalopa­ thy, and other adverse effects, sernm phosphorus concentrations should be

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HEPATIC DISEASE IN SMALL ANIMALS

serially monitored and supplemental potassium phosphate judiciously provided. Routine IV potassium phosphate supple­ mentation is administered when feeding is initiated to obviate persistent or feeding­ induced hypophosphatemia. If gastritis is suspected, an H 2-blocker (eg, famotidine or ranitidine) may be used, and carafate administered PO (but not via E-tube). If the cat tolerates oral medications, SAMe at 40 mg/kg/day is given between meals once N-acetylcysteine treatment is completed. SAMe supplementation must be accompa­ nied by sufficient B 12, folate, and other water-soluble vitaJnins to ensure optimal metabolic benefit (metabolism to glu­ tathione and methyl group donation for transmethylation reactions). Use of ursodeoxycholate in HL may be det1imental because TSBAs are extraordinarily high in these cats and because bile acid profiles resemble those associated with EHBDO (increased secondary bile acids). All bile acids are toxic to cells in high concentra­ tions and, in HL, bile acids are seemingly trapped by canalicular compression. In the rare circumstance that signs of HE are encountered, lactulose, amoxici.llin, or low-dose metronidazole (�7.5 mg/kg, PO, bid) may be useful. In symptomatic pancrea­ titis, feeding distal to the pancreas is done using a constant-rate infusion of CliniCare® mixed with supplemental pancreatic enzymes through ajejunostomy tube. Alternatively, parenteral nutrition can be provided, although this may delay recovery and provoke hepatic triglyceride retention. Prognosis for cats with HL is good with early diagnosis, full treatment support, and control of underlying disease. Monitoring liver enzymes has no value in predicting recovery. However, a decline in total bilirubin by 500/llwithin the first 7-10 days portends an excellent chance of full recovery. Concurrent pancreatitis is a poor prognostic indicator. Monitoring ALP of obese cats undergoing weight reduction may identify emerging HL that will allow suspension of the weight loss program and early treatment intervention. Recurrence of HL is rare in recovered cats.

BILIARY CIRRHOSIS Biliary cirrhosis refers to periportal bridging fibrosis associated with marked hepatic architectural remodeling and biliary hyperplasia subsequent to chronic (months) of EHBDO or years of nonsuppurative cholangiohepatitis. However, it is uncom­ mon in cats with cholangitis/cholangiohepa­ titis, because these animals usually

459

succumb before biliary cirrhosis develops. Biliary cirrhosis is misidentified in cats with ductal plate malfonnations (a form of polycystic liver disease). Clinical features of biliary cirrhosis include variable inappe­ tence, cachexia,jaundice, variable liver size, and ascites. Liver enzymes may be normal. Hypoalbuminemia, hyperglobulinemia, hyperbilirubinemia, and coagulopathies are common. The liver may be considered large on abdominal radiographs and appears nodular on ultrasonographic evaluation. Biopsies are needed for definitive diagnosis. Coagulation deficits complicate tissue sampling and necessitate vitan1in K1 supplementation and fresh frozen plasma transfusions before procedures. Tl'eatment is symptomatic, requiring management of HE, hypoalbuminemia, EHBDO, and ascites. Prognosis is generally poor. Biliary cirrhosis is most commonly seen in animals with chronic EHBDO caused by obstructive neoplasia. Although cholecystoenterostomy or choledochoenterostomy can avert progression of EHBDO to biliary cirrhosis, it introduces recurrent retrograde infection through biliary structures causing chronic or recurrent septic cholangitis.

CANINE CHOLANGIOHEPATITIS Cholangiohepatitis in dogs is rare and usually associated with suppurative inflammation and ascending biliary tree infection with a wide variety of bacterial organisms (both gram-negative and gran1-positive enteric bacteria, Salmonella, Campylobacterjejuni, coccidiosis). Canine cholangiohepatitis is most commonly associated with disorders causing stasis of bile flow, biliary mucocele fonnation, cholelithiasis, and surgical manipulations of the biliary tree. Clinical signs include anorexia, vomiting, diarrhea, lethargy, PU/PD, fever, and abdominal pain. Laboratory abnormalities are consistent with hepatic cholestasis and include hyperbili.rubinemia and increased activities of ALP, GGT, and transaminases. Ultra­ sonography may or may not reveal abnom1alities involving the biliary tree or gallbladder. In some cases, a coarse hepatic echogenicity is identified, reflecting portal tract inflan1matory infiltrates and connec­ tive tissue. In some cases, ultrasonographic findings may indicate need for emergency surgical intervention (eg, mature gallblad­ der mucocele, cholelithiasis associated with EHBDO). Aspirates or inlpression smears of liver or bile may reveal suppurative septic inflan1mation. Samples collected from liver, bile, and sections of the biliary tree should

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be submitted for aerobic and anaerobic culture and sensitivity. Antibiotic treatment should be based on cultured organisms, and other treatments should target underlying disease processes. Initial treatment with combination of ticarcillin, metronidazole, and enrofloxicin is commonly used before culture and biopsy results are available. For best outcome in animals undergoing surge1y, antinlicrobials should be started before the surgical procedure.

CANINE CHRONIC HEPATITIS Chronic hepatitis that does not focus on biliary structures is more common in dogs than cats. Several breeds are predisposed including Bedlington Terriers, Labrador Retrievers, Cocker Spaniels, Dobem1an Pinschers, Skye Terriers, Standard Poodles, West Highland White Terriers, Springer Spaniels, Chihualmas, and Maltese. Although there is an identifiable etiology for some categories of chronic hepatitis, in most cases the cause remains unidentified. Increased hepatocellular copper and Kupffer cell iron stores are common in dogs with chronic hepatitis. The degree of metal accmnulation and its acinar location help determine its relevance to tissue injmy. Other associated conditions include infectious canine hepatitis, chronic hepatitis secondaiy to infectious processes, and chrome exposure to xenobiotics (including certain drugs, biologic toxins, and chemicals). Terminology that reflects specific etiology or breed predilection, such as drug-associated chronic hepatitis infectious chronic hepatitis, copper-�soci­ ated hepatitis, etc, is preferred. The tem1 idiopathic chronic hepatitis indicates that an etiology has not been determined. Histopathologic changes.are generally similar in all cases of chronic hepatitis, regardless of the underlying cause, and include a lyrnphocytic-plasmacytic inflanunation with infiltrates extending into hepatic parenchyma, variable single cell or piecemeal necrosis, and in advanced disease development of bridging fibrosis and nodulal regeneration. The acinai· zone of involve­ ment varies with the tu1derlying cause.

Copper-associated Hepatopathy

Copper-associated hepatopathy is a leading cause of chronic hepatitis in dogs, increasing in prevalence since 1997 when copper supplements in cmmnercial dog foods were modified to a more bioavailable fonn. Retrospective evaluation ofliver

biopsies from Labrador Retrievers and Doberman Pinschers from 1980 to 2013 indicated that dogs of these breeds, with and without chronic hepatitis, had significantly higher hepatic copper concentrations in the last 10 yr of the study. Management of body copper homeostasis relies on ntu11erous copper transporters, chaperones, and binding proteins, as well as biliaiy canalicular egress. Copper-associ­ ated hepatopathy is best characterized in Bedlington Terriers, which have a mutation (deletion of exon 2) of the COMMD1 copper transpo1ter protein. Careful breeding prograins guided by liver biopsy and genetic testing (PCR gene mutation test) have remarkably reduced disease frequency in Bedlington Terriers. However, some Bedli..ngton Terriers with biopsy-confirmed copper-associated hepatopathy lack this specific gene mutation. Failure to excrete copper into bile leads to chronic hepatitis and, eventually, cirrhosis and liver failure. Affected dogs develop high liver copper concentrations by 1 yr of age (normal: 12,000 ppm). Liver injmy is reflected by increased ALT activity and has been shown in dogs with hepatic copper as low as 600 ppm. Three disease phases were historically chai·acterized in Bedlington Terriers. Acute hepatic necrosis occurred in dogs 1 mo. Horses treated with flunixin meglwnine should also be observed for signs of GI ulceration, and concurrent prophylactic ad!ninistration of omeprazole (2 mg/kg/day, PO) may be indicated. Iffluni.xin meglunune is not tolerated, phenylbutazone (2-4 mg/kg, PO, once to twice daily) or aspirin (10-25 mg/kg, PO, once to twice daily) can be used alternatively, but neither is as potent or effective. Historically, horses with frequent recurrences or chronic, low-grade uveitis were managed medically with daily (or every

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other day) doses of oral phenylbutazone or aspirin. Although most horses tolerate this regimen well, these medications can have adverse GI, hematologic, or renal effects, and these regimens frequently do not eliminate recurrence. Systelnic steroids, specifically pred!Iisolone (100-300 mg/day) and dexan1etl1asone (5-10 mg/day) have also been successfully used to treat acute uveitis episodes, but their longtern1 use has been associated with larninitis. Except in cases when bacterial infection is present, systelnic antibiotics are not indicated. Topical steroidal medications, including dexamethasone (0.1% suspension or ointment) and prednisolone acetate (1% suspension), are very effective at decreasing inflanm1ation. Topical acetate and suspen­ sion preparations of steroids a.re designed to penetrate tl1e cornea and achieve adequate uveal concentrations and a.re thus preferred to sodium phosphate fornmla.tions. Topical hydrocortisone should be a.voided, because it lacks adequate corneal penetration and is not sufficiently potent to treat anterior uveitis. A fluorescein stain is warranted before initiation of topical steroids, because tl1ese medications are contraindicated witl1 corneal ulceration and/or infection. Topical nonsteroidal medications include flurbipro­ fen (0.03"Aisolution) and diclofenac (0.1% solution); they are less potent than topical steroids but offer a wider safety margin in cases of concurrent corneal disease. Frequency of administration depends on inflammation severity; initially, administra­ tion may be 4-6 times daily. With improve­ ment in clinical signs, frequency of administration of topical steroidal or nonsteroidal medications can be gradually decreased. However, therapy should continue for 1 mo after complete resolution of active inflanm1ation. Topical atropine (1 % solution or ointment) ca.uses mydriasis (which decreases the likelihood of posterior synechia fonnation) and cycloplegia. (which decreases pain associated with ciliary body muscle spasm) and stabilizes the blood­ a.queous barrier. Atropine is applied topically 2--3 times daily w1til the pupil is widely clilatecl; tl1e frequency can then be adjusted to maintain myd!iasis. Because atropine decreases GI motility, horses treated with topical atropine should be monitored for signs of ileus. If frequent topical medication is not possible, subconjw1ctival injections of triamcinolone acetanucle (1-2 mg) provide adequate intra.ocular anti-inflanm1atory concentrations for 7 1-0 days and are less likely to cause abscess or granuloma formation than other steroids, including methylprednisolone acetate (10-40 mg).

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However, all subconjunctival steroids should be used with caution, because they cannot be easily removed once iJ\iected and can have devastating consequences if an infectious component is present or a corneal ulcer develops. Two surgical procedures are commonly used in longterm management. A supracho­ roidal cyclosporine implant is a sustained­ release medication device that provides ther­ apeutic concentrations of cyclosporine A, an immunosuppressive T-cell inhibitor, for -3yr after implantation. During this pro­ cedure, a cyclosporine A disk ( -5 mm in diameter) is implanted under a scleral flap created -8 mm posterior to the dorsolat­ eral aspect of the limbus. Horses with implants have markedly fewer uveitic episodes than they did before surgery, and this device results in effective longterm control ofERU. Core vitrectomy removes virtually all of the vitreous through an incision posterior to the dorsolateral

aspect of the limbus. The vitreous is then replaced with either balanced salt solution or saline. The theorized benefit of this procedure is that organisms, especially Leptospira spp, and/or inflammatory cells in the vitreous significantly contribute to the chronic inflanunation ofERU. By removing these factors, the frequency and severity of uveitic episodes are minimized. Good husbandry practices to manage ERU ensure proper health maintenance, prevent ocular trauma, and reduce environmental triggers. Specific manage­ ment recommendations include routine dewornling and vaccinations, proper nutrition and dental care, a quality fly mask, minimizing contact with cattle or wildlife, draining stagnant ponds or restiicting access to swampy pastures, effective fly control, and frequent bedding changes. Although such measures benefit individual horses, the extent to which they impact the clinical course ofERU has not been evaluated.

EYEWORM DISEASE (Thelaziasis)

LARGE ANIMALS Etiology and Epidemiology: Eye­ worms (Thelazia spp) are common parasites of horses and ca.ttle in many countries, including those of North America. Horses are infected primarily by T lacrymalis, whereas cattle are mainly infected by T gulosa, T skrjabini, and T rhodesii. The latter is the most common and harmful to cattle in the Old World, but it has not been recently reported in North America. The prevalence of Thelazia spp in livestock has declined in at least some areas where macrocyclic lactone endecto­ cides such as ivennectin and doramectin are in common use. Thelazia spp are also found in pigs, sheep, goats, deer, water buffalo, dromedaries, hares, dogs and cats (seep 512), birds, and people. The face fly, Musca autumnalis, is the vector of T lacrymalis, T gulosa, and T skrjabini in North America. Feeding habits of this fly include a preference for ocular secretions, which are ideal for transmission. The life cycle of Thelazia is as follows: female wom1s are ovovivi p a ­ rous and discharge larvae into the ocular

secretions; the larvae are ingested by the fly and become infective in 2-4 wk. Infective third-stage larvae emerge from the labellae of infected flies and are mechanically deposited in the host's eye by the fly during feeding. Development of sexually mature worn1s takes 1-4 wk in cattle, depending on worm species, and 10-11 wk for T lacry­ malis in horses. Infections may be found year-round, but clinical disease outbreaks, particularly in cattle, usually are associated with warm season activities of the flies. Thelazia sp larvae may overwinter in face flies. Infection rates generally tend to increase witll advancing host age, although some studies report maxin1al levels in hosts 2 3 - yr old. Pathogenesis: The lacrimal gland and its ducts are conunon sites for T lacrymalis and T gulosa, with the glands of the nictitating membrane and the nasolacrimal ducts less so. T skrjabini is normally found within the lacrimal ducts of the nictitating membrane. Superficial locations on the cornea, in the cortjunctival sac, and under the eyelids and nictitating membrane are more typical for T rhodesii, but T lacryma-

EYEWORM DISEASE

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lis, Tskrjabini, and Tgulosa may be found

in these sites, too. Wonns may also be found on the periorbital hair or skin dming anesthesia or following migration after death of the host. Localized irritation and inflammation is likely due to the serrated cuticle of the worms, especially for Trhodesii. Invasion of the lacrin1al gland and excretory ducts may cause inflan1ma­ tion and necrotic exudation. Inflan1mation of the lacrimal ducts and sac has also been reported in horses. Mild to severe conjunc­ tivitis and blepharitis are common. Also, keratitis, including opacity, ulceration, perforation, and permanent fibrosis, may develop in severe cases, particularly with Trhodesii infection in cattle. Clinical Findings and Diagnosis:

Asymptomatic infections in horses and cattle appear to be typical of thelaziasis in North America. Infection may be encountered incidentally during surgery or at necropsy. However, 17ielazia infections in cattle in North America may not always be innocuous. They may produce mild conjunctivitis, excessive lacrimation, localized edema, corneal clouding, and occasionally, subconjuncti­ val cysts. In Europe and Asia, thelaziasis is commonly associated with severe clinical manifestations, including conjunctivitis, photophobia, and keratitis. Characteristically, there is chronic conjunctivitis with lymphoid hyperplasia and a seromucoid exudate. A clinically feasible technique for reliable detection of adult eyeworrns is lacking. Gross inspection of the eyes may reveal the worms and is generally recommended for Trhodesii, commonly found in the conjunctiva! sac. However, Tgulosa and T skrjabini in cattle, and Tlacrymalis in horses, tend to be more invasive and are less apt to be seen. Topical anesthetics allow for tissue manipulation and are useful for detection and recovery of worn1s. Microscopic examination of lacrimal fluids for embryonated eggs or larvae may be attempted. Clinical signs may be helpful in differential diagnosis. Thelaziasis tends to cause a chronic conjunctivitis. In cattle, infectious keratoconjunctivitis (see below) is an acute, rapidly spreading infection of the cornea. In horses, infective larvae of the stomach worms Draschia and Habronema sp may also produce ophthalmic lesions. These tend to occur near the medial canthus of the eyelid and are raised, ulcerative granulo­ mas, often containing characteristic

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yellow, plaque-like "sulfur granules" 1 2mm in diameter. Likewise, microfilariae of Onchocerca sp invade the eye and may result in ophthalmic manifestations. Small ( 75% recurrence rate. Median survival time for animals with malignant ear canal tumors has been reported to be >58 mo in dogs and>11.7 mo in cats. Dogs with extensive tumor involvement had a less favorable prognosis. Radiation therapy can be used to treat excised ceruminous gland adenocarcinomas in dogs and cats, with a 56% 1 -yr survival rate reported. No data are available on the efficacy of chemotherapy for otic tumors of dogs and cats. Prognosis of animals with otic neoplasms can best be determined by histopathologic examination of removed tissues.

NASOPHARYNGEAL POLYPS Nasopharyngeal polyps are uncommon, benign, smooth, pink, fleshy, pedunculated, inflammatory growths of connective tissue found in the external ear canals of young cats. They arise from the mucosa! lining of the tympanic bulla, the pharyngeal mucosa, or the auditory tube. These polyps may be congenital, or they may result from chronic bacterial otitis media, commonly found in cats with upper respiratory diseases. They are rarely found in dogs. They are not neoplastic, and viruses have not been identified in polyp tissue. Diagnosis involves sedation and deep otoscopic examination of the horizontal canal. Purulent discharge from the bulla may need to be flushed and suctioned from the ear canal to visualize the polyp. Use of a video otoscope greatly facilitates visualization and treatment of polyps. Polyps originating from the eustachian tube may be seen by retracting the soft palate rostrally. Radiography of the bullae may reveal an opacity in the affected bulla. CT or MRI may be helpful if a mass is suspected in the tympanic bulla that cannot be seen otoscopically. Definitive diagnosis is made via histopathology. Surgical removal is curative as long as the entire polyp and stalk are removed. This often involves performing a bulla osteotomy, because the base of the polyp is often in the tympanic bulla. Incomplete removal of the base of the polyp by traction avulsion alone leads to rapid regrowth and return of clinical signs in 15o/o-50% of cats. Topical steroids in the bulla for 30-45 clays seems to retard this regrowth. Systemic antibiotic therapy for the bacterial otitis media is also indicated.

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ENDOCRINE SYSTEM 538 General Chemical Structure and Function Measurement of Hormones 540 Regulation of Endocrine Systems 540 Pathogenesis of Endocrine Disease 541 Principles of Therapy 542

INTRODUCTION

538

542 Hyperadrenocorticism 543 Nonfunctional Pituitary Tumors 547 Hirsutism Associated withAdenomas of the Pars Intermedia Adult-onset Panhypopituitarism 548 Juvenile-onset Panhypopituitarism 549 Diabetes Insipidus 550 FelineAcromegaly 551

THE PITUITARY GLAND

547

552 Hypothyroidism 553 Non-neoplastic Enlargement of the Thyroid Gland (Goiter) 558 Hyperthyroidism 559

THE THYROID GLAND

THE PARATHYROID GLANDS AND DISORDERS OF CALCIUM METABOLISM 561

Calcium Physiology and Calcium-regulating Hormones 561 Hypercalcemia in Dogs and Cats 562 Hypercalcemia of Malignancy 563 Primary Hyperparathyroidism 564 HypercalcemiaAssociated with Hypoadrenocorticism 565 Renal Failure 565 Idiopathic Hypercalcemia of Cats 565 Other Causes of Hypercalcemia 566 Diagnostic Tests 567 Treatment 568 Hypercalcemia in Horses 570 Hypocalcemia in Dogs and Cats 570 Hypoparathyroidism 570 Other Causes of Hypocalcemia 571 Treatment 572 Hypocalcemic Disorders of Horses 572

573 Adrenal Cortex 573 Hyperadrenocorticism 573 Hypoadrenocorticism 574 Adrenal Medulla 575

THE ADRENAL GLANDS

538

ENDOCRINE SYSTEM

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NEUROENDOCRINE TISSUE TUMORS

Adrenal Medulla 576 Thyroid C-cell Tumors 577 Chemoreceptor Organs 578

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579 Diabetes Mellitus 579 Functional Islet Cell Tumors 582 Gastrin-secreting Islet Cell Tumors 583

THE PANCREAS

ENDOCRINE SYSTEM INTRODUCTION The endocrine system encompasses a group of tissues that release hormones into circ­ ulation for travel to distant targets. An endocrine tissue is typically a ductless gland (eg, pituitary, thyroid) that releases its hormones into capillaries permeating the tissue. These glands are richly supplied with blood. However, nontypical endocrine tissues also contribute important hom1ones to circulation, eg, secretion of atrial natriuretic peptide from the heart, erythropoietin from the kidney, insulin-like growth factor from the liver, and leptin from fat. New hormones continue to be discovered. Some act only on a single tissue, whereas others have effects on virtually all cells of the body. The effects of hormones on tl1eir targets are varied­ from enhancement of nutrient uptake to altering cell division and differentiation, among many others.

GENERAL CHEMICAL STRUCTURE AND FUNCTION There are three main chemical categories of hom1ones: protein/polypeptides, steroids, and those made from modified an1ino acids. Protein/Polypeptide Hormones:

Examples of protein/polypeptide hom1ones include adrenocorticotropin (ACTH) from the pituitary, insulin from the pancreas, and parathyroid hormone (PTH). These honnones range in size from three an1ino acids (thyrotropin-releasing hom1one) to considerably larger proteins with subunit structure (eg, luteinizing hormone). They are produced in their endocrine tissue of origin by transcription/translation of the gene coding for the hormone and synthe-

sized initially as larger products (preproor pre-fom1s) that undergo processing to authentic hormone inside tl1e cell before secretion. Embedded in the gene coding for protein structure are amino acid sequences (signal peptides) that conununicate to the cell that these molecules are destined for tl1e regulated secretory pathway. Other post-translational modifications may occur during processing, including folding, glycosylation, disulfide bond formation, and subunit assembly. The folded and processed hormone is then stored in secretory granules or vesicles in preparation for release by the exocytotic process. Release of hormone is triggered by unique signals; eg, secretion of PTH is stimulated by a decline in the concentration of ionic or free calcium present in the extracellular fluid bathing the parathyroid chief cells. In most cases, cells producing protein/polypeptide hormones store significant amounts of these substances intracellularly; therefore, they can respond quickly when increased amounts are needed in circulation. Gener­ ally, protein/polypeptide hormones have relatively short half-lives in blood (minutes) and do not travel in blood-bound carrier proteins (exceptions exist, eg, insulin-like growth factor 1 is highly protein bound). Protein/polypeptide hormones act on their target cells by binding to receptors located on the cell surface. These receptors are proteins and glycoproteins embedded in the cell membrane that traverse the membrane at least once so that tl1e receptor is exposed to both tl1e extracellular and intracellular environments. There are several classes or types of cell surface hom1one receptors tl1at translate tl1e hormonal message to tl1e cell

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interior by different means. Some are the G-protein (guanosine) coupled type, with seven transmembrane spanning domains. After hormone binding, these receptors activate a G-protein that is also located in the membrane. One or more of the G-protein subunits affects other downstream molecules (known as effectors) such as enzymes (eg, adenylate cyclase or phospho­ lipase C) or ion channels. Activation may result in production of a second messenger, such as cyclic AMP, that can then bind to protein kinase A, causing its activation and subsequent phosphorylation of other proteins. Thus, signal transduction is a cascading and often an1plifying series of events triggered when a hormone binds to its receptor. The ultin1ate effects in target cells are multiple and include such things as triggering secretion, increasing uptake of a molecule, or activating mitosis. Other receptors, such as the one for insulin, not only bind h01mone but also act as enzymes, with the ability to phosphorylate tyrosine residues. The phosphorylated tyrosines in turn serve as docking sites for downstream signaing proteins. Cell surface receptors are dynamic; their numbers and/or activity change with physiologic conditions. In some cases, such as exposure to excessive amounts of hom1one, receptor down-regulation can occur. Down-regulation and a decline in target tissue responsiveness may be due to internalization of receptors after ligand binding or to desensitization whereby the receptor is chemically modified and becomes less active. Conversely, a lack of hormonal exposure can lead to an increase in receptor numbers on target cells ( up-regulation). Diseases have been linked to mutations in hormone receptors, which can result in inactivation or constitutive or nonhom1onal activation of the pathway. In some instances, a single an1ino acid substitution is responsible.

Steroid Hormones: Steroid honnones are derivatives of cholesterol and include products of the adrenal cortex, ovaries, and testes as well as the related molecule, vitamin D. Unlike protein/polypeptide hormones, steroid hormones are not stored in large amounts. When needed, they are rapidly synthesized from cholesterol by a se1ies of enzymatic reactions. Most of the cholesterol needed for rapid steroid hormone synthesis is stored intracellularly in the tissue of origin. In response to approp1iate signals, the precursor is moved to organelles (mitochondria and smooth endoplasmic reticulum), where a series of

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enzymes (eg, isomerases, dehydrogenases) rapidly convert the molecule to the appro­ priate steroid hormone. The identity of the final steroidal product is thus dictated by the set of enzymes expressed in that tissue. Steroid hom10nes are hydrophobic and pass through cell membranes easily. In the blood, they are bound to a great extent to cairier proteins. Albumin binds many steroids fairly loosely; in addition, specific binding globulins exist for many steroid hormones. Most of the steroid hormone in circulation is botmd to catTier proteins, and a small fraction circulates free or unbound. This latter fraction is thought to be available for target cell entry, ie, the biologically active portion. A rapid equilibrium exists between protein-bound and unbound steroid in extracellulai· fluid. Possible roles for steroid hormone-binding proteins include aiding in tissue delivery of steroids by providing an even distribution to all cells within a target tissue, buffe1ing against large fluctuations in free honnone, and prolong­ ing the half-life of steroids in blood. Relative to protein/polypeptide hon11ones, steroids usually have longer half-lives, often in the range of many minutes to hours. Steroid hormones act on target cells via receptors located in the cell interior. These receptors are generally found in the nucleus, although some appeai· to reside, when unoccupied, in the cytoplasm. There are several classes of steroid receptors-those for glucocorticoids, rnineralocorticoids, progestins, etc. Steroid receptors comp1ise a family of related proteins that also show homology to receptors for the thyroid hormones and vitan1in D. The receptor has regions or domains that CatTY out specific tasks: one for recognition and binding of the steroid, another for binding to a specific region on chromosomal DNA, and a third for helping regulate the transcriptional complex. Steroid hormones enter targets by diffusing through the cell membrane and then binding to the receptor, causing a confom1ational change in the new complex. This, in turn, leads to release of associated proteins (eg, heat-shock proteins) and movement to the nucleus (if necessary), followed by binding of the complex to regions of DNA located near specific steroid-regulated genes. The result is a change in the rate of transc1iption of specific genes, either increasing or decreasing their expression. Thus, steroid hon11ones prin1aiily function by affecting the production rates of specific messenger RNA and proteins in targets. Steroid action is relatively slow in onset (hours) but may be long lasting because of the duration of production and half-lives of the messenger

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RNA and proteins induced in target cells. It is increasingly clear that some steroids also act via nongenomic mechanisms. For exan1ple, many of the anti-inflammatory effects of glucocorticoids are thought to be due to the glucocorticoid-receptor complex binding to, and inhibiting the action of, pro­ inflan1111ato1y transcription factors inside cells. Steroids in the blood are elin1inated by metabolism in the liver. Reduced forms are produced and subsequently coajugated to glucuronic acid and sulfate. These metabolites a.re freely soluble in blood and are eliminated from the body by renal excretion and tllrough the GI tract. Small amounts of free steroid h01mone are also directly excreted by the kidneys. Modified Amino Acid Hormones:

This class of hom1ones is made by chemi­ cal modification of amino acids, mainly tyrosine. They include thyroid hormones and the catecholamines epinephrine and norepinephrine. Thyroxine (T4) and triiodothyronine (T3) are stored in the thyroid as a part of thyroglobulin; secretion of these hormones involves thyroidal cell uptake and breakdown of this large molecule liberating T4 and T3• Thyroid hormones act on targets much like steroids; they are relatively water insoluble, transported by carrier proteins in blood, and act on targets via intracellu­ lar receptors. Catecholamines are manufactured by hydroxylation, decar­ boxylation, and methylation of tyrosine and are secreted into the blood from the adrenal medulla: They have exceedingly short half-lives ( 3 yr) and the occurrence of hypopituita.J.ism, cranial and optic nerve damage, and radiation injury to the hypothalamus. The short-te1111 prognosis in cats with untreated acromegaly is fair to good. Insulin resistance is generally controlled satisfacto­ rily by using large doses of insulin divided into several daily doses. Mild cardiac disease can be managed with diuretics and vasodilators. The longterm prognosis is relatively poor, however, and most cats die of congestive heart failure, chronic renal failure, or signs of an expanding pituitary mass. The longterm prognosis may improve with early diagnosis and treatment.

THE THYROID GLAND All vertebrates have a thyroid gland. In mammals, it is usually bilobed and located just caudal to the larynx, adjacent to the lateral surface of the trachea. The two lobes may be connected by a fibrous isthmus (eg, ruminants, horses), or a connecting isthmus may be indistinct (eg, dogs, cats). The gland is extremely vascular. In birds, it is found within the thoracic cavity; both lobes are located near the syrinx, adjacent to the

carotid artery near the origin of the vertebral artery. Ectopic or accessory thyroid tissue is relatively common in most species, especially dogs and cats. It may be located anywhere from the larynx to the diaphragm and may be responsible for maintaining nom1al thyrnicl function after surgical thyroidectomy. In addition, ectopic thyroid tissue occasionally is the site of hyperpla­ sia or neoplasia.

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Physiology: Thyroid hormones are the only iodinated organic compounds in the body. Thyroxine (T4) is the main secretory product of the nonnal thyroid gland. However, the gland also secretes 3,5,3' triiodothyronine (T3), reverse T3, and other deiodinated metabolites. T3 is -3-5 tin1es more potent than T., whereas reverse T3 is thyromimetically inactive. Although all T4 is secreted by the thyroid, a considerable amount of T3 is derived from T,1; therefore, T4 has been called a proh01° mone. Its activation to the more potent T3 is a step regulated individually by peripheral tissues. Thyroid ho1mone secretion is regulated primarily via negative-feedback control through the coordinated response of the hypothalamic-pituitary-thyroid axis: thyrotropin-releasing honnone (TRH) binds to the thyrotroph ceU in the pituitary and stimulates secretion of thyrotropin (thyroid-stimulating honnone, TSH), which binds to the follicular ceU membrane and stinrnlates thyroid honnone synthesis and secretion. Thyroid h01mones a.re water-insoluble lipophilic compounds that a.re bound to plasma proteins (thyrnxine-binding protein, thyroxine-binding prealbun1in [ transthyre­ tin], and albunlin). The major function of the thyroid honnone-binding proteins is probably to provide a hormone reservoir in the plasma and to "buffer" hormone delivery into tissue. In healthy �uthyroid animals, 0.1%of total semm T4 is free (not bound to thyroid honnone-binding proteins), whereas -1 %of circulating T3 is free. Evidence suggests that the fractions of circulating free T4 and free T3 dete1mine the an1ount of honnone available for uptake by tissues. Action of Thyroid Hormones: Thyroid

honnones act on many different cellular processes; however, no single reaction or metabolic event can be equated with their action. Although both T4 and T3 have intrinsic metabolic activity, T3 is 3-5 times more potent in binding to the nuclear receptors and sinlila.rly more potent in stimulating oxygen conswnption. Effects of thyroid hormones generally a.re divided into two categories: tl10se that mani­ fest within minutes to homs after honnone receptor binding and do not require protein synthesis, and those that manifest later (usually >6 hr) and require synthesis of new proteins. About half the increase in oxygen consun1ption produced by thyrnid h01mones is related to activation of the plasma membrane-bound Na+/K+ ATPase;

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thyroid horn1ones also stimulate mitochon­ drial oxygen consumption. These changes a.re linked directly to the calorigenic effect of thyroid honnones. More chronic effects invariably a.re related to the cellular actions that require interaction with nuclear T3 receptors, foUowed by an increase in protein synthesis crucial to physiologic processes such as growth, differentiation, proliferation, and maturation. Thyroid honnones, in physiologic quan­ tities, a.re anabolic. In coajunction with growth hormone and insulin, protein synthesis is stimulated and nitrogen excretion is reduced. However, in excess 01ype1thyroidism), they can be catabolic, witil increased gluconeogenesis, protein breakdown, and nitrogen wasting.

HYPOTHYROIDISM In hypothyroidism, impaired production and secretion of tile tl1yroid hormones result in a decreased metabolic rate. This disorder is most common in dogs but also develops rarely in otiler species, including cats, horses, and otiler large, domestic animals.

Etiology: AJU1ough dysfunction anywhere in tile hypotilalamic-pituitary-thyroid a.xis may result in tilyroid honnone deficiency, >95% of clinical cases of hypotilyroidism in dogs appear to result from destruction of tile tilyrnid gland itself (primary hypotlw­ roidism). The two most common causes of adult-onset primary hypotilyroidism in dogs include lymphocytic tilyroiditis and idippatllic atrophy of tile tl1yroid gland. Lymphocytic tilyroiditis, probably immune-mediated, is characterized histologically by a diffuse infiltration of the gland by lyn1phocytes, plasma cells, and macrophages and results in progressive destruction of follicles and secondary fibrosis. Idiopatllic atrophy of tl1e thyrnid gland is characterized histologically by loss of thyroid pa.renchyma and replacement by adipose tissue. (See also AUTOIMMUNE THYROIDITIS, p 831.) In dogs, the most common cause of secondary hypotilyroidism is destruction of pituitary thyrotrophs by an expanding, space-occupying tumor. Because of tile nonselective natme of tile resulting compressive atrophy and replacement of pituitary tissue by such large tumors, deficiencies of otiler (one or more) pituitary hormones also usually occm. Other rare fonns of hypothyroidism in dogs include neoplastic destruction of tilyrnid tissue and congenital (or juvenile-onset) hypotily:roidism. Congenital

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primary hypothyroidism may result from one of various forms of thyroid dysgenesis (eg, athyreosis, thyroid hypoplasia) or from dyshormonogenesis (usually an inherited inability to organify iodide). Congenital secondary hypothyroidism (associated with clinical signs of disproportionate dwarfism, lethargy, gait abnormalities, and constipation) has been reported in Giant Schnauzers, Toy Fox Terriers, and Scottish Deerhounds. Congenital secondary hypothyroidism also has been reported in Gennan Shepherds with pituitary dwarfism associated with a cystic Rathke's pouch. However, the degree ofTSH deficiency in these dogs is variable, and clinical signs are usually caused primarily by deficiency of growth hormone (rather than thyroid hormone). In cats, iatrogenic hypothyroidism is the most common form. Hypothyroidism develops in these cats after treatment for hyperthyroidism with radioiodine, surgical thyroidectomy, or use of an antithyroid drug. Although naturally occurring hypothyroidism is an extremely rare disorder in adult cats, congenital or juvenile-onset hypothyroidism does also occur. Recognized causes of congenital hypothyroidism in cats include intrathyroi­ dal defects in thyroid hormone biosynthesis (dyshonnonogenesis), an inability of the thyroid gland to respond toTSH, and thyroid dysgenesis. All reported cats with hypothyroidism have had the primary (thyroidal) disorder. Secondary (pituitary) or tertiary (hypothalamic) hypothyroidism has not been well described in either juvenile or adult cats but has been reported after severe head trauma. In foals, congenital hypothyroidism may develop when pregnant mares graze plants that contain goitrogens, or are fed diets either deficient in or containing excessive amounts of iodine. Most commonly, congenital hypothyroidism develops in association with a specific syndrome of neonatal foals characterized by thyroid gland hyperplasia together with multiple congenital musculoskeletal anomalies. This syndrome, reported most commonly in western Canada, has been referred to as either thyroid hyperplasia and musculoskeletal deformities syndrome or as congenital hypothyroid­ ism and dysmaturity syndrome and may be related to feeding a high nitrate diet to pregnant mares. In adult horses, hypothyroidism appears to be very rare but, as in other species, is commonly misdiagnosed.

Clinical Findings: Although onset is

variable, hypothyroidism is most common in dogs 4--10 yr old. It usually affects mid­ to large-size breeds and is rare in toy and miniature breeds. Breeds repmted to be predisposed include the Golden Ret1iever, Doberman Pinscher, Irish Setter, Miniature Schnauzer, Dachshund, Cocker Spaniel, and Airedale Terrier. There does not appear to be a sex predilection, but spayed females appear to have a higher risk of developing hypothyroidism than intact females. A deficiency of thyroid ho1mone affects the fw1ction of all organ systems; as a result, clinical signs are diffuse, variable, often nonspecific, and rarely pathogno­ monic. Although the disorder should be highly suspect, overdiagnosis should be avoided, because many diseases, especially those of the skin, can easily be misdiag­ nosed as hypothyroidism. Many of the clinical signs associated with canine hypothyroidism are directly related to slowing of cellular metabolism, which results in development of mental dullness, lethargy, exercise intolerance, and weight gain without a corresponding increase in appetite. Mild to marked obesity develops in some dogs. Difficulty maintaining body temperature may lead to frank hypother­ mia; the classic hypothyroid dog is a heat-seeker. Alterations in the skin and coat are common. Dryness, excessive shedding, and retarded regrowth of hair are usually the earliest dennatologic changes. Nonpruritic hair thinning or alopecia (usually bilaterally syn1rnetric) that may involve the ventral and lateral trunk, the caudal surfaces of the thighs, dorsum of the tail, ventral neck, and the dorsurn of the nose is seen in about two-thirds of clogs with hypothyroidism. Alopecia, sometimes associated with hyperpigmentation, often starts over points of wear. Occasionally, secondary pyodenna (which may produce pruritus) is seen. In moderate to severe cases, thickening of the skin occurs secondary to accwnula­ tion of glycosanlinoglycans (mostly hyaluronic acid) in the dennis. In such cases, myxedema is most common on tl1e forehead and face, resulting in a puffy appearance and thickened skin folds above the eyes. This puffiness, together with slight drooping of the upper eyelid, gives some clogs a "tragic" facial expression. These changes also have been described in the GI tract, heart, and skeletal muscles. In intact dogs, hypothyroidism may cause vaiious reproductive disturbances: in females, failure to cycle (a11estms) or

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sporadic cycling, infertility, abortion, or poor litter survival; and in males, Jack of libido, testicular atrophy, hypospennia, or infertility. A variety of neurologic disorders, including megaesophagus, laryngeal paralysis, facial nerve paralysis, and vestibular disease, have been related to hypothyroidism. However, all such peripheral and central nervous disease is uncommon, at least compared with the metabolic and dermatologic changes commonly seen in hypothyroid dogs. In addition, such neurologic signs do not always resolve after thyroid ho1mone replacement therapy. Myxedema coma, a rare syndrome, is the extreme expression of severe hypothyroid­ ism. The course can develop rapidly; lethargy progresses to stupor and then coma. The conunon signs of hypothyroid­ ism (eg, hair loss) are usually present, but other signs, such as hypoventilation, hypotension, bradyca.rdia, and profound hypothe1mia, are usually seen as well. During the fetal period and in the first few months of postnatal life, thyroid hormones are crucial for growth and development of the skeleton and CNS. Therefore, in addition to the well-recognized signs of adult-onset hypothyroidism, dispropor­ tionate dwarfism and impaired mental development (cretinism) are prominent signs of congenital and juvenile-onset hypothyroidism. In primary congenital hypothyroidism, enlargement of the thyroid gland (goiter) also may be detected, depend­ ing on the cause of the hypothyroidism. Radiographic signs of epiphyseal dysgen­ esis (underdeveloped epiphyses throughout the Jong bones), shortened vertebral bodies, and delayed epiphyseal closure are common. In dogs with congenital hypopituitarism (pituitary dwarfism, see p 549), there may be variable degrees of thyroidal, adrenoc01� tical, and gonadal deficiency, but clinical signs are primarily related to growth honnone deficiency. Signs include proportionate dwarfism (rather than the disproportionate fom1 of dwarfism characteristic of congenital hypothyroid­ ism), loss of primary guard hairs with retention of the puppy coat, hyperpigmenta­ tion of the skin, and bilaterally symmetric alopecia of the trunk. In adult cats, clinical signs associated with advanced or severe hypothyroidism include lethargy, dullness, nonpruritic seborrhea sicca, hypothem1ia, decreased appetite, and occasionally bradycardia. Obesity may develop, especially in cats with

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iatrogenic hypothyroidism, but it is not a consistent sign. Bilaterally syn1metric alope­ cia, except for pim1al involvement, does not appear to develop, but focal areas of alopecia over the craniolateral carpi, caudal hocks, and dorsal and lateral tailbase have occasionally been seen. However, in many cats with mild iatrogenic hypothyroidism, very mild or no obvious clinical signs are seen. In young cats with congenital or juvenile-onset hypothyroidism, the clinical signs are more obvious and include disproportionate dwarfism, severe lethargy, mental dullness, constipation, inappetence, and bradycardia. Diagnosis of Hypothyroidism: Hypothyroidism is probably one of the most overdiagnosed diseases in dogs. Many diseases and conditions can mimic hypothyroidism, and some of the clinical signs, even in dogs with normal thyroid function, can improve after administration of exogenous thyroid honnone. In addition, a variety of nonthyroidal factors (eg, nonthyroidal illness and prior administra­ tion of certain drugs) can lead to low serum thyroid hom1one measurements in euthyroid dogs, cats, and other species. Definitive diagnosis of canine hypothyroid­ ism requires careful attention to clinical signs and results of routine laboratory testing. Tests that may confirn1 the diagnosis include measurement of the serum concentrations of total T4, free T4, and TSH; provocative thyroid function tests (eg, TSH stimulation test); thyroid gland imaging; and response to thyroid hormone supplementa­ tion. Choice and interpretation of diagnostic tests is based heavily on the index of suspicion for hypothyroidism. There are well-recognized clinicopatho­ logic abnormalities associated with hypothyroidism, the severity of which usually correlates with the severity and chronicity of the hypothyroid state. These changes are nonspecific and may be associated with many other diseases in dogs. Their presence, however, adds supportive evidence for a diagnosis of hypothyroidism in a dog with relevant clinical signs. The classic hematologic finding associated with hypothyroidism, found in 400h-500/o of cases, is a normocytic, n01mochromic, nonregenerative anemia. The classic serum biochemical abnormality is hypercholesterolemia, which occurs in -800/o of dogs with hypothyroidism. The value of serun1 cholesterol dete1mination as a screening test for hypothyroidism cannot be overemphasized, because cholesterol con­ centrations are a sensitive and inexpensive

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biochemical marker for this disease in dogs. Other clinicopathologic abnorn1alities may include high serum concentrations of tri­ glyce1ides, alkaline phosphatase, and CK. TotalT, concentration is the most commonly performed static thyroid hormone measurement and is a good initial screening test for hypothyroidism, with a diagnostic sensitivity of -900/o. A dog or cat with aT4 concentration well within reference range limits may be assumed to have normal thyroid function. However, a subnormal basal T4 concentration alone is not diagnostic; it may indicate an animal that is norn1al, hypothyroid, or suffering from a nonthyrnidal illness with a second­ ary decrease in the basal T, concentration (sick euthyroid syndrome; see below). Because only the unbound fraction of sernmT4 is biologically active, measure­ ment of freeT4 has been hypothesized to be more useful to differentiate euthyroid 0.007% iodine) may resolve the goiter and associated clinical signs, but many die before or soon after birth. Prophylaxis is more effective than treatment. Using stabilized iodized salt or ensuring that the ration is balanced for iodine content is recommended in all areas known or suspected to be iodine deficient.

Iodine Toxicity: Goiter and hypothyroid­ ism occur in foals of dams fed excess iodine during gestation. Mares supplemented with iodine at �35 mg/day may produce affected foals. Foals receive the excess iodine both in utero and via the milk, because mares on high-iodine diets secrete higher than normal amounts of iodine in their milk. Clinical signs vary and may include goiter, weakness, and musculoskeletal abnormali­ ties. Mares are invariably asymptomatic. Foals may improve or recover once the excess iodine is removed.

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Goitrogenic Substances: Certain plants may produce goiter when ingested in sufficient an1ounts, especially in the absence of adequate iodine intake. Soybeans are most notable, but cabbage, rape, kale, and turnips all contain less potent goitrogens. Cooking or heating (and the usual processing of soybean meal) destroys the goitrogenic substance in these plants. All of the goitrogenic substances act by interfering with production of thyroid hormone. As with iodine deficiency, the pituitary responds to the reduced circulat­ ing thyroid honnone levels by increasing its secretion ofTSH, which results in thyroid gland enlargement. In adult animals the disease is usually not significant, but severe thyroid enlargement and hypothyroidism may develop in newborns. Congenital Hypothyroidism and Dysmaturity Syndrome of Foals:

Congenital hypothyroidism and dysmatmity syndrome of neonatal foals was first recognized in the early 1980s and is characterized by hyperplasia of the thyroid gland, goiter, and multiple congenital musculoskeletal anomalies. It is most conunon in western Canada but has been seen in the Pacific Northwest and sporadi­ cally in other areas of the USA. There is no sex or breed predilection. Foals with this syndrome are born after a prolonged gest­ ation (340-400 days) but appear dysmature with pliable ears, muscle weakness, and incomplete skeletal development. Conunon musculoskeletal defects include flexural defomtities of the forelimbs, ruptured tend­ ons of the common digital extensor muscles, mandibular prognathia, and inunature carpal and tarsal bones. Multiple cases may appear on a farm, with no recurrence in subsequent years.The underlying etiology is unknown but may be the result of diets that contain high levels of nitrate ( eg, greenfeed) combined with low iodine intake or ingestion of an unidentified goitrogen. Most affected foals either die or are euthanized within the first week of life. Familial Dyshormonogenetic Goiter: Fanillial dyshonnonogenetic

goiter has been repmted in sheep, cattle, goats, and pigs and appears to be inherited as an autosomal recessive trait. Essentially, it is a genetic enzyn1e defect in the biosynthesis of thyroid hormones. As with iodine deficiency, reduced thyroid hormone production leads to secretion of increased levels ofTSH and subsequent goiter. Clinical signs may include subnormal growth rate, absence of normal wool development or a

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sparse coat, myxedematous swelling of subcutaneous tissues, and weakness. Many affected animals die shortly after bilth or are very sensitive to adverse environmental conditions. HYPERTHYROIDISM

Excessive secretion of the thyroid hormones, T4 andT3, results in signs that reflect an increased metabolic rate and produces clinical hyperthyroidism. It is most common in middle-aged to old cats but also develops rarely in dogs. Functional thyroid adenoma (adenoma­ tous hyperplasia) is the most conunon cause of feline hyperthyroidism; in --7CJ'lo of cases, both thyroid lobes are enlarged. Thyroid carcinoma, the prin1ary cause of hype1thyroidism in dogs, is rare in cats (1%-2%of hyperthyroidism cases). Clinical Findings and Diagnosis: The

most common signs include weight loss, increased appetite, hyperexcitability, polydipsia, polyuiia, and palpable enlarge­ ment of the thyroid gland. GI signs are also common and may include vomitiI1g, diatThea, and increased fecal volwne. Cardiovascular signs include tachycru·dia, systolic murnmrs, dyspnea., cru·diomegaly, and congestive heatt failure. Ra.rely, hype1thyroid ca.ts exhibit a.pathetic signs (eg, at1orexia, lethargy, and depression); weight loss remains a conunon sign in these cats. High basal serwn total thyroid hormone concentration is the hallmark of hyperthy­ roidism and confirms the diagnosis. Although serun1 total T,1 concentrations are high in most cats with hyperthyroidism, -5o/e>--Hl0A, of ca.ts have norn1al T4 values. Most ca.ts with normal serumT4 values have either mild or early hyperthyroidism or hyperthyroidism with concurrent nonthy­ roidal illness, which has caused suppression of a high totalT4 concentration to within reference range limits. In these ca.ts, a high freeT,1 concentration along with consistent history and physical exan1ina.tion findings is diagnostic of hype1thyroidism. Treatment: Cats with hyperthyroidism

can be treated by ra.dioiodine therapy, thyroidectomy, chronic administration of at1 antithyroid drug, or lifelong nutlitional therapy (iodin e -deficient diet). Radioactive iodine provides a silnple, effective, and safe treatment and is considered the trea.tlnent of choice.The ra.dioiodine is concentrated within the thyroid tun1or, where it selectively in·a.diates and destroys hyperfunctioning thyroid tissue.

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Surgical thyroidectomy is also an �ffective treatment for hyperthyroidism m cats. With unilateral thyroid tumors, r1emithyroidectomy corrects the hyperthy­ roid state, and thyroxine supplementation usually is not necessary. For bilateral thyroid tumors, complete thyroidectomy is indicated, but parathyroid function must be preserved to avoid postoperative hypocal­ cemia.Thyroxine supplementation should be started 1-2 days after complete thyroidectomy. If iatrogenic hypoparathy­ roidism develops, treatment with vitamin D and calcium is also indicated. Treatment with methimazole, an antithyroid drug, controls hyperthyroidism by blocking thyroid hormone synthesis. Carbimazole is a similar antithyroid drng available in many European countries, Australia, and Japan; it exerts its effects through immediate conversion to methima­ zole after administration. Propylthiouracil, another antithyroid drug, is not recom­ mended for use in cats because of the high incidence of serious adverse effects (especially hemolytic anemia and thrombo­ cytopenia).The recommended initial daily dose of methimazole is 2.5-5 mg in two divided doses.The dosage is acljusted to maintain circulating thyroid hormone concentrations within the mid-normal range and is given daily. Adverse effects, the more serious of which are ag.ranulocytosis and thrombocytopenia, develop in 600/o of cats treated. lpodate (308 mg iodine/500 mg calcium ipodate) is no longer marketed in the USA, but iopanoic acid (333 mg iodine/500 mg iopanoic acid) and diatrizoate meglumine (370 mg iodine/mL) have been used anecdotally in hyperthyroid cats at comparable dosages. None of these drugs provides complete resolution of clinical signs or biochemical features associated with hype1thyroidism. In addition, waning of the thyroid-lowering effect is common after 3 mo of therapy with any of these drugs. A fouth treatment option for cats witl1 hyperthyroidism is the use of a prescription diet with severely restricted iodine levels (Hill's® y/d FelineThyroid HealthTM).The basis for using this diet is that iodine is an essential component of bothT4 andT3; witl10ut sufficient iodine, tl1e thyroid cannot produce excess thyroid honnones.This is an iocline-deficient diet, containing iodine levels below the minimun1 daily require­ ment for adult cats. A major indication for use of this diet for management of feline hypeithyroidism is in cats that are not candidates for definitive treatment of the underlying thyroid tumor(s) with surgery or radioiodine, which remain the treatments of choice. In addition, nutritional management could be considered in cats whose owners are not able to give oral medication or i.n cats that develop adverse effects from methimazole or carbin1azole. Most hyperthyroid cats exclusively fed this iodine-restricted diet become euthyroid in 8-12 wk.This therapy appears to be more effective in cats with only moderate increases ofT4 than in cats with severe hyperthyroidism. Despite some advantages, nutritional management has disadvantages: 1) feeding this diet can only control (by withholding "fuel" for the thyroid tumor) but not cure hypertl1yroidism; 2) cats fed this diet must not eat any other cat diet, table food, or treats, because even tiny amounts of iodine can render the diet ineffective in controlling hyperthyroidism; and 3) relapse will occur if the diet is stopped, so the cat must eat only this diet for the rest of its life.

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THE PARATHYROID GLANDS AND DISORDERS OF CALCIUM METABOLISM In dogs, a thyroid tumor causing hyperthyroidism should always be presumed to be a carcinoma until proved otherwise. This is in contrast to the case in hyperthyroid cats, in which thyroid carcinoma is present in 18 mg/dL are often associated with severe, life-threatening signs. Polydipsia and polyuria are the most common signs of hypercalcemia and result from an impaired ability to concentrate urine and a direct stimulation of the thirst center. Anorexia, vomiting, and constipa­ tion can also develop as a result of decreased excitability of GI smooth muscle. Decreased neuromuscular excitability may lead to signs of generalized weakness, depression, muscle twitching, and seizures. There are many potential causes of hypercalcemia (see TABLE l ). In hypercalce­ mic dogs, neoplasia (lymphosarcoma) is

THE PARATHYROID GLANDS AND DISORDERS OF CALCIUM METABOLISM

563

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•4i=i•i• CAUSES OF HYPERCALCEMIA IN DOGS AND CATS Acromegaly

Apocrine gland adenocarcinoma Carcinoma (squamous cell, mammary, bronchogenic, prostate, thyroid, nasal cavity) Chronic and acute renal failure Factitious: lipemia, postprandial, young dog ( 1 yr) of --15%. Alternatively, glirnepiride and glyburide (other sulfonylureas) may be administered to cats at2 mg/day (glirne­ pi.ride) or 0.625 mg/day (glyburide). Acarbose, an oral a-glucosidase inhibitor, has also been used in cats at a dose of 12.5-25 mg, bid-tid, in cor\junction with diet and/or insulin to control hyperglycemia. Ketoacidosis is a serious complication of diabetes mellitus and should be regarded as a medical emergency. Therapy includes correcting dehydration by administration of IV fluids, such as 0.9% NaCl or lactated Ringer's solution; reducing hyperglycemia and ketosis by administration of crystalline zinc (regular) insulin; maintaining serum electrolyte levels, especially potassium, through supplemental administration of appropriate electrolyte solutions; and identifying and treating underlying and

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582

THE PANCREAS

complicating diseases, such as acute pancreatitis or infections. Numerous insulin regimens have been used in treatment of ketoacidotic diabetes mellitus. In the intermittent insulin regimen, regular insulin at 0.2 U/kg, IM, is the initial dosage, followed by hourly administration ofO.l U/kg. Once the serum glucose is 1 yr with acceptable quality of life if all visible tumors are debulked at surgery. Dogs with inoperable tumors may be managed fairly well with multiple feedings per day and glucocorticoid administration (0.5-1 mg/kg/clay). Diazoxide (20-80 mg/kg/day, divided into three equal doses) may also alleviate clinical signs in some dogs, although problems with availability have limited its use. The chemotherapeutic agent streptozotocin has been investigated for the treatment of islet cell tumors in dogs and may be considered after surgical resection.

GASTRIN-SECRETING ISLET CELL TUMORS Gastrinomas of the pancreas have been reported in people, dogs, and a cat. Hype1� secretion of gastrin in people results in the Zollinger-Ellison syndrome, consisting of hypersecretion of gastric acid and recurrent peptic ulceration in the GI tract. The tumors, derived from ectopic amine precursor uptake decarboxylase (APUD) cells in the pancreas, produce an excess of the hormone gastrin, which normally is secreted by cells of the antral and duodenal mucosa. Clinical Findings: These tumors are rare; they occur less frequently than the insulin-

583 .

secreting 13-cell neoplasms. The few docu­ mented cases have had anorexia, hematem­ esis, intermittent diarrhea (usually with dark blood present), progressive weight loss, and dehydration. The prominent functional distLU·bances appear to result from multiple ulcerations of the GI mucosa that develop from gastrin hypersecretion. Lesions: Animals studied with the Zollinge1�Ellison-like syndrome have had single or multiple tumors of varying size in the pancreas. The tumors were firm on palpation because of an increase of fibrous connective tissue in the stroma, and all had evidence of metastasis before diagnosis. Diagnosis: Serum gastrin levels have been evaluated in a limited number of clogs with gastrinomas. Gastrin levels in a dog with a Zollinger-Ellison-like syndrome varied from 155 to 2, 780 pg/mL, whereas the mean serum gastrin in clinically normal (control) dogs was 70.9 pg/mL. Recurrent gastric or duodenal ulcers in dogs with no identified cause warrants exploratory surgery and careful inspection of the pancreas. Treatment: Excision of the gastrin­ secreting mass in the pancreas can be attempted. However, all such tumors that have been studied in dogs have had evidence of local invasion into adjacent parenchyma and had metastasized to regional lymph nodes and liver. The clogs had either single or multiple ulcerations in the gastric or duodenal mucosa associated with free blood in the lumen. Medical management with H2-receptor antagonists (famotidine or ranitidine) or the proton­ plllllp inhibitor omeprazole may temporar­ ily alleviate clinical signs in animals with inoperable disease.

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GENERALIZED CONDITIONS MORE THAN ONE SPECIES ACTINOBACILLOSIS 589 ACTINOMYCOSIS 590

592

AMYLOIDOSES ANTHRAX

593

BESNOITIOSIS 597 CHLAMYDIOSIS 598

601 Bacillary Hemoglobinuria 601 BigHead 602 Blackleg 602 Infectious NecroticHepatitis 603 Malignant Edema 604 Botulism 605 Clostridium difficile and Clostridium perfringens Infections 607 Enterotoxemias 609 Clostridium perfringens Type A 609 Clostridium perfringens Types B and C 609 Type D Enterotoxemia 610 Tetanus 611 Clostridial Vaccines 613

CLOSTRIDIAL DISEASES

CONGENITAL AND INHERITED ANOMALIES 613

Akabane Virus Infection 620 Border Disease 622

COXIELLOSIS

623

ERYSIPELOTHRIX RHUSIOPATHIAE INFECTION Swine Erysipelas 626 Nonsuppurative Polyarthritis in Lambs 628 Postdipping Lameness in Sheep 629

FOOT-AND-MOUTH DISEASE FUNGAL INFECTIONS

Aspergillosis 633 Blastomycosis 634 Candidiasis 636

632

629

625

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586

GENERALIZED CONDITIONS

Coccidioidomycosis 637 Cryptococcosis 637 Epizootic Lymphangitis 639 Histoplasmosis 639 Hyalohyphomycosis 640 Mycetomas 640 Oomycosis 641 Penicilliosis 643 Phaeohyphomycosis 643 Rhinosporidiosis 644 Sporotrichosis 644 Zygomycosis 645

LEPTOSPIROSIS 646 Dogs 650 Horses 652 Ruminants 653 Swine 654

LIGHTNING STROKE AND ELECTROCUTION 655 LISTERIOSIS

656

LYME BORRELIOSIS MELIOIDOSIS

659

661

NEOSPOROSIS 663 NOCARDIOSIS 666 PERITONITIS 670 PLAGUE 677 RHODOCOCCOSIS 679 SWEATING SICKNESS 684 TOXOPLASMOSIS 685 TUBERCULOSIS AND OTHER MYCOBACTERIAL INFECTIONS Cattle 689 Sheep and Goats 689 Deer and Elk 689 Horses 690 Elephants 690 Pigs 690 Dogs 690 Cats 690 Rabbits 690

687

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GENERALIZED CONDITIONS

Guinea Pigs 691 Nonhuman Primates 691 Free-ranging and Captive Hoofed Animals 691 Marine Mammals 691 Mycobacterial Infections Other than Tuberculosis 692 TULAREMIA

692 694

VESICULAR STOMATITIS

HORSES

696

AFRICAN HORSE SICKNESS

EQUINE GRANULOCYTIC EHRLICHIOSIS EQUINE INFECTIOUS ANEMIA

699

701

EQUINE VIRAL ARTERITIS GLANDERS

697

706 707

HENDRA VIRUS INFECTION SEPSIS IN FOALS

2089 (MGN) PIGS

AFRICAN SWINE FEVER

711

CLASSICAL SWINE FEVER EDEMA DISEASE

713

716

ENCEPHALOMYOCARDITIS VIRUS INFECTION GLASSER'S DISEASE

718

720

NIPAH VIRUS INFECTION

721 723

PORCINE CIRCOVIRUS DISEASES

PORCINE HEMAGGLUTINATING ENCEPHALOMYELITIS

728

PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME STREPTOCOCCAL INFECTIONS

731

Streptococcus suis Infection 731 Streptococcus dysgalactiae equisimilis Infection Streptococcus porcinus Infection 734

734

Other Streptococcal and Enterococcal Infections 735

SWINE VESICULAR DISEASE TRICHINELLOSIS

735

736

VESICULAR EXANTHEMA OF SWINE

738

729

587

588

GENERALIZED CONDITIONS

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RUMINANTS BLUETONGUE 738 BOVINE EPHEMERAL FEVER BOVINE LEUKOSIS

741

743

BOVINE PETECHIAL FEVER

745

CAPRINE ARTHRITIS AND ENCEPHALITIS 747 COLISEPTICEMIA

749

CRIMEAN-CONGO HEMORRHAGIC FEVER 751 HEARTWATER

751

HISTOPHILOSIS 754 HEMORRHAGIC SEPTICEMIA 756 MALIGNANT CATARRHAL FEVER NAIROBI SHEEP DISEASE PARATUBERCULOSIS

758

760

762

PASTEURELLOSIS OF SHEEP AND GOATS 765 PESTE DES PETITS RUMINANTS 766 RIFT VALLEY FEVER 768 RINDERPEST

771

TICKBORNE FEVER TICK PYEMIA

772

774

WESSELSBRON DISEASE

775 SMALL ANIMALS

CANINE DISTEMPER

777

CANINE HERPESVIRAL INFECTION 779 CANINE LYMPHOMA

40 (crn)

FELINE INFECTIOUS ANEMIA 28 (cm) FELINE INFECTIOUS PERITONITIS 780 FELINE LEUKEMIA VIRUS AND RELATED DISEASES FELINE PANLEUKOPENIA

796

INFECTIOUS CANINE HEPATITIS 798

790

ACTINOBACILLOSIS

589

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LEISHMANIOSIS 800 RICKETTSIAL DISEASES 803

Ehrlichiosis and Related Infections 803 Rocky Mountain Spotted Fever 806 Murine Typhus 807 Salmon Poisoning Disease and Elokomin Fluke Fever

808

ACTINOBACILLOSIS Actinobacillosis refers to a group of diseases caused by gram-negative coccobacilli in the genusActinobacillus. Although there are >22 different bacterial species in this genus, only four (A pleuro­ pneumoniae, A suis, A equuli, and A lignieresii) are frequently associated with disease in animals. A pleuropneumoniae causes contagious pleuropneumonia in pigs (seep 1469). Disease ranges from acute, severe fibrinous pleuropneumonia to subacute or chronic infection with pleuritis and pulmonary abscessation. Immune complexes fanned as a result of host response may damage endotl1elial cells, resulting in vasculitis and tlrrombosis, with edema, necrosis, infarc­ tion, and hemorrhage. Infection is usually restricted to pigs 4-5 min are salient features. Other clinical signs include dysphagia, constipation, mydliasis, and frequent mination. As the disease progresses, dyspnea with extension of the head and neck, tachycardia, and respiratory arrest occur. Death ensues most often 24-72 hr after the onset of clinical signs due to respiratory failure. The most consistent necropsy findings are pulmonary edema and congestion and excessive pericardia! fluid, which contains free-floating strands of fibrin.

Diagnosis: Although sporadic cases of botulism often are suspected because of the characteristic motor paralysis, it is difficult to establish the diagnosis by demonstrating the toxin in anin1al tissues or sera or in the suspect feed. Commonly, the diagnosis is made by eliminating other causes of motor paralysis (flaccid paralysis). Filtrates of the stomach and intestinal contents should be tested for toxicity in mice, but a negative answer is unreliable. Primary supportive evidence is provided by feeding suspect material to susceptible animals. In peracute cases, the toxin may be detectable in the blood by mouse inoculation tests but usually is not detectable in the average field case in fann animals. Use of ELISA methodology for detection of the toxin makes it feasible to test large munbers of san1ples, increasing the chances of diagnosis confirmation. In toxicoinfectious botulism, the organism may be cultured from tissues of affected anin1als. Treatment and Control: Any dietary

deficiencies in range animals should be corrected and carcasses disposed of, if possible. Decaying grass or spoiled silage should be removed from the diet. Inmmniza­ tion of cattle with types C and D toxoid has proved successful in South Africa and Australia. Toxoid is also effective in immunizing mink and has been used in pheasants. Botulinmn antitoxin has been used for treatment with varying degrees of success, depending on the type of toxin involved and the species of host. Treatment of ducks and mink with type C antitoxin is often successful; however, such treatment is rarely used in cattle. Early administration of antitoxin (type B) specific or polyvalent to foals before recmnbency (30,000 ill, IV) is reported to be successful. Supportive care in valuable animals is essential; prognosis is poor in recmnbent animals. In endemic areas (eg, Kentucky), vaccination with type B toxoid appears to be effective.

607

CLOSTRIDIUM DIFFICILE AND C PERFRINGENS INFECTIONS Clostridium difficile is a large, gram-posi­ tive, anaerobic, spore-forming motile rod and is the major cause of antibiotic-associ­ ated colitis in people. C difficile-associ­ ated diarrhea and disease develops spontaneously in a variety of other species including horses, pigs, calves, dogs, cats, han1sters, guinea pigs, rats, and rabbits. C difficile produces protein toxins A, B, ancV or the binary toxin CDT in the intestine. Toxin A is an enterotoxin that causes hypersecretion of fluid into the intestinal lun1en and also causes tissue dan1age. Toxin B is a potent cytotoxin that induces inflanunation and necrosis. The mechanism of action of CDT is not known. Disruption of colonic microflora together with the presence of toxigenic C dijj'icile strains that overgrow in the intestines are the prerequisites for disease. Diagnostic tests for C difficile toxins include cell cytoxicity assays and ELISA on fecal san1ples, anaerobic culture, and PCR to discrin1inate between toxigenic and nontoxigenic strains. C p@:fringens is widely distributed in the soil and the GI tract of anin1als and is charactetized by its ability to produce potent exotoxins, some of which are responsible for specific enterotoxemias. Five types (A, B, C, D, and E) have been identified and produce one or more of four major toxins ( alpha, beta, epsilon, and iota). C p@fringens type A is most conunon and the most variable strain in toxigenic properties. Alpha toxin production is associated with gas gangrene, traumatic infections, avian and canine necrotic enteritis, colitis in horses, and diarrhea in pigs. C pmfringens types B and C cause severe enteritides, dysentery, toxemia, and high mortality in young lambs, calves, pigs, and foals (beta toxin). 'Iype C causes enterotoxemia in adult cattle, sheep, and goats. The diseases are listed below, catego­ rized as to cause and host.

Clostridia-associated Enterocolitides in Horses

Clostridium dilf'icile and C pmfringens have been implicated in this acute, sporadic disease of horses characterized by diarrhea and colic. Because of uncertainty about the etiology, the condition has also been referred to as idiopathic colitis, but there is now good evidence that these organisnu; are responsible for enterocolitis in horses in approximately 20%-30% of cases of acute diarrhea. (See also p 285.)

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CLOSTRIDIAL DISEASES

Etiology: C difficile may be found in low concentrations in the feces of as many as lO"Aiof healthy horses. C difficile and C perfringens organisms may be present in soil or the environment and be ingested by horses. The factors that t1igger disease are not well known, but it is presumed that some alteration in the nom1al flora permits excessive multiplication of the bacteria, which produce toxins capable of causing intestinal damage and systemic effects. Predisposing factors that have been suggested include change in diet and antibiotic therapy. Other host factors that may determine whether disease develops include age, inununity, and presence or absence of intestinal receptors for the clostridial toxins. Recent antibiotic therapy is a common feature of the history of horses with C dl(ju;ile-induced diarrhea Certain antibiotics, notably macrolides and especially erythromycin ethylsuccinate, 13-lactam antibi­ otics, and trimethoprim/sulfonarnide, are more likely than others to be associated with C difficile colitis. Mares with foals that are being treated with erythromycin ethylsucci­ nate appear to be at high risk Elimination of roughage from the diet before surgery is also reported to predispose to C cll(ju;ile colitis. Acute diarrhea has been reproduced in healthy neonatal foals using C difficile spores and vegetative cell fomis. Acute anterior enteritis (duodenitis-jejunitis, seep 285) has also been associated with C difficile in a case-control study. C pe'ljhngens type A is believed to cause diarrhea by elaboration of an enterotoxin (CPE), which is released during sporulation and stimulates intestinal epithelial cells to secrete excess fluid into the lumen. A novel necrotizing toxin, called 132, produced by some strains of C pe'ljhngenS, has recently been strongly associated with colitis in horses. Clinical Findings: Foals and adult horses may be affected. Typically, there are signs of abdominal pain and diarrhea witl1 or without blood. There may be abdominal distention, especially in cases of C difficile-induced diaiThea. Dehydration, toxemia, and shock may develop, and the mortality rate is variable. One or several animals on a faim may be affected. Horses with anterior enteritis have associated severe recurrent nasogastric reflux, fever, and malaise. Lesions: The characteristic lesion is a necrotizing enterocolitis-typhlitis. There is severe loss of colonic and cecal mucosa! epithelial cells, hemorrhagic colitis and typhlitis, and thrombosis in capillaries of

the intestinal mucosa. Horses with anterior enteritis will mostly have hemorrhagic duodenitis. Diagnosis: Clinical features of the disease ai·e sinlilar to those of acute salmonellosis (seep 195), Potomac horse fever (see p 283), or monocytic ehrlichiosis. The identification of C pe'l:fringens as the cause of diarrhea in horses depends on demonstra­ tion of the presence of enterotoxin or the gene for CPE in the feces or intestinal fluid and the absence of other likely etiologic agents. Most C pe'lfringe'lis fow1d in the intestine of horses lack the gene for CPE expression. Large numbers of C perfringens in anaerobic fecal culture of horses with diaJThea is not diagnostically significant. The diagnosis of C difficile diarrhea is suggested by a history of recent treatment with antibiotics and is supported by demonstration of the presence of C difficile toxin A and/or B in a freshly passed or frozen fecal sample submitted to a laboratory using a human ELISA validated in horses, with good sensitivity and specificity. The toxin gene may be identified by PCR ribotyping. Control: Steps may be taken to reduce the opportunity for C difficile infections in horses. Proper isolation procedures and infectious disease control should be applied to high-risk horses receiving antibiotics. The environmental load of C difficile spores may be reduced by surface disinfection with spo1icidal disinfectants, and the spread may be reduced by hand washing and by isolation of infectious horses and foals. There are no control measures available for prevention of C perf1inge'lis-induced diarrhea. Oral metronidazole ( 15 mg/kg, tid) is recommended for treatment of either of these clostridial infections. Metronidazole might be teratogenic, so its use should be avoided if possible in pregnant mares.

Clostridium difficile in Swine

Clostridium difficile has emerged as an

inlportant cause of diarrhea in neonatal swine. In some studies, it has been identified as tl1e second most frequent cause of diarrhea in 1- to 7-day-old pigs. Mesocolonic edema is a characteristic feature of the disease seen in almost all affected pigs, but this lesion is not pathognomonic. Diagnosis of the disease depends on detection of toxins as desc1ibed for the disease in horses. Porcine, equine, bovine, and canine C difficile isolates may show an antinlicro­ bial susceptibility profile overlapping tl1at of isolates from hwnan patients, raising tl1e

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CLOSTRIDIAL DISEASES

possibility for interspecies transmission of C difficile. Donmnt C dijficile spores have been fow,d in meat of pigs and beef cattle. Some of the ribotypes isolated were similar or identical to human pathogenic strains.

Clostridium difficile in Dogs Cwstridium difficile has not been

established as a p1imary pathogen in dogs. However, human toxigenic C difficile strains have been frequently isolated from rectal swabs of dogs visiting hwnan patients in hospitals. Hw,1an ELISA for C difficile toxins does not perfo1m well in dogs with diarrhea and has poor sensitivity and specificity. Approximately lOOAi of asymptomatic dogs shed toxigenic C difficile in feces.

Clostridium difficile in Calves Clostridium difficilehas been identified

as a potential cause of diarrhea in yow,g calves. The disease could not be reproduced in colostrwn-deprived neonatal calves with spores or vegetative cells. C difficile has been fow,d in high prevalence in veal calves early in the veal production process.

C/ostridium perfringens in Adult Cattle ln the past few years, hemorrhagic bowel, bloody gut, or jejw,al hemorrhage syndrome has emerged sporadically in individual, high-producing dairy cows in early lactation. Although no specific etiology has been established, it is assw,1ed tl1at Clostridiumperjringens type A is involved, because large nw,1bers of this clostridia may be recovered in most cases. The clinical course is peracute, with anorexia, colic, drop in milk yield, hemorrhage into the intestine, and sudden death despite aggressive supportive and surgical treatment. Gross postmortem findings include severe hemorrhage and necrosis in tl1e intestines. Prevention consists of optinlizing nutritional manage­ ment and avoiding sudden feed changes. Autogenous vaccines in affected dairy herds have been tried with anecdotal success.

ENTEROTOXEMIAS (C/ostridium perfringens infections)

Enterotoxemia Caused by C/ostridium perfringens Type A Type A strains of Cperfringens are

commonly fow,d as part of the normal intestinal microflora of animals and lack some of the powerful toxins produced by

609

strains of other types. C perftingens enterotoxin (CPE) is the principal toxin involved in Cpeijringens foodbome illness and is associated with nonfood borne diarrheal disease in different animals. Cperfiingens also produces a necrotizing toxin associated with necrotic enteritis in poult1y (seep 2802) and dogs, colitis in horses, and diarrhea in pigs. C peifringens type A is in1plicated in a rarely occurring hemorrhagic cliarThea in clogs and has been associated with nosocomial and acquired acute and chronic diarrhea in clogs. The acute form is characterized by a necrotic enteritis in which there is massive destruction of the villi and coagulation necrosis of the small intestine. Many lar·ge, grar11-positive rods ar·e visible in fecal smear·s, and large nwnbers of Cperjringens type A are recovered on anaerobic culture of feces of dogs with acute diarrhea. Fecal tests ar·e not useful in cletem1ining the cause of diarThea, however, because of a high nw,1ber of false-positive results. A commercial ELISA for CPE in dogs is quite specific. PCR for CPE gene expression in clogs is being evaluated. Type A strains from pigs with diarrhea have produced entero­ toxin in vitro, and anti-enterotoxin antibodies in sows indicate that enterotoxin is produced in vivo. Enterotoxin has also been demonstrated in the feces of pigs with diarrhea but not in feces of healthy aninlals. Cpeij1ingens isolated from pigs with diarrhea are typically nonenterotoxigenic but produce the cytotoxic 132 toxin, which possibly plays a role in disease. Experimen­ tal disease has been produced in pigs challenged orally with C peijhngens type A.

Enterotoxemia Caused by C/ostridium perfringens Types B and C Wection with Cpeifringens types Band C

causes severe enteritis, dysentery, toxemia, and high mortality in yow,g lambs, calves, pigs, and foals (see TABLE 1). Types Band C both produce tl1e highly necrotizing and lethal beta toxin responsible for severe intestinal damage. This toxin is sensitive to proteolytic enzymes, and disease is associated with inhibition of proteolysis in the intestine. Sow colostrW11, which contains a trypsin inhibitor, has been suggested as a factor increasing the susceptibility of yow,g piglets. Type C also causes enterotoxemia in adult cattle, sheep, and goats.

Clinical Findings: Lamb dysentery is an

acute disease of lan1bs 250 km (155 miles) from Brittany, France, to the Isle of Wight, UK, in 1981, but it usually travels no more than 10 km ( -6 miles) over land. FMD has high agroterrorism potential because of its infectivity, high transmissibility through wind and inanimate objects, and potential for large economic losses. People can act as mechanical vectors of FMD by carrying virus on clothing or skin. FMD is not considered a public health problem, but there are reports of people who work in FMD vaccine laboratories who have developed antibodies to the virus. There are few reports of people with laboratory-confirmed cases of clinical illness between 1921 and 1969. The disease in people is usually short-lived and mild, with symptoms including"vesicular lesions and influenza-like illness.

Pathogenesis: The primary site of

infection and replication of FMEl is in the mucosa of the pharynx. The virus may also enter through skin lesions or the GI tract. Once distributed throughout the lymphatic system, the virus replicates in the epithe­ lium of the mouth, muzzle, teats, feet, and areas of damaged skin (eg, knees and hocks of pigs). Vesicles then develop at the organs and rupture within 48 hr. More than 500A, of ruminants that recover from illness and those that are vaccinated and have been exposed to virus can carry virus particles in the pharyngeal region-up to 3.5 yr in cattle, 9 mo in sheep, and >5 yr in African buffalo. FMD virus is environmentally resistant and inactivates outside the pH range 6-9 and desiccation and at temperatures >56° C (132.8° F). It is resistant to lipid solvents such as ether and chloroform, but sodium hydroxide (lye), sodiun1 carbonate (soda ash), citric acid, and acetic acid (vinegar) are effective disinfectants. Iodophores,

quaternary an1rnonium compounds, hypochlorite, and phenols are less effective disinfectants, especially in the presence of organic matter. FMD is shed into milk in dairy cows before clinical signs develop, so there is opportunity for virus to spread fann to fam1 and from cow to calf via raw milk FMD may survive pasteurization depending on the method (ltigh temperature sh01t time, ultra high temperature, laboratory pasteuriza­ tion); the lipid component of milk protects virus during heating. FMD virus survives up to 20 wk on hay or straw bedding, in dry fecal matter for up to 14 days in sun1rner, in a fecal slw·ry for up to 6 mo in winter, in wine for 39 days, and in soil for 3 (swnmer) to 28 (winter) days. The incubation period of FMD is variable and depends on the host, environment, route of exposure, and virus strain. After infection with FMD vims, the average incubation period for sheep and goats is 3-8 days, �2 days for pigs, and 2-14 days in cattle. The incubation period can be as short as 18 hr for host-adapted strains in pigs, especially W1der intense direct contact.

Clinical Findings: Clinical signs in cattle

include pyrexia of -104° F, followed by vesicular development on tl1e tongue, hard palate, dental pad, lips, gums, muzzle, coronary band, interdigital cleft, and teats in lactating cows. Acutely affected individuals may salivate profusely, stamp their feet, and prefer to lie down. Ruptured oral vesicles can coalesce and fonn erosions but heal rapidly, roughly 11 days after vesicle formation. Feet vesicles take longer to heal and are susceptible to bacterial infection leading to chronic lameness. Secondary bacterial mastitis is common due to infected teat vesicles and resistance to milking. After vesicular disease develops, cattle quickly lose condition and milk yield, which can persist chronically. Infected pigs show mild lameness and blanching around the coronary band and may develop a fever of up to 107° F. Affected pigs become lethargic, huddle among other pigs, and have little interest in feed. Vesicles develop on the coronary band, heel of the foot including accessory digits, snout, mandible, and tongue. Additional vesicles may form on the hocks and knees of pigs housed on rough surfaces. Depending on the severity of vesicles, the horn of the foot may completely slough off and cause chronic lan1eness in recovered pigs. Young pigs 250 different serovars of pathogenic Leplospira identified (based on surface antigens) throughout the world. The serovars are often grouped into antigeni­ cally related serogroups. With the increased use of genomic infom1ation for the classification of bacteria, the genus Leptospira was reorganized. There are currently 21 recognized genomospecies of leptospires, including both pathogenic, intem1ediate, and nonpathogenic organ­ isms. Pathogenic leptospires are now

identified in 9 species of Leptospira, with 6 species being regarded as intermediate in pathogenicity, and 6 being nonpathogenic. Some of the conunon leptospiral pathogens of domestic animals now have different species nan1es. For example, L interrogans serovar Grippotyphosa is now L kirschneri serovar Grippotyphosa. The two types of serovar Hardjo have been formally split into two species: serovar Hardjo type hardjo­ bovis (found in the USA and much of the world) is now L borgpetersenii serovar Hardjo and the less conunon serovar Hardjo type hardjo-prajitno (found primarily in tl1e UK) is now L interroga'YJ,S serovar Hardjo. The revised nomenclature is now reflected in the scientific literature but not on labels for vaccines and phannaceutical products. Fortunately for clinicians, the serovar and serogroup names remain in common use and are useful when discussing the epidemiology, serology, clinical features, treatment, and prevention of leptospirosis. Host Susceptibility, Epidemiology, and Transmission: Essentially all

mammals are susceptible to infection with pathogenic Leptospira, although some species are more resistant to disease. Among conunon companion animals and livestock, leptospirosis is most frequently recognized in cattle, swine, dogs, and

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LEPTOSPIROSIS horses. Cats have historically been considered to be resistant to disease but have been shown to seroconvert on exposure to leptospires. Recent evidence suggests that the role of leptospires in the pathogenesis of feline renal disease should be reexamined. Leptospirosis in wildlife is common, although the disease is most often noticed only when the wildlife serve as a source of infection for domestic animals or people. Leptospi.rosis is found throughout the world. The infection(and disease) is more prevalent in warn1, moist climates and is endemic in much of the tropics. In temperate climates, the disease is more seasonal, with the highest incidence after pe1iods of rainfall. Although >250 serovars of pathogenic Leplospira are recognized, a subset of leptospiral serovars are prevalent within a particular region or ecosystem and are associated with one or more maintenance hosts, which serve as reservoirs of infection (see TABLE 4). Maintenance hosts are often wildlife species and, sometimes, domestic animals and livestock. Each serovar behaves differently within its maintenance host species than it does in other, incidental host species. In maintenance hosts, leptospirosis is generally characterized by a high prevalence of infection, relatively mild acute clinical signs, and persistent infection in the kidneys and sometimes the genital tract. Diagnosis of maintenance host infec­ tions is difficult because of relatively low antibody responses and the presence of few organisms in the tissues of infected animals. Examples of this type of infection are serovar Bratislava infection in swine and serovar Hardjo infection in cattle. In incidental hosts, leptospirosis is character­ ized by a low prevalence of infection, severe

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clinical signs, and a short renal phase of infection. Diagnosis of incidental host infections is less problematic because of a marked antibody response to infection and the presence of large numbers of organisms in tissues of infected animals. Examples of this type of infection are serovar Grippoty­ phosa infection in dogs or serovar Ictero­ haemorrhagiae infection in cattle and swine. Characterization of a host/serovar inter­ action as a maintenance or incidental host infection is not absolute. For exan1ple, swine and cattle infected with serovar Pomona behave as a host intermediate between the two forms, with the organism persisting in the kidneys but the host showing a marked antibody response to infection. Transmission an1ong maintenance hosts is often direct and involves contact with infected urine, placental fluids, or milk. In addition, the infection can be transmitted venereally or transplacentally with some host/serovar combinations. Infection of incidental hosts is more commonly indirect, by contact with areas contaminated with urine of asymptomatic maintenance hosts that shed leptospires in their urine. Environmental conditions are critical in determining the frequency of indirect transmission. Survival of leptospires is favored by moisture and moderately warm temperatures; survival is brief in dry soil or at temperatures 34 °C. The organisms are killed by freezing, dehydra­ tion, or direct sunlight.

Pathogenesis: Despite the many serovars of Leplospira and host species, t11e key steps in pathogenesis of the disease are sin1ilar in all host/serovar combinations. Leptospires invade tl1e body after penetrat­ ing exposed mucous membranes or

COMMON MAINTENANCE HOSTS OF THE PATHOGENIC LEPTOSPIRES ASSOCIATED WITH DISEASE IN DOMESTIC ANIMALS IN THE USA AND CANADA Leptospiral Serovar

Maintenance Hosts

Canicola

Dogs

Pomona

Pigs, cattle, opossums, skunks

Grippotyphosa

Raccoons, muskrats, skunks, voles

Hardjo

Cattle

Icterohaemorrhagiae

Rats

Bratislava

Pigs, mice(?), horses(?)

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damaged skin. After a variable incub ation period (4-20 days), leptospires circulate in t he blood and replicate in many tissues including the liver, kidneys, lungs, genital tract, and CNS for 7 10 - days. During the period of bacteremia and tissue coloniza­ tion, the clinical signs of acute leptospirosis, which vaiy by serovar and host, occur. Agglutinating antibodies can be detected in sernm soon after leptospi.remia occurs and coincide with clearance of the leptospires from blood and most organs. As the organisms are cleared, the clinical signs of acute leptospirosis begin to resolve, although damaged organs may take some time to return to normal function. In some cases, severely damaged organs may not recover, leading to chronic disease or death. At this point, the disease in incidental and maintenance hosts diverges. Leptospires remain in the tubules of the kidneys of incidental hosts for a short period of time and are shed in the urine for a few days to several weeks. In maintenance hosts, however, leptospires often remain in the renal tubules, genital tract, and less commonly, the eyes, despite the presence of high levels of sernm antibody. Leptospires are shed in the urine and genital secretions of persistently infected anin1als for months to years after initial infection, and these anin1als become an important reservoir of infection, with the potential to transmit infection to other reservoir hosts or to incidental hosts at risk of developing clinical disease.

Clinical Findings: The clinical signs of

leptospirosis depend on the host specie s, the pathogenicity of the strain and serovar of Leptospira, and the age an_d physiologic state of the animal. Subclinical infections are common, particularly in the mainte­ nance host. In incidental hosts, leptospiro­ sis is an acute, systemic, often febrile illness characterized by renal and/or hepatic damage. In addition, there may be effects on other body systems resulting in clinical problems such as uveitis, pancreatitis, bleeding, hemolytic anemia, muscle pain, or respiratory disease. In botl1 incidental and maintenance hosts that are pregnant at tile time of infection, localization and persistence of the organism in the u terns may result in fetal infection, with subsequent abortion, stillbirth, birth of weak neonat es, or birth of healthy but infected offsp1ing. In general, incidental hosts abort acutely, whereas in mainte­ nance hosts, abortions or other reproduc­ t ive sequelae may be delayed by several weeks or months.

Diagnosis: Diagnosis of leptoEl>Pirosis depends on a good clinical and v1accination history and laboratory testing. I))iagnostic tests for l eptospirosis include th1ose designed to detect antibodies a�ainst the organism and those designed to det ect the organism in tissues or body fluid1s. Serologic te sting is recommended in each case, combined with one or more tect:miques to identify the organism in tissue mr body fluids. Serologic assays are the most- commonly used technique to diagnose leptc0spirosis in anin1als. The microscopic aggluttination test (MAT) is most frequently used. involves mixing appropriate dilutions of 53ernm with live leptospires of serovars prev,alent witl1in the region. The presence of antill:>odies is indicated by the agglutination oJf the leptospires, with the reported titter being the highest dilution of serun1 tllat re,sults in 500;6 agglutination. The MAT is a corruplex test to perfonn and interpret, and it rec,.uires the maintenance of live leptospiral cultures. An ELISA test to diagnose canine l�ptospirosis is offered by a comm ercial labocatory in tile USA. This test detects antibodie ·s to LipL32, a membrane protein found on pl!lthogenic leptospires. The currently avaib,.ble assay provides a qualitative negative o.r positive result and will also detect antibodies induced by vaccination. A comp,arison of this te st to t he MAT has not beer'I reported, and it is likely that the numerical titers provided by the MAT will provide more diagnostically useful informatio n than a qualita tive ELISA. Interpretation of serologic results from the MAT is complicated by a nu(llbe r of factors, including cross-rea ctiviJ!;y of antibodies, antibody titers induced by vaccination, and l ack of consensus about the level of antibody titer that in.dicates infection. Antibodies produced :in an animal in response to infection with a g iven serovar of Le'J)tospira often cross-react with other serovars. In some cases, these patterns of cross-reactivity are predictable based on the antigenic relatedness of the various serovars of Le'J)tospira, but tl1e 9attems of cross-reactive antibodies vary between host species. Paradoxical re actions may occur with the MAT early in the course of an acute infection, with a marked aggluti nating antibody response to a serovar other than the infecting serovar. In additior1, there is evidence of lack of consistency between diagnostic laboratories. For the�e reasons, the infecting serovar in an indivJdual animal carmot be reliably identified as the s erovar to which the animal develops the highest titer. The re al value of the MAT is in

n

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LEPTOSPIROSIS providing a numerical titer to allow comparison of acute and convalescent values. Widespread vaccination of dogs and livestock with leptospiral vaccines also complicates interpretation of leptospiral serology. In general, vaccinated animals develop relatively low agglutinating antibody titers (1:100 to 1:400) in response to vaccination, and these titers persist for 1-4 mo after vaccination. However, some animals develop high titers after vaccination which persist for �6 mo. Consensus is lacking as to what constitutes a diagnostic titer for leptospiral infection. A low antibody titer does not necessarily exclude a diagnosis of leptospirosis, because titers are often low in acute disease and in maintenance host infections. In cases of acute leptospirosis, a 4-fold rise in antibody titer is often observed in paired serum samples collected 7-10 days apart. Diagnosis of leptospirosis based on a single serum sample should be made with caution and with full consideration of the clinical picture and vaccination history of the animal. In general, with a compatible clinical history and vaccination >3 mo ago, a titer of 1:800 to 1:1,600 is good presumptive evidence of leptospiral infection. The use of paired acute and convalescent titers is strongly recommended whenever possible. Antibody titers can persist for several months after infection and recovery, although there is usually a gradual decline with time. Immunofluorescence can be used to identify leptospires in tissues, blood, or urine sediment. The test is rapid and has reasonable sensitivity, but interpretation requires a skilled laboratory technician. Immunohistochemistry is useful to identify leptospires in formalin-fixed tissue but, because there may be small numbers of organisms present in some tissues, the sensitivity of this technique is variable. A number of PCR procedures are available, and each laboratory may select a slightly different procedure. Unfortunately, few publications have confirmed the validity of all the commercially available PCRs, which likely vary considerably in their perfor­ mance. PCR techniques allow detection of pathogenic leptospires in blood, urine, or tissue samples but do not determine the infecting serovar. Culture of blood, urine, or tissue specimens is the only method to definitively identify the infecting serovar. Blood may be cultured early in the clinical course; urine is more likely to be positive 7-10 days after clinical signs appear. Culture is rarely positive after antibiotic therapy has

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begun. Culture of leptospires requires specialized culture medium, the organisms are fastidious and slow-growing, and diagnostic laboratories rarely culture specimens for the presence of leptospires. Thus, culture is of little value to clinicians. Prevention: Avoidance of exposure to free-ranging wildlife and domestic animals that may be maintenance hosts for Leptospira is difficult because rodents, raccoons, opossun1s, and skunks are frequently found in rural and urban environments. The cornerstone of leptospirosis prevention is vaccination with polyvalent inactivated vaccines. Inmmnity to leptospirosis is believed to be serovar specific and, therefore, vaccines are formulated for various species to include the relevant serovars. There are cruTently no leptospiral vaccines for horses. Lepto­ spiral vaccines are generally designed and evaluated for the ability to prevent clinical signs of disease, although some vaccines have also been shown to significantly reduce renal colonization and urine shedding. Zoonotic Risk: People are susceptible to infection with most of the pathogenic serovars of Leptospira but are incidental hosts and, therefore, not important reservoirs of infection. Occupational exposure is a rick factor, and veterinarians, veterinary staff, livestock producers, and dairy workers are at increased risk. In addition, recreational exposure to waters contaminated with urine of domestic animals or wildlife presents a risk. Animal owners have contracted leptospirosis via contact with infected companion animals and livestock. The principal route of infection is contact with infectious body fluids (blood in acute cases or urine) via mucous membranes. In people, the disease varies from subclinical to severe and can be fatal when renal or hepatic failure occurs. The most common signs are fever, headaches, rash, ocular pain, myalgia, and malaise. Transplacental infection, abortion, and infection of infants via breast feeding have been described, making exposure of pregnant women of particular concern. Laboratory techniques are necessary for a definitive diagnosis. Because diagnosis of leptospirosis in animals is difficult based on clinical signs, veterinarians may wish to implement an infection control program in which animal body fluids are handled only with gloved hands and hand washing is routine. It is also essential for staff to take precautions when

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handling or nursing animals suspected or confirmed to have leptospirosis. Appropri­ ate precautions include wearing gowns, shoe covers, and gloves to avoid contami­ nating exposed skin or spreading organ­ isms. Face shields should be worn when handling wet bedding or cleaning cages, stalls, or rnns to avoid contact of aero­ solized organisms with mucous mem­ branes.

LEPTOSPIROSIS IN DOGS Dogs are the maintenance host for

Leptospira interrogans serovar Canicola,

and before widespread vaccination programs, serovars Canicola and Ictero­ haemorrhagiae were the most common serovars in dogs in the USA. The prevalence of canine serovars has shifted significantly in the last 20 years; currently the most prevalent serovars are believed to be Grippotyphosa, Pomona, and Bratislava; however, this belief is largely based on serologic results that are now known to be inaccurate in predicting the infecting serovar in dogs with leptospirosis. The serovars that cause disease in dogs are likely to vary with geographic region and the presence of reservoir hosts. Unfortu­ nately, current understanding of the serovars that cause natural disease in dogs is limited by tl1e fact that isolation of leptospires is rarely perfonned; thus, studies to date have relied on serologic data. As noted above, it is now accepted that the results of the MAT do not reliably predict the infecting serovar in dogs (or people) with leptospirosis; thus, the trne infecting serovar is unknown in most cases. How­ ever, it is likely that the serovars that cause disease in dogs are those circulating in local wildlife. Experimental infections and isolation of organisms from a small number of sick dogs have shown that serovars Icterohaemorrhagiae, Canicola, Auturnna­ lis, Pomona, Bratislava, Sejroe, and Ballun1 are capable of causing disease in dogs. Knowledge of the infecting serovar in dogs is essential for epidemiologic studies and vaccine development; it is less important for clinicians managing individual cases. It is currently not Imown whether specific serovars are associated with specific clinical signs in dogs, and there is no published evidence to guide therapy based on serovar identification. It is, however, extremely impmtant for veterinarians to maintain a high inclex of suspicion for leptospirosis, because this is a zoonotic disease and has a wide range of clinical presentations in dogs. Any age, breed, or

sex of dog is susceptible to leptospirosis, and the diagnosis should not be excluded on the basis of signalment or lifestyle. Canine leptospirosis is not restricted to large-breed dogs, male dogs, or dogs with a predomi­ nantly outdoor lifestyle. Acute kidney injury has been the most common presentation for canine leptospiro­ sis in recent years. Affected dogs may present with lethargy, anorexia, vomiting, abdominal pain, and history of polyuria, oliguria, or anuria. Dogs that survive acute renal failure may return to baseline or progress to chronic kidney disease. Leptospirosis should also be considered in any dog with previously diagnosed chronic kidney disease that develops "acute-on­ chronic" kidney injury. Renal tubular dan1age in leptospirosis may manifest as cylindrmia, proteinuria, or glycosuria. In people, acute kidney injury due to leptospirosis is often nonoligmic and can be associated with hyponatremia and hypokalemia. These electrolyte changes have also been noted in canine leptospi..ro­ sis, along with the expected changes of azotemia, hyperphosphatemia, and acidosis of renal failure. Hyperkalemia is also possible. Polyuria and polydipsia (PU/PD) in the absence of azotemia is a less conu11on manifestation of the renal effects of leptospirosis. PU/PD may be due to a decrease in glomernlar filtration rate that is sufficient to cause loss of renal concentrat­ ing ability without azotemia. However, PU/PD can also be due to nephrogenic diabetes insipidus. Acute liver disease may accompany acute renal failure in dogs with leptospirosis, or it may occur alone. Affected dogs may be icteric, and serurn biochemistry analysis reveals increased bilirubin and alkaline phosphatase. ALT is typically less markedly increased than alkaline phosphatase. In people and dogs, the jaundice of acute leptospirosis appears to be associated with minimal histopathologic changes in the liver, suggesting that it is due to the "cholestasis of sepsis" ratller than to hepatocellular damage. Muscle pain, stiffness, weakness, trembling, or reluctance to move can be seen in dogs with leptospirosis. These may be the result of vasculitis, myositis, or nephritis. Myalgia is commonly reported in hun1an leptospirosis and is associated with the septicemic phase of the disease. Less common manifestations of canine leptospirosis include bleeding disorders characterized by petechial hemorrhages, epistaxis, melena, and hematemesis. These findings are most likely due to vasculitis.

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LEPTOSPIROSIS Affected dogs may also be thrombocyto­ penic; however, platelet counts are rarely low enough to be responsible for spontane­ ous bleeding. The causes and mechanisms of bleeding disorders in leptospirosis are poorly understood, but they have been suggested to be associated with endothelial cell damage. Pulmonary hemorrhage is now one of the most common clinical signs in outbreaks of hun1a.n leptospirosis. This is a less common finding in canine leptospirosis; however, cough or dyspnea, or radiographic abnom1alities have been noted in a number of affected dogs. Uveitis is an uncommon manifestation of leptospirosis in dogs. It appears to be infrequently associated with experimental ca.nine leptospi.rosis, but rare case reports exist. Additional clinical signs reported in dogs with leptospirosis include vomiting, diarrhea, weight loss, fever, hypothermia, oculonasal discharge, lymphadenopa.thy, effusions, and edema. CBC changes may include neutrophilia, lymphopenia., monocytosis, and mild anemia. These changes are nonspecific; however, mild to moderate thrombocytope­ nia is seen in >500A, of cases and, if detected in combination with azotemia or evidence of cholestasis, should prompt diagnostic testing for leptospirosis. Coagulation abnonnalities may include increased fibtin degradation products and prolonged prothrombin tinle (PT) or activated partial thromboplastin time (APTT). Urinalysis may reveal hyposthenuria., isosthenuria, or hypersthenuria, depending on the degree of renal involvement. Other changes may include proteinmia, glucosuria, cylind.ruria, hema.turia, and pyuria Leptospirosis could also potentially be associated with renal tubular acidosis. Reticulonodular pulmonary opacities have been desc1ibed in the thoracic radiographs of dogs with leptospirosis and attributed to pulmona.iy hemorrhage. These changes may be diffuse or predominantly involve the ca.udodorsal lung fields. Abdominal radiogra.phs may be unremark­ able or may show renomegaly or hepato­ megaly. Changes noted on ultrasonography include renomegaly, pyelectasia, increased cortical echogenicity, perinephric effusion, and a hyperechoic medullary band. However, these changes are not specific for leptospirosis, and absence of these findings does not exclude the diagnosis. Gross necropsy findings can include jaundice, effusions, and petechial or ecchymotic hemorrhages on any orga.11, pleural, or peritoneal surface. The kidneys and liver may be enlarged, and lungs may be wet, heavy, and discolored. The liver is often

651

friable with an accentuated lobular pattern and may have a. yellowish brown discolora­ tion. The kidneys may have white foci on the subcapsula.i· surface. Microscopic findings in the liver may include mild random hepatocytic necrosis, nonsuppura.­ tive hepatitis, and intral1epatic bile stasis, while swollen tubula.i· epithelial cells, tubular necrosis, and a mixed infla.n1111ato1y reaction may be seen in the kidneys. Idea.lly, a combination of serology and organism detection should be used for diagnosis of ca.nine leptospirosis. Serology is the most frequently used diagnostic test for dogs. Acute and convalescent titers may be necessary to confim1 a diagnosis; hence, tl1e use of the MAT is preferred over the ELISA. PCR-based tests a.i·e widely available, and collection of both blood and urine sa.inples before adnlinistration of antibiotics should be considered for maximal sensitivity. The results of a.II diagnostic tests should be interpreted in light of tl1e animal's vaccination history, clinical signs, and cli.nicopathologic findings. Renal failure and liver disease a.i·e treated witl1 fluid tl1erapy and other supportive measures to maintain normal fluid, electrolyte, and acid-base balance. Supportive measures may include a.ntiemet­ ics, GI protecta.nts, phosphate binders, and hepatic suppo1t medications. Renal replacement therapy with intennittent hemodialysis or continuous renal replace­ ment therapy should be considered for dogs that are a.nuric or oliguric despite appropri­ ate suppmtive tl1erapy. Antibiotic therapy is indicated whenever leptospirosis is suspected and should be instituted before confinnatory test results are available. There a.re no experimental studies in dogs to guide selection of antibiotic protocols for this species. Cun·ent recommendations are to treat with doxycycline (5 mg/kg/day, IV or PO) for 2 wk For dogs that ca.1U1ot tolerate doxycycline, initial tl1erapy with a penicillin is appropriate, but this should be followed by a 2-wk course of doxycycline to eliminate the renal ca.iTier phase of infection. Dogs recently exposed to leptospirosis may be treated prophylactica.lly with oral doxycy­ cline for 14 days. Con1111ercial ba.cterins for dogs a.i·e available for serovars Ca.nicola, Ictero­ haem01Thagia.e, Gtippoty phosa, and Pomona. Vaccinated dogs may potentia.lly be susceptible to infection with other serovars, although this has not been tested in an experinlental setting. In general, currently available vaccines provide good protection from clinical disease and also

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appear to reduce renal colonization and urine shedding. Concerns exist regarding hypersensitivity reactions after leptospiral vaccination in dogs, but these appear to be Ulljustified based on more recent studies and perhaps associated with the use of more highly purified vaccines. Canine challenge studies have demonstrated duration of inununity of at least 1 yr; thus, prior recommendations for vaccinating every 6 mo are no longer justified. Because leptospirosis is a zoonotic disease, all veterinary personnel should take appropriate precautions when handling known or suspected infected animals. Such dogs do not need to be placed in isolation but should be nursed with barrier precautions, paying particular attention to avoiding exposure of skin or mucous membranes to urine or blood. Infected dogs should be allowed to urinate in designated areas that can subsequently be cleaned and disinfected. The organisms are killed by all commonly used disinfect­ ants. Owners of dogs recently diagnosed with leptospirosis should be advised of the zoonotic nature of the disease and contact their physicians with any health concerns. Owners should wear gloves when cleaning up urine and should wash their hands after handling the dog, at least until the course of antibiotic therapy is completed.

LEPTOSPIROSIS IN HORSES In the USA and Canada, Leptospira interrogans serovar Pomona type

kennewicki and serovar·Grippotyphosa are the most common causes of equine leptospi­ rosis. The prevalence of leptospirosis in horses is unknown, but serologic evidence indicates a higher incidence than is apparent clinically. Antibodies to serovar Bratislava are reported frequently in horses in the USA and in Europe; horses are thought to be a maintenance host for this organism, and clinical disease has not been confirmed with Bratislava infections. Acute Pomona infections also commonly cause cross-reacting antibodies for Bratislava and Icterohaemorrhagiae on the MAT, which may explain some of the commonly observed high titers to Bratislava. Clinical leptospirosis in horses is most commonly associated with abortions, acute renal failure, rarely pulmonary or systemic illness in foals, and most importantly recurrent uveitis. Leptospira, interrogans serovar Pomona abortions may account for -13% of bacterial abortions in mares in endemic regions, although incidence vaiies considerably

between years. The reason for the yearly variation in incidence of abortions is not clear. Serovar Pomona type kennewicki is responsible for most of the leptospiral abortions in North America, but serovars G1ippotyphosa and Hardjo have also been reported. Skunks, raccoons, and red foxes are known to harbor Pomona type kennewicki. Most abortions occur after 9 mo of gestation, and rarely a live foal may be born ill from leptospirosis. Macroscopic lesions are edema, areas of necrosis in the chorion, and placentitis that does not involve the cervical star. Microscopic lesions include necrosis and calcification of the placenta. Placental disease may result in the mare developing hydroallantois. Macroscopically, the fetal liver may have yellow discoloration. Liver disease in the fetus is a multifocal necrosis and giant cell hepatopathy. Tubulonephrosis and interstitial nephritis may be detected in the kidneys of the aborted fetus. Inflainmation of the umbilical cord (funisitis) may be recognized by diffuse yellowish discolora­ tion. Aborting mares typically have very high leptospiral antibody titers at the time of abortion and, although quite variable, the time of urine shedding of leptospires after an abortion is often 2-3 mo. Occasionally, Leptospira interrogans serovar Pomona causes fever and acute renal failure in horses. The kidneys become swollen as a result of tubulointerstitial nephritis, and urinalysis may reveal hematuria and pyuria without visible bacteria. On rare occasions, multiple weanling or yearling horses may be affected with fever and acute renal failure after infec­ tion. The most in1portant clinical disease associated with L inter rogans serovai· Pomona infection in adult horses in North America and L kirschneri serovar Grippotyphosa in Europe is equine recurrent uveitis (ERU). ERU is believed to be an inunune-mediated disease sometimes involving antibody against certain Leptospira antigens, specifically the LruC outer membrane protein, which cross­ reacts with tissues of the lens, cornea, and possibly retina. Live Leptospira organisms can be found in the aqueous or vitreous fluid of horses with ERU. High concentration of antibody againstL interrogans serovar Pomona in the aqueous humor, compared with serum titers, also suggests persistent local antigenic stimulation. Survival of the organism in the face of high ocular antibody indicates an absence of cells or molecules (eg, complement) involved in bacterial clearance, suggesting an ocular immune

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LEPTOSPIROSIS privilege similar to that of the CNS. Recurrent episodes of the disease may be related to a Thl7 response of autoreactivity following mimicry and inter- or intramo­ lecular epitope spreading, or both. Genetic factors are likely involved in the disease process, helping to explain why only some horses infected with Leptospira develop uveitis. Appaloosas are thought to be genetically predisposed, and specific MHC markers on ECAl, ELA class 1, and an ELA class II microsatellite are strongly associated with the disease. The prevalence of ERU is unknown, but reports suggest that :2c 1% of horses will develop the disease during their lifetime. It is probable that some cases of ERU are not associated with Leptospira infection, and this may vary by geographic region. In some regions, more than 500/o of ERU cases are associated with persistent ocular infections with Lepto­ spira. Leptospira-associated uveitis may cause corneal, anterior chamber, and posterior chamber disease. Therefore, clinical findings may vary from corneal edema, clinically quiet retinal lesions observed on funduscopic examination, and most dramatically recurrent and progres­ sive painful uveitis. The chronic disease of the globe may cause cataracts, retinal degeneration, or even glaucoma. Diagnosis of Leptospira abortion is best accomplished by fluorescent antibody testing (FAT) or inununohistochemical evaluation of the placenta, umbilical cord, fetal liver, or fetal kidney. The sensitivity and specificity of the FAT in these tissues (but not urine) are nearly 1000/o. Examina­ tion of silver-stained kidney samples in horses with renal disease does not yield high accuracy, because there may be false-negative and false-positive findings, likely a result of nonpathogenic serovars. PCR testing is preferred for evaluation of fluids, such as urine, ocular fluids, and blood. Marked increases in serun1 antibody titers often accompany Leptospira abortions or acute renal failure, but serw11 titers may be low in horses with recurrent uveitis because of the chronic and localized nature of infection. Acute L interrogans serovar Pomona infections often cause marked increases in antibody titers to several serovars (especially Icterohemor­ rhagiae and Bratislava, but the noninfecting serovar titers usually decline much more quickly over several weeks than the titers to the actual infecting serovar. Collection of a voided urine sample after furosemide administration may in1prove sensitivity of PCR, darkfield staining, or culture testing. A combination of serology, culture, and PCR

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testing of aqueous fluid may be the only way to confinnLeptospira-associated uveitis. In ERU, the organism is most commonly found in the vitreous rather than aqueous fluid, which limits the practical application of ocular fluid PCR testing. In acute disease, systemic antibiotics such as enrofloxacin, penicillin, tetracy­ clines, or aminoglycosides are useful, but this has not been proved to be the case with recurrent uveitis. There are no leptospiral vaccines approved for horses, although many vete1inarians have used vaccines approved for cattle on horse farms that have endemic Leptospira abortions or uveitis.

LEPTOSPIROSIS IN RUMINANTS Leptospiral serovars of major importance in cattle are Hardjo and Pomona in North America, with serovars Grippotyphosa, Bratislava, Icterohaemorrhagiae, and Canicola occasionally implicated. The most commonly documented cause of leptospiro­ sis among cattle in the USA and throughout much of the world is serovar Hardjo, for which cattle are the maintenance host. Risk factors for Hardjo infection in cattle have been reported to include open herds, access to contaminated water sources, co-grazing with sheep, and use of natural breeding. Serovar hardjo has the ability to colonize and persist in the genital tract of infected cows and bulls. Many leptospiral infections in cattle are subclinical, particularly in nonpregnant and nonlactating anin1als. Acute or subacute leptospirosis is most commonly associated with incidental host infections and occurs during the leptospiremic phase of infection. Clinical signs associated with chronic infections are usually associated with reproductive loss through abortion and stillbirth. Persistent colonization by serovar Hardjo of the uterus and oviducts may be associated with infertility characterized by increased services per conception and prolonged calving intervals. Uncommonly, severe acute disease occurs in young stock infected with incidental serovars, particularly serovar Pomona and less commonly Icterohemor­ rhagiae. Clinical signs include high fever, hemolytic anemia, hemoglobinuria, jaundice, pulmonary congestion, occasion­ ally meningitis, and death. In lactating cows, incidental infections may be associated with agalactia with small quantities of blood­ tinged milk. A less severe form of this "milk drop syndrome" may occur in Hardjo­ infected lactating cows in the absence of other clinical evidence of infection. In

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lactating cows,incidental infections have been reported to cause blood-tinged milk. The chronic phase of disease is assoc i ­ ated with fetal infection in pregnant cows presenting as abortion,stillbirth, or birth of premature and weak infected calves. Infected but healthy calves also may be born. Abortion or stillbirth is commonly the only manifestation of infection but may sometimes be related to an episode of illness up to 6 wk (Pomona) or 12 wk (Hardjo) earlier. Abortions associated with incidental host infection tend to occur late term and in groups or so-called "abortion storms." ln contrast,abortions occurring after infection with serovar Hardjo tend to be more sporadic and can occur mid- to late pregnancy and several months after initial infection. Diagnosis of incidental host infections in cattle is relatively straightforward. ln general, infected animals develop high titers to the infecting serovar; an antibody titer > 1 :800 at the time of abortion is considered evidence of leptospfrosis. Leptospfres can be demonstrated in placenta and the fetus in some cases by inmmnofluorescence,PCR, and inununohistochemistry. Diagnosis of serovar Hardjo infection is more difficult and requfres a combination of approaches. Serology alone often fails to identify animals infected with serovar Hardjo, because seronegative shedders are conunon in infected cattle herds. The recommended diagnostic testing strategy includes the primary use of a test (inununofluorescence or PCR) to detect the organism in the urir1e from a sample of cattle·in the herd followed by serologic testing to provide insight into the likely infecting serovar of Leptospira. Cattle with acute leptospu·osis can be treated with the label dosage of tetracycline, oxytetracycline,penicillin,ceftiofur, tilmicosin, or tulathromycin. Leptospires also are highly susceptible to erythromycin, tiamulin,and tylosin,although these antibiotics cannot be relied on to remove the renal carrier state. lf\iectable,long­ acting oxytetracycline (20 mg/kg) and sustained-release ceftiofur have been shown to effectively eliminate shedding in cattle infected with serovar Hardjo. Vaccination can be combined with antibiotic treatment in the face of an outbreak of leptospirosis,but vaccination alone will not reduce urinary shedding. All appropriate withdrawal times should be observed. Bovine leptospfrosis vaccines available in the USA and Canada are pentavalent and contain leptospfral serovars Pomona, Grippotyphosa,Canicola,Icterohaemorrha-

giae,and Hardjo. These vaccines provide good protection against disease caused by each of these serovars,with the possible exception of serovar Hardjo. Experimental and field evidence indicates that some traditional five-way leptospirosis vaccines do not provide good protection from serova.r Ha.rdjo irlfection. New vaccines have been introduced to address this issue. If a primary goal of a vaccination program is protection of cattle against Hardjo,care should be taken in selection of a vaccine product. In general, annual vaccination of all cattle in a closed herd or low incidence area,or twice-yearly vaccination in an open herd or high incidence area, is the most effective approach to control. Relative to cattle and pigs,sheep and goats have been considered resistant to leptospfral infection,with low seropreva­ lences and only a small number of serogroups being irnplicated in clinical disease. Sheep can serve as a maintenance host for serovar Hardjo and therefore spread Wection to cattle. lncidental infections may cause sporadic outbreaks of acute disease characterized by hematuria, hemoglobinuria,jaundice,and death (usually in lan1bs),and occasional abmtions.

LEPTOSPIROSIS IN SWINE Leptospira interrogans (serovars Pomona, Icterohaemorrhagiae, Canicola, Hardjo, and Bratislava),L borgpetersenii (serovars Sejroe and Tarassovi),and L kirschneri (serovar Grippotyphosa) are all reported to infect pigs. Serovars Pomona and Bratislava are uniquely adapted to swine; others are maintained in other species but sometin1es infect swine. Swine are maintenance hosts for serovar Bratislava, and Wected pigs rarely develop signs typical of acute leptospfrosis-rather, reproductive failure as evidenced by infertility and sporadic abortion is the most common clinical sign, and venereal transmission may occur. Serovar Pomona, in contrast, is of intermediate pathogenicity for swine,with acute clinical signs seen in young pigs and abortions (often in groups) occurring in pregnant swine. Although Pomona infections are associated with acute, sometimes severe clinical signs suggestive of an incidental host infection,pigs often remain Wected and shed serovar Pomona for weeks to a few months after infection. This feature of Pomona infection can be associated with high rates of pig-to-pig transmission among swine reared in

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confinement. Incidental infections may occur from strains belonging to the G1ippotyphosa, lcterohaemorrhagiae, and Canicola serogroups. Abortions occurring 2-4 wk before term are the most common manifestation of leptospirosis in pigs. Piglets produced at term may be dead or weak and may die soon after bilth. The p1incipal differential diagnosis is porcine reproductive and respiratory syndrome (seep 729), although brucellosis, parvovirus, and SMEDI (stillbirth, mummification, embryonic death, and infertility) share some features with leptospirosis. Acute

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leptospirosis, as described in calves, has been described in piglets but is rare. Treatment and control are similar to those described for cattle, using a combination of medication either to prevent infection or to decrease shedding, vaccination, rodent and small mammal control, and feed and water free of Leptospim organisms. Immunization through use of bacterins is widely practiced in breeding herds and will reduce the prevalence of infection and abo1tions. The bacterin must be serovar specific for protection. Bacterins should not be expected to eliminate infection in carriers.

LIGHTNING STROKE AND ELECTROCUTION Injury or death of an animal due to high-voltage electrical currents may be the result of lightning, fallen transmission wires, faulty electrical circuits, or chewing on an electrical cord. Electrocution due to lightning stroke is seasonal and tends to be geographically restricted. Investigation of possible electrocution should always proceed with caution, because the electrification resulting from broken transmission wires, for example, may still be present. Once the site is clearly safe, the investigation should include the location of the dead animals, examination of all affected animals, and necropsy of those that died. Ce1tain types of trees, especially hardwoods such as oaks and those that are tall and have spreading root systems just beneath the ground surface, tend to be struck by lightning more often than others. Electrification of such roots charges a wide surface area, particularly when the ground is already damp; passage of charged roots beneath a shallow pool of water causes it to become electrified. A tile drain may spread an electric charge throughout its course. Fallen or sagging transmission wires also may electrify a pool of water, fence, or building, and an anilnal may also dfrectly contact such wires. Differences exist in conductivity of soil; loan1, sand, clay, marble, and chalk are good conductors (in decreasing order), whereas rocky soil is not. Accidental electrocution of farm animals in a barn or adjacent confinement pen usually occurs as a result of faulty wiring. Electrification of a water or milk line

stanchion or a metal creep or guard rail can result in widespread distribution of an electric current throughout the stable (see also STRAY VOLTAGE IN ANIMAL HOUSING, p 2113) tl1at may result in signs of water deprivation or feed refusal. Death from electric shock usually results from cardiac or respiratory arrest. Passage of current through the heait usually produces ventricular fibrillation, and involvement of the CNS may affect the respiratory or other vital centers.

Clinical Findings: Vaiying degrees of electric shock may occur. In most il1stances of electrocution by lightning stroke, death is instantaneous and the animal falls without a struggle. Occasionally, the anin1al becomes unconscious but may recover in a few minutes to several hours; residual ne1vous signs (eg, depression, paraplegia, cutaneous hyperesthesia, blindness) may persist for days or weeks or be permanent. Singe marks on or damage to tl1e cai·cass, damage to the immediate envfronment, or both, occur in -90"Ai of cases of lightning stroke but are less likely to be fom1d if the ai1imal is electrocuted by standing on electrified earth. Singe marks tend to be linear and are more commonly found on the medial sides of the legs, although rai·ely much of the body may be affected. Beneatl1 the singe marks, capillary congestion is conunon; the arboreal pattern chai·acteristic of lightning stroke can be visualized best from the dermal side of the skin by subcutaneous extravasations of blood. Singe marks are rai·ely found on recovered animals. Smaller

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animals such as pigs that contact electrified water bowls or creeps may be killed instantly or be thrown some distance by the strength of the shock. Electrocuted pigs are often recumbent and may have sustained spinal, pelvic, or limb fractures, resulting from severe muscular contractions.

Diagnosis: The diagnosis is almost always made on circumstantial evidence, ie, location of the carcass(es) and absence of any disease processes when examined by necropsy. The presence of dead animals under a tree, hanging through or near a wire f ence, or clustered around a light pole is strong evidence of electrocution by lightning stroke even in the absence of physical evidence like recent burning of tree bark or splitting of poles or boards in a fence. Rigor mortis develops and passes quickly. Postmortem distention of the rumen occurs rapidly and must be differentiated from antemortem rurninal tympany (seep 227); in both conditions, the blood tends to clot slowly or not at all. The rnucosae of the upper respiratory tract, including the turbinates and sinuses, are congested and hemorrhagic; linear tracheal hemorrhages are common, and large blood clots are occasionally found in the trachea, but the lungs are not compressed as in bloat. All other viscera are congested, and petechiae and ecchymoses may be found in many organs. Due to postmortem rurninal distention, the poorly clotted blood is passively moved to the periphery of the body, resulting in postmor­ tem extravasation of blood in muscles and

superficial lymph nodes of the head, neck, and thoracic limbs, and to a lesser extent in the hindquarters. Probably the best indication of instantaneous death is the presence of hay or other feed in the animal's mouth; supportive evidence includes the presence of nonnal ingesta (especially in the run1en), lack of frothy ingesta (frothy bloat), and presence of normal feces in the lower tract and occasionally on the ground behind the animal. Few conditions affecting livestock cause such peracute death clustered in a small area Farm animals often are insured against lightning stroke, and the insurance claims agent or the veterinarian requested to sign an insurance form should closely observe the situation that initiated the claim. The investigator should ascertain that the animal actually died in the high-risk location rather than having been moved after death. This could be done to merely clean up or to deliberately confuse the investigation. Similarly, examination of recent weather information confirming thw1derstonns is an in1portant part of the process to substanti­ ate an insurance clain1. A well-documented description of where the animal(s) died and the results of a necropsy examination are usually acceptable to support an insurance claim of lightning stroke.

Treatment: Those animals that survive

may require supportive and symptomatic therapy. Euthanasia is warranted for those animals recumbent with fractures or severe muscle injuries.

LISTERIOSIS (Listerellosis, Circling disease) Listeriosis is a sporadic bacterial infection tl1at affects a wide range of animals, including people and birds. It is seen worldwide, more frequently in temperate and colder clin1ates. There is a high incidence of intestinal carriers. Encephalitis or meni:ngoencephalitis in adult ruminants is the most frequently recognized fom1.

Etiology and Epidemiology: Listeria rnonocylogenes is a small, motile, gram­ positive, nonsporeforming, extremely resistant, diphtheroid coccobacillus that grows under a wide temperature range

4 ° -44°C (39°-111° F). Its ability to grow at 4° C is an important diagnostic aid (the "cold enrichment" method) for isolation of the organism from brain tissue but not from placental or fetal tissues. Primary isolation is enhanced under microaero­ philic conditions. It is a ubiquitous saprophyte that lives in a plant-soil environment and has been isolated from -42 species of domestic and wild mammals and 22 species of birds, as well as fish, crustaceans, insects, sewage, water, silage and other feedstuffs, milk, cheese, meconium, f eces, and soil.

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The natural reservoirs ofL monocy­ togenes appear to be soil and mammalian GI tracts, both of which contan1inate vegetation. Grazing animals ingest the organism and fmther contaminate vegetation and soil. Animal-to-animal transmission occurs via the fecal-oral route. Listeriosis is primarily a winter-spring disease of feedlot or housed ruminants. The less acidic pH of spoiled silage enhances multiplication of L monocytogenes. Outbreaks typically occur 2'10 days after feeding poor-quality silage. Removal or change of silage in the ration often stops the spread of listeriosis; feeding the same silage months later may result in new cases.

The uterus of all domestic animals, especially ruminants, is susceptible to infection with L monocylogenes at all stages of pregnancy, which can result in placentitis, fetal infection and death, abortion, stillbirths, neonatal deaths, rnet1itis, and possibly viable carriers. The metritis has little or no effect on subsequent reproduction; however, Listeria may be shed for;:,! mo via the vagina and milk. Infections acquired via ingestion tend to localize in the intestinal wall and result in prolonged fecal excretion. It has been postulated that contan1inated silage results in latent infections, often approaching lOO"A, of the exposed herd or flock, but clinical listeriosis in only a few animals.

Pathogenesis: Listeria organisms that are ingested or inhaled tend to cause septicemia, abo1tion, and latent infection. Those that gain entry to tissues have a predilection to localize in the intestinal wall, medulla oblongata, and placenta or to cause encephalitis via minute wounds in buccal mucosa. The various manifestations of infection occur in all susceptible species and are associated with characteristic clinical syndromes: abortion and perinatal mortality in all species, encephalitis or rneningoen­ cephalitis in adult ruminants, septicemia in neonatal rmninants and monogastric animals, and septicemia with myocardial or hepatic necrosis (or both) in poultry (see p 2839). Listeric encephalitis affects sheep, cattle, goats, and occasionally pigs. It is essentially a localized infection of the brain stern that develops when L monocytogenes ascends the trigeminal nerve. Clinical signs vary according to the function of damaged neurons but often ar·e mlilateral and include depression (ascending reticular activating system), ipsilateral weakness (long tracts), trigeminal and facial nerve paralysis, and less commonly, circling (vestibulocochlear nucleus). Neurologic signs indicating bilateral cranial nerve deficits are occasion­ ally seen in lambs 30 have been described as causes of opportunistic human infections, and at least 30 as responsible for animal diseases. Recent use of molecular techniques has led to large taxonomic changes in the Nocardia classification, and new species continue to be described. Epidemiology: Nocardia spp are ubiquitous organisms, a component of normal soil microflora; they are commonly foWld in soil, organic material, freshwater and saltwater, dust, compost vegetation, and other environmental sources. Nocardiosis is considered an uncommon disease in animals and people. However, reports of animal nocardiosis have increased worldwide. Infections in livestock and companion animals caused by Nocardia spp are acquired by inhalation, traW11atic percuta­ neous introduction of the microorganism, ingestion, or by the intramanllllary route. The occurrence of disease and infective Nocardia spp may vary geographically, influenced by animal ma.11agement strategies as well as environmental factors, such as dry, dusty, or windy conditions. Nocardia spp is considered an agent of mastitis of environmental origin in cattle and small rW11inants. Nocardial mastitis usually affects herds witll a history of inadequate milking management and/or poor hygiene conditions before and after milking. Man1mary infections are predomi­ nantly caused by soil contanlination of teat dips, udders, and milking equipment during washing procedures and by intran1arnrnary infusion therapy. Dairy herds affected by nocardial mastitis also have a history of inadequate concentrations of antiseptics in teat dips. Outbreaks of nocardial mastitis have been reported associated witll dry-cow tllerapy (eg, neomycin) or improper intramammary therapy. In companion animals, disease trans­ mission is related to the inoculation of organisms tllrough pW1cture woW1ds

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NOCARDIOSIS or foreign bodies, or secondary to bites, wounds, or scratches after cat fights. Canine infections have rarely been related to inhalation of the bactelium. The occurrence of nocardiosis in dogs and cats is intimately associated with underlying immunosup­ pressive disorders, particularly dogs infected by distemper virus and cats affected by leukemia or in1n1unodeficiency virus. Canine nocardiosis occurs at any age group and in both sexes, although it appears to affect mainly males, particularly between l 2yr old. Nocardiosis in horses is recognized as an opportunistic infection and is usually related to inlffiune disorders. In most reported cases of equine clinical nocardio­ sis, there were underlying in1n1unosuppres­ sive problems, particularly pituitary pars intermedia dysfunction (seep 547) or severe combined immw10deficiency in Arabian foals (seep 818).

Pathogenesis: Pathogenicity of

Nocardia in domestic anin1als is attributed

to the virulence of the st.rain, the structure of the bacterial cell wall, host susceptibility, route of transmission, coinfection with inlffiunosuppressive diseases, and development of pyogranulomatous lesions. However, the outcome of Nocardia infections is intimately linked to the ability of the st.rain to resist the initial neut.rophil and activated macrophage attack and the cell-mediated inlffiune response. Immune response against nocardial infections is plimalily cell-mediated. These intracellular organisms are able to inhibit phagosome-lysosome fusion in neut.rophils and macrophages because of the presence of mycolic acids in their bacterial cell wall. Nocardia is also resistant to acids, oxidative enzymes (ca.ta.lase and superoxide dismutase), and other enzymatic mecha­ nisms of phagocytic cells. In addition, some toxins have been identified inNocardia spp that appear to contribute to the vi..tulence of pathogenic st.rains. Nocardia does not induce an effective hwnoral in1mune response mediated by the action ofB lymphocytes.

Clinical Findings: Mastitis, cutaneous/ subcutaneous lesions, abscesses in organs, and pnewnonia are the most con1n1on clinical signs of noca.rdiosis in livestock and companion animals. Mastitis in Ruminants: Former

N asteroides, N nova, N otitidiscavimum, and N farcinica are the most con1n1on species desclibed in man1n1ary nocardiosis

667

of domestic ruminants. More recently, based on 16S rRNA sequencing, N nova and N farcinica were the most frequent species detected in 80 different cases of bovine mastitis inBrazil and, unexpectedly,

N puris, N veterana, N cyriacigeorgica, N arthril'idis, and N africana were

identified as well. Nocardial mastitis is generally character­ ized by a history of chronic evolution and is usually refractory to antimicrobial therapy. Classically, clinical cases of mammary nocardiosis were predominantly seen in one or two animals in the herd, duling lactation or the dry peliod. Clinical examination of the udder shows enlargement, edema, fibrosis, either diffuse or multifocal nodules, and occasionally draining tracts. Strip cup testing reveals serous to purulent milk secretion, showing white to yellow particles ("sulfur granules"). Infected cows have high somatic cell counts. Less frequently, the organism may disseminate from the man1n1ary gland to other organs, causing regional lymphadenitis and pyogranuloma­ tous lesions.

Bovine Farcy: This particular manifesta­ tion of bovine nocardiosis is usually limited to the tropics. Bovine farcy is caused by former N farcinica. Occasionally, Mycobacteriumfa1-cinogenes and M senegalense are also identified in similar lesions.Bovine farcy is an uncommon cause of chronic lymphangitis, lymphadenitis, and cutaneous nodules. Initially, the lesions consist of cutaneous nodules, particularly in the leg and neck regions. These nodules may slowly enlarge and coalesce to lesions of up to 10 cm in dian1eter, which rarely ulcerate. The lymphatic vessels appear cord-like. Horses: Noca.rdiosis is an uncommon disease in horses. Most nocardial infections in horses were described involving former N asteroides and occasionally N brasilien­ sis. More recently, based on molecular assays, N nova was desclibed causing recurrent airway obstruction in a horse. Severe pnewnonia, pleuritis, disseminated (systemic) abscesses in organs, cutaneous lesions, mycetomas, and rarely, abortion represent the main clinical signs of equine noca.rdiosis. Systemic nocardiosis occw-s by hematogenous dissemination of bacteria causing abscesses in various organs. Pulmonary nocardiosis is charactelized by increased respiratory rate, cough, labored breathing, and nasal secretion. Cutaneous and subcutaneous lesions are generally secondary to t.rawnatic introduction of

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Nocardia into the skin, leading to pyoder­

matitis, cellulitis, and cutaneous nodules located anywhere in the body. The lesions may ulcerate and have an odorless, gray to white discharge. Mycetomas are another type of cutaneous infection and consist of chronic and progressive skin lesions caused after transcutaneous inoculation of Nocardia spp. Painless nodules, purulent to necrotic, commonly form, usually limited to the site of injury, and occasionally show purulent discharge through the sinus tract. Abortion rarely occurs in mares. Two cases were reported in Arabian and Thoroughbred mares at -6 mo of gestation, both with histocy of failure to maintain gestation to term. Fetal necropsies showed lesions in lung and liver. N asteroides was cultured from the uterus of the Arabian mare. Companion Animals: In dogs and cats, former N asteroides, N brasiliensis, N otitidiscaviarum, and N nova are the most frequent species identified. Recently, based on molecular methods, N africana, N elegans, and N tenerifensis were reported in cats, and N abscessus in a dog. Superficial skin, ly:mphocutaneous, and thoracic infections, as well as disseminated forms, are the major clinical pictures of nocardiosis in dogs and cats. Cutaneous/ subcutaneous abscesses with fistulous tracts, ulcers, mycetomas, and regional lyrnphadenitis are frequent clinical manifestations of the disease, associated with local skin or lyrnphocutaneous lesions in cats and resembling human nocardiosis. Skin lesions are seen mainly in the extremities, flank, nose, and neck areas. Canine and feline pulmonary nocardiosis are characterized by mucopurnlent oculonasal discharge, anorexia, hype1ther­ mia, weight loss, cough, dyspnea, and hemoptysis. Other systemic or disseminated forms of the disease in companion animals are represented by the presence of abscesses or lesions in two or more sites, including liver, kidneys, spleen, eyes, bones, joints, and abdominal lymph nodes, as well as development of pe1itonitis, pleuritis, and pyothorax. GI infection can lead to gingivitis, halitosis, and ulceration of the oral cavity. Rarely, the organism affects the urinary tract and heart. Nocardial infection in the CNS is associated with seizures, alertness, and deficits in proprioception. Miscellaneous: Bovine or equine oral infection secondary to ingestion of fibrous foods can lead to development of pyogranu­ lomatous lesions in the jaw. Abortion may also occur in sows and cows. Submandibu-

Jar and mesenteric lymphadenitis was reported in pigs. Nocardiosis in wildlife and fishes generally causes organ abscesses and pneun1onia. Diagnosis: Routine diagnosis is based on epidemiologic findings, clinical signs, and microbiologic exanlination. Samples of abscesses, skin, tracheobronchial lavage fluid, milk, aspirates, organs, or other tissues should be cultured on sheep blood and/or Sabouraud agar and incubated aerobically for 2-7 days at 37° C and 25° C [98.6°F and 77° FJ, respectively. However, growth of some Nocardia spp in culture media is slow, and incubation should be extended for at least 2 wk. Colonies are circular, convex, smooth or rough, finnly adherent to agar surface, odorless, with various carotenoid-like pigments (cream, white, orange, pink, or red), and present aerial hyphae and typical powdecy and dry surface, like fungal organisms. Because Nocardia spp are ubiquitous in the environment, microbiologic isolation of a small number of organisms from clinical specimens must be evaluated together with clinical signs and other diagnostic methods. Microscopically, gram-positive, typically filamentous organisms are seen, with a tendency to fragmentation. Modified Ziehl-Neelsen stain shows partially acid-fast organisms. Fine-needle aspiration has been used in the diagnosis of skin nocardiosis in companion animals. Gram, Giemsa, and panoptic stains show filamentous organ­ isms in aspirated specimens. The leukogram reveals mainly leukocytosis with neutro­ philia and monocytosis, whereas the ecythrogram shows moderate anemia. Radiographic images of dogs with pulmonary nocardiosis show diffuse inflammation, nodules, abscesses, and lobar consolidation. Differential diagnoses in domestic animals include infections with Actinomyces or Streptomyces spp because of the similarities in microbiologic appearance and clinical signs. Face and jaw enlargement in cattle and horses caused by oral nocardiosis should be differentiated fromActinomyces bovis (actinomycosis, seep 590), Actinobacillus lignieresii (actinobacillosis, seep 589), and Staphylo­ coccus aureus (botcyomycosis). Postmortem examination of internal organs and tissues reveals abscesses and/or numerous small to large nodules, discrete to coalescing, of white to gray color. Histologic findings of nocardiosis are characterized by pyogranulomatous to suppurative lesions with areas of necrosis. The lesions or

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nodules show a suppurative, necrotic center containing filamentous organisms surrounded by macrophages, lymphocytes, and plasma cells. Occasionally, epithelioid and multinucleated giant cells are found. Histolopathology sometin1es reveals small, soft granules in discharges of lesions, formed by microcolonies of the organism. Lymph nodes are enlarged. Different serologic (immunodifusion, complement fixation, and ELISA) and cutaneous hypersensitivity tests have been proposed to diagnose nocardiosis in animals. However, host animals commonly develop a nonspecific antibody response against Nocardia, limiting the use of serologic tests in routine diagnosis. Currently, phenotypic diagnoses of Nocardia spp have been confinned using molecular metl10ds, including PCR, restriction endonuclease analysis of amplified 65--kDa heat shock protein gene (hsp65), 16S rRNA gene sequence, essential secretory protein A (secAl ), gyrase B (gyrB), and DNA-DNA hybridization. These molecular techniques offer a timesaving and reliable means of speciation and have led to a number of taxonomic changes and the identification of new species of Nocardia. Treatment: Animal and human nocardio­ sis is usually refractory to conventional therapy because of the intracellular location of the bacterium, development of pyogranu­ lomatous lesions, and antimicrobial resistance patterns. The antimicrobial susceptibility profile varies dramatically between Nocardia spp and geographic areas. The National Conunittee for Clinical Laboratory Standards approved an in vitro standardized susceptibility test for Nocardia by broth microdilution. The modified disc diffusion method has been used as well. Trirnethoprim-sulfonamides, arninogly­ cosides (an1ikacin, gentamicin), linezolid, amoxicillin-clavulanate, imipenem, and some cephalosporins (cefotaxime, ceftria­ xone) are considered drugs of choice for nocardiosis therapy in animals and people. Ampicillin, clarithromycin, doxycycline, erythromycin, and minocycline are desc­ Iibed as treatment alternatives for animals. Combined therapy using an'likacin with sulfonamides, and amikacin with imipenem or cephalosporins (cefotaxime, ceftriax­ one) also have been proposed. lntramam­ mary infusions of trin1ethoplim-sulfon­ amides, cephalosporins or arninoglycosides (gentamicin) have been used for 5-7 days to treat clinical mastitis in cattle and goats.

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Long-term therapy (1-6 mo in domestic anin1als and 6-12 mo in people) is required because of clinical relapses after short-tern1 protocols. In companion animals, surgical procedures (debridement, drainage, extirpation of foreign bodies, and washing of lesions with antiseptic solutions) are indicated in cutaneous/subcutaneous lesions and osteomyelitis. However, antin'licrobial therapy is successful in only 30%--500,i, of cases of mastitis in cattle and goats, as well as in pulmonary or extrapul­ monary (disseminated or systemic) infections in companion animals and horses. The mortality of animal nocardiosis is attributed mainly to underlying condi­ tions, delayed diagnosis, and in1proper therapy. Control and Prevention: There are no specific or effective measures to control animal and human nocardiosis, probably because of the wide distlibution of the microorganism in the environment. In companion animals, immunosuppres­ sive pathogens or debilitating conditions should be investigated as predisposing factors to development of nocardiosis. Control and prevention of nocardial mastitis is based on measures recom­ mended for environmental agents. Thus, the best measures to control and/or prevent nocardial mastitis remain the early microbiologic diagnosis of mastitis, proper hygiene conditions, cleaning the environ­ ment during milking, correct antiseptic concentrations in post- and mainly iu pre-dipping solutions, high-q_uality water to wash the animals and milking equipment, removal of organic material from the milking area, and appropriate intramam­ mary therapy procedures. Because of poor success rates in treatment of manimary infections, segregation of infected anin1als, chemical drying of affected quarters, or culling of animals are also recommended in control of nocardial mastitis in dairy herds. Public Health Considerations: Human nocardiosis is an opportunistic disease. In some countries, the clinical impact of nocar­ diosis is fragn1entary, indicating that diagnosis of disease may be neglected or underestimated. Curiously, reports of human nocardiosis have recently increased all over the world. Although the disease typically occurs in immunocompromised patients, nocardiosis has been described in i.nununocompetent people as well. Former N asteroides complex is the main species

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described in human nocardiosis. Currently, based on molecular methodologies and rearranged taxonomy, N cyriacigeorgica,

N brasiliensis, N asteroides, N nova, Nfarcinica, N transvalensis, N pseudobra­ siliensis, and N otitidiscaviarum have most frequently been detected in human patients. Pneumonia, cutaneous-subcutaneous lesions, mycetoma, and neurologic manifestations are the most common clinical signs. However, clinical cases of human nocardiosis are intimately associ­ ated with inununosuppressive or debilitat­ ing disorders, such as AIDS, organ trans­ plants, cirrhosis, diabetes, alcoholism, rheumatic and malignancy diseases (lymphosarcoma, lymphoma), or prolonged use of corticosteroids. The environment is the natural reservoir of Nocardia spp for human and animal infections. Most cases of transmis­ sion to people probably occur by inhalation of the organism in dry and warm climate regions (aerosolization). Trauma with skin inoculation is another form of transmission of the bacterium to

people. Cases of cutaneous/subcutaneous nocardiosis have been reported in some patients, secondary to bites or scratches of clinically ill dogs and cats. However, human nocardiosis is apparently not directly transmitted person-to-person or by nosocomial infections. Interestingly, studies have shown great similarity between Nocardia spp involved in human and animal infections. Experimental studies regarding temperature resistance using former N asteroides and N brasiliensis isolated from bovine milk and submitted to time/temperature conditions used in usual pasteurization procedures indicated a potential risk of Nocardia transmission by milk. Precautions should be taken an10ng human patients who have immune dysfunctions or debilitating diseases, with special reference to contact with soil or organic material from environments contaminated by domestic animals, contamination of traumatic cutaneous lesions, or close contact with animals suspected of having nocardiosis.

PERITONITIS Peritonitis is an inflammation of the se_rous membranes of the peritoneal cavity. It may be a primary diseas_e or secondary to other pathologic conditions. Different infectious and noninfectious agents may cause peritonitis, which may result in a variety of clinical manifestations, disease progression, and outcome. Peritonitis fnay be acute or chronic, septic or nonseptic, local or diffuse, or adhesive or exudative. The term "tertiary peritonitis," used in human medicine for particular cases of chronic peritonitis with a small number of bacteria or fungi, is not used in veterinary medicine. Etiology: Primary peritonitis is less common than secondary peritonitis and may be infectious or idiopathic. In infectious primary peritonitis, infectious agents spread via the bloodstream into the peritoneal cavity of animals that are often inununocompromised. Such infectious agents include feline corona.virus (FCoV), which causes feline infectious peritonitis (FIP); Nocardia spp; Mycobacterium spp; Haemophilus parasuis; and other infectious agents. Progression of primary peritonitis tends to be chronic.

Peritonitis occurs secondary to another disease as the result of exposure of the peritoneal cavity to nonspecific infectious or noninfectious agents. It is often acute and frequently results in a progressive, systemic disease. Secondary septic peritonitis is commonly associated with perforation of and leakage from GI organs (eg, traumatic reticuloperitonitis in cattle), with subse­ quent processes allowing transmural migration of bacteria (eg, neoplasia, intestinal ischemia), or with perforation/ rupture of or leakage from other infected viscera (eg, abscesses in liver, spleen, omentun1, cystitis, endometritis, pyometra). Furthermore, migration of parasites through the abdominal cavity may also result in leakage of chyme with subsequent septic peritonitis. Perforating wotmds of the abdominal wall (eg, dog bites) or dehis­ cence of abdominal wound closure may result in laceration of viscera and inocula­ tion of foreign material and microorganisms into the peritoneal cavity. Microorganisms associated with septic peritonitis usually reflect the source of contan1ination. A mixed bacterial population is seen in GI tract perforation, whereas

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PERITONITIS perforation of nongastrointestinal viscera (eg, urinary or gall bladder, uterus, prostate) or hematogeous infection of the peritoneal cavity may be more typically associated with aerobic organisms, includingEsclwichia

coli, Streptococcus equi zooepidemicus, Staphylococcus, Proteus, Rhodococcus, Klebsiella, Salmonella, Enterobacter, Pseudomonas, or Corynebacte,ium.

Secondary aseptic peritonitis occurs after contamination of the abdominal cavity with chemical irritants (eg, bile, urine, drugs) or intestinal ischemia Common conditions are urolithiasis and rnpture of the Uii.nary or gall bladder; however, these conditions are not

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always aseptic. The originally aseptic peritoneal inflanm1ations may later become septic. In addition, intraperitoneal adminis­ tration of drugs or fluids may result in temporary inflanm1at01y reactions of the peritoneum. Because New World can1elids show severe inflanmiatory reactions to infections withDicrocoelium de,itriticum, peritonitis may develop subsequent to the severe hepatitis. In large anin1als, peritonitis is most commonly seen in cattle, less often in horses, and rarely diagnosed in pigs, sheep, and goats. It is a serious and often fatal condition in cats (FIP). For conunon causes of peritonitis in vaiious species, see TABLE 5.

COMMON CAUSES OF PERITONITIS

Species

Cause

Cattle

Traumatic reticulope1itonitis; rnmenitis; abomasal ulcer (perfora­ tion); abomasal volvulus; cecal torsion; dystocia (uterine torsion, cesarean section); metritis or pyometra; abdominal surgery; intestinal, rectal, or uterine rnpture; liver or abdominal abscess rnpture; omphalitis (calves); fat necrosis/pancreatitis; neoplasia (eg, mesothelioma, ileal adenocarcinoma); iatrogenic (eg, rectal perforation, liver biopsy, intraperitoneal i.Itjection, rw11enocente­ sis); green algae infection (rare); Setaria infection (rai·e)

Horses

Parasitic (larval) migration; intestinal injUIY and ischemia (colic); abdominal abscess rupture (Rhodococcus, Streptococcus); abdominal surgery (colic surgery, castration); gastric, intestinal, or uterine rupture; gastroduodenoenteritis, colitis; omphalitis, persistent urachus, or bladder rupture (foals); gastric ulcer (perforation); fat necrosis/pancreatitis; neoplasia (eg, cholangio­ cellular carcinoma); penetrating trallllla to abdominal wall; iatrogenic (rectal perforation, intraperitoneal injection)

Small ruminants

Primary peritonitis (Mycoplasma spp); parasitic (larval) migration ( eg, liver fluke, lungwom1, Seta1ia sp); traumatic reticuloperitonitis (less common than in cattle); abdominal abscess rupture; neoplasia (eg, mesothelioma, cholangiocellular carcinoma); iatrogenic ( eg, liver biopsy, intraperitoneal injection)

New World canlelids Sequela of parasitic migration/acute hepatitis (dicrocoeliosis of special importance); pe1forating third-compartment or duodenal ulcers; sequela of urolithiasis/ruptured urinary bladder; traumatic reticuloperitonitis (rare) Pigs

Glasser's disease (Haemophilus parasuis); intestinal (ileal) perforation; dystocia; sequela of septicemic infections (Salmo­ nella Choleraesuis, Streptococcus siiis); polyserositis (Myco­

plasma hyorhinis) Dogs and cats

Feline infectious peritonitis (FCoV); ingested intestinal foreign bodies; gastric, intestinal, rectal, bladder, or uterine rupture; abdominal or intestinal surgery; gastric and duodenal ulcers/ perforation; abdominal neoplasia ( eg, mesothelioma); hepatitis, gallbladder diseases/rupture; pancreatitis/fat necrosis; gastric dilatation volvulus (dog); penetrating trauma to abdominal wall; Candida albicans (rare); Neospora caninum (rare)

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Pathogenesis: Inflammation of the peritonewn is the result of a vaiiety of possible pathogenetic pathways that are species-dependent (eg, peritoneal inflammatory response in cattle is characterized by extensive fibrin fonnation, horses tend to develop exudative peritoni­ tis) and mainly influenced by etiology (eg, primaiy or secondaiy, septic or nonseptic). Because of the release of inflammato1y mediators after contact with mechanical, chemical, or infectious agents, serosal capillaiy permeability is increased and results in leakage of plasma proteins, solutes, and water into the peritoneal cavity. Exudation of protein-rich fluid may result in hypoproteinemia and facilitates bacte1ial proliferation. The combined effect of large fluid losses into the peritoneal cavity and vasodilatory effects of absorbed toxins may produce profound hypotension and hypovolemia. The inflan1IT1ation may decrease the animal's antioxidative capacity and result in oxidative stress. Rupture or perforation of the forestom­ ach, stomach, or intestine with spillage of large vohunes of gastric or intestinal contents and rupture or perforation of the contaminated uterus leads to an acute septic peritonitis. Toxins produced by bacteria and tissue breakdown are readily absorbed through the peritoneum and have severe systemic effects leading to hypo­ tension, shock, systemic inflammatory response syndrome (SIRS), and dissemi­ nated intravascular coagulation (DIC). Endotoxins and acid-base and electrolyte disturbances directly affect cardiac function, leading to reduced cardiac output and circulatory failure. Paralytic ileus is considered to be a frequent result of acute peritonitis, causing functional.obstruction and an increased mortality rate. Large volwnes of inflan1rnatory exudates may be secreted into the peritoneal cavity during peritonitis and may lead to impaired respiration by impinging on the diaphragm. Spillage of small an10unts of gastric or intestinal content ( eg, after transcutaneous run1enocentesis, bar suture techniques for left displaced abomaswn surgery) nom1ally result in local peritonitis. Chronic peritonitis is often characterized by extensive secretion of fibrinogen and subsequent formation of fib1inous/fibrous adhesions. Such adhesions help localize the inflainmatory process (eg, trawnatic reticuloperitonitis in cattle, type 3 abomasal ulcers in cattle) but may cause mechanical or functional obstruction of the GI tract. Chronic peritonitis in horses often results in recurrent colic episodes.

Clinical Findings: Clinical signs vaiy depending on the type and etiology of peritonitis. Affected animals may develop toxemia and septicemia, shock, hemor­ rhage, abdominal pain, paralytic ileus, fluid accwnulation, and adhesions in varying degrees. However, there are reports of apparently clinically healthy animals having chronic bacterial peritonitis. Shock, hypotension, acid-base distur­ bances, and circulatory collapse after acute septic peritonitis associated with rupture of intestines or utems often lead to sudden death. These animals normally show only limited clinical signs of peritonitis. In less severe cases, abdominal pain and fever are common. Hypothem1ia can also be seen as a result of dehydration, hypovolemia, and sepsis. Abdominal pain may be permanent and severe, characterized by guarding the abdomen, stiff gait, or recwnbency. In all species, pain responses are most evident in the early stages. Abdominal distention, which may be inapparent, usually is due to accwnulation of peritoneal exudates, paralytic ileus, or peritoneal adhesions. Fecal output is often decreased, although frequency of defecation may be increased in tl1e early stages of peritonitis. Animals with secondaiy pe1itonitis may also show clinical signs associated with the primaiy disease. Rectal palpation is a useful diagnostic technique to evaluate the peritoneum and accessible abdominal organs in large animals; however, local peritonitic processes in the cranial abdomen (eg, trawnatic reticuloperitonitis in cattle) do not result in clinical signs that can be diagnosed by rectal exan1ination. Abdomi­ nal radiography may be used in small animals. In horses and cattle, radiography can be also used as a diagnostic tool, but high-power x-ray macl1ines are required; therefore, this technique is limited to stationaiy units in vete1inaiy clinics. Generally, ultrasonography is the most valuable diagnostic tool to exan1ine the abdominal cavity and assess the extent, localization, and character of peritonitis. Additionally, ultrasonography allows a guided abdominocentesis, which can be used (in both large and small anin1als) to obtain fluid for cytologic and biochemical exainination and bacte1iologic culture. Diagnostic peritoneal lavage can be used if peritoneal fluid caJU1ot be obtained by abclominocentesis. Diagnostic laparoscopy or laparotomy can be considered to verify the diagnosis. Diagnostic laparotomy is frequently used in cattle because it is inexpensive, can be performed in standing position, and is associated with few or

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PERITONITIS minor complications; it also makes additional diagnostic procedures unneces­ sary and can often be combined with therapeutic measures. Cattle: Clinical signs of peritonitis in cattle are often nonspecific and character­ ized by reduced feed intake, drop in milk production, and decreased rumination activity. In chronic cases, rurninal con­ tractions may be present but reduced in intensity. Abdominal percussion may reveal rurninal tympany or pneumoperitoneum. Moderate fever is typical during the first 24-36 hr in cattle with acute, local peritonitis. High fever suggests acute, diffuse peritonitis. Cattle with peritonitis often have a shuffling, cautious gait with a rigid arched back, and grunt when walking or passing urine or feces. Deep palpation of the abdominal wall and pain provocation tests result in pain response. Chronic peritonitis is associated with development of fibrous adhesions. Depending on localization, rectal palpation may reveal adhesions between intestinal loops and peritoneum. Cattle may suffer from chronic indigestion (Hoflund syndrome, abomasal impaction) or toxemia, with periods of acute, severe illness caused by partial intestinal obstruction. The majolity of cattle develop a localized pelitonitis by extensive fibrin formation; however, in a few cases the abdominal cavity contains large volumes of turbid, infected peritoneal fluid. Small Ruminants, New World Camelids, and Pigs: Generally, the clinical signs in small ruminants, New World camelids, and pigs are similar to those in other animals. However, peritonitis is rarely diagnosed . clinically in pigs, sheep, or goats, although 1t is not an uncommon finding on routine meat inspection after slaughter of pigs. It is more common in llamas and alpacas. Horses: Clinical signs include colic, distended intestines on rectal examination, gastric reflux, and occasionally diarrhea. Rectal palpation may reveal tacky, dry mucosa and in some cases fibrinous or fibrous adhesions between intestinal loops and other abdominal organs. Intestinal peristaltic sounds are reduced. Tachycardia, weak pulses, poor pelipheral perfusion, and fever are common. Weight loss and intermittent abdominal pain (colic) may be seen in horses with chronic peritonitis. Dogs and Cats: In small animals, anorexia and depression are nonspecific signs of peritonitis, often accompanied by vomiting and decreased defecation. The abdomen may be distended. Abdominal

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palpation may be painful, and abdominal masses may be detected. Icterus may be present in generalized biliary peritonitis in small animals. Abdominal radiographs may reveal GI obstruction, bowel dilatation, free abdominal air, ascites, or radiodense foreign matelial. Loss of serosal details in radio­ graphs indicates abdominal fluid. Diagnosis: Laboratory analyses are helpful to confirm the clinical diagnosis and determine the severity of peritonitis, and should include a CBC and several biochemi­ cal paran1eters in blood and peritoneal fluid. Acute, diffuse pe1itonitis with toxemia is usually accompanied by leukopenia, neutropenia, and a marked increase in immature neutrophils (degenerative left shift). In less severe acute peritonitis, leukocytosis may occur as a result of increased neutrophil production. Acute, localized peritonitis may reveal a nonnal WBC count with a regenerative left shift. The total WBC count in chronic peritonitis may be normal, with an occasional increase in lymphocytes and monocytes. Anemia may occur due to hemorrhage into the peritoneal cavity but is also commonly associated with chronic inflan1matory processes. A nw11ber of abnonnalities of serum biochemical parameters (eg, total protein, albumin, fibrinogen, bilirubin, LDH, alkaline phos­ phatase, CK) may accompany peritonitis. Hypoalbunlinemia, hyperglobulinemia, and hyperbilirubinemia are frequently present. Generally, the changes in hematologic and biochemical parameters indicate inflan1ma­ tory processes and tissue damage, but they are not pathognomonic for peritonitis. The peritoneal fluid is a plasma dialysate witl1 specific physical and chemical properties that depend on membrane permeability, concentrations and electrical charges of ions, and osmotic pressure. The fluid contains cells deriving from the mesothelium and the blood or Jyn1phatic vessels. Under physiologic conditions, peritoneal fluid is a tJ.·ansudate, whereas pelitonitis results in a fluid that is typically characterized as an exudate. Analysis of peritoneal fluid is a useful diagnostic method in gastroenterology, because tl1e fluid generally reflects abdominal condi­ tions. The volume of peritoneal fluid is frequently increased in peritonitis. In cases of septic peritonitis, samples of peritoneal fluid should be exanlined microbiologically to characterize infectious pathogens. The parameters of the classic transudate­ exudate categorization system are shown in TABLE 6. A peritoneal fluid showing proper­ ties of both a transudate and an exudate is

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conunonly called a modified transudate. Use of a scoring system allows further classifica­ tion as mild, moderate, or severe peritonitis. In practice, however, analysis of peritoneal fluid may be inconsistent, leading to inconclusive results. Therefore, the diag­ nostic value of this traditional concept is limited. To improve the sensitivity of the distinction between an exudate and transudate of pleural and peritoneal effusions in human medicine, Light's criteria (fluid to serum protein ratio >0.5, fluid to serum LDH ratio >0.6, or fluid LOH activity >200 U/L), cutoff values for ratios between peritoneal fluid and plasma or serum of vaiious paraineters (eg, lactate, glucose, enzymes), a.11d the serum-ascites albumin gradient (SAAG) have been established. These concepts have been applied to some animal species (ie, horses, cattle, small anin1als). Under physiologic conditions, the ratio between lymphocytes and neutrophils is close to 1:1. Acute peritonitis usually results in an increased number of leukocytes, and the percentage of neutrophils ca.11 be 60%--900A,. However, in cases of peracute septic inflanm1ation, the number of leukocytes may decrease due to necrosis and cell dainage. Histologically, a high rate of degenerative leukocytes (cytolysis, kai,1orrhexis, or kal}'olysis) can be found. In chronic peritoneal inflanunation, the proportion of neutrophils decreases and the proportion of monocytes increases. The presence of intra- or extracellular bacteria confirms septic peritonitis. Grain-staining enables differentiation between gran1-posi­ tive and grain-negative bacteria and facilitates early antibiotic treatment. The physiologic total protein concentra­ tion in peritoneal fluid is 20--25 g/L. The nom1al protein ratio between peritoneal

fluid and serum is lower than 1:2. The SAAG is calculated by subtracting the peritoneal fluid albumin concentration from the serum concentration. The cutoff value of 11 g/L for people seems suitable for monogastric ai1in1als. However, the reference values for protein ratio and SAAG ai·e not applicable to dairy cattle, mainly because of their higher serwn protein and albumin concentrations than those of monogastric anin1als and people. In addition, in cattle, the protein ratio a.11d SAAG did not show higher diagnostic values than the total protein concentration in peritoneal fluid alone. In healthy anin1als, glucose concentration is the saine in both serum and peritoneal fluid. Bacterial infection of the peritoneal cavity results in a major decrease of peritoneal glucose concentration. A peritoneal fluid:serum ratio of glucose concentrations A, in untreated cats. Ten of 16 (62.5%) cats exposed orally developed enlarged lymph nodes in the medial retropharyngeal, submandibulal·, sublingual, and tonsillar regions, palpable 4--0 days after exposure. Ypeslis was isolated from the throats of 15 of these cats. In 6 subcutaneously exposed cats (mimicking a flea bite), none had palpably enlal·ged lymph nodes in the head or neck region, but four had subcutaneous abscesses at the inoculation site. Cats with primaly septicemic plague have no obvious lymphadenopathy but present with fever, lethargy, and anorexia. Septic signs may also include diarrhea, vomiting, tachycal·dia, weak pulse, prolonged capillaly refill time, disseminated intravas­ cular coagulopathy, and respiratory distress. Prin1ary pneun1onic plague has not been docun1ented in cats. Cats with secondaly pneun1onic plague may present with all the signs of septicemic plague along with a cough and other abnom1al lung sounds. Characteristic necropsy findings Call include livers that are pale with light-colored necrotic nodules, enlarged spleens with necrotic nodules, and lungs with diffuse interstitial pnewnonia, focal congestion, hemorrhages, and necrotic foci.

Dogs infected with plague are less likely to develop clinical illness than cats, although cases have been seen in enzootic areas. Symptomatic plague infection has been docun1ented in three naturally infected dogs; clinical signs included fever, lethargy, submandibular lymphadenopathy, a purnlent interrnandibulal· lesion, oral cavity lesions, and cough. Cattle, horses, sheep, and pigs are not known to develop symptomatic illness from plague, whereas clinical illness has been documented in goats, camels, mule deer, pronghorn antelope, nonhuman primates, alld a llalna. Infected mountain lions and bobcats have shown clinical signs and mortality similal· to those of domestic cats. Diagnosis: Plague must be differentiated from other bacterial infections, including tularemia (seep 692), abscesses due to wounds (cat fight bites), and staphylococ­ cal and streptococcal infections. During acute illness, preferred filltemortem Salllples for culture include whole blood, lymph node aspirates, swabs from draining lesions, alld oropharyngeal swabs from cats with oral lesions or pneun1onia. Diagnostic sal11ples should be taken before filltibiotics are ad.ministered. Y peslis cultures Call take 48 hr for visible growth to develop. An air-dried glass slide smear of a bubo aspirate can be used for a fluorescent filltibody test that detects the Fl filltigen on Y peslis cells. This test Call be performed in a matter of hours in fill experienced laborato1y and is both sensitive alld specific. Postmo1tem specimens should include samples of liver, spleen, and lung (for pnewnonic cases) alld affected lymph nodes. In areas where tularemia is also present, Salllples should be collected under a biosafety hood, or the entire animal submitted to a veterinary diagnostic laboratory where aerosol precautions Call be implemented. Serologic antibody tests can be confinnatory but require acute alld convalescent Salnples taken 2-3 wk apart, demonstrating a 4-fold rise in filltibody titer. Single acute sera are often negative if taken early in the cow-se of illness or Call be problematic in fill enzootic al·ea where aninlals may retain filltibody titers from previous exposw·es. Treatment: Because of the rapid

progression of this disease, treatment for suspected plague (filld infection control practices) should be started before a definitive diagnosis is obtained. Streptomy-

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cin has been considered the drug of choice in human cases but is difficult to obtain and rarely used today. Gentan1icin is currently used to treat most human plague cases and should be considered a suitable alternative choice in veterinary medicine for seriously ill aninmls, although it is not approved for this purpose. Aninlals with renal failure require adjusted dosages. Doxycycline is appropriate for treatment of less complicated cases and to complete treatment of seriously ill anin1als after clinical in1provement. Tetracycline and chloran1phenicol are also options. Penicillins are not effective in treating plague. In treatment studies with experimentally infected mice, the fluoroquinolones perfom1ed as well as streptomycin. F1uoroquinolones have not been studied in any veterinary clinical trials, but there is growing evidence from their use in enzootic areas that they are effective in the treatment of plague in dogs and cats. The recommended duration of treatment is 10-21 days, with clinical improvement (including defervescence) expected within a few days of treatment initiation. The duration of infectivity in treated cats is not definitively known, but cats are thought to be noninfectious after 72 hr of appropriate antibiotic therapy with indications of clinical in1provement. During this infectious period, cats should remain hospitalized, especially if there are signs of pneumonia. Human cases have occurred in cat owners trying to give oral medications at home, exposing them to contact with the oral cavity and associated infectious secretions. Prevention and Zoonotic Risk: Along with treatment and diagnostic considera­ tions, protection of people and other animals and initiation of public health

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interventions are critical when an animal is suspected to have plague. Animals with signs suggestive of plague should be placed in isolation, with infection control measures inlplemented for the protection of staff and other animal patients without waiting for a definitive diagnosis. The use of gloves, surgical masks, eye protection (if splashes or sprays are anticipated), patient isolation (animal or human), and standard hygiene and disinfection procedures for protection from potentially contan1inated respiratory droplets, body fluids, and secretions from the patient (animal or human) are essential. Of the 23 human patients who developed cat-associ­ ated plague in the USA between 1977 and 1998, 6 were veterinary staff; the rest were cat owners or others handling a sick cat. After pneumonia has been excluded, or once there is evidence of clinical inlprove­ ment after 72 hr of appropriate therapy, isolation procedures may be relaxed, but standard disinfection and hygiene procedures should continue. Local or state public health officials should be notified promptly when plague is suspected to help conduct appropriate diagnostic tests, initiate an environmental investigation, and assess the need for fever watch or prophylactic antibiotics in potentially exposed people. To decrease the risk of pets and people being exposed to plague, pet owners in enzootic areas should keep their pets from roaming and hU11ting, linlit their contact with rodent or rabbit carcasses, and use appropriate flea control. Epidemiologic data, fact sheets, public education brochures, and other information on plague is available on the Web sites of the CDC and the New Mexico Depaiiment of Health.

RHODOCOCCOSIS Rhodococcosis is a pyogranulomatous disease of domestic animals, wildlife, ai1d people. It is caused by Rhodococcus equi (fonnerly Corynebacterium equi), the pathogenicity of which has been mainly attributed to the presence of virulence­ associated antigens and plasmids. Etiology: Rhodocucc:us spp belong to the aerobic actinomycetes in the order Actinomycetales, which is taxonomically related to the generaMycobacterium,

Co1ynebacterium, and Nocardia. R equi is a facultative intracellular opp01tunistic pathogen. In Grai11 smears, the bacteria appear as gram -positive rods, cocci, or rod-shaped (pleomorphic) organisms. The virulence of R equi is intinlately associated with its ability to survive and multiply inside macrophages, mainly the presence of a large plasmid that contains genes encoding a number of proteins associ­ ated with virulence (Vap). Seven genes have been classically associated with R equi

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virulence, the most important being the VapA plasmid because of its probable regulatory action over other genes. This gene regulation of R equi is a complex mechanism, influenced by vaiious factors, including iron and magnesium availability, as well as environmental conditions such as temperature and pH.

Epidemiology: R equi has been isolated from a wide vaiiety of species, including horses, cattle, swine, sheep, goats, dogs, cats, camelids, birds, and wild animals. R equi is distributed worldwide. It is widespread in surface soil, particularly in feces of foals and other herbivores, and in their environment. R equi may survive up to 12 mo in soil and can multiply in a wide temperature range (15 °-40° C) and neutral pH (6.5-7.3). Inhalation of soil dust particles is considered the main route of infection for domestic animals. Contan1inated water and food is a less frequent route of infection, except for swine. Infected sputum may be swallowed by foals with pneumonia, causing ulcerative colitis and mesenteric lyrnphadenitis. Foals showing clinical and subclinical disease may spread R equi via aerosol. Risk factors associated with a higher prevalence of disease in horses include large numbers of foals and mares, transient equine population, high foal density, foals born to mares that shed high numbers of the microorganism in the feces, and inadequate transfer of maternal ai1tibo(j.ies. Poor animal management, housing, seasonal effect on foals' birth, and environmental conditions (eg, dry, dusty, windy) have also been reported as predisposing conditions. VapA plasmid is usually found ii1 foal and bovine rhodococcosis cases, indicating a major risk of infection to companion animals by contact with livestock or their environment. Pathogenesis: The outcome of exposure to R equi is strongly influenced by the virulence, infective dose, and age and immune response of the host. Virtually all foals are exposed to R equi shortly after birth, although most do not develop clinical signs. Adult horses are commonly resistant to the clinical disease, because they have developed effective immune responses againstR equi. R equi may invade the animal via the respiratory or digestive tracts or the skin. It then spreads through hemolyrnphatic vessels, reaching different tissues and

orgai1S and developing pyogenic reactions in the liver, spleen, kidneys, bones, brain, and lymph nodes. The basis of pathogenicity is attributed to the ability of the organism to survive and multiply inside macrophages, subsequently destroying these phagocytic cells. Other factors that contribute to the pathogenesis include the iron acquisition mechanism and the presence of phospholipase C and cholesterol oxidase (so called "equi factors"). In nonequine species, in1muno­ suppressive conditions of the host may enable avirulent or less virulent strains to persist inside phagocytes. Passive humoral immunity generated by ingestion of mare colostrum contributes to the control of R equi infection in foals. However, Immoral response by itself does not confer complete protection. Consistent evidence supports the essential role of cellular in1mune response in control of R eqiii infections.

Clinical Findings: Suppurative broncho­ pneurnonia and ulcerative colitis in foals, lymphadenitis in cattle and swine, and cutaneous or organ abscesses are the major clinical manifestations of rhodococcosis in domestic animals. R equi infections are frequently found only in foals and swine, whereas they ai·e rare or uncommon in small ruminants, companion animals, birds, and wildlife. In horses, R equi is a commensal intestinal organism; it can actively multiply in the intestines of foals up to -3 mo old and can also be isolated from the feces of adult horses. Suppurative bronchopneumonia is tl1e primary clinical sign in foals. Foals are affected between 2 wk and 6 mo of age, although foals 1-3 mo old are most commonly affected, possibly because of the decline in maternal antibodies at -6 wk of age. On endemic farms, it is estimated that 5o/o-4QOA, of foals may develop clinical signs, and up to 5()0A, of cases may be fatal. Foals >6 mo old appear to be refractory to development of clinical signs. (See also Rf/0/JOCOCCUS EQUI PNEUMONIA IN FOALS, p 1451.) Initially, foals show nonspecific signs, including fever, lack of appetite, and reluctance to move and suckle. Most foals with lung infections show respiratory distress, with tachycardia, tachypnea, and a strong inspiratory effo1t manifested by abdominal movement and nostril flaring. On auscultation, inspiratory and expiratory wheezes and crackles are possibly audible, predominantly in the cranioventral region. Decreased ailway sounds suggest

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RHODOCOCCOSIS consolidation, extensive abscess fom1ation, or occasional pleural effusion. Mucous membranes may be pale or cyanotic. Weight loss, cough, and serous to mucopurulent nasal secretion are not consistent signs. Typically, the disease is insidious in foals because of the ability of horses to compen­ sate for respiratory lesions, making early diagnosis difficult. Abdominal R equi infections in foals are clinically manifest by diarrhea, ulcerative colitis, mesenteric lymphadenitis, abdominal abscesses, typhlitis, and peritonitis. Foals rarely develop intestinal signs without pulmonary signs, but intestinal lesions are found in --30%--5096 of foals with pulmonary rhodococcosis. Colic, diarrhea, and weight loss are the major clinical signs of the intestinal fmm. Immune-mediated polysynovitis affects --20%--30% of foals, caused by immune complex deposition in joints. Any joint may be involved, although the tibiotarsal and stifle joints are most commonly affected. Synovial fluid aspiration reveals nonseptic mononuclear pleocytosis, without isolation of R equi. Septic aithritis of foals is another joint lesion caused by R equi. Different from immune-mediated polysynovitis, the septic lesion is usually combined with lan1eness signs. A variety of other R equi infections are sporadically seen in horses, including cellulitis, ulceration, subcutaileous abscesses, lymphangitis, lymphadenitis, renal abscesses, pleuritis, hepatitis, and hepatoencephalopathy. Ocular signs, such as hypopyon and immune-mediated uveitis, may be seen. Osteomyelitis causing ataxia, decubitus, and limb paralysis is uncommon. Rai·ely, R equi is associated with abortion, placentitis, and infertility in mares, and it has been occasionally isolated from equine semen. Clinical manifestations in adult horses are uncommon. The disease probably affects immunocompromised horses, or animals coinfected with in1munosuppres­ sive agents, infected by plasmid strains expressing VapA. The predominant clinical signs in adult horses ai·e sinillar to those in foals, with suppurative bronchopneumonia, pleuritis, enteritis, lymphadenitis, and osteomyelitis. In swine, R equi infections ai·e basically restricted to the lyn1phatic tract. Usually, pyogranulomatous cervical lymphadenitis is seen, although mesenteric, bronchial, and otl1er lymph nodes may be involved. R equi has also been isolated from apparently normal lymph nodes. Occasionally, pneumonia may be seen. Gross lesions in

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lymph nodes caused by R eqiti observed in slaughterhouses resemble those caused by Mycobacterium spp, a major cause of swine lymphadenitis (seep 690). Rhodococcosis is rare in dogs and cats, although it is more conunonly reported in cats than in dogs. The most common routes of infection in dogs and cats are traumatic percutaileous introduction of microorgan­ isms, p1imary contamination of wounds, or secondary to scratches in cat fights. Most cats present with cutaileous lesions on one extremity, along with localized swelling, ulcers, and fistulas with purulent drainage. The lesions are conunonly painful, and usually no systemic signs are seen. Regional lymph nodes may be enlarged. Respiratory and visceral involvement represents the systemic or disseminated form of disease. Pyothorax is usually caused by dissemina­ tion of the organism from mediastinal lymph nodes. These animals present witl1 fever, ai1orexia, dyspnea, and weight loss. In visceral infections, there is abdominal distention with palpable fluid, splenome­ galy, hepatomegaly, and mesenteric lymphadenomegaly. Underlying conditions, including irnmunosuppressive viral infections, should be investigated in cats with rhodococcosis. In rwninants, lymphadenitis (mesen­ teric, submaxillary, and bronchial), pneumonia, pyometra, ulcerative lyn1phan­ gitis, and occasionally mastitis have been reported in cattle and buffalo. Pneumonia is the most common clinical picture in goats. Sporadic abortion and organ abscesses have been reported in sheep and goats. Diagnosis: Periodic clinical exainina­ tions, WBC counts, serum fibrinogen levels, serologic tests, and diagnostic imaging have been proposed as measures for early diagnosis, mainly because of the insidious and precocious characteristic of foal rhodococcosis. Weekly physical exainina­ tion, including thoracic auscultation, is an effective clinical practice for early diagnosis. Monthly or more frequent monitoring of increased WBC counts (> 13,000 cells/µL), serum fibrinogen concentration (>400 mg/clL), and thoracic ultrasonography are also valuable procedures for early diagnosis. Efficacy of periodic inununodiffusion testing in predicting individual cases in affected foals is controversial. Supportive clinical and epidemiologic findings are in1po1tant in presumptive diagnosis, but diagnosis by isolation, microbiologic culture, and phenotypic characterization of R equi is considered the

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"gold standard." Tracheobronchial lavage, skin, synovial and pe1itoneal fluid, organs, and abscesses are the main clinical specimens used. On staining, the presence of gram-positive pleomorphic organisms supports a presumptive diagnosis, although this preliminary identification of the organism should be carefully evaluated, because few bacteria may be present m some clinical samples. Tracheobronchial lavage is the main clinical specimen for isolation of R equi in foals. However, the organism may occasionally be isolated from the trachea of foals without signs of pneumonia. Nasal swabs of foals are not indicated as evidence of rhodococcos1s because of contamination with local microflora. Likewise, the presence of R equi in the nasal region is not predictive of pulmonary infection. R equi is naturally isolated from feces of most livestock species, especially foals. Despite the fact that foals often swallow sputum containing R equi, 40 ° C]) at 6----8 hr after SC inoculation with tuberculin. The Stormont test uses an intradermal inoculation of PPD followed by a second inoculum at the same site 7 days later. The test is read for swelling 24 hr later. False-negative results may occur in animals with poor immune response such as those in the early stages of infection, nonresponsive cases in advanced disease, or old animals. Cattle that have recently calved may also have false-negative results. Current research is focused on the identification of antigens such as secretory proteins and genetically engineered proteins of M bovis for use in improved in vitro diagnostic tests. Serologic tests such as ELISA appear to be of limited diagnostic use, consistent with the lesser role of antibody compared with the cellular immune response in TB. In vitro cellular assays have been developed (ie, interferon--y assay) using WBCs stimulated with M bovis antigen and may be used as a supplemental test to the widely used SID test; however, they have not come into widespread use in many nonindustrialized countries because of cost and the necessity to conduct cellular assays in the laboratory witllin 24 hr after collection of blood specin1ens.

Control: The main reservoir of M bovis infection is cattle. However, other animals have been found to be reservoirs in some countries, including badgers and red deer (England, Ireland); red deer, possums, and ferrets (New Zealand); mule deer, white­ tailed deer, elk, and American bison (North America); African buffalo (South Africa); and water buffalo (Australia). The prevalence of disease in such reservoirs influences the incidence of disease in other species. Carnivores and scavengers can acquire M bovis by consumption of inf ected carcasses. These species include lion, coyote, wolf, hyena, cheetall, black bear, bobcat, and leopard. Warthogs, ferrets, raccoon, European wild boar, opossums, and feral pigs have also been found to be infected withM bovis. The three principal approaches to the control of TB are test and slaughter, test and segregation, and chemotllerapy. The test and slaughter policy is the only one assured of eradicating TB and relies on tile slaughter of reactors to the tuberculin test. In an affected herd, testing every 2 mo is recommended to rid tile herd of individuals tllat can disseminate infection. Routine hygienic measures aimed at cleaning and disinfecting contaminated food, water troughs, etc, are also useful. Test and

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slaughter has been used widely in tile UK, USA, Canada, Germany, New Zealand, and Australia. In some European countries, where test and slaughter would have been impractical, varying forms of test and segregation have been used, witll test and slaughter used only in the final stages of eradication. The BCG (bacille Calmette-Guerin) vaccine, sometin1es used to control TB in people, has proved to provide little protection against virulent M bovis in most animal species, and inoculation often provokes a severe local granulomatous reac­ tion. Moreover, ECG-vaccinated animals usually respond on the tuberculin skin test.

CATTLE Most of tile general discussion above applies to bovine TB. The introduction of milk pasteurization was a major step in the fight against Mycobacterium bovis TB and continues to be an important control procedure in many nonindustrialized countries.

SHEEP AND GOATS Lesions caused by Mycobacterium bovis in the lungs and lymph nodes of sheep and goats are similar to tllose seen in cattle, and the organism may sometimes disseminate to oilier organs. Sheep and goats are quite resistant to M tuberculosis inf ection. The intradermal skin test is commonly used for diagnosis. The comparative tuberculin skin test conducted in tile cervical region using biologically balanced pwified protein dclivative tuberculins of M bovis and M avium can be used to differentiate sensitization to oilier mycobacteria. The responses should be observed at 48 and 72 hr for induration and swelling.

DEER AND ELK Tuberculosis due to Mycobacterium bovis is an important problem in most species of farmed and wild cervids, including axis deer, fallow deer, roe deer, mule deer, sika deer, as well as red deer/elk/wapati. Deer appear to be unusually susceptible to M bovis infections. M avium infections may produce sinlilar lesions. M tuberculosis infection is tmcomn1on. Tuberculous lesions may be confined to isolated lymph nodes of tile head, or they may be found extensively in lymph nodes and organs after a rapid, fulminating disease course. Abscessation in deer should always raise suspicions of tuberculosis. A presumptive

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diagnosis may be made using the tuberculin skin test and/or by in vitro cellular assays (blood lymphocyte immune-stimulation test or 'I interferon assay), or a combination of these tests. Infection should be confirmed by an organism-based test.

HORSES Horses are relatively resistant to tuberculo­ sis caused by Mycobacterium tuberculosis; however, they are susceptible to M bovis. When tuberculosis does develop, tubercu­ lous, noncalcified lesions are often found in the liver, mesenteric lymph nodes, lungs, and other sites. Tuberculin test results are rather erratic.

ELEPHANTS Tuberculosis due to Mycobaclerium tuberculosis has been reported in captive elephants. Lesions most often involve the lw1g and associated lymph nodes. Nonspe­ cific responses are obse1ved on tuberculin skin tests and on some in vitro in1munologic tests; therefore, diagnosis should be made on an organis m b- ased test of trunk washes. Multidrng regin1ens, including isoniazid and rifan1pin, have been developed that eliminate shedding ofM tuberculosis in discharges and mininuze development of mug-resistant strains. It is important to emphasize that d!ug sensitivity tests should be conducted to determine the susceptibility of the organism. Also, blood concentrations should be monitored periodically to confinn they are high enough to kill the bacte1ia.

PIGS Pigs are susceptible to M tuberculosis, M bovis, and M avium complex. M avium avium and M avium hominissuis are most frequently isolated; serologic identification of isolates is useful in epiderniologic investiga­ tions. Granulomatous lesions are most often fow1d in the cervical, submandibular, and mesenteric lymph nodes, but in advanced disease lesions may also be found in the liver and spleen. Typically, enlarged nodes contain small, white or yellow, caseous foci, usually without any evidence of mineralization. Pigs witl1 disease due toM tuberculosis may have similar regionalized lesions. Pigs are particularly susceptible toM bovis, which is usually acquired from shared grazing or ingestion of contaminated dairy products. This can ca.use a rapidly progressive, disseminated disease with caseation and liquefaction of lesions. The single intra.der­ mal test conducted on the dorsal surface of

tl1e ear or in skin of the vulva is often useful for diagnosis. Test responses should be obse1ved at 48 hr after iJ\iection of tuberculin.

DOGS Dogs may be infected with Mycobacterium tuberculosis, M bovis, and occasionally with M avium complex or Mfortuitum, commonly from a hwnan or bovine source. Tuberculous lesions are usually found in the lungs, liver, kidney, pleura, and peritoneum; they have a gray appearance, usually with a noncalcified, necrotic center. Lesions a.re often exuda.tive and can produce a large quantity of straw-colored fluid in the thorax. False-negative tuberculin tests a.re often seen in dogs. Ra.diogra.ph.s and a thorough lustory are useful in diagnosis. Treatment is not often recommended. Affected dogs in close contact with people should be euthanized because of public health concerns.

CATS Ca.ts are quite resistant to infection with Mycobaclerium tuberculosis but are susceptible to M bovis, M avium complex, or M micmti. M lepraemurium has been isolated from granuloma.tous lesions in the skin. Some unclassified acid-fast bacilli have also been isolated. Contaminated nulk ca.using GI tract lesions, typically in the mesente1ic lymph nodes, is tl1e most common circumstance, and historically this was responsible for a very high percentage of tuberculous ca.ts in Europe. Rapid, hema.tog­ enous dissemination to other organs, including tl1e lungs and regional lymph nodes, can occur. Infected skin or deeper wounds sometimes give rise to tuberculous sinuses. Lesions have a central area of necrosis, usually witl10ut calcification. The tuberculin skin test is considered unreliable in cats. Diagnosis may be assisted by radiography and ELISA Identification of tl1e organism is necessary to confirm a diagnosis. Efficacious treatment protocols are not available. Therefore, it is recommended tl1a.t ca.ts infected with M bovis be eutha.nized because of public health concerns.

RABBITS Naturally occurring, or so-called spontane­ ous tuberculosis in rabbits is an unconunon fu1ding; most cases are ca.used by Mycobac­ terium bovis or M avium. Rabbits apparently become infected when exposed to other tuberculous a.nin1als or by ingesting milk from tuberculous cattle. M avium has been reported in rabbits that are housed in

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TUBERCULOSIS AND Orn ER MYCOBACTERIAL INFECTIONS close contact with domestic or exotic birds infected with M avium. Rabbits are relatively resistant to M tuberculosis; such infections are seldom reported. Rabbits infected with M avium complex may develop miliary lesions involving the Jung and liver. Tuberculin skin tests may be conducted on the skin of the abdomen. Test sites should be observed for induration and swelling at 24 and 48 hr after injection of M bovis purified protein delivative.

GUINEA PIGS Guinea pigs are quite susceptible to infection with either Mycobactmium tuberculosis or M bovi,S. Lesions are most often seen in the parenchyma of the Jung and adjacent lymph nodes. Also, guinea pigs are susceptible to certain serovars of M avium complex with lesions seen in lymph nodes associated with the GI tract. Tuberculin skin tests can be conducted by injection of purified protein delivative of M bovis and of M avium ( 1: 100 dilution containing 5,000 tuberculin units) at separate sites in the skin of the abdomen. 'TI1e preferred iajection site is 2 cm posterior to the xyphoid cartilage and 2cm lateral on each side of the Jinea alba. The iajection sites should be observed at 24 and 48 hr for indura­ tion and swelling. The presence of erythema at the injection site is of little or no signifi­ cance.

NONHUMAN PRIMATES In monkeys and large apes, Mycobactmium tuberculosis, M bovis, andM avium complex can cause severe disease of the lungs and other organs. Epidemics in plimate colonies may be caused by contact with infected human caregivers. Transmission is usually by aerosol with respiratory infection, but the oral route is also possible. Bacilli may also be shed in mine. Old tuberculin is used in skin tests in preference to purified protein derivative (PPD), because it provides greater sensitivity in detecting animals infected with M tiiberculosis or M bovis. Biologically balanced PPDs prepared from M bovis or M avium can be injected intradem1ally at separate sites on the abdomen to conduct a comparative test. Skin tests are observed at 24, 48, and 72hr for induration and swelling. Tuberculins prepared for use in people are not of sufficient potency to elicit a response in no.nhU111an plimates. Treatment of cases of tuberculosis in nonhU111an plimates has been attempted using drugs that have had success in people, eg, isoniazid, ethan1butol, and 1ifarnpin. Drug sensitivity tests should be conducted to deteffi1ine sensitivity of

691

isolates. Efficacy is lin1ited, and there are overriding argu.n1ents against therapy, based on the removal of infected animals, zoonotic risks, and the danger of developing drng resistance. Exacerbations may occm·.

FREE-RANGING AND CAPTIVE HOOFED ANIMALS The major wildlife reservoirs of Mycobacte­ rium bovis infection in addition to cervids are Afiican buffalo, wood bi.son, North American bi.son, white-tailed and mule deer, lechwe, and elk. Also, brushtail possums and European badgers are considered reservoirs of M bovis infection. Other species in which M bovis infection has been rep01ted but not in1plicated as rese1voirs and are considered spillover hosts include fennic fox, coyote, Arabian oryx, muntjac, in1pala, sitatunga, sp1ingbok, moles, voles, hares, eland, yak, bactrian can1el, wildebeest, European wild goat, large spotted genet, tapir, moose, otters, feral water buffalo, hedgehogs, European wild boar, greater kudu, tiger, white and black rhinoceros, and giraffe. M tuberculosis has been isolated from oryx, black rhinoc­ eros, Asian elephant, addax, and Rocky Mountain goats. Tuberculous lesions vary in consistency from purulent to caseous and often involve the lungs and regional lymph nodes, with liver, spleen, and serosal surfaces as other potential sites. Tuberculin skin tests are conducted in the cervical region using M bovis purified protein derivative (PPD) containing 5,000 tuberculin units prepared for veterinary use. Nonspecific responses may occur in some species with no hi.story of tuberculosis. Therefore, it may be necessary to use biologically balanced PPDs prepared from M avium and M bovis iajected at separate injection sites. Skin tests are observed for swelling and induration at 48and 72hr.

MARINE MAMMALS Mycobacterium pinnipedii (a seal-adapted variant of M bovis) causes tuberculous lesions in fur seals and sea lions. The organism has been isolated from four species of fur seals and two species of sea lions in several countries as well as from some other animals. In seals, the organism causes lesions in the peripheral lymph nodes, spleen, peritoneun1, and lungs. The presence of acid-fast organisms in the granulomatous lesions va.iies. Aerosols are considered the main route of transmission. Because of the zoonotic risk, precautions should be taken when handling these animals. (See also MYCOBACTERIOSIS IN MARINE MAMMAI.S, p 1863.)

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MYCOBACTERIAL INFECTIONS OTHER THAN TUBERCULOSIS Mycobacteria found in soil and water have been isolated from tissues of animals. Mycobacleliumfoituitum, a rapidly growing organism highly resistant to penicillin G, streptomycin, ampicillin, sulfamethoxazole, and chloramphenicol, has been associated with mastitis in cows, pulmonary infections in dogs, lymph node lesions in pigs and certain exotic animals, and cutaneous lesions in cats and dogs. Drug susceptibility tests indicate the organism is inhibited by capreomycin and by ethionamide. M chew­ nae, another rapidly growingMycobaclelium similar to Mfortuitum in biochemical reactions, has been isolated from contami­ nated wounds and ir\jection abscesses. These organisms must be distinguished fromM phlei, M srnegmatis, andM vaccae, which are rarely if ever pathogenic. Fish and other cold-blooded animals may be infected with M marinum, certain serovars of M avium complex, or M intra­ cellula,re, which have been recognized as human pathogens. A photochromogenic organism, M kansasii, has been isolated from pigs, cattle, and nonhuman primates. These organisms can be differentiated by biochemical and seroagglutination tests. M avium paratuberculosis, the cause of Johne's disease, has been isolated from domestic and wild ruminants (see al.so PARATUBERCULOSIS, p 762). It is a slowly progressive diarrheal disease resulting in weight loss and emaciation. Lesions are most often seen in the ileocecal valve and associated lymph nodes. Diagnosis should be based on an organism-based test. No treatment is available. M scrofulaceum, a scotochromogen, has been isolated from lymph node lesions in

pigs, cattle, and certain nonhuman primates.

M xerwpi, a slowly growing scotochromo­

gen, has been isolated from pigs, seafowl, and amphibians. These organisms should be differentiated from Mgordonae and M.fla,vescens and from other slowly growing scotochromogenic mycobacteria that are common contaminants of water. Numerous nonpathogenic, nonphoto­ chromogenic mycobacteria that closely resemble potential pathogens can be isolated from water and soil; M nonchromo­ genicum, M gastri, M triviale, and M terrae, which closely resemble strains of the M avium complex, may be differenti­ ated by in vitro laboratory examinations, including molecular techniques. Although opportunistic mycobacteria usually do not produce progressive disease, they may be important in inducing transient tuberculin skin sensitivity in animals. The application of comparative skin tests, using biologically balanced purified protein derivative tuberculins prepared from culture filtrates of M bovis and M avium, provides useful information on tl1e possible cause of tuberculin skin sensitivity. Tuberculins prepared for veterinary use, containing -5,000 tuberculin units per test dose, should be used for skin tests in free-ranging, captive, wild, and exotic aninlals. M lepraemurium, a nonphotochromo­ genic, slow-growing, acid-fast bacillus, causes a disease in cats and rats similar in some respects to leprosy in people. It can be grown on media containing cytochrome C and a-ketoglutarate. M leprae, the cause of leprosy in people, has been found in spontaneously occuning disease in armadillos. This organism has not been grown on artificial culture medium; however, M leprae DNA can be identified by molecular techniques.

TULAREMIA Tularemia is a bacterial septicemia that affects >250 species of wild and domestic mammals, birds, reptiles, fish, and people. It is listed as a category A bioterrorism agent because of the potential for fatality, airborne dissemination, and societal disruption if released. Etiology: The causative bacterium,

Prancisella tularensis, is a nonspore-form-

ing, gram-negative coccobacillus anti­ genically related to Biucella spp. It is a facultative intracellular parasite that is killed by heat and proper disinfection but survives for weeks or months in a moist environment. It can be cultured readily on blood supplemented with cysteine but must be differentiated from other gram-negative bacteria on blood agar. The taxonomic status of Francisella has been revised and

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TULAREMIA debated, but recent consensus establishes the subspecies F tularensis tularensis, associated with type A tularemia; F tularensis holarctica, which causes type B tularemia; and a third type, C, associated with F novicida, which has low virulence and is less common than the other two. Type A has been found predominantly in North Ame1ica and is more virulent; in people, the mortality rate may be as high as 3()0A, if untreated. Type Bis less virulent and occurs in both the Old and New Worlds. Epidemiology and Transmission: Among domestic animals, sheep are the most common host, but clinical infection has also been reported in cats, dogs, pigs, and horses. Cats are at increased risk because of predatory behavior and appear to have an increased susceptibility, whereas cattle appear to be resistant. Little is known of the true incidence and spectrum of clinical disease in domesticated animals. Important wild animal hosts for F tularensis tularen­ sis include cottontail and jackrabbits, whereas the most common vectors are the ticks Dernwcentor andersoni (the wood tick), Amblyomma americanum (the lone star tick), D variabilis (the American dog tick), and Chrysops discalis (the deer fly). Animal hosts of F tularensis holarctica are lagomorphs, beaver, muskrat, voles, and sheep. Ticks, flies, fleas, and exposure to contaminated water sources are all associated with transmission of this subspecies, which has also been found to persist naturally in a water-associated amoeba Natural foci of infection exist in North America and Eurasia. Although found in every state except Hawaii, tularemia is most often reported in the southcentral and western USA (eg, California, Missouri, Oklahoma, South Dakota, and Montana). Tularemia can be transmitted by aerosol, direct contact, ingestion, or arthropods. Inhalation of aerosolized organisms (in the laboratory or as an airborne agent in an act of bioterrorism) can produce a pneumonic form. Direct contact with, or ingestion of, infected carcasses of wild anin1als (eg, cottontail rabbit) can produce the ulceroglandular, oculoglandular, oropharyn­ geal (local lesion with regional lymphadeni­ tis), or typhoidal form. Immersion in or ingestion of contaminated water can result in infection in aquatic anin1als. Ticks can maintain infection transstadially and transovarially, making them efficient reservoirs and vectors. The most common source of infection for people and herbivores is the bite of an

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infected tick, but people who prepare or eat improperly cooked wild gan1e are also at increased risk. Dogs, cats, and other carnivores may acquire infection from ingestion of an infected carcass. Case reports have implicated cats as a source of infection in people. Clinical Findings: The incubation period is 1-10 days. The most severely and conm10nly affected livestock species are sheep; Type A tularemia is particularly pathogenic for lagomorphs, and cats and nonhuman primates have been reported to be infected. The clinical presentation depends on host species, subspecies of the bacteria, and route of infection. Sheep and cats may be subclinically infected or develop bacteremia, fever, and respiratory infection. Cats may also develop ulceroglan­ dular or oropharyngeal disease, presumably through exposure to infected prey items. Clinical signs include increased pulse and respiratory rates, coughing, diarrhea, and pollakiuria with lymphadenopathy and hepatosplenomegaly. Prostration and death may occur in a few hours or days. Sporadic cases are best recognized by signs of septicemia. Outbreaks in untreated lambs may have up to 15% mortality. Lesions: The most consistent lesions are rniliary, white to off-white foci of necrosis in the liver and sometimes in the spleen, lung, and lymph nodes. Organisms can be readily isolated from necropsy specinlens by use of special media. The infective dose required to transmit this pathogen is extremely low; thus, risk of infection dming necropsy or to laboratory personnel is significant, and special procedures and facilities are essential.

Diagnosis: Tularemia must be differenti­ ated from other septicemic diseases (especially plague and pseudotuberculosis) or acute pneumonia. When large nun1bers of sheep show typical signs during periods of heavy tick infestation, tularemia or tick paralysis (seep 1314) should be suspected. Tularemia should be considered in cats with signs of acute lymphadenopathy, malaise, oral ulcers, and history of recent ingestion of wild prey. Diagnosis of acute infection is confirmed by culture and identification of the bacteriun1, direct or indirect fluorescent antibody test, or a 4-fold increase in antibody titer between acute and convales­ cent serum specimens. A single titer of �1:80 by the tube agglutination test is presumptive evidence of prior infection. When tularemia is suspected, laboratmy personnel should

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be alerted as a precaution to reduce the risk of laboratory-acqulred infection. In some jurisdictions,tularemia in animals is reportable to public health authorities. Treatment and Control: Streptomycin,

gentamicin, and tetracyclines are effective at recommended dose levels. Gentamicin should be continued for 10 days. Because

tetracycline and chloramphenicol are bacteriostatic,they should be continued for 14 days to minimize the risk of relapse. Early treatment is important to minimize 1isk of fatality. Because of the substantial sylvatic (wildlife and tick) component of the Francisella life cycle,control is limited to reducing arthropod infestation and to rapid diagnosis and treatment.

VESICULAR STOMATITIS Vesicular stomatitis is a viral disease caused by two distinct serotypes of vesicular stomatitis virus-New Jersey and Indiana. Vesiculation,ulceration,and erosion of the oral and nasal mucosa and epithelial sruface of the tongue, coronary bands,and teats are typically seen in clinical cases,along with crusting lesions of the muzzle,ventral abdomen,and sheath. Clinical disease has been seen in cattle,horses,and pigs and very rarely in sheep,goats, and llan1as. Serologic evidence of exposure has been found in many species,including cervids, nonhuman primates,rodents,birds, dogs, antelope,and bats. Etiology: The viruses are members of the family Rhabdoviridae and genus Vesiculovi' rus. Vesicular stomatitis viruses are the prototypes of the Vesicutovirus genus. They are bullet shaped and generally 180 nm long and 75 nm wide. The genomic structure is a single strand of negative-sense RNA composed of five genes (N,P,M, G,and L, representing the nucleocapsid protein, phosphoprotein, matrix protein,glyco­ protein,and the large protein, which is a component of the viral RNA polymerase). Although there are many members of the Vesiculovirus genus,the New Jersey and Indiana serotypes are of particular interest in the Western hemisphere. These two viruses are sinlilar in size and morphology but generate distinct neutralizing antibodies in infected animals. They have both been isolated in recent outbreaks in the USA. Epidemiology and Transmission:

Vesicular stomatitis is seen sporadically in the USA. Outbreaks historically occurred in all regions of the country but since the 1980s have been limited to western states and occur seasonally,usually May through October. Outbreaks occurred in the USA in 1995,1997,1998,2004,2005,2006,2009,2010,

and 2012. The largest outbreak in the past decade occurred in 2005 and affected nine states. Vesicular stomatitis viruses are endemic in South America,Central America, and parts of Mexico but have not been seen naturally outside the Western hemisphere. The virus can be transmitted through direct contact with infected animals with clinical disease (those with lesions) or by blood­ feeding insects. In the southwestern USA, black flies (Sirnulidae) are the most likely biologic insect vector. In endemic areas, sand flies (Lutzomyia) are proven biologic vectors. Other insects may act as mechanical vectors. Exposure to insects that carry the virus is often associated with nearby moving water sources such as creeks or rivers or irrigation of pastures. Experimental studies have shown that feeding of infected insects on mucosa! srufaces and nonhaired areas of the body were more often associated with development of lesions at those sites than if insects fed on haired areas of the body. The prevalence of clinical cases in a herd is generally low (10%-209fi), but seroprevalence within the herd may approach lOOOAi. Viremia has not been detected in livestock species that exhibit clinical signs of vesicular stomatitis,although experimental studies have shown transmission of virus,presum­ ably via lymphatics,between co-feeding black flies on cattle. Virus is routinely isolated from active lesions in affected animals,and these lesions serve as a source of virus spread by direct contact and contam­ ination of shared feed and water stations. Many vertebrate species have serologic evidence of exposure and may serve as reser­ voirs of infection. No definitive reservoir or amplifying host of vesicular stomatitis viruses in the USA has been identified. Clinical Findings: The incubation period

is 2-8 days and is typically followed by a fever. By the time animals develop other

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VESICULAR STOMATITIS signs and are exanlined, however, they are rarely febrile. Ptyalism is often the first sign of disease. Vesicles in the oral cavity are rarely seen in naturally occurring cases because of rupture soon after formation; therefore, ulcers are the most common lesion seen during initial exan1ination. Ulcers and erosions of the oral mucosa, sloughing of the epithelium of the tongue, and lesions at the mucocutaneousjunctions of the lips are commonly seen in both cattle and horses. Ulcers and erosions on the teats are not uncommon in cattle and may result in secondary cases of mastitis in dairy cows. Coronitis with erosions at the coronary band are seen in some cattle, horses, and pigs, with subsequent development of lameness. Crusting lesions of the muzzle, ventral abdomen, sheath, and udder of horses are typical during outbreaks in the western USA. Loss of appetite due to oral lesions, and lan1eness due to foot lesions, are nom1ally of short duration, because the disease is generally self-limiting and resolves completely within 10-14days. Virus-neutral­ izing antibodies to either serotype persist and have been documented in individual horses that had previous clinical disease for >8 yr after an outbreak, but reinfection can occur after a second exposure. Diagnosis: In most areas, including the USA, vesicular stomatitis is a reportable disease. Samples for diagnostic purposes are generally taken by a foreign anin1al disease diagnostician or other regulatory veterinar­ ians and are tested by officially designated government laboratories. Diagnosis is based on the presence of typical signs and either antibody detection through serologic tests, viral detection through isolation, or detec­ tion of viral genetic material by molecular techniques. San1ples for viral isolation may include vesicular fluid, epithelial tags from lesions, or swabs of lesions. Vesicular stomatitis viruses are easily propagated in cell culture. Three commonly used serologic tests are competitive ELISA, virus neutraliza­ tion, and complement fixation. PCR tests may also be used to identify the virus. Of primary concern in diagnosis is differentia­ tion of vesicular stomatitis from clinically indistinguishable but much more devastating viral diseases, including foot-and-mouth disease in ruminants and swine (seep 629), swine vesicular disease (seep 735), and vesicular exanthema of swine (seep 738). Horses are not susceptible to foot-and­ mouth disease. Both noninfectious and infectious causes of oral lesions must be considered.

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Treatment, Control, and Prevention:

No specific treatment is available or warranted. Cachexia can be avoided by providing softened feeds. Cleansing lesions with mild antiseptics may help avoid secondary bacterial infections. Management factors suggested to reduce risk of exposure to the virus include limiting time on pasture dming insect season, providing shelters or barns during insect feeding times, and implementing other procedures that reduce aninlal contact with insects, such as application of insecticides. This should include application to the inner surface of the pinna, where black flies feed. If livestock need to be kept on pasture during outbreaks of vesicular stomatitis, then keeping them pastured away from moving smface water (such as streams, irrigation canals, or rivers) may reduce the risk of exposure to Vesiculovirus. Affected aninlals should be isolated, and movement of other anin1als from the affected premises restricted. Vesicular stomatitis is a reportable disease in most areas, including the USA, so state and federal aninlal health officials must be notified when it is suspected. Commercially produced vaccines are not available in the USA, but vaccines for livestock are available in some Latin American countries. Veterinarians act as a part of the surveil­ lance network as they examine animals involved in shows, exhibitions, races, and interstate or international movement in order to write a health certificate (ie, ce1tificate of veterinary inspection). When practitioners observe suspect cases of vesicular stomatitis, they should report to both their state and federal animal health officials. Reporting will prompt a regulatory investigation. Mucosa! swab and serum samples from suspected animals are submitted for testing to veterinary diagnostic laboratmies. During outbreak years, data regarding laboratory­ confinned cases of vesicular stomatitis, along with the number of premises with cases, are posted on the Web site of the Animal and Plant Health Inspection Se1vice of the USDA. Zoonotic Risk: The vesicular stomatitis

vi.ruses are zoonotic and may cause self-limiting influenza-like disease (head­ ache, fever, myalgia, and weakness) lasting 3--5 days in people working in close contact with the virus (eg, laboratory exposure, direct contact with lesions in infected aninlals). Rarely, people can develop vesicles on the buccal and pharyngeal mucosa, lips, and nose. More severe signs, including encephalitis, are rare.

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AFRICAN HORSE SICKNESS

AFRICAN HORSE SICKNESS African horse sickness (AHS) is an insect­ borne, viral disease of equids that is endemic to sub-Saharan Africa It can be acute, subacute, or subclinical and is characterized by clinical signs and lesions associated with respiratory and circulatory irnpainnent.

Etiology and Epidemiology: AHS is caused by African horse sickness virus (AHSV), which is 55--70 nm in diameter and of the genus Orbivirus in the family Reoviridae. There are nine immunologically distinct serotypes of AHSV. The virus is inactivated at a pH of 50 yea.rs so far, and phylogenetic studies indicate that PCV2 has probably circulated in pigs duling the past 100 yea.rs.

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PORCINE CIRCOVIRUS DISEASES

Initially, PCV2-SD was identified in high health herds that were free of most common swine pathogens. However, under field conditions, swine that show signs of PCV2-SD usually are infected with multiple agents, including porcine parvovirus, porcine reproductive and respiratory syndrome virus, Mycoplasma hyopneumo­

niae, Actinobacillus pleuropneumoniae, Pasteurella multocida, Haemophilus parasuis, Staphylococcus spp, and Streptococcus spp.

Accounts of multiple attempts to experimentally reproduce PCV2-SD have been published. Some early trials (using tissue homogenates from pigs affected with PCV2-SD or a PCV2 isolate) reproduced PCV2-SD-like histologic lesions but not the wasting condition. However, occasional studies subsequently reproduced clinical disease and lesions consistent with PCV2-SD using only PCV2, preswnably, as inoculwn. Consequently, it was suggested that PCV2 infection, linked to other cofactors, was necessary for the consistent development of full clinical disease. It appears that a nwnber of factors, such as age and source of pigs, envirorunental conditions, genetics, the nature of the PCV2 inoculwn used, and the in1munologic status of the pig at PCV2 infection, play a significant role in the consistent experimen­ tal reproducibility of the disease. In fact, the more consistent and repeatable PCV2-SD disease models have been obtained using infectious and noninfectious cofactors as triggers. Also, the coinfection of PCV2a and b genotypes has been linked to reproduc­ tion of clinical disease under experimental conditions. The mechanisms by which other viruses or inlmunostimulation may trigger tl1e development of wasting in PCV2-. infected pigs is still unknown. High loads of PCV2 in blood, lymphoid, and oilier tissues and in potential excretion routes are associated with the expression of disease. When multisystemic disease and wasting is apparent, danmge to the inlmune system is the main feature suggesting that affected pigs have an acquired immunodeficiency. Lymphocyte depletion of lymphoid tissues, changes in peripheral blood mononuclear cell subpopulations, and altered cytokine expression patterns have all been demon­ strated in pigs naturally and experimentally affected with PCV2-SD. The identification of cells that support PCV2 replication has been a matter of controversy. The large amount of PCV2 virus antigen found in the macrophages and dendritic cells of diseased pigs appears to be the result of accwnulation of viral

particles. However, epithelial and endothe­ lial cells seem to be the main target for PCV2 replication, as well as a small proportion of macrophages and lymphocytes. Much less is known regarding the pathogenesis of other PCVDs. PCV2 is able to replicate in fetuses as well as in zona pellucida-free embryos. Moreover, an experiment with embryos exposed to PCV2 and then transferred to receptor sows suggested that infection can lead to embryonic death. Therefore, it is believed that one of the potential outcomes of PCV2 infection in sows could be return to estrus. Transplacental transmission of PCV2 has been demonstrated. However, experiments using pregnant sows inoculated intranasally have yielded variable results. When successful, those studies have shown that PCV2 may cause fetal death, similar to that of porcine parvovirosis, with live pigs together with dead piglets and mUTilffiies of different sizes. PONS is considered a type III hypersensi­ tivity reaction in which the antigen present in the immune complexes is unknown. It has been speculated that PCV2 could be the antigen, but there is no definitive proof that PCV2 causes PDNS lesions. Indirect evidence exists, such as significantly higher serum antibody titers to PCV2 in affected pigs compared with healthy or PCV2-SD­ affected pigs. Epidemiology and Transmission:

PCV2 is considered a ubiquitous virus in countries with and without PCVDs, including PCV2-SD. PCV2 infection and PCV2-SD have also been described in wild boars. The disease has been reported worldwide. Transmission may be by direct contact with infected pigs. PCV2 has been detected in almost all potential excretion routes such as nasal, ocular, and bronchial secretions; saliva; urine; and feces. The virus can be found in semen, but the practical impor­ tance of this is probably negligible. Artificial insemination (Al) of sows with PCV2infected semen from experimentally inoculated boars did not result in sow infection or fetal infection. However, when such Al was perfonned with PCV2-spiked semen, reproductive problems were developed. Therefore, it seems that reproductive disease linked to Al is possible, but only when semen has a high virus load, which is wilikely under natural conditions. Although not demonstrated, it is asswned that contact with contaminated fomites, exposure to contanlinated feeds or biologic products, multiple use of

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PORCINE CIRCOVIRUS DISEASES

hypodermic needles, or biting insects may play a role in transmission. PCV2 may persist in swine for several months under either experimental or field conditions. Convalescent swine may carry virus for extended periods and be important in disease transmission. PCV2 is fairly resistant to commonly used disinfectants and to irradiation, probably allowing it to accumulate in the environment and be infective for new groups of susceptible pigs if rigorous sanitary measures are not followed. The decline of colostral antibody titer in pigs is associated with onset of PCV2-SD in late nursery or finishing pigs. Transplacental infection with PCV2 has been documented, but it is not lrnown whether pigs infected in utero are able to subsequently develop clinical PCV2-SD. Some reports have suggested that anin1als other than swine may be infected with PCV2 or PCV-like viruses. However, results of serologic studies for antibody against PCV in cattle and other livestock have been contradictory, and experimental induction of disease using PCVl or PCV2 in species of livestock other than swine has not been successful. Mice may be able to replicate and harbor the virus.

Clinical Findings: PCV2-SD is character­ ized by overt weight loss. Disease often occurs in the fattening units in pigs 8-18 wk old, although the disease can be also seen in older or y0tmger pigs. Morbidity is typically 5%-200/o among cohorts in the late nursery or finishing stages. Mortality in swine with signs of PCV2-SD can occasionally be >500/o. In addition to death loss, PCV2-SD in finishing pigs may cause a substantial increase in time to reach market weight, resulting in economic Joss. Growth retardation, wasting, and dyspnea are the clinical signs seen most frequently in outbreaks. Pallor, anemia, jaundice, diarrhea, and palpable inguinal lymphadenopathy also are seen in some affected pigs. A low-grade fever (104°-106°F [40°-41 °C]) iliat lasts several days may be seen as well. Overcrowding, poor air quality, insufficient air exchange, and commingled age groups seem to exacerbate ilie course of the disease. Usually, only a few pigs in a group show wasting. The onset of disease may be acute, leading to deaili wiiliin a few days in some pigs. Other pigs show a more chronic disease and fail to gain weight or thrive. PCV2-SI is believed to occur in pigs that become infected witl1 the virus and suffer from growth retardation (significantly lower average daily weight gain [ADWG]) but not overt clinical signs. In fact, in a farm affected

725

by PCV2-SD, a variable proportion of pigs developed ilie systemic disease, while most had only subclinical infection. PCV2-SI had been unnoticed for many years until the advent of vaccines drew attention to this condition. Vaccinated pigs have an increased ADWG compared with nonvaccinated, apparently healthy counterparts. Such difference has been demonstrated to vary between 10-40 g/d, depending on the farm. PCV2-RD characterized by late-term abortions and stillbirths in the absence or presence of other well-lrnown reproductive pailiogens seems to be the hallmark of clinical PCV2 infection in sows. Most of these descriptions come from North America and usually occur in start-up herds. Return to estrus due to embryonic death as a potential outcome of intrauterine PCV2 infection has been suggested based on experimental data. However, there are no field data unequivo­ cally supporting this effect. PDNS may affect nursery and growing pigs and, sporadically, adult anin1als. The prevalence of the syndrome in affected herds is relatively low (200/o) have been described occasionally. Pigs with severe acute disease die wiiliin a few days after the onset of clinical signs, due to acute renal failure with a significant increase in serum levels of creatinine and urea. Surviving pigs tend to recover and gain weight 7-10 days after the begi.Jming of the syndrome. Affected pigs have anorexia, depression, prostration, stiff gait and/or reluctance to move, and normal temperatures or mild fever. The most obvious sign in the acute phase is the presence of irregular, red-to­ purple macules and pa.pules on the skin of the hindlirnbs and perinea! area, although distribution may be generalized in severely affected ani.Jnals. With ti.Jne, the lesions become covered by dark crusts and fade gradually (usually in 2-3 wk), someti.Jnes leaving scars. Lesions: PCV2-SD is diagnosed by characteristic histopathologic findings in affected pigs. Grossly, lymph nodes may be substantially enlarged and pale on cut swface, the thymus atrophied, and the tonsils thinner than normal. Splenic infarcts also may be present in a low proportion of pigs affected with PCV2-SD. Histopatho­ Jogic lymphoid lesions are characteristic, showing lymphocytic depletion and granulomatous inflammation, someti.Jnes with the presence of multinucleate giant cells and an1phophilic botryoid intracyto­ plasmic inclusion bodies of different sizes caused by accumulation of PCV2 particles.

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PORCINE CIRCOVIRUS DISEASES

Lesions in the lung are common in affected pigs; their severity is influenced by duration of disease and presence of concurrent infections. Gross lung lesions may include failure to collapse, firmness, diffuse pulmonary edema, mottling, and consolidation. Microscopically, a variable degree of lymphohistiocytic interstitial pneumonia to granulomatous bronchointer­ stitial pneumonia with bronchiolitis and bronchiolar fibrosis can be seen. Grossly, the liver may appear icteric and/ or atrophic in a low proportion of affected pigs. lnterlobular connective tissue may be prominent. Microscopic lesions range from single cell necrosis (apoptosis) with mild lymphocytic infiltration of portal zones to extensive lymphohistiocytic periportal hepatitis with diffuse necrosis of hepato­ cytes. The kidneys may be enlarged and show scattered to diffuse white foci on the cortical surface. Microscopic lesions include interstitial lymphohistiocytic infiltration. Other lesions seen in affected pigs include gastric ulceration (probably due in part to a prolonged fattening period in chronically affected pigs) and occasional multifocal lymphohistiocytic myocarditis. ln severely affected pigs, lymphohistiocytic infiltrates can be seen in virtually all tissues. PCV2-SI pigs do not show gross lesions attributable to PCV2 infection. These animals may show microscopic lymphoid lesions similar to those seen in pigs with PCV2-SD, although only to a mild degree. ln PCV2-RD, stillborn and nonviable neonatal piglets show chronic passive congestion of the liver and cardiac hypertrophy with multifocal areas of myocardial discoloration. The key histopathologic feature is fibrosing and/or necrotizing myocarditis in fetuses.• PONS is easy to detect from a clinical point of view because of the red-to-dark macules and papules, which correspond microscopically to necrosis and hemorrhage secondary to necrotizing vasculitis of dermal and hypodermal capillaries and arterioles. Necrotizing vasculitis is a systemic feature, but it is more prominent in the skin, renal pelvis, mesentery, and spleen (splenic infarcts may also be present as a result of necrotizing vasculitis of splenic arteries or arterioles). Apart from skin lesions, pigs that die acutely with PONS have firm, bilaterally enlarged kidneys, with a fine granular cortical surface and edema of the renal pelvis. The renal cmtex displays multiple, small, reddish pinpoint lesions, similar to petechial hemorrhages, which microscopi­ cally correspond to enlarged and inflan1ed glomeruli (fibrinonecrotizing glomerulitis).

Histologically, a moderate to severe nonpurulent interstitial nephritis with dilation of renal tubules is also seen. Usually, both skin and renal lesions are present, but in some cases, skin or renal lesions may occur alone. Lymph nodes may be enlarged and red due to blood drainage from affected zones with hemorrhages (mainly skin). Histopathologically, PCV2-SD-like lesions such as lymphocyte depletion and histio­ cytic and/or multinucleate giant cell infiltration (although less severe) are usually found in lymphoid tissues of affected pigs, although to a milder degree. Diagnosis: The PCV2-SD case definition includes three main diagnostic criteria: 1) clinical signs of wasting or ill thrift, 2) presence of gross and microscopic (moderate and severe) lesions characteris­ tic of the disease, and 3) presence of viral antigen or DNA (moderate to high amount) in the microscopic lymphoid lesions. Visualization of viral DNA or antigen in lesions is usually done using in situ hybridization or irnmunohistochemistry, respectively, and moderate to high amounts of virus are linked to the disease. A herd case definition has been proposed, which includes two main criteria: 1) significant increase of mortality and number of runt pigs or pigs failing to gain weight or thrive in comparison to previous values for the farn1, and 2) fulfillment of the three individual criteria listed above in at least one of five ·examined pigs. Differential diagnoses include conditions causing increased mortality and growth retardation, such as PRRS, chronic respiratory disease, Gliisser's disease, salmonellosis, porcine intestinal adenomatosis, and many others. Because PCV2 is ubiquitous and the virus replicates in individual pigs for weeks to months, isolation of virus, detection of PCV2 DNA in serum or tissues, or detection of PCV2 antibodies in serum is not'sufficient to establish a diagnosis of PCV2-SD. Antibodies against PCV2 may be detected by ELISA, indirect fluorescent antibody, or inununoperoxidase staining of infected cell cultures. Viral isolation can be done on several porcine cell lines (mainly porcine kidney cells) using serum, bronchiolar lavage fluid, or tissue homogenates. Viral DNA can be detected using PCR in most tissues or in serum from affected pigs. Several tissue san1ples from multiple pigs may be required for detection of virus in cases of chronic disease. Virus quantifica­ tion in serum by real time quantitative PCR (qRT-PCR) has been suggested as a potential diagnostic method in live pigs. Values of

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PORCINE CIRCOVIRUS DISEASES > 107 PCV2 genome copies/mL of sennn usually have been linked with PCV2-SD occurrence. However, PCV2 infection is extremely common in clinically healthy pigs, and interpretation of positive qRT-PCR results is not always straightforward. The diagnostic approach of PCV2-SI is of less interest for clinicians, because lack of overt clinical signs plus demonstration of infection by PCR would be enough to establish such a diagnosis. Values of> 105 or 106 PCV2 genome copies/mL of sernm usually have been linked with the subclini­ cal infection. The diagnosis of PCV2-RD should include the following criteria: 1) late-term abortions and stillbirths, sometimes with hypertrophy of the fetal heart, 2) extensive fibrosing and/ or necrotizing myocarditis, and 3) high concentrations of PCV2 in the myocardial lesions and other fetal tissues. Differential diagnoses for PCV2-RD include PRRS, porcine parvovirus, pseudorabies (Aujeszky disease), leptospirosis, and other diseases that cause late abortions, stillbirths, and weak piglets. So far, there are no formal criteria to diagnose a putative return to estrns associated with PCV2 infection. However, the occurrence of such signs together with evidence of viral circulation during the clinical episode should be demonstrated. The case definition for PONS is relatively simple and includes two main criteria: 1) presence of hemorrhagic and necrotizing skin lesions, mainly located on the hind­ lirnbs and perinea! area, and/or swollen and pale kidneys with generalized cortical petechiae, and 2) presence of systemic necrotizing vasculitis as well as necrotizing and fibrinous glomernlonephritis. From a diagnostic point of view, detection of PCV2 is not included in the diagnostic criteria. Differential diagnosis of PONS depends on the most significant pathologic outcome. Cutaneous manifestations may be confused with classical and African swine fever, swine erysipelas, septicemic salmonellosis, infection withActinobacillus suis, porcine stress syndrome, transit erythema (urine-soaked floors, chemical burns, etc), and other bacterial septicemias. Differential diagnoses for kidney lesions include classical and African swine fever, swine erysipelas, and septicemic salmonellosis. Sernm biochemical analyses may help differentiate PONS from other diseases; urea and creatinine concentrations are markedly increased. Treatment and Control: Because PCV2-SD is a multifactorial disease,

727

effective control measures before the advent of PCV2 vaccines were focused on control or eradication of these triggers. The most widely used control measures were the use of antibiotics to prevent concurrent bacterial infections, improve­ ment of biosecurity and sanitary measures such as isolation of affected pigs and disinfection of pens after their use, decreasing stressors (eg, high stocking density, inadequate ventilation, inad­ equate temperature control), and control of concomitant viral infections, especially PRRS. Other prevention and control measures used on young pigs before the anticipated time of onset include injection of vitamins, IP injection of serum harvested from finishing pigs, and vaccination against common pathogens. Currently, control of PCV2-SD as well as PCV2-SI is based on use of PCV2 vaccines. There are four major commercial vaccines worldwide (plus a higher number with regional availability, mainly in southeast Asia). The first conunercial vaccine was based on an inactivated PCV2 isolate and was licensed for use in sows and gilts. The same vaccine was later licensed for use in piglets. Subsequently, three more vaccines have been developed, all for use in piglets -2--3 wk old or older. Two of these are subunit vaccines (PCV2 capsid protein produced in a baculovirus system), and the third is an inactivated virus constructed by replacing the capsid gene of the nonpatho­ genic PCVl with that of PCV2. In addition to significantly reducing mortality and runting percentages, these vaccines seem to improve ADWG, batch unifornlity, slaughter weight unifonnity, and feed conversion rate. All commercial PCV2 vaccines are based on PCV2a isolates, but cross-protection has been demonstrated against PCV2b. All PCV2 vaccines are able to generate both cellular and hwnoral inunune responses, which are believed to be the key features to control the subsequent PCV2 infection that occurs under field conditions. No treatment has proved successful for PONS. Only those epizootic cases with moderate to high morbidity and mortality rates may be important in terms of economic losses. Treatment using a wide range of antin1icrobial agents has been unsuccessful. Because the antigen responsible for triggering PONS is not known, no preventive recommendations are indicated. hnportantly, the use of PCV2 vaccines worldwide has significantly reduced occurrence of this condition, emphasizing tl1e putative implication of PCV2 in its pathogenesis.

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PORCINE HEMAGGLUTINATING ENCEPHALOMYELITIS

PORCINE HEMAGGLUTINATING ENCEPHALOMYELITIS (Vomiting and wasting disease, Coronaviral encephalomyelitis) Porcine hemagglutinating encephalo­ myelitis, a viral disease of young pigs, is characterized by vomiting, constipation, and anorexia and results either in rapid death or chronic emaciation (vomiting and wasting). Also, motor disorders due to acute encephalomyelitis (hemagglutinating encephalomyelitis) are often seen during field outbreaks.

Etiology, Epidemiology, and Patho­ genesis: The causal coronavirus, porcine

hemagglutinating encephalomyelitis virus (PHEV), is of a single antigenic type, and it grows in several types of porcine cell cultures, in which it causes syncytia. It agglutinates RBCs of several animal species. Pigs are the only natural host. The virus is spread via aerosol. It has no public health significance. Based on virus detection and/or serology, PHEV Infection has been reported from several countries in Europe and from North and South America (Argentina), Australia, and Asia (China, Taiwan, South Korea); thus, it appears to be widespread. The virus is endemic in most breeding herds, and a . herd immunity exists. The infection usually remains subclinical. Immune sows transfer maternal antibodies to their piglets, which are protected until they have developed an age resistance; thus, clinical outbreaks are rare. However, if the virus enters a susceptible herd with neonatal"piglets, morbidity and mortality may be high. The virus first replicates in the nasal mucosa, tonsils, lungs, and to a very limited extent, in the small intestine. From these sites of entry, the virus invades defined nuclei of the medulla oblongata via the peripheral nervous system and subse­ quently spreads to the entire brain stem, and possibly to tl1e cerebrun1 and cerebellum. Vomiting is tl10ught to be caused by viral replication in the vagal sensory ganglion. Wasting is due to vomiting and delayed emptying of the stomach, which is the result of virus-induced lesions in the intramural plexus. Infection of cerebral and cerebellar neurons may cause motor disorders.

Clinical Findings: Both clinical syn­ dromes, the vomiting and wasting disease

(VWD) and the encephalitic fom1s, are confined almost exclusively to pigs 2-3 days. Other diagnostic techniques, based on antigen or nucleic acid (RT-PCR) detection, have been developed and applied recently. A significant rise in antibody titer can be demonstrated in paired serum samples. Because of the rather long incubation period, pigs may start to build up a low antibody titer 2-3 days after the first signs

Control: There is no treatment. Once signs are evident, the disease runs its coLu-se. Spontaneous recove1ies are rare. Piglets born from noni.nmnme sows dwing the outbreak can be protected by being injected, at birtl1, either with hyperimrnune semm or, if this is not available, witl1 pooled serwn collected from older sows at a slaughterhouse. However, the time lapse between diagnosis and cessation of the disease is usually too sho1t for this procedure to be effective. Maintaining the virus on tl1e farm (thus retaining naturally induced i.rnnnmity in the sows) avoids outbreaks in piglets.

PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME Porcine reproductive and respiratory syndrome (PRRS) was first reported in the USA in 1987. Since then, outbreaks of PRRS and successful isolation of the virus have been confirmed throughout Notth America and Europe. Etiology and Epidemiology: The etiologic agent is a virus in the group ArteJiviJidae. The virus is enveloped and ranges in size from 45 to 80 mm. lnactiva­ tion is possible after treatment with ether or chloroform; however, the virus is very stable under freezing conditions, retaining its infectivity for 4 mo at -70°C (-94° F). As the temperature Jises, infectivity is reduced (15-20 min at 56°C [132.8° F]). After infection of a naive herd, exposure of all members of the breeding population is inconsistent, leading to development of naive, exposed, and persistently infected subpopulations of sows. This situation is exacerbated over time through the addition of improperly acclimated replacement gilts and leads to shedding of the virus from

earlier animals to those that have not been previously exposed. The primary vector for transmission of the virus is the infected pig. Contact transmission has been demonstrated experimentally, and spread of virus from infected seedstock oJiginating from a single source has been desc!ibed. lntroduction of infected seedstock can lead to the introduction and coexistence of genetically diverse isolates of PRRS virus on the san1e farm. Controlled studies have indicated that infected swine may be longtern1 carriers, with adults able to shed PRRS virus for up to 86 clays after infection, and weaned pigs able to harbor virus for 157 days. Experi­ mentally infected boars can shed virus in the semen up to 93 days after infection. Aerosol transmission of the virus has been confirmed as an indirect route of transmission and may depend on isolate pathogeni.city. Highly virulent isolates that produce high titers of virus in blood and tissues have been shown to be spread via aerosols at a significantly higher frequency

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PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME

than less pathogenic isolates. Environmen­ tal factors, such as wind direction and velocity, significantly impact spread via this route as well. PRRS virus can also be transmitted by fomites, such as contami­ nated needles, boots, coveralls, transport vehicles, and shipping containers. Farm persorn1el are not a risk, unless hands are contan1inated with blood from viremic pigs. Finally, transmission via certain species of insects (mosquitoes [Aedes vexans] and house flies [Musca domestica]) has been reported.

Clinical Findings: PRRS appears to have two distinct clinical phases: reproductive failure and postwea.ning respiratory diseases. The reproductive phase of the disease includes increases in the number of stillborn piglets, mummified fetuses, premature fan-owings, and weak-born pigs. Stillbilths and mummies may increase up to 25%-35%, and abo1tions can be > l ()OA,. Anorexia and agalactia are evident in lactating sows and result in i11crea.sed (30"/o--500;6) preweaning mortality. Suckling piglets develop a characteristic thumping respiratory pattern, and hlstopathologic exan1mation of lung tissue reveals a severe, necrotizmg, interstitial pnew11onia. PRRS is capable of crossing the placenta m the third and possibly second tri111ester of gestation. Piglets may also be born viremic and transmit the virus for 112 days after mfection. Perfo1mance after weaning is also affected. Infection with PRRS virus results in destruction of mature alveolar mac­ rophages, which has led to the hypothesis that mfection results in inlmune suppres­ sion; however, controlled studies indicate that the virus may actually enhance specific parameters of tl1e ilnmw1e response. Outbreaks of the reproductive form of PRRS have been reported to last 1-4 mo, dependmg on the facilities and initial healtl1 status of the pigs. In contrast, the postwean­ ing pneumonic phase can become chronic, reducing daily gain by 85% and increasmg mortality to lOo/o--25%. Nun1erous other pathogens are commonly isolated along with PRRS virus from affected nursery or finishing pigs. Other bacteria such as

Streptococcus suis, Escherichia coli, Salmonella Choleraesuis, Haemophilus parasuis, and Mycoplasma hyopneumo­ niae have been reported, as well as viruses

such as porcme respiratory coronavirus and swine influenza virus. Finally, differences in the clinical response to PRRS virus may also be due to strain variation. Studies have demonstrated the ability of different isolates to induce varymg degrees of

interstitial pneun1onia in cesarean-derived/ colostnl.111-deprived (CD/CD) piglets after intranasal inoculation.

Diagnosis: The most commonly used serologic assay is the ELISA It measures IgG antibodies to PRRS virus. It cannot measure the level of ilrn11wlity in an a.nil11al or predict whether the a.nilnal is a carrier. Titers are detected within 7 10 days after mfection and can persist for up to 144 days. Tests for PRRS virus include PCR, virus isolation, and in1111unohistochemistry. Nucleic acid sequencing of the open reading frame 5 region of the virus is an excellent tool for epidemiologic investigations in the field to confirm similarity between isolates recovered from different sites. Recently, oral fluid san1pling has been widely applied as a means to sample a population of pigs. This method is cost effective and conveni­ ent and can be used for botl1 virus and antibody detection at the pen level. Treatment and Control: Cun-ently, there a.re no effective treatment programs for acute PRRS. Attempts to reduce fever using NSAIDs (aspirin) or appetite stimulants (B vitanlins) appear to have minimal benefit. The use of antibiotics or autogenous bacterins to reduce the effects of opportun­ istic bacterial pathogens has also been reported; however, results have been mixed. Prevention of mfection appears to be the prilnary means of control. Understanclmg the PRRS status of replacement gilts and boars, as well as proper isolation and acclimatization of mcommg stock, are critical measures to prevent viral introduc­ tion. Pigs should be retested on arrival at the isolation facility and 45----60 days later, before entry to the herd. Elilnination of existmg mfection by multisite production and segregated early weanmg has also been described. Although these strategies have had some success, the longterm risks of reinfection appear high. Prevention of viral spread by nursery depopulation has been described. This is successful when virus transmission is not occuning m the sow herd (usually 12-18 mo after initial outbreak), but the nurse1ies and growing/ finishing pigs are still mfected. All nursery pigs are removed from the farm to be finished elsewhere. The nurseries are then aggressively washed and disinfected and left empty for 7-14 clays, after which they can be used normally. The technique has successfully elimmated PRRS virus from several herds, and pigs have remained

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STREPTOCOCCAL INFECTIONS IN PIGS

seronegative (for >l yr) to market age; production in the nurseries has improved, both in growth rate and mortality. Commercial modified-live vaccines have been licensed and have been effective in controlling outbreaks, reducing shedding, and preventing economic losses. Elimination of PRRS virus has been demonstrated to be possible on an individual farm basis. Metl10ds such as whole herd depopulation-repopulation, test and removal, and herd closure have been docwnented as effective methods to eliminate PRRS virus from endemically infected herds. Unfortunately, a nun1ber of eradication efforts have failed because of introduction of new isolates thrnugh

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LUlidentifiable routes. This has resulted in an increased level of biosecurity on farms. Strict quarantine and testing progran1s, the purchase of PRRS virus-naive breeding stock and semen, sanitation of transport vehicles, and strict protocols of fomite and personnel movement between farms are critical components of an effective program. Recent advances in monitoring the status of artificial insemination centers include PCR analysis of blood samples collected from ilie auricular vein (blood swab). In addition, the application of air filtration to artificial insemination centers and breeding herds has been shown to significantly reduce the risk of airborne entry of the virus.

STREPTOCOCCAL INFECTIONS IN PIGS Of the bacterial group of gran1-positive cocci comprising the genera Streptococcus, Enterococcus, and Peptostreptococcus, streptococci constitute the most significant pathogens of swine. Streptococci are also as ociated wiili infectious conditions of people, cattle, sheep, goats, and horses. Relative to pigs, S suis (an et-hemolytic Streptococcus) is by far U1e most imp01tant agent of infectious diseases in this group, affecting mainly nursing and recently weaned pigs. Septicemia, meningitis, polyserositis, polyarthritis, and broncho­ pneumonia are associated with S suis infections. Streptococcus dysgalactiae equisimilis is considered the most important 13-hemolytic Streptococcus involved in lesions in pigs, and it has been judged to be of etiologic significance in autopsy reports. S porcinus, ·another 13-hemolyticStreptococcus, has been associated particularly in the USA with a contagious clinical entity in growing pigs known as streptococcal lymphadenitis,jowl abscesses, or cervical abscesses. Entero­ cocci reside in the intestinal tract and may cause disease in multiple species. In pigs, tl1e E faecium species group, mainly E durans and E hirae, are especially associ­ ated with enteritis and diarrhea.

STREPTOCOCCUS SUIS INFECTION S suis is a significant pathogen of swine and

one of the most important causes of bacterial mortality in piglets after weaning. It is

considered a normal inhabitant of the upper respiratory tract (especially nonvirulent strains) and can be easily f0tmd in tonsils, which are considered a natural niche. It can also be isolated from the reproductive and GI tracts of clinically healthy pigs. Etiology and Pathogenesis: S suis possesses antigens somehow related to Lancefield group D streptococcus , but it is taxonomically far from other members of this group. It is considered a facultatively anaerobic, gram-positive, nonn1otile coccus, oriented in chains of varying lcngilis. S suis produces et-hemolysis (incomplete hemolysis) on blood agar and is catalase negative. It has a worldwide distribution, and originally 35 serotypes based on capsular antigens had been described (serotypes 1 to 34 and serotype 1/2). However, there is still some controversy, because serotypes 20, 22, 26, 32, 33, and 34 have been suggested as not being part of ilie S suis species. Nonetheless, ilie nun1ber of serotypes considered as highly virulent is relatively small and depends mainly on geographic location. Most studies on virulence factors of S suis have been performed witl1 serotype 2 only. 'Iype 2 virulent and nonvirulent strains exist, but characte1ization of virulence factors is still incomplete. Capsular polysaccharide is so far U1e most in1portant critical virulencP factor. However, well encapsulated nonvirulent serotype 2 strains do exist. Some proteins, such as the muran1idase­ released protein, the extracellular factor,

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and the hemolysin (suilysin), constitute virulence-related proteins for serotype 2 strains isolated in Europe and Asia but not for North American strains. So far, there is no single true predictor of pathogerticity. In fact, serotype 2 strains from different continents are phenotypically and genotypi­ cally very different. Most strains from Asia and Europe belong mainly to the sequence type or STl, as characte1ized by multilocus sequence typing, and are highly vimlent. Serotype 2 strains from North America belong to ST25 and ST28, presenting lower vintlence capacities, which may explain the importance of other serotypes in this continent, such as serotypes 3 and 1/2. The mechanisms that enable S suis to disseminate throughout the anin1al are not weJI understood. The bacterium is able to spread systemically from the nasopharynx, occasionally resttlting in septicemia and death. The palatine and pharyngeal tonsils are both potential portals of entry for S suis, leading to subsequent hematogenous or lymphogenous dissemination. Survival of the organism once in the bloodstream may be facilitated by the capsular polysaccha­ ride as weJI as ceJI wall components, which ef'ficiently hamper phagocytosis. lf S suis does not cause acute fatal septicemia, bacteria are able to reach the CNS via mechanisms that are only partially elucidated, such as invasion of brain microvascular endothelial ceJls or through the choroid plexus epithelial ceJls. In both septicemic and CNS cases, excessive host inflan1mation seems to play an important role in the pathogenesis of infection. Epidemiology and Transmission: S suis is present in all parts of the world in swine intensive areas. Serotypes 1 9 (including serotype 1/2 that shares antigens with serotypes 1 and 2) represent >7096 of S suis isolates recovered from diseased pigs, mainly in North America where most studies have been done. Serotype 2 is, in general, the most prevalent worldwide, but its importance is lower in North America and higher in Asia and some countries in Europe, such as France. Serotype 9 is the most frequently isolated type in other European countries, such as Spain, Germany, and the Netherlands. Most clirtically healthy pigs are carriers of multiple serotypes of S suis, although a few are colonized by vintlent strains. Piglets become colonized with S suis from vaginal secretions during parturition and while nurs­ ing. Asymptomatic carriers serve as a source of infection for their pen mates after they are mixed and commingled in the nursery, when

maternal antibodies are no longer present. Clirtical infections are seen mainly in weaned pigs (2-5 wk after weaning), growing pigs, and less frequently, suckling piglets and adult aninrnls. Transmission between herds occurs by the movement and mixing of healtl1y caii:ier pigs. The introduction of a highly vintlent strain into a naive herd may result in subsequent onset of disease in weaned and/or growing pigs. However, some herds with animals hai·boring vimlent strains but not showing illness may suddenly develop serious clinical disease in the presence of other predisposing factors such as overcrowding, poor ventilation, excessive temperature fluctuations, mixing of pigs with an age spread of >2 wk, and coinfections with other pathogens. Disease outbreaks due to S suis infection have been frequently repmted with coinfections of porcine reproductive and respiratory syndrome virus (seep 729). S suis might also be transmitted via fomites and flies, although probabilities are low. Although S suis has been isolated from different mainmal species and birds, the importance of such reservoirs is unknown. Clinical Findings: Even when the carrier rate in pigs is near lOOOA,, tl1e incidence of the disease vaiies from period to period and is usually 65%. Etiolo�y, Epidemiology, and Patho­ genesis: The CAE virus is an enveloped,

single-stranded RNA lentivi.ms in the fan1ily Retrovi.ridae. There are several, geneticaJJy distinct isolates of the vi.ms that differ in vi.mlence. The CAE virus of goats is closely related to the ovine lentivi.mses causing ov.ine progressive pneun1onia and maedi-visna in North America and Europe, respectively. Cross-species transmission is possible through feeding of infected milk and colostrun1. Therefore, the ov.ine and cap1ine lentivimses are now commonly referred to as small rwninant lentivimses. CAE vi.ms infection is widespread in dairy goat breeds but unconunon in meat- and fiber-producing goats. Th.is has been attributed to genetics, management praclices such as feeding colostrunl and milk from a single dam to multiple kids, and industrialized farming practices (eg,

frequent introductions of new aninlals into a herd). Prevalence of infection increases with age but is not influenced by sex. Most goats are infected at an early age, remain virus positive for life, and develop disease months to years later. The chief mode of spread of CAE is through ingestion of vi.ms-infected goat colostrum or milk by kids. The feeding of pooled colostrunl or milk to kids is a particularly risky practice, because a few infected does will spread the virus to a large number of kids. Hmizontal transmission also contributes to disease spread with.in herds and may occur through direct contact, exposure to fomites at feed bw1ks and waterers, ingestion of contaminated milk in milking parlors, or serial use of needles or equipment conta.illinated with blood. Unlikely methods of transmission, as indicated by experimental studies, include in utero transmission to the fetus, infection of the kid dwing parturition, and infection through breeding or embryo tra.J1Sfer. The pathogenesis of CAE is not fully w1derstood. Vi.ms-infected macrophages in colostrw11 and milk are absorbed intact through the gut mucosa Wection is subsequently spread throughout the body via infected mononuclear cells. Periodic viral replication and macrophage matura­ tion induces the characteristic lyrnphopro­ liferative lesions in target tissues such as the lungs, synoviun1, choroid plexus, and udder. Persistence of the CAE vi.ms in the host is facilitated by its ability to become sequestered as provirns in host cells. Infection induces a strong hwnoral and cell-mediated inunune response, but neither is protective. Clinical Findings: Clinical signs are seen in -200Ai of CAE vi.ms-infected goats during their lifetime. The most common manifesta ­ tion of infection is polysynovitis-arthlitis,

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CAPRINE ARTHRITIS AND ENCEPHALITIS

which is primarily seen in adult goats but can occur in kids as young as 6 mo old. Signs of polysynovitis-arthritis include joint capsule distention and varying degrees of lameness. The carpaljoints are most frequently involved. The onset of arthritis may be sudden or insidious, but the clinical course is always progressive. Affected goats lose condition and usually have poor hair coats. Encephalomyelitis is generally seen in kids 2--4 mo old but has been described in older kids and adult goats. Affected kids initially exhibit weakness, ataxia, and hindlimb placing deficits. Hypertonia and hyperreflexia are also common. Over time, signs progress to paraparesis or tetraparesis and paralysis. Depression, head tilt, circling, opisthotonos, torticollis, and paddling have also been described. The interstitial pneu­ monia component of CAE virus infection rarely produces clinical signs in kids. However, in adult goats with serologic evidence of CAE virus infection, chronic interstitial pneumonia that leads to progressive dyspnea has been documented. The "hard udder" syndrome attributed to CAE virns infection is characterized by a firm, swollen mammary gland and agalactia at the time of parturition. Milk quality is usually unaffected. Although the mam­ mary gland may soften and produce close to normal amounts of milk, production remains low in many goats with indurative mastitis. Lesions: Pathologic lesions of CAE virus infection are generally described as lyrnphoproliferative wi.th degenerative mononuclear cell infiltration. Lesions in joints are characterized by thickening of the joint capsule and marked proliferation of synovial villi. In chronic cases, soft-tissue calcification involving joint capsules, tendon sheaths, and bursae is not uncom­ mon. Severe cartilage destruction, rupture of ligan1ents and tendons, and periarticular osteophyte formation have also been described in advanced cases. Microscopic features of articular lesions include synovial cell hyperplasia, subsynovial mononuclear cell infiltration, villous hypertrophy, synovial edema, and synovial necrosis. Gross lesions associated with the neuro­ logic form of CAE include asynm1etric, brownish pink, swollen areas, most corrunonly in the cervical and lumbosacral spinal cord segments. Histopathologically, these lesions are characterized by multi­ focal, mononuclear cell inflanm1atory infiltrates and varying degrees of demyeli­ nation. On gross exanlination, lw1gs of affected goats are firm and gray-pink with

multiple, small, white foci, and do not collapse. The bronchial lymph nodes are invariably enlarged. Histologic findings include chronic interstitial pneumonia with mononuclear cell inflltration in alveolar septae and in perivascular and peribron­ chial regions. In does witl1 udder induration, mononuclear infiltration of periductular stroma obliterates normal man1mary tissue. Diagnosis: A presumptive diagnosis can be based on clinical signs and history. Infectious arthritis caused by Mycoplasma spp and traumatic aithritis are differential diagnoses for arthritis induced by CAE virus. Differential diagnoses for the progressive pai·esis ai.1d pai·alysis exhibited by young kids should include enzootic ataxia, spinal cord abscess, cerebrospinal nematodiasis, spinal cord trauma, and congenital anomalies of the spinal cord and vertebral colwnn. If the neurologic exainination indicates brain involvement, polioencephalomalacia, listeriosis, and rabies should be considered as possible causes. The pulrnonai-y form of caseous lyrnphadenitis may have a similai· clinical presentation to the pulmonary form of CAE in adult goats. Botl1 an agar gel inunw10diffusion test and ELISA for CAE virus are considered sufficiently reliable for use in control programs. The agar gel inunw10diffusion test is reported to be more specific but less sensitive than the ELISA. A positive test result in an adult goat in1plies infection but does not confirm that the clinical signs are caused by CAE virus. Kids infected at birth develop a measurable antibody response 4-10 wk after infection. However, positive test results in kids 1 YT old with an attenuated cell culture vaccine. ln these areas, outbreaks were controlled by quarantine and "ring vaccination" and sometimes by slaughtering. ln epidemics, the disease was best eliminated by imposing quarantine and by slaughte1ing affected and exposed animals. Control of anin1al movements was paramount to control rinderpest; many outbreaks were clue to the introduction of infected cattle to hitherto uninfected herds. The lessons learned from this huge success will be instrun1ental in the fight against peste des petits rnminants.

TICKBORNE FEVER (Pasture fever) Tickborne fever is a febrile disease of domestic and free-living rnminants in the temperate regions ofE.urope. It is prevalent in sheep and cattle in the UK, Ireland, Norway, Finland, The Netherlands, Austria, and Spain. Disease is transmitted by the hard tick Ixodes ricinus. A similar disease transmitted by other ticks has been described in India and South Africa. The main hosts are sheep and cattle, but goats and deer are also susceptible. Etiology: The causative agent is now classified as a member of the order Rickettsiales, family Anaplasmataceae, asAnaplasma phagocytophilum, which includes the granulocytic agents formerly known as Ehrlichia phagocytophila, Ehrlichia equi, and the agent of human granulocytic ehrlichiosis. The organism infects eosinophils, neutrophils, and monocytes, in that order. Cytoplasmic inclusions are visible as grayish blue bodies in Giemsa-stained blood smears and may contain one or more rickettsial particles of variable size and shape. The varied morphologic types in the cytoplasmic inclusions do not represent

stages of development, as in chlamydiae, but rather are rickettsial colonies within cytoplasmic vacuoles. The disease is transmitted by the hard tick I 1icinus. Adult ticks infected as larvae or nymphs can transmit the disease as can nymphs infected as laivae, but infections do not appear to pass from the adult female to the laiva via the egg. The rickettsiae can survive in infected ticks for long periods and, because I ricinus can swvive wued for> 1 yr awaiting a new host, ticks infected in their previous instar can still be infective after long periods of hibernation. The ready transmission of infection by injecting infected blood suggests that the organism could be transmitted mechanically by biting insects. In addition, if the organisms reported to cause a similar disease in rnrninants in India and South Af1ica are indeed A phagocytophilum, it is most likely that ticks other than I ricinus a.i·e involved. Clinical Findings: After infestation witl1 infected ticks, the incubation period may be 5--14 days, but after il,iection with infected blood, the incubation period is 2-6 days. In sheep, the main clinical sign is a sudden

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TICKBORNE FEVER

fever (105°-108° F [40.5°-42.0°C]) for 4-10 days. Other signs are either absent or mild, but the animals generally appear dull and may lose weight. Respiratory and pulse rates are usually increased, and a cough often develops. In cattle, the disease is known as pasture fever in many parts of Europe, including Finland, Norway, Austria, Spain, and Switzerland. The disease occurs as an annual minor epidemic when dairy heifers and cows are turned out to pasture in the spring and early summer. Within days, the cows are dull and depressed, with a marked loss of appetite and milk yield. Affected cows usually suffer from respiratory distress and coughing. Clinical signs are more obvious and last longer in newly purchased animals than in home-bred animals. Often, veterinary advice is sought after a sudden drop in milk yield. Abortions affect susceptible ewes and cows newly introduced onto tick-infested pastures during the last stages of gestation, with abortions occurring 2-8 days after the onset of fever. Except for aborting ewes, death due to tickbome fever is rare. The semen quality of infected rams and bulls may be greatly reduced. Variations in severity of the clinical effects may be related to differences between strains of A phagocytophilum or in host susceptibility. Perhaps the most significant effect of infection is its serious impairment of hwnoral and cellular defense mechanisms, which results in increased susceptibility to secondary infections such as tick pyemia, pnewnonic pasteurellosis, louping ill, and listeriosis. Lesions: Tickbome fever is character­ ized by transient but distinct hematologic changes. A modest neutrophilia develops 2-4 days after natural or experimental infection and is followed by a severe leukopenia due to lymphocytopenia and neutropenia. The lymphocytopenia lasts 4-6 days, whereas the neutropenia develops progressively and becomes more marked -10 days after infection. Studies witl1 monoclonal antibodies that recognize surface markers for lymphocyte subsets have shown that both T and B lymphocytes are reduced. The number of circulating eosinophils is also depressed for as long as 2 wk. After the febrile period has subsided, the number of monocytes may increase. At the peak of reaction, >90% of circulating neutroph.ils and eosinoph.ils may be infected. The monocytes are predominantly infected during the later stages of bactere­ mia, whereas the granulocytes are usually

773

infected throughout the pe1iod of bactere­ mia. The nwnber of circulating thrombo­ cytes is also rep01ted to be depressed during the febrile period, and tile occasional hemorrhagic syndromes associated with tickbome fever are probably related to the reduction in circulating th.rombocytes. Diagnosis: In sheep, tile onset of high fever in tick-infested areas during the spring and summer in association with hemato­ logic changes and the presence of inclu­ sions within granulocytes or the detection of specific DNA by PCR is diagnostic. PCR and other molecular methods are particu­ larly useful during the late stages of primary bacteremia and during persistent infection when it is difficult to detect inclusion bodies in blood smeai"S. Clinical disease usually is seen only in young lambs born in tick­ infested areas or in older animals newly introduced to such areas. Demonstration of typical inclusion bodies in blood smeai"S or specific DNA by PCR should indicate the association of tickbome fever and cases of tick pyemias and abortions, particularly when abortions occur after pregnant animals are moved from tick-free to tick-infested pastures. Wection could be established retrospectively by demonstrat­ ing a rise in aJ1tibody titers by indirect imrnunofluorescence or ELISA. In affected dairy cattle, tile main signs ai·e abortions a!ld a sudden drop in milk yield. The other common clinical sign in infected cattle is respiratory illness after a herd is introduced to tick-infested pastures. Tickbome fever must also be considered when abortions a!ld stillbirtlls, particularly in heifers, occur soon after tlleir introduc­ tion to tick-infested pastures. Therefore, in areas where the disease is enzootic, blood smeaJ"S must be exainined for the presence of organisms in all cases of abortion in sheep a!ld cattle and when milk yield drops suddenly soon after the animals have returned to pasture. Treatment and Control: The short­ acting oxytetracyclines ai·e regarded as the most effective treatment, because otl1er aJ1tibiotics such as penicillin, streptomycin, a!ld ampicillin do not prevent relapses. SulfaJ11etha.zine has also proved useful. If dairy cattle are treated with oxytetracy­ clines within a few days of infection, the pyrexia is reduced quickly aJ1d milk yield restored. There are three important aspects of control: vector control, chemotherapy, a!ld immunity. Effective control Call be achieved by eliminating or markedly reducing

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contact with the tick vector either by grazing sheep and cattle on tick-free pastures in lowland areas or by use of acaricides. In sheep practice, this com­ monly involves keeping ewes and lan1bs in a fenced, relatively tick-free pasture until the lan1bs are -6 wk old. Lambs also benefit from improved nutrition of the ewes. Dipping lambs within 1-2 wk of birth is not commonly practiced because of difficulties of gathering the lambs on widely dispersed hill farms, the risks of mismothering, and the relatively short duration of protection provided by acaricides, possibly because of the short fleece and rapid growth rate of lambs. However, dipping twice with a 2- to 3-wk interval or use of pour-on preparations or smears applied before lambs are moved from lambing fields to hill pastures reportedly controls ticks effectively. Pregnant aninlals should not be moved from tick-free to tick-infested pastures. In enzootic areas, treatment with long-acting tetracyclines may be used as a prophylactic measure. When susceptible aninlals, particularly pregnant ewes and cows and newborn lambs, are to be moved from tick-free to tick-infested areas, it may be necessary to combine dipping with prophylactic use of long-acting tetracy­ clines. Such treatment of lambs in the first 2 3- wk of life can be protective for as long

as3 wk and helps reduce secondary infections such as tick pyemia, pasteurel­ losis, and colibacillosis. It may also improve growth rate. Several aspects of inln1unity remain controversial, but it is generally accepted that sheep and cattle are immune to challenge after recovery from one or two bouts of clinical disease caused by tickbome fever. The immunity may last for several months but wanes rapidly if the animals are removed from tick-infested areas. Secondary infections are usually milder as residual immunity persists. There is a variable degree of cross-protection among strains of A phagocytophilum. No effective vaccines are available to protect ruminants from clinical tickbome fever. However, if susceptible aninlals are being brought into tick-infested pastures, it may be sensible to deliberately infect them before introduction and treat them with oxytetracyclines before or immediately after the onset of fever. This allows multiplication of the organism and therefore stimulation of immune responses without uncontrolled clinical disease; a minimum duration of bacteremia may be required for protective immunity to develop. Because not all strains of A phagocytophilum are cross-protective, strains specific to the area must be used.

TICK PYEMIA Tick pyemia affects lambs 2-12 wk old and is characterized by debility, crippling lan1eness, and paralysis. Pyernic abscesses are common in joints but may be found in virtually any organ. The disease causes significant economic loss through debilita­ tion and death. The disease is enzootic in many regions of the UK and Ireland where the tick Ixodes ricinus is common, and it is likely to be present in other parts of Europe where the same tick is found.

Etiology: Staphylococcus aureus is regarded as the main cause of the pyemic abscesses, because it has been isolated consistently from superficial and deep­ seated lesions and it is rare to find other bacteria. The bacteria are believed to gain entry into the bloodstrean1 either by direct inoculation during tick feeding, from local

superficial wounds, or through the infected umbilicus. However, there is clinical and experimental evidence that I ricinus does not simply act as a vector directly injecting staphylococci into the bloodstream. The main role of I ricinus is as a vector of the rickettsial agentAnaplasma phagocytophi­ lum, which causes tickbome fever (see p 772), which in tum creates factors favorable to development of pyemia Lambs affected with tickbome fever have severe leukopenia, and their peripheral blood neutrophils are less capable of phagocy­ tizing and killing S aureus. Experimental studies have shown that lambs with tickbome fever were more susceptible to experin1ental infections with S aureus during the period of neutropenia and that as many as300/o of lambs with tickbome fever may develop staphylococcal infections.

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The epidemiology of the disease is closely related to the biology of I ricinus. The disease is limited to areas populated by I ricinus and to seasons of the year climatically favoring high tick population and activity.

septicemic diseases. Tick pyemia may also resemble other suppurative infections of the newborn, including navel ill andjoint ill due to infections by other bacteria such as streptococci and Trueperella pyogenes.

Clinical Findings: Abscesses form in various parts of the body, mainly in the joints, tendon sheaths, and muscles, resulting in lameness-hence the common use of the tem1 "crippled Jambs." In some outbreaks, >30% of lambs may be affected; they are usually dull and lame and often suffer from loss of body condition. Internal abscesses withoutjoint lesions may result in no clinical signs other than the loss of condition, but when lesions are present in the CNS, there may be ataxia, paraplegia, or other nervous signs. ·me crippling disease lasts for days or weeks, but the disease may also appear as an acute septicemia. On occasion, there may be sudden deaths resulting from multiple internal abscesses without other visible signs. As many as 5096 of affected lambs may die, and the survivors recover slowly.

Treatment and Control: Treatment of

Lesions: Apart from the joints and other superficial structures, abscesses are commonly found in the liver, lungs, and kidneys. They may also be present in the meninges of the spinal cord and in the pericardiun1 and myocardium. The diaphragm, thymus, and adrenal glands are less conunonly affected. Ticks are often found attached to an inflamed area. Diagnosis: History and clinical signs are valuable indicators. The restriction of the disease to tick-infested areas, its occurrence during seasons of tick activity, and demon­ stration of A phagocytophilum or specific DNA by PCR in the blood of affected lambs or other sheep in the flock are diagnostic features. Isolation of S aureus from lesions and the absence of other bacteria will help to confirm tick pyemia The Joss of condition and ill-thrift without lameness may be difficult to recognize as tick pyemia, and the acute condition can be confused with other

clinical cases of tick pyemia with penicillin or tetracycline can be effective, provided the lesions are not too advanced. Control of tick infestation is the most effective prevention. This can be achieved either by restricting lambs and ewes to low-ground, tick-free pastures for the first few weeks of life or by dipping ewes before Jambing and administering aca.iicides as dips or smears on lambs. In young lambs, pour-on preparations of cypermethrin or smears applied before Jan1bs are moved from lambing fields to hill pastures reportedly control ticks effectively. Ad.ministration of long-acting oxytetracy­ cline at the time of risk Ca.J.l help prevent both tickbome fever and tick pyem.ia during the first weeks of life. A single irtjection at double the standard dose given at 3 wk of age can significantly reduce mortality and morbidity in young hill lambs on tick­ .infested pastme and inlprove weight gains and condition in the remainder. Prophylactic treatment with a long-acting antibiotic may prevent development of tickbome fever for as long as 3 wk, without pyrexia and inununosuppression, so that the incidence of tick pyemia and other infections such as pasteurellosis and colibacillosis are reduced.. Although treatment with oxytetracycline may inhibit tl1e development of in1munity, if the Jan1bs eventually develop tickbome fever, they are several weeks older and apparently less susceptible to tick pyemia. Deliberate exposme of Jambs by irtjections, followed by treatment with oxytetracycline, could provide some i.J11munity before the Jambs enter tick-infested areas; however, strains specific to the area must be used because some strains of A phagocytophilum have no cross-inlrnunity.

WESSELSBRON DISEASE Wesselsbron disease is an acute, arthropod­ borne flavivi.Jus infection of mainly sheep, cattle, and goats in sub-Sallaran Africa. Infection is common, but clinical clisease is

infrequent although likely under-reported. Newborn Jambs and goat kids are most susceptible, and mortality may occur. Infection in adult sheep, cattle, and goats

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is usually subclinical, but disease may be severe in sheep with preexisting liver pathology. Occasional abortion in ewes, together with congenital malformation of the CNS with arthrogryposis of the ovine (and also the bovine) fetus and hydrops arnnii in ewes, is seen. Incidental spillover occurs to people, causing a nonfatal, influenza-like disease. Etiology and Epidemiology: Wessels­ bron disease is caused by a flavivirus, which is an enveloped, positive-sense RNA virus. It has not been well character­ ized but has properties typical of a hemagglutinating flavivirus. It has been isolated from vertebrates and arthropods from many sub-Saharan African countries, and serologic surveys provide evidence of its occurrence in other countries. Evidence of infection has been reported in cattle, sheep, goats, camels, pigs, donkeys, horses, ostriches, and wild ruminants. Based on the distribution of aedine mosquitoes associated with Wesselsbron disease, the incidence of infection is likely greater than is generally realized. The high prevalence of antibodies in warmer and moister coastal areas of southern and eastern Africa suggests that domestic herbivores may play a significant role in maintenance of the virus, and activity appears to occur year round. In drier areas, however, seroprevalence is generally lower, with irregular disease outbreaks occurring, usually in conjunc­ tion with Rift Valley fever. (seep 768) when abnormally heavy rains lead to an abundance of floodwater-breeding mosquitoes. People may become infected by mosquitoes or by handling organs from • infected animals. Clinical Findings: After an incubation

period of 1-3 days in newborn lan1bs, nonspecific signs of illness, including fever, anorexia, listlessness, weakness, and increased respiration, become evident. Death may occur within 72 hr. In calves and adult sheep, goats, and cattle, nonfatal febrile or inapparent infection occurs. Occasional abortion, congenital CNS malformations with arthrogryposis, and hydrops amnii are seen in ewes. Wesselsbron disease and Rift Valley fever share many clinical and pathologic features. However, Wesselsbron disease is usually milder, producing much lower mortality, fewer abortions, and less destructive liver lesions. The virus appears to be more neurotropic than that

of Rift Valley fever, and severe fetal teratology of the CNS is seen after experimental infection. Use of the attenuated vaccine in pregnant ewes may result in early embryonic death, severe teratology of the CNS, arthrogryposis, hydrops arnnii, abortion, or fetal mummifi­ cation. In people, mild to severe, nonfatal influenz a -like symptoms are seen. Lesions: In newborn and young animals, a moderate to severe icterus and hepatomegaly are seen with Wesselsbron disease; the liver is yellowish to orange brown. Petechiae and ecchymoses are commonly found in the mucosa of the abomasum, the contents of which are chocolate-brown in color. Histopathology reveals mild to extensive necrosis of the parenchyma as well as individual or small, scattered groups of necrotic hepatocytes. Lesions in adult animals are usually much milder. Diagnosis: The clinical signs and epidemiology, together with a relatively high mortality in lambs, are an indication of Wesselsbron disease. It should, however, be distinguished from Rift Valley fever, and the two diseases may occur together. The virus can be isolated from almost all organs of lambs that have died during the clinical stage of the disease. Intracerebral inoculation of newborn mice is the best method of isolation. The virus can be distinguished from that of Rift Valley fever by intraperitoneal inoculation of weaned mice; Wesselsbron disease virus will not kill such mice, whereas Rift Valley fever virus will. Confirmation of the viral identity can be accomplished by virus neutralization. Serodiagnosis has been based on hemagglutination-inhibition, complement fixation, and virus neutralization. Flavivirus cross-reactivity is marked in li.emagglutina­ tion-inhibition tests but less so in comple­ ment fixation, a test that is specific in cattle sera. Nevertheless, homologous Wessels­ bron titers greatly exceed heterologous flavivirus titers. Control: Production of an attenuated vaccine was discontinued shortly before 2000. Incidence of disease is low in sheep, but injudicious use of the vaccine in pregnant ewes resulted in severe economic losses in the past due to abortion and fetal malformations. Attempts to control mosquito vectors are of little value as a preventive measure.

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CANINE DISTEMPER Canine distemper is a highly contagious, systemic, viral disease of dogs seen worldwide. Clinically, it is characterized by a diphasic fever, leukopenia, GI and respiratory catarrh, and frequently pneumonic and neurologic complications. Its epidemiology is complicated by the large number of species susceptible to infection. The disease is seen in Canidae (dog, fox, wolf, raccoon dog), Mustelidae (ferret, mink, skunk, wolverine, marten, badger, otter), most Procyonidae (raccoon, coatirnundi), some Viveridae (binturong, palm civet), Ailuridae (red panda), Ursidae (bear), Elephantidae (Asian elephant), primates (Japanese monkey), and large Felidae. Domestic dogs (including feral populations) are considered to be the reservoir species in most, if not all, locations. Antigenic drift and strain diversity is increasingly docun1ented in association witl1 outbreaks in wild species, domestic dogs, and exotic animals held in zoos and parks. Etiology and Pathogenesis: Canine distemper is caused by a paran1yxovirns closely related to the vimses of measles and rinderpest. The fragile, enveloped, single-strand RNA vims is sensitive to lipid solvents, such as etl1er, and most disinfec­ tants, including phenols and quaternary an1monium compounds. It is relatively unstable outside tl1e host. The main route of infection is via aerosol droplet secretions from infected animals. Some infected dogs may shed virus for several montl1s. Virus initially replicates in the lymphatic tissue of the respiratory tract. A cell-associ­ ated vi.remia results in infection of all lymphatic tissues, which is followed by infection of respiratory, GI, and urogenital epitl1eliun1, as well as the CNS and optic nerves. Disease follows vims replication in tl1ese tissues. The degree of viremia and extent of viral spread to various tissues is moderated by tl1e level of specific humoral immunity in tl1e host during tl1e viremic period. Clinical Findings: A transient fever usually occurs 3-6 days after infection, and there may be a leukopenia (especially lymphopenia) at this time; tl1ese signs may go unnoticed or be accompanied by anorexia. The fever subsides for several days before a second fever occurs, which

may be accompanied by serous nasal discharge, mucopurulent ocular discharge, letl1argy, and anorexia. GI and respiratory signs, typically complicated by secondary bacterial infections, may follow; rarely, pustular dern1atitis may be seen. Encepha­ lomyelitis may occur in association with these signs, follow tl1e systemic disease, or occur in the absence of systemic manifesta­ tions. Dogs surviving the acute phase may have hyperkeratosis of the footpads and epitl1elium of tl1e nasal planun1, as well as enamel hypoplasia in incompletely erupted teetl1. Overall, a longer comse of illness is associated with tl1e presence of neurologic signs; however, tl1ere is no way to anticipate whether an infected dog will develop neurologic manifestations. CNS signs include circling, head tilt, nystagn1us, paresis to paralysis, and focal to generalized seizures. Localized involuntary twitching of a muscle or group of muscles (myoclonus, chorea, flexor spasm, hyperki.nesia) and convulsions characterized by salivation and, often, chewing movements of the jaw ("chewing-gun1 fits") are considered classic neurologic signs. Emerging viral strains may be associated witl1 greater neurotropism; increased morbidity and mortality from neurologic complications has been observed. A dog may exhibit any or all of these multisystemic signs during the course of tl1e disease. Infection may be mild and inapparent or lead to severe disease with most of the described signs. The course of the systemic disease may be as short as 10 days, but the onset of neurologic signs may be delayed for several weeks or months as a result of chronic progressive demyelination within the CNS. Clinicopathologic findings are nonspe­ cific and include lymphopenia, with the possible finding of viral inclusion bodies in circulating leukocytes very early in the course of tl1e disease. Thoracic radiographs may reveal an interstitial pattern typical of viral pneumonia Chronic distemper encephalitis (old dog encephalitis, [ODE]), a condition often marked by ataxia, compulsive movements such as head pressing or continual pacing, and incoordinated hypern1etria, may be seen in fully vaccinated adult dogs without a history suggestive of systemic canine distemper infection. Although canine

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distemper antigen has been detected in the brains of some dogs with ODE by fluores­ cent antibody staining or genetic methods, dogs with ODE are not infectious, and replication-competent virus has not been isolated. The disease is caused by an inflammatory reaction associated with persistent canine distemper virus infection in the CNS, but mechanisms that trigger this syndrome are unknown. Lesions: Thyrnic atrophy is a consistent postmortem finding in infected young puppies. Hyperkeratosis of the nose and footpads is often found in dogs with neurologic manifestations. Depending on the degree of secondaiy bacterial infection, bronchopneumonia, ente1itis, ai1d skin pustules also may be present. In cases of acute to peracute death, exclusively respiratory abnormalities may be found. Histologically, canine distemper virus produces necrosis of lyn1phatic tissues, interstitial pneumonia, and cytoplasmic and intranuclear inclusion bodies in respiratory, winaiy, and GI epithelium. Lesions found in the brains of dogs with neurologic complications include neuronal degenera­ tion, gliosis, noninflainmatory demyelina­ tion, pe1ivascular cuffing, nonsuppurative leptomeningitis, and intranuclear inclusion bodies predominately within glial cells. Diagnosis: Distemper should be

considered in the diagnosis of ai1y feb1ile condition in dogs with multisystemic manifestations. Characte1istic signs sometimes do not appeai· until late in the disease, and the clinical picture may be modified by concurrent parasitism and nwnerous viral or bacterial infections. Distemper is sometimes confused with other systemic infections such as lepto­ spirosis (seep 650), infectious canine hepa­ titis (seep 798), or Rocky Mountain spotted fever (seep 806). Intoxicants such as lead or organophosphates can cause sinmlta.neous GI and neurologic signs. A febrile catarrhal illness with neurologic sequelaejustifies a clinical diagnosis of distemper. In dogs with multisystemic signs, the following can be exainined by immuno­ fluorescent assay or reverse transcriptase (RT) PCR: smears of conjw1ctival, tracheal, vaginal, or other epithelium; the buffy coat of the blood; urine sediment; or bone matTow aspirates. Commercially available quantitative R T P - CR can usually distinguish natural infection from vaccinal virus. A combined two-step RT-PCR to distinguish vaccinal strains from emerging wild-type

strains has also been desc1ibed; this assay would be of particular value in epidemio­ logic investigations or in outbreaks in non-canine species. Antibody titers or ELISA can be pe1formed on CSF and compared with peripheral blood; a relatively higher level in the CSF is typical of natural infection versus vaccination. Viral antigen inununofluorescent assay (IFA) or fluorescent in situ hybridization for viral DNA can be perfom1ed on biopsies from the footpads or from the haired skin of the dorsal neck At necropsy, diagnosis is usually confinned by histologic lesions, IFA, or both. These sainples are often negative when the dog is showing only neurologic manifestations or when circulating ai1tibody is present (or both), requiring that the diagnosis be made by CSF evaluation or RT-PCR as described above. Treatment: Treatments are syn1ptomatic

ai1d supportive, aimed at lin1iting secondaiy bacterial invasion, supporting fluid bal­ ance, and controlling neurologic mani­ festations. Broa d -spectrum antibiotics, balanced electrolyte solutions, pai·enteral nutrition, antipyretics, analgesics, and an­ ticonvulsai1ts are used, and good nursing cai·e is essential. No single treatment is specific or wlifonnly successful. Experi­ mental in vitro work with antiviral agents shows promise, but these agents have not yet been widely used. Unfortunately, treatment for acute neurologic manifestations of distemper is frequently unsuccessful. If the neurologic signs are progressive or severe, the owner should be appropriately advised. With prompt, aggressive care, dogs may recover completely from multisystemic manifesta­ tions, but in other cases, neurologic signs may persist after GI and respiratory signs have resolved. Some dogs with chronic progressive or vaccine-induced forms of neurologic disease may respond to immunosuppressive tl1erapy with anti­ inflanunatory or greater dosages of glucocorticoids. Prevention: With the potential increasing virulence of emerging strains and the wide host range of canine distemper virus, widespread vaccination of domestic dogs is essential. Successful immUllization of pups with canine distemper modified-live virus (MLV) vaccines depends on the lack of inter­ ference by maternal antibody. To overcome this batTier, pups are vaccinated with MLV vaccine when 6 wk old and at 3- to 4-wk

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intervals until 16 wk old. Alternatively, measles virus vaccine induces inmrnnity to canine distemper virus in the presence of relatively greater levels of maternal distemper antibody. MLV measles vaccine is administered IM to pups 6---7 wk old and is followed with at least two more doses of MLV distemper vaccine when 12-16 wk old. Many varieties of attenuated distemper vaccine are available and should be used according to manufacturers' directions. MLV vaccines should not be used in late-pregnant or early-lactation bitches. MLV vaccines can produce postvaccinal illness in some imrnunosuppressed dogs. A recombinant canarypox vector vaccine expressing distemper vims proteins is licensed for use in ferrets; the American

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Assocation of Zoo Veterinarians recom­ mends its extra-label use in many at-risk species held in zoos and parks. Historically, annual revaccination has been standard because of the breaks in protection that can occur in stressed, diseased, or immunosup­ pressed dogs, and because vaccines have been labeled for annual use. Substantial evidence supports the finding that inm1unity induced by MLV distemper vaccines lasts �3 yr. However, in most cases, this remains an extra-label use of the vaccine; thus, decisions to revaccinate less often than annually should be considered in light of local prevalence of the disease and other potential risk factors, as well as industry and professional organization recommendations.

CANINE HERPESVIRAL INFECTION Canine herpesvirus is best known as a severe viral infection of puppies worldwide, which often has a lO()OA, mortality rate in affected litters. Increasingly sensitive molecular diagnostics have enabled its recognition in adult dogs with upper respirntory infection, ocular disease, vesicular vaginitis or posthitis, and in dogs with no clinical signs. As is typical of herpesvirnses, recovery from clinical disease is associated with lifelong latent infection. Only canids (dogs, wolves, coyotes) are known to be susceptible. The seroprevalence in dog populations worldwide ranges from 200A, to 98% depending on the region. Because latently infected animals may transiently convert to seronegative status, any seroprevalence study likely underestimates the tme rate of exposure and carriage.

Etiology and Pathogenesis: The disease is caused by an enveloped DNA canine herpesvirus (CHV) that is sensitive to lipid solvents (such as ether and chlorofonn) and most disinfectants. CHV is relatively unstable outside the host, so close contact is required for transmission. Transmission usually occurs by contact between susceptible individuals and the infected oral, nasal, or vaginal secretions of shedding dogs. Many dogs shedding vims exhibit no clinical signs. Inm1unologically naive pregnar1t bitches are at risk of acute infection, which may be traI1Sn1itted to fetuses or neonatal pups; previously infected bitches are unlikely to traI1Sn1it infection. TI1e most significar1t systenlic disease

occurs in fetal or neonatal puppies from in utero infection, or infection in the fil'St 3 wk of life. After tllis tin1e, natural resistar1ce to infection improves as puppies mature and maintain a higher body temperature. Infection of susceptible aninlals results in replication of CHV in the surface cells of the nasal mucosa, pharynx, and tonsils. In the case of newborn susceptible pups or other dogs with compromised in1rnune response, viremia and invasion of diverse visceral organs occur. Primary systemic infection is associated with a high degree of viral shedding; shedding by latently infected aninlals after clinical or subclinical recmdes­ ence is of lesser severity and duration.

Clinical Findings: Deaths due to CHV infection usually occur in puppies 1-3 wk old, occasionally in puppies up to 1 mo old, and rarely in pups as old as 6 mo. Typically, onset is sudden, and death occul'S after an illness of !>24 hr. If clinical signs ar·e obse1ved, they may include lethar·gy, decreased suckling, diarrhea, nasal dischar·ge, conjunctivitis, corneal edema, erythematous rash, rarely oral or genital vesicles, and the notable absence of fever. Thoracic radiographs show a diffuse unstrnctured interstitial pattern that is typical of viral pnemnonia, but, in contrast to other viral diseases of puppies, leukocyto­ sis may be present. Older dogs exposed to or experimentally inoculated with CHV may develop a mild rhinitis, which may be part of the "kennel cough" syndrome (infectious tracheobron-

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chitis, seep 1490) or a vesicular vaginitis or posthitis. There are also reports of conjunctivitis and dendritic corneal ulcers in the absence of other upper respiratory signs. Acutely infected pregnant bitches may abort a litter, or deliver a partially stillborn litter; however, they seldom exhibit other clinical signs, and future breedings are likely to be successful. Lesions: The characte1istic gross lesions

at necropsy consist of disseminated focal necrosis and hemorrhages. The most pronounced lesions are seen in the lungs, cortical portion of the kidneys, adrenal glands, liver, and GI tract. All lymph nodes are enlarged and hyperemic, and the spleen is swollen. Lesions may also be found in the eyes and CNS. The basic histologic lesion is necrosis with hemo1Thage in the adjacent parenchyma. The inflammatory reaction in many organs may be limited, but marked neutrophilic and mononuclear infiltration is seen in ocular lesions. Single, small, basophilic, intranuclear inclusion bodies are most common in areas of necrosis in the lung, liver, and kidneys; occasionally, they are seen as faintly acidophilic bodies located within the nuclear space. Diagnosis: 1n systemically affected puppies, CHV infection may be confused with infectious canine hepatitis (seep 798), but it is not accompanied by the thickened, edematous gallbladder often associated with the latter. The focal areas of necrosis and hemorrhage, especially those that are seen in the kidneys, distinguish it from hepatitis and neosporosis (seep 663). CHV causes serious disease only in very young puppies. The rapid death and characteristic lesions distinguish it from canine distemper (seep 777). • Hemagglutination, ELISA, and immw10fluorescence antibody tests are available, and PCR is highly sensitive and specific when used on fresh tissue and fluid samples. 1n cases of neonatal mortality, the diagnosis typically is made postmo1tem with virus isolation from fresh lung, liver, kidney, and

spleen by cell culture techniques and subsequent identification by PCR and sequencing, transmission electron microscopy, immunoftuorescence, or fluorescence in situ hybridization. The tissues should be submitted to the laboratory refrigerated but not frozen. Treatment: Therapy is typically

unrewarding in systemically affected puppies, and the prognosis for puppies that do survive is guarded because damage to lymphoid organs, brain, kidneys, and liver may be iITeparable. Before onset of clinical signs in littermates or other nearby puppies, reaiing in incubators at an increased temperature (95 °F [35 °CJ, 50%relative hwnidity), and/or passive iinmunization with intraperitoneal senm1 may reduce losses within an exposed litter. Lin1ited studies with antiviral agents such as vidarabine are inconclusive, but iinmediate recognition and treatment would be needed to have any possibility of success. Adult dogs with ocular, respiratory, or genital disease often experience mild and self-liI11iting signs. Ophthalmic antiviral cidofovir (0.5%bid) has been used success­ fully in one reported case of primary ocular iI1fection in an adult dog ai1d may be useful for persistent or painful ocular lesions. Prevention: No vaccine is available in the USA Infected bitches develop antibodies, and litters subsequent to the first infected litter receive maternal antibodies in the colostrw11. Puppies that receive maternal antibodies may be infected with the virus, but disease does not result. Isolation of preg­ nant bitches from other dogs during the last 3 wk of gestation and first 3 wk postpartw11, with excellent hygiene by hW11an handlers, is the most effective way to minimize risk to puppies. Because of the high seroprevalence among adult dogs and because virus may be shed by asymptomatic individuals, complete avoidance of exposure is not a reasonable management strategy for most dogs.

FELINE INFECTIOUS PERITONITIS Feline infectious peritonitis (FIP) is an iinmune-mediated disease triggered by infection with a feline coronavirus (FCoV). FCoV belongs to the family Coronaviridae, a group of enveloped, positive-stranded RNA viruses frequently found in cats.

Coronavirus-specific antibodies ai·e present in as many as 90%of cats in catteries and in as many as 500A, of those in single-cat households. However, 3 mg/mL) of a-1-acid glycoprotein (AGP), a semm acute phase protein that is increased in cats with FIP, can supp01t diagnosis, but levels also are increased in other inflanunatory conditions; thus, these changes are not specific. Additionally, AGP may also be high in asymptomatic cats infected with FCoV, especially in households where FCoV is endemic. However, the most prominent increases in serwn AGP concentration have been recorded in cats with FIP Levels of AGP in semm and effusions increased 2- to 5-fold in cats with FIP, more than in diseases such as neoplasia and cardiomyopathy. In a study with a small number of cases, measurement of semm AGP concentrations was demonstrated to be most helpful, because it was the only diagnostic test in complete concordance with inununohisto­ chemistry. Two factors must be considered when evaluating AGP concentration to support a clinical diagnosis of FIP: the magnitude of the increase in concentration and the pretest probability of FIP (compat­ ible history and clinical findings). Semm an1yloid A (SAA), another acute phase protein, increases 10-fold in the semm of cats with FIP compared with asymptomatic cats exposed to feline enteric coronavimses. SAA may be a useful biomarker in the future. Diagnostic Imaging: A recent study highlighted specific concurrent ultrasono­ graphic findings that should increase the index of suspicion for FIP, including abdominal lymphadenopathy, peritoneal or retroperitoneal effusion, renomegaly, irregular renal contour, hypoechoic subcapsular echogenicity, and diffuse changes within the intestines. In most cats in the study population, the liver and spleen were normal in echogenicity. A nom1al abdominal ultrasound does not exclude the possibility of FIP infection. Effusion Fluid: Tests on effusion have a much higher diagnostic value than tests performed on blood. Fluid can be obtained through ultrasound-guided fine-needle aspiration or by using the "flying cat technique" in case of ascites. Although clear

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yellow effusions of sticky consistency are considered typical, the presence of this type of fluid in body cavities alone is not diagnostic. Cases with pure chylous effusion have been reported. Usually, the protein content is very high (>3.5 g/dL), consistent with an exudate, whereas the cellular content is low ( 300 IU/L). Cytology is vatiable but often consists predominantly of macrophages and nondegenerate neutro­ phils (in much lower numbers than seen with bacterial infection). These effusions can usually be differentiated from bacterial infection or lymphoma by the presence of malignant cells, degenerate neutrophils, or intracellular bacteria on cytology and bacterial growth on culture, respectively. The albumin to globulin ratio of the effusion can be measured: a ratio of 100 cells/itL, which consisted predominantly of neutrophils. Measurement of Antibodies: There is noFIP-specific antibody test; all that can be measured is antibodies againstFCoV. Antibody titers measured j.n serum are extensively used as a diagnostic tool. However, mostFCoV antibody-positive cats never developFlP. Thus, antibody titers must be interpreted extremely cautiously and should never be used as tl1e sole test to diagnose FlP. Antibody testing still has a certain role h1 the diagnosis and, more importantly, in the management of multicat households, when done by appropriate methodologies and when results are properly inte1preted. However, antibody testing can only be useful if the laboratory is reliable and consistent. Low or mediwn titers have no diagnostic value. If interpreted carefully, however, ve1y high titers can be of certain diagnostic value. A very high titer in a cat with compatible clinical signs (1:1,600) has a 94% PPVforFlP; a negative titer has a 90%NPVforFIP Cats with high antibody titers are more likely to shedFCoVand to shed more consistently higher amotµ1ts of the vi.ms. Thus, the titer is directly correlated with virus replication rate and tl1e an1ount of vims fn the intestines. S creening a cattery for the presence ofFCoVor screening a cat before introduction into an FCoV-free cattery are additional indications. Measuring antibodies in fluids (eg, effusion, CSF) other than blood has been investigated. D etection of anticoronavirus antibodies in effusion fluid has a PPVofOO'Ai and aNPVof29"Aifor diagnosis ofFIP. Presence of antibodies in effusion is correlated with tl1e presence of antibodies in blood; thus, antibody titers in effusions are not very helpful. One study investigating the diagnostic value of antibody detection in CSF reported a very good correlation to the presence ofFIP when compared with histopathology; however, two studies investigating a large nun1ber of cats presented to veterinary teaching hospitals revealed no significant difference in antibody titers in CSF from cats with neurologic signs due toFIP compared witl1 cats with other nemologic diseases confinned by histopathology.

Feline Coronavirus Reverse Transcrip­ tase PCR: FCoVreverse transcriptase PCR in blood is used with increasing frequency as a diagnostic tool forFlP. However, so far, no PCR has been developed that can defini­ tively diagnose FlP. PCR can be false-nega­ tive (eg, because the assay requires reverse transcription of viral RNA to DNA before amplification of DNA, and degradation of RNA can occLrr clue to contan1ination with ubiquitous RNAases) or false-positive (eg, the assay does not distinguish between vimlent and avirulentFCoVstrains and will not discrin1inateFCoVfrom coronavimses of other species). Furthermore, viremia appears to occur not only in cats withFIP but also in healthy carriers. FCoV RNA has been detected in the blood of cats withFIP but also in healtl1y cats that did not develop FlP for as long as 70 mo. Therefore, tl1e results of PCR tests in general must be interpreted carefully, and PCR catmot be used as a tool to definitively diagnose FlP. PCR has been used to detect rcov in fecal samples, and it is sensitive and useful to clocw11ent that a cat is shedding FCoVin feces. The strengtl1 of the PCR signal in feces correlates with the amount of virus present in the intestines. These results can be useful to detect cats that chronically shed high virus loads and that pose a high risk in multicat households. lmmunostaining of Feline Coronavirus Antigen: Direct staining ofFCoVs within macrophages by inununofluorescence in cytocentrifuged effusions or inu11unohisto­ chemistry in tissue is considered the most specific test to confirm FlP. Inm1unostai11ing crumot differentiate between tl1e "hru·mless" FCoVandFIP-causingFCoV, butfmding irLfected macrophages in characteristic pyogranulomatous lesions or in inflruruna­ tory effusions is highly associated with FlP. In a recent study in which a large nwnber of cats with coniinnecl FIP and controls with other confirmed dis!'!ases were investigated, positive imrnunofluorescence staining of intracellularFCoV anti.gen in macrophages of tl1e effusion was 100%predictive ofFIP. Unfortunately, theNPVof the test is not very high (57%), which can be explained by low nwnbers of macrophages on effusion smears resulting in negative staining. Inm1unohistochemistry can be used to detect the expression ofFCoVantigen in tissue and is also 100% predictive ofFIP if positive. However, invasive methods (eg, laparotomy or laparoscopy) are usually necessary to obtain appropriate tissue san1ples. Eitl1er histology itself is confirma­ tive, or immunohistochemistry staining of

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FCoV antigen in tissue macrophages can be used to diagnose FIP. Treatment, Control, and Prevention:

Because of the high prevalence of FCo V antibodies in healthy cats, widespread antibody testing of healthy cats is not an appropriate screening test for FIP in pet cats. Nor should cats in shelters be screened for antibodies before adoption. No treatment of healthy antibody-positive cats has been shown to prevent develop­ ment of FTP. Treatment of cats with FIP remains frustrating and is lin1ited to the cases that respond favorably within the first few days. The prognosis for a cat with FIP is very poor. In a prospective study including 43 cats with confirmed FIP, the median survival after the definitive diagnosis was 9 days. Some cats, however, may live for several months. Factors that indicate a poor prognosis and a short survival time are low Karnofsky score (index for quality of life), low platelet count, low lymphocyte count, high bilirubin concentration, and a large amount of effusion. Seizures are an unfavorable prognostic sign; they are significantly more frequent in cats with marked extension of the inflan1matory lesions to the forebrain. Cats that show no improvement within 3 days after treatment initiation are unlikely to show any benefit from therapy, and euthanasia should be considered. Longer survival or remission from clinical signs is rare. Supportive treatment is aimed at supp­ ressing the immune overreaction, usually using corticosteroids. However, there are no controlled studies that indicate whether corticosteroids have any beneficial effect. Cats treated with corticosteroids have shown anecdotal improvement for as long as several months. Inununosuppressive drugs such as pred.nisolone (2-4 mg/kg/day, PO) are commonly used. More potent cytotoxic drugs such as cyclophosphamide (4 mg/kg/ day) have also been suggested. Cats with large effusions benefit from removal of the fluid; ir\jection of dexan1ethasone into the abdominal or thoracic cavity may follow (1 mg/kg/day until no effusion is present). Cats with FIP should receive supportive therapy, including fluids and nutritional support, and their quality of life should be monitored. Anecdotal reports suggest that ozagrel hydrochloride, a thromboxane sy.nthetase inhibitor that inhibits platelet aggregation, and pentoxifylli.ne, a drug that decreases vasculitis and inhibits several cytokines (such as interleukins and TNF-a), may be beneficial in some cats.

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Immune modulators (eg, Propionibacle­ rium acnes, acemannan, tylosin, promodu­ lin, interferon-a) have been used to treat cats with FIP. However, controlled trials are lacking, and anecdotal reports often lack definitive diagnosis. It has been suggested that these agents may benefit infected ani.nlals by restoring compromised inunune function. However, a nonspecific stimula­ tion of the inunune system would seem to be contraindicated in FIP, because clinical signs develop and progress as a result of an immune-mediated response. A nun1ber of studies have investigated effectiveness of various antiviral treatments in cats with FIP, including interferons and libavirin. To date, none have proved to be very successful. See TABLE 7. Interferons have been used frequently in cats with FIP. Human interferon-a has a direct antiviral effect, and in vitro antiviral efficacy against an FIP-causing FCoV strain has been demonstrated. In a controlled study, cats with confirmed FIP treated with interferon-a at 106 IU/kg in combination with Propionibacterium acnes survived for -3 wk. Feline interferon-wis available in some European cow1tries and Japan. FCoV replication is i.nllibited by feline interferon-win vitro, but there was no statistically significant difference in the mean survival time of cats enrolled in a randomized placebo-controlled double­ blind treatment trial. Cats survived for 3-200 days, regardless of whether they received the drug or placebo. Management of Exposed Cats:

When a cat in a household develo{ls FIP, all in-contact cats will have already been exposed to the same FCoV. Under natural circwnstances, it appears that the FIP-caus­ ing virus strain is not excreted in such cases, and FIP is not transmitted from cat to cat. However, under experimental conditions it has been possible to transmit FIP-causing virus from a cat with FIP to in-contact cats. Still, it appears to be relatively safe for a cat with FIP to remain in the same household with cats that have already been in contact to the FCoV strain. However, it is not recommended to allow contact between a cat with FIP and any new "naive" cat. Kittens, which are more susceptible to FIP than adults, should not be introduced to households with a recent history of FIP. If a cat has been euthanized or has died due to FIP, the owner should wait 2 mo before obtaining another cat. FCoV can remain infectious for at least 7 wk in the environment, particularly where litter boxes are in use. Other cats currently in the

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household are most likely infected with and shedding FCoV. Cats are conunonly presented to the veterinarian for evaluation after contact with a cat with FIP or a suspected or known virus excretor. The owner may want to know the prognosis for the exposed cat or whether it is shedding FCoV. Such cats will likely be antibody positive, because 95%-lOOOAi of cats exposed to FCoV become infected and develop antibodies -2-3 wk after exposure. A few cats may be resistant to FCoV infection. Some cats in FCoV-endemic multicat households continuously remain antibody negative. The mechanism of action for this resistance is unknown. Although exposed cats will most likely have antibodies, this is not necessarily associated with a poor prognosis. Most cats infected with FCoV will not develop FIP, and many cats in single- or two-cat households will eventually clear the infection and become antibody negative in a few months to years (usually -61110). If titers are monitored, cats should be retested (using the same laboratory) every 6--12 mo until the antibody test is negative. Some cats will remain antibody positive for years. The value of serial antibody or PCR testing is mostly limited to protocols aimed at creating FCoV-free closed catteries. Management of Multicat Households: In most multicat households with unusually high cat numbers, FCoV is endemic and FIP is almost inevitable. Households of 10 cats per group, this is almost impossible because the virus passes from one cat to another, maintaining the infection. In these FCoV-endemic environments, such as breeding catteries, shelt,ers, foster homes,

and other rnulticat homes, there is virtually nothing to prevent FIP Various tactics have been used to eliminate FCoV from an endemic cattery. Reducing the number of cats (especially of kittens 6 wk, it should be placed in a single-cat environment or with other chronic shedders. Kittens of FCoV-shedding queens are often protected from infection by mater­ nally derived antibodies until they are 5-6 wk old. An early weaning protocol for prevention of FCoV infection in kittens has been proposed and consists of isolation of queens 2 wk before parturition, strict quarantine of queen and kittens, and early weaning at 5 wk of age. Early removal of kittens from the queen and prevention of infection from other cats may succeed in keeping kittens free of infection. Kittens should be taken to a new home (with no FCoV -infected cats) at 5 wk of age. Although straightforward in concept, the protocol requires quarantine rooms and procedures to ensure that new virus does not enter. Special care must be taken during this

DRUGS THAT HAVE BEEN SUGGESTED FOR USE IN FELINE INFECTIOUS PERITONITIS CASES Druga

ABCD Recommendation (EBM LeveJb)

Comment ANTIVIRALS

Ribavirin

Active in vitro but toxic in cats

Not reconunended (2)

Likely ineffective (4) Active in vitro but toxic in cats Vidarabin Human interferon-a, Although effective in vitro Ineffective (2) SC, high dose against FCoV, SC treatment did not work in an experimental trial

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DRUGS THAT HAVE BEEN SUGGESTED FOR USE IN FELINE INFECTIOUS PERITONITIS CASES (continued) ABCD Recommendation (EBM Levelb )

Druga

Comment

Human interferon-ex, PO,low dose

No trials. Only acts as immu­ nostimulant if given orally; inunune stinrnlation should be avoided in cats with FIP

Feline interferon-w

Single placebo-controlled study No benefit was observed (level of naturally occurring cases and 1 study); may require further one uncontrolled study studies in view of anecdotal clinical evidence (4)

Polyprenyl immunostinrnlant (investigational drug)

Upregulation biosynthesis of May have some beneficial mRNA ofTHl cytokines, effect in noneffusive FIP (3); uncontrolled study treating three controlled studies required noneffusive cases,long survival

Contraindicated (4)

IMMUNOSUPPRESSANTS No controlled studies; some cats improved during treatment and survived for several months; does not cure FIP

Currently supportive treatment of choice (3); if effusion is present,dexamethasone intrathoracic or intraperitoneal may be helpful

Pentoxyfylline

Aimed at treating vasculitis

Ineffective in one case study (4)

Ozagrel hydrochloride

Thromboxane synthesis inhibitor Controlled studies needed (3) aimed at treating inflammatory response; only used in two cases with beneficial effect

Cyclosporin A

Irnrnunosuppressive; no published studies

Not recommended; more direct­ ed against cellular inlfnunity than humoral (lack of data) (4)

Cyclophospharnide

Irnrnunosuppressive; no published studies

Might be considered in combina­ tion with glucocorticoids (4)

Chlorambucil

Immunosuppressive; no published studies

Might be considered in combina­ tion with glucocorticoids (4)

Azathioprine

Toxic in cats; irnmunosuppres­ sive; no published studies

Not recommended (4)

Acetylsalicylic acid (aspirin), platelet inhibitory dosage

To treat inflammatory response as well as vasculitis; no published studies

May have some beneficial effect, but adverse effects possible if used in combination with high-dose glucocorticoids

Prednisolone/ dexarnethasone (immunosuppres­ sive doses)

a

Many of the treatments listed represent extra-label use for treatment of FIP.

b Evidence-based medicine (EBM) level 1 = confirmed by randomized controlled clinical trials in target species; EBM level 2 = confhmed by randomized controlled experimental studies in target species; EBM level 3 = suppmted by case series, other experimental studies, nonrandomized clinical trials; EBM level 4 = based on expe1t opinion, case reports, studies in other species. Modified, with permission, from Feline infectious pe1itonitis. Guidelines of The Ew-opean Advisory Board on Cat Diseases (ABCD), © 2012 Advisory Board on Cat Diseases.

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FELINE INFECTIOUS PERITONITIS

period to socialize the kittens. The success of early weaning and isolation depends on effective quarantine and low numbers of cats ( 5--7 days. Mortality is highest in young kittens 33 countries worldwide and does not respond well to therapy. Efforts to control canine leislunaniosis and the hwnan disease in endemic areas focus on disrupting the transmission of infection and preventing canine infection at the population level.

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RICKETISIAL DISEASES

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RICKETTSIAL DISEASES EHRLICHIOSIS AND RELATED INFECTIONS In the past, a number of obligate intracellu­ lar organisms that infect eukaryotic cells were classified in the genusEhrlichia on morphologic and ecologic grounds. With newer genetic analyses, these agents have been reclassified into the genera of Ehrlichia, Anaplasma, and Neorickellsia, all of which are in the family Anaplasmata­ ceae. However, usage of the tern1 "ehrlichio­ sis" to broadly describe these infections may still persist. Etiology: Canine ehrlichiosis is primarily caused by Ehrlichia canis, which predominantly involves monocytes; although it is not considered a primary zoonosis, human infection with this agent has been occasionally reported. Another common ehrlichial pathogen of dogs is E chaffeensis, which causes a monocytic form of illness and is the primary species causing human ehrlichiosis infection in the USA. Human cases are reported throughout the mid to southeastern and central USA. Several published reports of monocytic ehrlichiosis in cats suggest that feline infection may occur, albeit uncommonly. E ewingii, which primarily infects the granulocytes of susceptible hosts, has been isolated from dogs and people in the southern, western, and midwestern USA. In 2009, an organism either identical or related to E muris was identified as a cause of human illness in the upper Midwest; the role of this E muris-like (EML) agent as a possible pathogen of dogs or cats is currently unknown. A phagocytophilum, formerly known as both E equi and the agent of hun1an granulocytic ehrlichiosis, has been reported as a cause of illness in dogs. It is known to cause human illness in the USA, prin1arily m northeastern, upper midwestern, and western states. Infection with this agent is most appropriately referred to as anaplas­ mosis, and the pathogen is found predomi­ nantly in granulocytes. A platys, which infects platelets, is the cause of infectious cyclic thrombocytope­ nia of dogs. Epidemiology: E canis is transmitted by the brown dog tick, Rhipicephalus

sanguineus, which is found worldwide·

accordingly, canine monocytic ehrlichi�sis also has a worldwide enzootic distribution. Acute E canis cases may resemble infection with Rickettsia rickettsii (the agent of Rocky Mountain spotted fever which can also b� transmitted by the b;own dog tick). Rhipicephalus ticks become infected with E canis after feeding on infected dogs, and ticks transmit infection to other dogs during blood meals taken in successive life stages. Blood transfusions or other means by which infected WBCs can be transferred, may also transmit the pathogen. E chaffeensis and E ewingii have sylvan cycles in the environment that involve tick species and wildlife reservoir hosts. In the USA, E chaffeensis and E ewingii are transmitted by Amblyomma americanum, the lone star tick, and white-tailed deer are thought to play an important role as reservoir hosts. Dogs are also considered a possible reservoir for E ewingii. A case of humanE ewingii contracted via blood infusion has been reported, and organ transplantation of E chaffeensis infection has been suspected. The ecologic cycle for the EML agent has not yet been elucidated but is suspected to involve Ixodes scapularis, the black­ legged tick. A phagocytophilum is transmitted by Ixodes species of ticks; in the northeastern USA, infection is transmitted by l'Scapula­ ris, whereas infection in western states is primarily associated with I pacijicus, the Western black-legged tick. In nature, the enzootic cycle is most likely associated with small rodents. People and domestic animals are incidental hosts of these pathogens. Human-to-hun1an transmission via transfusion of packed RBCs has been reported; the risk of canine-associated infections after blood transfusion is unknown. A platys is transmitted by R sanguineus and is enzootic in many parts of the USA and worldwide. Coinfection withE canis may occur, because the same tick vector is responsible for transmission of both pathogens. Clinical Findings: In dogs, E canis causes the most potentially severe clinical presentation of the Ehrlichia spp. Signs arise from involvement of the hemic and

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RICKETISIAL DISEASES

lymphoreticular systems and commonly progress from acute to chronic, depending on the strain of organism and immune status of the host. In acute cases, there is reticuloendothelial hyperplasia, fever, general.ized lymphadenopathy, splenomeg­ aly, and thrombocytopenia. Variable signs of anorexia, depression, loss of stan1ina, stiffness and reluctance to walk, edema of the limbs or scrotwn, and coughing or dyspnea may be seen. Most acute cases are seen in the warmer months, coincident with the greatest activity of the tick vector. Clu·onic cases may present at any time of year. During the acute phase of E canis infection in dogs, the hemograrn is usually nom1al but may reflect a mild nom10cytic, nmmochromic anemia; leukopenia; or mild leukocytosis. Thrombocytopenia is conunon, but petechlae may not be evident, and platelet decreases may be mild in some animals. Vasculitis and inunune-med.iated mechanisms induce a thrombocytopenia and hemorrhagic tendencies. Lymph node aspiration reveals hyperplasia. Death is rare during this phase; spontaneous recovery may occur, the dog may remain asympto­ matic, or chronic d.isease may ensue. Chronic ehrlichiosis caused by E canis may develop in any breed, but certain breeds, eg, German Shepherds, may be pred.isposed. Seasonality is not a specific hallmark of clu·onic infection, because appearance of chronic signs may be variably delayed after acute infection. In chronic cases, the bone marrow becomes hypoplas­ tic, and lymphocytes and plasmacytes infiltrate various organs. Clinical findings vary based on the predominant organs affected and may include marked spleno­ megaly, glomerulonephritis, renal failure, interstitial pnewnonitis, anterior uveitis, and meningitis with associated cerebellar ataxia, depression, paresis, and hyperesthe­ sia Severe weight loss is a prominent finding. The hemogran1 is usually markedly abnormal in chronic cases. Severe thrombocytopenia may cause epistaxis, hematuria, melena, and petechlae and ecchymoses of the skin. Variably severe pancytopenia (mature leukopenia, nonregenerative anemia, thrombocytope­ nia, or any combination thereof) may be seen. Aspiration cytology reveals reactive lymph nodes and, usually, marked plasmacytosis. Frequently, polyclonal, or occasionally monoclonal, hypergarnma­ globul.inemia develops. Other ehrlichial infections caused by E chaffeensis, E ewingii, or A phagocytophi-

lum appear clinically similar to acute E canis infection, but the clinical course is

usually more self-lim.iting. Shlfting leg lan1eness and fever of unknown origin may be present. Thrombocytopenia and mild leukopenia or leukocytosis may occur during the acute course of infection, whlch is clinically more discrete. Chronic can.ine d.isease, as seen with E canis infection, is not typically seen with other infections. Dogs infected with A platys generally show minimal to no signs of infection despite the presence of the organism in platelets. The primary finding is cyclic thrombocytopenia, recurring at 10-day intervals. Generally, the cyclic nature diminishes, and the thrombocytopenia becomes mild and slowly resolves.

Lesions: During the acute or self-limiting phase of E canis infections, lesions generally are nonspecific, but splenomegaly is common. Histologically, tl1ere is lymphoreticular hyperplasia and ly:mpho­ cytic and plasmacytic perivascular cuffing. In chronic cases, these lesions may be accompanied by widespread hemorrhage and increased mononuclear cell infiltration in perivascular regions of many organs.

Diagnosis: Because tlu·ombocytopenia is a relatively consistent finding with these infections, a platelet count is an important screening test. Clinical d.iagnosis may be confirmed by demonstrating the organisms within WBCs or platelets, seen in intracyto­ plasmic inclusion bod.ies called morulae. Th.is method of diagnosis lacks sensitivity, because low nwnbers of organisms make demonstration difficult. More commonly, a diagnosis is made by a combination of clinical signs, positive serwn indirect fluorescent antibody (IFA) titer, and response to treatment. In-house tests for E canis, A phagocytophilum, A platys, and E ewingii based on enzyme in1munoassay methods are also available, The antibody response may be delayed for several weeks; thus, serologic testing may not be a reliable diagnostic tool early in the course of tl1e disease. Furthermore, antibodies can persist for months or years after infection, making in-house tests for tl1e organisms problematic for confirmation of acute infection, particularly in highly enzootic areas where many dogs may have antibod­ ies to these agents because of previous infections. Testing of paired sera and demonstration of increased antibody titers is recommended to confirm infection when possible, although treatment of suspected cases should never be delayed or withheld

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RICKETISIAL DISEASES on the basis of test results, either positive or negative. Serologic cross-reactivity is strong between E canis, E clwffeensis, and E ewingii; some cross-reactivity to A plwgocytophilum is also seen. In people, the EML agent shows cross-reactivity to E chaffeensis. In some areas, -500/o of dogs infected with E canis also have a titer to A platys, which likely reflects coinfection; cross-reactivity between these agents is not seen. PCR has been used to detect and identify specific Ehrlichia andAnaplasma species in infected people and animals. Samples appropriate for PCR include blood, tissue aspirates, or biopsy specimens of reticu­ loendothelial organs, such as lymph nodes, spleen, liver, or bone marrow. PCR can also be used to detect the effectiveness of treatment in clearing infection. PCR is not routinely available through commercial veterinary laboratories, although some veterinary schools and research institutions offer it. PCR is available through several commercial human laboratories. During the acute stage, differential diagnoses include other causes of fever and lymphadenomegaly (eg, Rocky Mountain spotted fever, brucellosis, blastomycosis, endocarditis), inunune-mediated diseases (eg, systemic lupus erythematosus), and lymphosarcoma. During the chronic stage of E canis infection, differential diagnoses include estrogen toxicity, myelophthisis, immune-mediated pancytopenia, and other multisystemic diseases associated with specific organ dysfunction (eg, glomerulo­ nephritis). Treatment: The drug of choice for

infection with Ehrlichia and Anaplasma spp is doxycycline because of its superior intracellular penetration and bacteriostatic properties against rickettsiae. Doxycycline is recommended for dogs of all ages. If infection is suspected, dogs should be treated empirically; treatment should not be withheld or delayed pending laboratory results. Early seronegative tests should not be considered a reason to stop therapy, because antibodies may take :?:l wk to develop in acute cases. The recommended dosage of doxycycline in dogs is 5-10 mg/ kg/day, PO or IV, for 10-21 days. Tetracy­ cline (22 mg/kg, PO, ti.ct) can also be used for ;:,2 wk in acute cases and 1-2 mo in chronic cases. Two doses of i.rnidocarb dipropionate (5-7 mg/kg, IM), 2 wk apart, are variably effective against both ehrlichio­ sis and some strains of babesiosis. In acute cases receiving appropriate antibiotic

805

therapy, body temperature is expected to return to normal within 24-48 hr after treatment. In chronic cases associated withE canis infection, the hematologic abnonnalities may persist for 3-6 mo, although clinical response to treatment often occurs much sooner. Supp01tive therapy may be necessary to combat wasting and specific organ dysfunction; platelet or whole-blood transfusions may be required if hemorrhage is extensive. Concurrent broad-spectrwn antibiotics may be needed if the dog has severe leukopenia. The E canis antibody titer should be measured again within 6 mo of illness to confirm a low or seronegative status indicative of successful therapy. Serwn titers that persist at lower but positive levels should be rechecked in another 6 mo to ensure that they are not increasing. Prevention: Prevention is enhanced by controlling ticks on dogs, through use of reliable methods. In particular, medications and products with proven efficacy againstR sanguineus are imp01tant to use. Because R sanguineus infestations can be problematic in kennels and around homes, and longtem1 tick control is needed for management, use of effective long-acting collars on all susceptible dogs might be considered; collars containing propoxur, amitraz, or flumethrin have proven activity against R sanguineus. Prevention of transfusion-associated transmission can be reduced by using seronegative screened blood donors. although new donors with a negative screen carmot be presumed free of infection for several weeks because they may be incubating infection. Prophylactic administration of tetracycline at a lower dosage (6.6 mg/kg/day, PO) is effective in preventing E canis infection in kennels where disease is endemic. Treatment must be extended for many months through at least one tick season if the endemic cycle is to be successfully elinlinated, and tick control should be in1plemented as well. Zoonotic Risk: E chaffeensis, E ewingii,

and A plwgocytophilum are considered zoonoses. Despite the occurrence of disease in both animals and people, the involvement of a required intermediate tick vector for transmission means dogs and other infected animals do not pose a direct transmission risk in normal circumstances. Infection in dogs may indicate a heightened risk of human infections related to tick exposure in a given area.

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RICKETISIAL DISEASES

ROCKY MOUNTAIN SPOTTED FEVER (Rickettsia rickettsii infection) Etiology: Rocky Mountain spotted fever (RMSF) is a disease of people and dogs caused by Rickettsia rickettsii. R rickettsii and closely related members of the spotted fever group of rickettsiae are considered endemic throughout much of North, South, and Central America. These pathogens are transmitted primarily through the bites of infected ticks. The ability of genetically similar rickettsial organisms, such as R parkeri, to cause clinically similar disease in dogs is unknown. Because of their susceptibility to R rickeltsii and relatively higher rates of tick exposure, dogs may serve as excellent sentinels of risk for R iickettsii infection in people. Clusters of disease are frequently reported in defined geographic areas, and temporally associ­ ated infections may be seen in both dogs and their owners. Epidemiology: In the USA, Dermacentor variabilis (the American dog tick) and D andersoni (the Rocky Mountain wood

tick) are considered the primary vectors for R rickettsii. In South America, several Amblyomma spp of ticks have been implicated in transmission. The organism has also been isolated from Rhipicephalus sanguineus ticks (the brown dog tick), which appear to be the primruy vector in some focal ru·eas of Arizona, particularly on American Indian tribal lands, and may also play an as-yet unappreciated role in outbreaks elsewhere in the USA. R san­ guineus ticks are also associated with transmission of R rickettsii in Central America and with large city-based" outbreaks in Mexico. The pathogen is acquired by larval and nymph stages of ticks while feeding on infected vertebrate hosts and is also passed from female ticks to progeny through transovarial transmission. An estimated < 1% of Dermacentor spp ticks cruzy R iickettsii, even in areas considered highly endemic. In highly enzootic regions of Arizona where R iickettsii is transmitted by the brown dog tick, as many as 5% of ticks may be infected. Seroprevalence in dogs from endemic areas ranges from 4.3o/o--77%, but these values do not accurately reflect infection rates because of the detection of cross­ reacting antibodies to other genetically similar rickettsiae. RMSF transmission through blood transfusion has been

documented in a single hun1an case and should be considered when selecting canine blood donors. Direct transmission from dogs to people has not been reported, although hun1an infection may occur after contact of abraded skin or cof\iunctiva with tick hemolymph or excreta duiing removal of engorged ticks from pets. Clinical Findings: Dogs are highly susceptible to clinical infection witl1 R rickettsii; in contrast, it is rarely diagnosed in cats. Early signs in dogs may include fever (up to 105°F [40.5°C]), anorexia, lymphadenopathy, polyarthritis, coughing or dyspnea, abdominal pain, vomit­ ing and diarrhea, and edema of the face or extremities. Petechial hemorrhages of the conjunctiva and oral mucosa may be seen in severe cases. Focal retinal hemorrhage may be seen during the early course of disease. Neurologic manifestations such as altered mental states, vestibular dysfunction, and paraspinal hypcresthesia may occur. Thrombocytopenia is common. Leukopenia develops during the early stages of infection and, in untreated cases, is followed by progressive leukocytosis. Sernrn biochemical abnom1alities may include hypoproteinemia, hypoalbumine­ mia, azotemia, hyponatremia, hypocalce­ mia, and increased liver enzyme activities. Case fatality rates of -lo/o--100,.6 are expected. Lesions: Vascular endothelial damage is due to direct cytopathic effects of the rickettsiae. Severity of the necrotizing vasculitis can be directly correlated to the infective dose. Vascular endothelial drunage and thrombocytopenia contribute to development of petechiae and ecchymoses. Necrosis of the extremities (acryl gangrene) or disseminated intravascular coagulation can develop in severely affected dogs.

Diagnosis: Currently, there are no in-house diagnostic tests available for diagnosis of acute RMSF in dogs. Indirect fluorescent antibody titer (IFA) is preferred for serologic testing. However, because of the high incidence of cross-reacting antibodies to a vaiiety of nonpathogenic spotted fever group rickettsiae, as well as longtenn persistence of antibodies after acute RMSF infection, demonstration of a 4-fold 1ise in titer should be documented in conjunction with a compatible clinical syndrome. Differential diagnoses include other causes of fever of unknown origin. The therapeutic response is usually dramatic, as it is in other canine rickett­ sial diseases. Animals with neurologic

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RICKETISIAL DISEASES dysfunction may have residual deficits. Immunity appears to be lifelong after natural infection; therefore, recurrent episodes should not be attributed to RMSF. Treatment: Antibiotic treatment should

be administered based on clinical suspicion without waiting for results of serologic tests, because delayed administration of antibiotics may result in higher rates of severe or fatal outcome. Doxycycline is the treatment of choice, regardless of age of the dog, and should be administered at a dosage of5-10 mg/kg/day, PO or IV, for 10-21 days. Tetracycline at 22 mg/kg, PO, tid for 2 wk is also effective. Chlorarnphenicol has been used to treat RMSF in the past, but its use is associated with higher rates of fatal outcome in hun1an patients, and it is not recommended. Other broad-spectrum antibiotics are ineffective againstR rickettsii infection, and there is some evidence in hun1an cases that use of fluoroquinolones may actually worsen infection. Early seronegative tests should not be considered a reason to stop therapy, because antibodies may take �1 wk to develop in acute cases. Suppo1tive care for dehydration and hemorrhagic diathesis may be necessary. Because of alterations in vascular integrity, conservative rates of fluid administration are advised. Precautions should be taken for the safe removal and control of ticks. In settings in which R rickettsii transmission from R san­ quineus is suspected, medications and products with proven efficacy against this tick species are important to use. Because R sanguineus infestations can be problematic in kennels and around homes, and longterm tick control is needed for outbreak control, use of effective long­ acting tick collars on all susceptible dogs might be considered; collars containing propoxur, arnitraz, or flumethrin have proven activity againstR sanguineus. Zoonotic Risk: R rickettsii is considered

a zoonotic pathogen. The potential for household clustering and large urban outbreaks, particularly in areas with transmission by brown dog ticks, makes RMSF a disease of significant public health concern. Although clinical disease occurs in both animals and people, the involve­ ment of a required intermediate tick vector for transmission means dogs and other infected animals do not pose a direct transmission risk in normal circumstances. Wection in dogs indicates a heightened risk of human infections related to tick exposure in a given area, and serologic

807

studies of dogs in emerging areas may help predict human risk of infection. Particu­ larly in areas where transmission occw-s viaR sanguineus, close cooperation between veterinary, medical, and public health officials is in1portant to achieve control.

MURINE TYPHUS (Rickettsia typhi infection, R felis infection)

Rickeltsia lyphi, the causative agent of murine typhus, and Rfelis are zoonotic

pathogens maintained primarily in rodent reservoirs (rats, mice) that may also be associated with enzootic cycles involving opossun1s and domestic cats. Infection is transmitted to people and other animals through contact with infected fleas.

Epidemiology: Infection in people

is primarily thought to occur through exposure of abraded skin with infectious flea feces; aerosolization of infectious materials may occur in limited settings. Dogs and cats are presumably exposed in a similar fashion. Although known to occur worldwide, currently fewer than several hundred human cases of murine typhus are reported in the USA each year. Enzootic infection is the most commonly reported from southern Texas, California, and Hawaii, although the disease is believed to be underreported. Clinical Findings: Clinical illness

associated with canine and feline infec­ tion with R lyphi and Rfelis is not well docwnented, but evidence of exposure based on presence of antirickettsial antibodies has been noted, particularly in association with outbreaks of hun1an disease. Although a role as a possible rese1voi.r for infection has been suggested, particularly for cats, the importance of domestic animals in maintenance of enzootic cycles has not been well eluci­ dated. Nonetheless, dogs and cats may, at a minimwn, serve as a source of fleas that may pose a transmission risk to people. Regular flea control is recommended to reduce risk of flea-associated transmission to people. Diagnosis: An indirect fluorescent antibody (IFA) titer assessed in paired sera is preferred for serologic testing and is most commonly used in coajunction with environmental assessments around a human outbreak. There is some degree of antibody cross-reactivity with antibodies

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RICKETISIAL DISEASES

from other rickettsial infections, including

R rickettsii, so assessments should ideally be made with paired sera. PCR of whole blood may also be used, but its utility in assessing canine and feline infection is unknown because the animals may not exhibit clinical signs during periods of rickettsemia, making it difficult to deter­ mine the optimal time for assessment.

Treatment: In the absence of clinical

signs, specific treatment is not recom­ mended. If clinical illness associated with R typhi or Rfelis infection is suspected in a dog or cat, doxycycline may be adminis­ tered at a dosage of 5-10 mg/kg/day, PO or IV, for 10-21 days. Animals should be provided with routine preventive treat­ ments to control fleas. Control progran1s involving animal removal from an area of enzootic activity should be accompanied by pesticide treatment of the environment to prevent fleas feeding on people after the removal of prefeITed blood-meal hosts.

Zoonotic Risk: R typhi is considered a zoonotic pathogen. Serologic evidence of exposure or past infection in dogs or cats indicates a heightened 1isk of human infections in a given area, and flea control for pets is an essential component of disease control. SALMON POISONING DISEASE AND ELOKOMIN FLUKE FEVER (Neorickettsia spp infection) Salmon poisoning disease (SPD) is an acute, infectious disease of can.ids, in which the infective agent is transmitted through the various stages of a fluke in a snail-fish-dog life cycle. The name of the dise.ase is misleading, because no toxin is involved. Elokomin fluke fever (EFF) is an acute infectious disease of can.ids, feITets, bears, and raccoons that resembles SPD but has a wider host range. In people, Neorickettsia sennetsu causes a disease known as Sennetsu ehrlichiosis, and in horses N risticii causes a disease known as Potomac horse fever; these have not been reported as a cause of illness in dogs except for one report of N ri.sticii in Illinois.

Etiology: SPD is caused by N helmin­ thoeca and is sometimes complicated by a second agent, N elokominica, which causes EFF. The vector for these Ne01ickettsia agents is a small fluke, Nanophyetus salmincola. Dogs and other anin1als

become infected by ingesting trout, salmon, or Pacific giant salan1anders that contain the encysted metacerca.ria stage of the rickettsia-infected fluke. In the dog's intestine, the metacercarial flukes excyst, embed in the duodenal mucosa, become gravid adults, and transmit the rickettsiae to monocytes-macrophages. The fluke infection itself produces little or no clinical disease. A recent repmt of SPD in two captive Malayan sun bears underscores the need to consider this etiology in non-native exotic species with compatible exposure and clinical histories.

Epidemiology: The life cycle of Neo­ rickettsia helminthoeca is maintained by

the release of infected fluke ova in the feces of the ma.nunalian host. Infected miracidia. develop from these ova and infect the snails Juga plicifera and Juga silicula to form infected redia.e. Redia.e develop into infected cerca.iia.e that a.re released from the snail, penetrate the salmon or trout, a.i1d develop into encysted metacercaria.e infected withNe01ickettsia. The cycle is completed when man1111als eat the fish, and infected metacercaria.e become infected gravid adults and pass Neorickettsia to fluke eggs. Although Ne01ickettsia infection of dogs is not required for the life cycle of Neorickettsia, mammalian infection is required to maintain U1e trematode life cycle. Transmission by cage-to-cage contact, rectal thermometers, or aerosols is rare. There a.re no age, sex, or breed predilec­ tions; however, the disease prevalence is higher when the availability of trema.tode­ infected fish is greater. Infected fish are found in the Pacific Ocean from San Francisco to the coast of Alaska, but SPD is more prevalent from northern California. to Puget Sound. It is also seen inland along the rivers of fish migration. SPD also has been reported in southern California and Brazil. The snail is the primary factor for geo­ graphic limitation, but dogs fed under­ cooked or raw fish from the superma.i·ket may have developed SPD.

Clinical Findings: In SPD, signs appear suddenly, usually 5-7 days after ea.ting infected fish, but may be delayed as long as 33 days, and persist for 7-10 days before culminating in death in up to 90% of untreated anin1als. Body temperature pea.ks at 104°-107.6°F (40°-42° C) 1 2 - days later, then gradually declines for 4-8 days and returns to nonnal. Frequently, a.i1imals a.re hypothermic before death. Fever is accompanied by depression and complete

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RICKETISIAL DISEASES anorexia in virtually all cases. Persistent vomiting usually occurs by day 4 or 5. Vomiting occurs in most cases, and diarrhea, which develops by day 5-7, often contains blood and may be severe. Dehydration and extreme weight loss occur. When severe, the GI signs are clinically indistinguishable from those of canine parvoviral infection. Generalized lyrnphad­ enopathy develops in -60% of cases. Nasal or conjunctiva! exudate may be present and mimic signs of distemper. Neutrophilia is conunon, but a marked, absolute leukope­ nia with a degenerative left shift may occur. Th.rombocytopenia is repo1ted in 94% of the cases. Serum chernistiy values are nom1al. Clinically, EFF is a milder infection than SPD. Severe GI signs are less conunonly seen in EFF infections, and lyrnphadenopa­ thy may be a more pronounced finding. Case fatality rates with EFF are lower, at -HJO/o of untreated cases. Lesions: Infection appears to chiefly affect the lymphoid tissues and intestines. There is enlargement of the GI lymph follicles, lymph nodes, tonsils, thymus, and to some extent, the spleen, with micro­ scopic necrosis, hemorrhage, and hyperpla­ sia Remarkable abdominal or mesenteric lyrnphadenomegaly may be seen. A variable but often severe nonhemorrhagic enteritis is seen throughout the intestine with SPD but is less commonly seen with EFF. Microscopic foci of necrosis also appear aprut from the follicles. Nonsuppurntive meningitis or meningoencephalitis has been identified in some dogs.

Diagnosis: Fluke ova are found on fecal exan1ination in -92% of cases, which supp01ts the diagnosis. The ova are oval,

809

yellowish brown, rough-surfaced, and -87-97 x 35-55 µm, with an indistinct operculum and a small, blunt point on the opposite encl. During the first day or two, few ova may be passed. Inti·acellular organisms have been demonstrated by Romanowsky staining on lymph node aspirates in -70% of cases. PCR testing to detect DNA-specific N helminlhoeca (or Neorickettsia genus) is recommended for accurate diagnosis. Serologic testing using the N helminthoeca organism has been developed. Other causes of fever of unknown 01igin, generalized lyrnphadenop­ athy, vomiting, and diruThea are differential diagnoses. When diruThea and exuclative coajunctivitis occur, distemper should be considered. Prevention and Treatment: Currently, the only means of prevention is to restrict t11e ingestion of uncooked salmon, ti·out, steellieacl, and sin1ilar freshwater fish. In animals that recover, a profound hw11oral inunune response persists, but there is no cross-resistance between N helminlhoeca and N elokominica. Sulfonru11ides are not effective and may exacerbate the clinical disease. Recommended treatinent is pru·enteral oxytetracycline (7 mg/kg, JV, tid for 5 days) or doxycycline (10 mg/kg, bid for 7 clays). Oral tetracycline or doxycycline is contraindicated because of in1pinging GI signs. Animals usually succwnb because of dehydration, electi·olyte and acid-base imbalances, and anemia. Therefore, general supportive therapy to maintain hydration and acid-base balru1ce, while meeting nutlitional requirements and conti·olling diarrhea, is often essential. Judicious use of whole blood tr3l1Sfusions may be helpful.

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IMMUNE SYSTEM THE BIOLOGY OF THE IMMUNE SYSTEM 811

Physical Barriers 812 Innate Immunity 812 Complement 813 Cells oflnnate Immunity 813 Adaptive Immunity 814 Antibody Responses (Humoral Immunity) 815 Cell-mediated Immunity 816 Immunologic Memory 817 Cytokines 817 Regulatory Cells 817

817 Immunodeficiency Diseases 818 Primary Immunodeficiencies 818 Defects in Innate Immunity 818 Deficiencies in Adaptive Immunity 819 Diagnosis 821 Secondary Immunodeficiencies 821 Virus-induced Immunodeficiencies 821 Excessive Immune Function 822 Excessive Innate Responses 822 Excessive Adaptive Responses 823 Type I Reactions (Atopic Disease, Anaphylactic Reactions) 823 Type 11 Reactions (Antibody-mediated Cytotoxic Reactions) 826. Type Ill Reactions (Immune Complex Disease) 828 Type IV Reactions (Cell-mediated Immune Reactions) 830 Tumors of the Immune System 831 Gammopathies 832

IMMUNOLOGIC DISEASES

THE BIOLOGY OF THE IMMUNE SYSTEM Animals are under constant threat of invasion by a diverse range of microor­ ganisms that seek to enter the body and exploit its resources for shelter and food. To ensure survival and prevent such exploitation, the body combats the most dangerous of these invaders with an equally complex set of defensive mecha-

nisms that can be thought of as a series of barriers. These mechanisms include physical barriers to invasion such as a tough, thick skin or the ability to cough and sneeze. The second line of defense is a "hard wired" system of innate immunity that depends on a rapid, stereotyped response to stop and kill both bacterial

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THE BIOLOGY OF THE IMMUNE SYSTEM

and viral invaders. This is typified by the process of acute inflammation and by the classic sickness responses such as a fever. The third line of defense is the highly complex, adaptable, and incredibly effective adaptive immune system. Innate immune responses are highly effective against opportwlistic organisms or those of low virulence, but by their very nature cannot do more than delay highly pathogenic nlicrobial invaders. Longterm resistance and swvival depends on adaptive immmlity. The adaptive immune system is effective against a wide variety of patho­ gens. Its effectiveness improves each time it is activated in response to nlicrobial invasion. Because the body accumulates in1mune memory cells as it ages, adaptive immunity provides an almost insunnount­ able barrier to most potential invaders. In its absence, the animal dies. The adaptive immune system faces complex challenges. Many different nlicroorganisms, including bacteria, viruses, protozoa, and helnlinths, may attempt invasion. The optimal inimune responses to this diversity of invaders must also be very diverse. For example, invaders such as bacteria that live outside body cells are best attacked by an antibody-mediated (or humoral) immune response, whereas virnses living within cells are best destroyed by the killing of infected cells through cell-mediated mechanisms.

PHYSICAL BARRIERS The physical barriers on the surface of the body play a significant role in slowing or blocking microbial invasion. Very few nlicroorganisrns can penetrate intact skin; instead, invaders usually enter through wounds or by being irtjected, such as by mosquito bites. Skin wounds heal rapidly to reestablish the protective barrier. A complex population of nom1al skin bacteria tends to exclude new invaders, while antinlicrobial molecules in sweat can kill many would-be invaders. In the airways, the structure of the upper respiratory tract serves as an effective filter of small particles. The airways themselves are lined with a layer of adhesive mucus that can entrap nlicrobes. The mucus contains multiple antinlicrobial proteins such as defensi.ns, lysozyme, and sur­ factants. "Dirty" mucus is constantly being replaced by clean mate1ial as ciliary action carries it to the pharynx where it is swallowed. Coughing and sneezing remove larger irritants from tl1e airways and nasal passages and are essential defensive reactions. The defense of the intestine

centers largely on the presence of the huge and in1mensely complex nom1al conimensal nlicrobiota. Potential invaders may be unable to colonize the intestine in the presence of a well-adapted population of conm1ensal nlicrobes. If all else fails, invaders may be rapidly removed from the GI tract by vonliting and diarrhea The intestinal nlicrobiota plays a critical role in maintaining animal health. First, it is a source of nutrients, especially in herbivores, in which it provides a means of exploiting a cellulose-rich diet and a source of essential vitanlins. This nlicrobiota also plays a critical role in the defense of the body. The large, well-adapted nlicrobial population excludes many potential pathogens through competition. More importantly, the constant stimulus provided by the presence of the nlicrobiota effectively stimulates the correct development of the adaptive immune system and regulates the level of inflanm1ation mediated by innate immune systems.

INNATE IMMUNITY Microbes that succeed in penetrating the physical barriers of the body are rapidly detected, and the innate defenses are activated. Although multiple innate mechanisms exist, acute inflammation is the central feature of innate immunity. The first step in the inflammatory process is the early detection of either invading organisms or damaged tissues. Most invaders are recognized by pattern­ recognition receptors that bind and recognize conserved molecules expressed on nlicrobial surfaces. There are many different pattern-recognition receptors, but the most in1portant are the toll-like receptors (TLRs). TLRs are a family of at least 10 different receptors found on the surface or in the cytoplasm of cells such as macrophages, intestinal epithelial cells, and mast cells. The TLRs on cell surfaces bind to molecules commonly expressed by extracellular bacteria such as lipopolysac­ charides or lipoproteins. The cytoplasnlic TLRs, in contrast, bind to the nucleic acids of intracellular viruses. Once they bind their ligands, the TLRs trigger the production of proteins such as inter­ leukin 1 (IL-1) or interferon a (IFN-a). IL-1 and the otl1er cytokines produced in response to TLR stimulation then trigger acute inflammation. They initiate the adherence of circulating leukocytes to blood vessel walls close to sites of invasion. These leukocytes, especially neutrophils, then leave the blood vessels and nligrate to invasion sites, attracted by nlicrobial

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products, small proteins called chemo­ kines and molecules from damaged cells. 'once they anive at the invasion site, the neutrophils bind invading bacteria, ingest them through the process of phagocytosis, and kill the ingested organisms. This killing is largely mediated by a metabolic pathway called the respiratory burst that generates potent _ oxidants such as hydrogen peroXIde and hypochloride ions. Neutrophils, however, have minimal energy reserves and can undertake only few phagocytic events before they are depleted. Even if the initial inflammatory response is successful in killing all invaders, the body must still remove cell debris, eliminate any swviving microbes and dying neutrophils, and repair the damage. This is the task of macrophages. Tissue macrophages originate as blood monocytes: They, like neutrophils, are attracted to sites of microbial invasion and tissue dan1age by chemokines and damaged tissues, where they finish off any swviving invaders. . They also ingest and destroy any remam­ ing neutrophils, thus ensuring that 1:he neutrophil oxidants are removed without toxic spills occurring in the tissues. Finally, another population of these macrophages begins the process of tissue repair. . Macrophages that complete the destrnctive process are optinlized for microbial destrnc­ tion and are called Ml cells. Macrophages optimized for tissue repair and removal of damaged tissues are called M2 cells. Many of the molecules produced as a result of inflammation and tissue damage, such as IL-1 and tumor necrosis factor, can reach the bloodstream where they circulate. They enter the brain and trigger sickness behavior; for example, they alter the thermoregulatory centers to cause a fever, act on appetite-controlling centers to suppress appetite, and act on sleep centers to produce sleepiness and depression. They also mobilize energy reserves from adipose tissue and muscle. This sickness behavior is believed to enhance the defense of the body by redirecting energy toward fighting off invaders. Circulating cytokines from inflammatory sites also act on liver cells, causing the cells to secrete a mixture of "acute-phase proteins," so-called because thei r blood _ levels climb steeply when acute mflamma­ tion develops. Different species have differ­ ent acute-phase proteins, including serum amyloid A, C-reactive protein, and many different iron-binding proteins. Acute­ phase proteins also serve to promote innate immunity.

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Complement

Although acute inflanunation is central to the processes of innate inm1unity, the body possesses other innate defenses. Tissues . contain antinlicrobial peptides that can bmd and kill invading bacteria. These include detergent-like molecules such as the defensins or cathelicidins that can lyse bacterial cell walls, enzymes such as lysozyrne that kill many gram-positive bacteria, and iron-binding proteins such as hepcidin or haptoglobin that prevent bacterial growth by dep1iving them of essential iron supplies. Perhaps the most in1portant of these innate defenses is the complement system, winch consists of a complex group of -30 proteins that act collectively to kill invading microbes. The prin1ary function of the complement system is to bind two proteins called C3 and C4 ilTeversibly to nlicrobial surfaces. Once bound these complement components may either kill microbes by rupturing them using another protein called C9 or sin1ply coat them so that they are rapidly and effectively phagocytized by leukocytes. . The complement system can be activated in tlu-ee ways. One way, called the alternative pathway, is niggered by the presence of bacterial surfaces that consist largely of carbohydrates and can bi.t1d the complement protei.11 C3. Once bound, the C3 acts as an enzyme to activate and bind more C3. These CS-coated bacteria are rapidly and effectively phagocytized and destroyed. Alternatively, srniace-bound C3 can activate additional complement components that eventually cause a p,otein called C9 to insert itself withm bacterial cell walls where it causes bacterial rupture. A seco�d complement-activating pathway is triggered when bacterial surface carbohy-. drates bind to a mannose-bmding protem m serum. This binding activates an enzyme pathway that leads to activation of C3 or C9. The third, or classic, pathway of coml?le­ ment activation is triggered when antibod­ ies bind to microbial swiaces. It is thus triggered by adaptive immune responses. As with the mannose pathway, this eventually leads to activation of C3 and C9. Because of its potential ability to cause severe tissue damage, the complement system is carefully regulated through multiple complex regulatory pathways.

Cells of Innate Immunity

The key to an effective innate immune response is prompt recognition of invasion and a rapid cellular response. Several cell types function as sentinel cells; three of the

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most important are macrophages, dendlitic cells, and mast cells. These cell types express pattern recognition receptors such as TLRs and can sense the presence of microbial invaders. They also express multiple other receptors that can detect microbes and tissue dan1age. When these receptors are engaged, they signal through a molecule called NF-KB to tum on the production of cytokines such as IL-1, IFN-a, and TNF-a. They also release vasoactive and pain molecules such as histamine, leukotrienes, prostaglandin, and specialized peptides that initiate the vascular events in inflan1rnation. The purpose of inflan1mation is to ensw·e that leukocytes are delivered as promptly as possible to sites of microbial invasion. This involves attracting these cells from tl1e bloodstrean1 where they circulate and inducing them to migrate through tl1e tissues to the invasion sites where they engulf and kill invaders. There are three major leukocyte populations that can kill invaders. Granulocytes are especially effective at killing invading bacteria. They engulf the invaders, activate a metabolic pathway called the respiratory burst, and generate letl1al oxidizing molecules such as hydrogen peroxide and hypochloride ions that kill most ingested bacteria. Eosinophils are specialized killers of invading parasites. They contain enzymes that are optimized to kill migrating helminth larvae. The third major killing cell population are Ml macrophages. These cells migrate into areas of microbial invasion more slowly than granulocytes. However, they are capable of sustained and effective phagocytosis. They contain the highly lethal antj.microbial factor nitric oxide and thus can kill organisms resistant to neutrophil killing. When inflanrn1ation leads to activation of macrophages, they secrete a cytokine called IL-23. This, in tum, acts on a popuiation of T cells (called Th17 cells), causing them to secrete IL-17. IL-17 recruits granulocytes to sites of inflai11rnation, infection, and tissue dainage. While mai1y leukocytes are optimized to kill invading bacteria, viruses also present a potent threat. Natural killer (NK) cells are a population of innate cells optimized to kill virus-infected cells. NK cells, a form of lymphocyte, ca11 kill virus-infected or other "abnormal" cells tl1at fail to express major histocompatibility complex (MHC) class I molecules. MHC class I molecules bind to NK cell receptors and switch off their killing abilities. In tl1e absence of this signal, the NK cells bind to target cells, ir\ject them with apoptosis-inducing proteins, and kill them.

ADAPTIVE IMMUNITY Innate in1munity, although critical to the defense of the body, is insufficient to guara11tee protection. It lacks the flexibility to respond optin1ally to a diversity of microorga11isms a11d by its very nature may cause significa11t tissue dainage. A third layer of defense is required that can act automatically in response to microbial invasion, generate resista11ce proportional to the threat, a11d improve with experience. These are the key features of the adaptive immune system. Adaptive immune responses are of two major types: a11tibody (hwnoral) immunity directed against extracellular invaders, and cell-mediated immwuty directed against intracellulai· invaders. Adaptive immune responses are complex a11d must be very carefully regulated. The immune defenses of the body constitute a potent system of protec­ tion that must be carefully controlled to minimize dainage to normal tissues. As a result, a major pmtion of the immune system is devoted to the production of regulatory cells that function to ensure that adaptive immune responses occur only under appropriate circun1sta11ces. If these regulatory pathways fail, disease or death may result. The adaptive immune system functions through a series of steps that must occur sequentially for eitl1er a11 antibody-mediated or cell-mediated il11rnune response to occur. The first step involves the capture and processing of foreign antigens. Once processed, these antigens are transported to cell surfaces, where they can be recognized by lymphocytes carrying receptors for specific antigens. Each a11tigen receptor is highly specific, a11d each lymphocyte expresses only a single fom1 of a11tigen receptor. Thus, millions of cells have tl1e potential to recognize millions of a11tigens. To ensure that only foreign a11tigens trigger adaptive irnmwuty, cells with (eceptors that bind and respond to nom1al body a11tigens are selectively killed early in their develop­ ment. The surviving cells are located within lymphoid orga11s at sites where they ca11 most effectively encounter antigens on microbial invaders, triggering tl1em to respond by motmting in1rnune responses. There are tJu·ee major populations of lymphocytes: B cells that are responsible for antibody responses, effector T cells that are responsible for cell-mediated in1mune responses, a11d regulatory T cells tl1at control these responses and minimize inappropriate responses.

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THE BIOLOGY OF THE IMMUNE SYSTEM

Antibody Responses {Humoral Immunity) Antibodies are protein molecules that seive asB-cell antigen receptors that can be synthesized in large quantities and secreted by the cell into the bloodstrean1 where they circulate. These proteins are produced by B cells and fromB cell-derived plasma cells. Antibodies bind to foreign molecules and mark them for destruction by phagocytic cells or complement-mediated lysis. Plasma cells are differentiatedB cells optimized to synthesize and secrete enom1ous quantities of antibodies. Antibodies are critical to host defense against extracellular invaders such as most bacteria, some blood parasites, and viruses traveling between cells. B cells originate in the bone marrow and reside in lyn1phoid tissues such as lymph nodes, bone marrow, Peyer's patches, and the spleen. EachB cell is covered by several thousand identical antigen receptors and can bind and respond to only a single antigenic molecule. When a microbe enters the body, it will inevitably encounterB cells that can bind to some of its surface antigens. As a result of antigen binding, and under suitable circun1stances, theseB cells divide repeatedly and differentiate into two subpopulations. One subpopulation is composed of antibody-producing plasma cells, which are capable of enormously increased protein synthesis and are the major sources of antibodies. The other subpopulation is composed ofB cells that develop into memoryB cells and persist in lymphoid tissues for months or years. When an animal encounters an antigen for a second time, these memoryB cells respond rapidly, producing large numbers of plasma cells (and more memory cells). As a result, the anin1al mounts a vastly improved antibody response and the invader is rapidly elin1inated. Subsequent exposure to a microbe leads in turn to the accumulation of more memory cells, resulting in better protection and virtually guaranteeing that the organism will never be able to cause disease in that anin1al. This response is the basis of all vaccination programs. Although simple in concept,B cell responses and antibody production are made more complex by the need to ensure their careful regulation. Thus, aB cell is not usually able to respond to a b0tmd foreign antigen unless it also receives "permission" in the form of a second signal from cells called helper T cells. These T cells in tum can only be activated if they are presented with antigen under carefully controlled circwnstances.

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Antibodies: Antibodies are composed of proteins called in1111unoglobulins. Mammals use five different classes of antibodies: in1111unoglobulin G (lgG), IgM, lgA, IgE, and IgD. The class of immunoglobulin secreted byB cells and plasma cells depends on their location. Cells located in lymphoid organs within the body secrete IgM and IgG, whereas cells located on body surfaces secrete IgM, lgA, and IgE. IgG is the most abundant immunoglobu­ lin found in the bloodstrean:i and plays the major role in eliminating organisms that succeed in penetrating deep into the body. IgM seives as a "back-up" for IgG and is usually confined to the bloodstream. IgM is produced early in the antibody response, when its high effectiveness compensates for its low quantity. IgA is produced byB cells and plasma cells located on mucosa! surfaces. As a result, IgA is produced and secreted in large amounts into the upper respiratory tract, the GI tract, tears, sweat, etc. In these locations, it complements the physical barriers of the body and prevents microbial invasion. IgE seives as a "back-up" for IgA and is also mainly produced on body surfaces. IgE is optinuzed to control invasion by parasites such as helminths or arthropods. However, it also mediates a rapid acute inflammation in allergic states and hence may mediate life-threatening anaphylaxis. The function of lgD is unclear, but it is believed to be of minimal signifi­ cance. T Cell Help: Most antibody responses are

regulated by the need to receive prior approval from T cells. The T cells in tum are activated only when they bind antigen fragments presented by specialized antigen­ presenting cells called dendritic cells. Dendritic cells are macrophage-like cells that capture and process foreign antigens. Their name derives from their many long, thin, filamentous processes or dendrites that extend through tissues to form an effective antigen-trapping web. For example, a subpopulation of dendritic cells (Langerhans cells) is found in the dennis, where its web of dendrites traps microor­ ganisms seeking to enter the body through damaged skin. Dendritic cells capture and phagocytize invading microorganisms. Fragments of these foreign antigens persist within the dendritic cells, where they become attached to receptor molecules (major histocompatibility complex [MHCJ molecules). Once fonned, these antigen­ receptor complexes move to the cell surface where they can be recognized by T cells.

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The receptors in dendritic cells that bind and present antigen fragments are special­ ized proteins encoded by genes clustered together in the MHC (originally identified as the antigens that cause graft rejection, hence their unusual nan1e).There are many thousands of different MHC molecules expressed within an animal population but relatively few (3-6) different molecules expressed in any individual anin1al. Because they play a critical role in binding antigen fragments and activatingT cells, MHC molecules effectively detennine whether an individual can respond to a foreign antigen. An individual anirnal possesses MHC molecules that can bind many, perhaps most, foreign antigens, but not all of them.If an animal lacks MHC molecules that can bind an antigen, it will be unable to respond to that specific antigen.The set of antigens to which an individual can respond (and against which it is protected) are determined by its MHC haplotype. All domestic animal species possess their own unique MHC. The receptors coded for these genes are named after the specific species; thus, BoLA is the name of these molecules in cattle, ELA in horses, SLA in swine, etc. As with B cells, T cells possess specific antigen receptors on their surface that are generated randomly when the cells are first produced. AsT cells mature within the thymus, cells with receptors that can bind normal body components are killed. Surviving T cells can respond only to foreign antigens. The antigen receptors on T cells, like those on B cells, are identical on any single cell. Unlike those on B cells, however, the receptors can recognize antigen only when it is bound to an MHC molecule. Thus, when a dend1itic cell presents MHC-associated antigen toT cells, only those T cells witb appropriate receptors will bind to the dendritic cells. Once in contact, the cells exchange signals that confirm that theT cell is responding to a correctly processed antigen. After T cells receive all the necessary signals, they secrete a mixture of cytokines that pennit their attached B cells to respond to antigens and allow antibody production to proceed. Antibodies are produced in response to, and directed against, extracellular bacteria. Cell-mediated responses, in contrast, are directed against viruses and intracellular bacteria. The detennination as to the appropriate form of the immune response is made at an early stage in the immune response. Thus, there are two populations of dendritic cells that can trap and process antigens. One population (DCl cells) triggers cell-mediated in1munity,

whereas the other (DC2 cells) triggers antibody formation. These dendritic cell populations send different messages toT cells, because they use different cytokines for signaling; DCl cells secreteIL-12, whereas DC2 cells secreteIL-1. In tum, these different cytokines stimulate two different T cell populations: Th l , which promotes cell-mediated in1munity, andTh2, which promotes B cell responses and antibody production. Th l cells secrete a mixture of cytokines typified by interferon-')! (IFN- ')I).Th2 cells secrete a mixture of cytokines typified by IL-4. B cells will usually respond optimally to a foreign antigen only if they are stimulated by the presence ofIL-4 from Th2 cells.

Cell-mediated Immunity As described above, cell-mediated inunune responses are required to combat intracel­ lular invaders such as viruses and some intracellular bacteria. The immune system blocks virus infections by killing tl1e cells that they infect. The cells responsible are called effector, or cytotoxic, T cells. Like T cells, effectorT cells w1dergo develop­ ment and selection witllin the thymus, so anyT cells capable of killing nom1al healthy cells are elinlinated. The survivingT cells are released into the body, where they circulate continuously tllrough the tissues seeking out abnonnal cells. All nucleated cells produce many different proteins when ftmctioning nom1ally. Virus-infected cells, however, are forced by tl1e virus to produce viral proteins. The body therefore requires that all nucleated cells send a sample of their newly synthesized proteins to the cell surface. This involves the cell diverting a small sample of each newly formed protein and fragmenting it in a complex enzyme system called a protea­ some. The resulting protein fragments are then attached to MHC molecules and carried to the cell surface, where they are available for inspection by effector T cells. If the cell's receptors do not engage a protein fragment, nothing happens. If, however, their antigen receptors bind to a foreign antigen fragment in an MI-IC-protein complex, tl1eT cell will be signaled to kill the offending cell. Like B cells, effectorT cells function only if they receive permission from a helperT cell, specifically aThl cell. The cytokines from Thl cells, especially IFN-')I, must be present if an effector T cell is to kill its target. Effector T cells bind tightly to target cells expressing foreign antigens and then signal them to destroy themselves through apoptosis. TheT cells ir\ject their targets

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IMMUNOLOGIC DISEASES with enzymes called granzymes that trigger this process. As a result, effector T cells eliminate virus-infected cells but not normal, healthy cells. Most effector T cells die within a few days once they are no longer needed, but a few survive to become long-lived memory cells that respond rapidly should the animal encounter the virus again. Effector T cells are especially effective at killing target cells that produce foreign antigens. However, some intracellular organisms, especially intracellular bacteria, are best destroyed by other cell-mediated mechanisms. In these cases, TFN--y from Thl cells activates M1 macrophages. As a result, bacteria that can survive within normal macrophages are rapidly destroyed by activated macrophages.

Immunologic Memory The effectiveness of adaptive immunity is largely a result of its ability to recognize antigens encountered previously and to mount an enhanced and accelerated response against them. The more an animal encounters an antigen, the greater will be its immune response. 1mmw1ologic memory depends on the presence of persistent populations of memory cells that accwnu­ late as an anin1al ages. These memory cells may be very long-lived or, more likely, turn over very slowly. As a result, animals may make small an1ounts of antibodies to vaccine antigens for many years after vaccination. Cell-mediated memory may also be due to the development of very long-lived populations of memory T cells. The effectiveness of vaccines in inducing long-lasting immunity depends in large part on their ability to induce memory cell populations.

Cytokines The cells of the adaptive in1mune system communicate in several ways. They can

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come into physical contact and exchange signals through receptors within the contact area or immunologic synapse. Exan1ples include the contact between T cells and dendritic cells or between effector T cells and their targets. ln1mune cells can also signal nearby cells by secreting small signaling proteins called cytokines. Several hundred different cytokines have been identified. Signaling cells secrete a mixture of cytokines that then bind to receptors on nearby cells. The target cell receives multiple signals that it must integrate to respond appropriately. Cytokines, acting through their specific receptors, can turn the synthesis of specific proteins on or off. They can cause the target cell to divide or differentiate, and they may nigger apoptosis. With hundreds of different cytokines acting in complex mixtmes it is sometin1es difficult to predict exactly how a specific target cell will respond. Major fan1ilies of cytokines include the interleukins that mediate signaling between leukocytes, interferons that mediate interactions between cells and have significant antiviral activity, growth factors that regulate growtl1 and differentiation of many different cell types, and tun10r necrosis factors that modulate inflan1matory responses.

Regulatory Cells The adaptive immune system is carefully regulated by several different cell popula­ tions. The most important are T..,8 cells, which secrete a mixtme of cytokines that inhibit conventional immw1e responses. They serve to turn off an in1mune response once it has completed its task ans the invading microorganism is eliminated. Tres cells also play a central role in preventing the development of autoimmunity. Anotl1er important population of regulatory T cells are called Th l 7 cells. These cells, so called because they secrete IL-17, regulate the innate immw1e system and the development of inflan1mation.

IMMUNOLOGIC DISEASES The primary role of the immune system is the detection and destruction of invading microorganisms. Because of the great diversity of microbial invaders, the immune system has evolved an equally complex mixture of protective mechanisms. These may be simply classified as innate

immunity (seep 812) and adaptive in1munity (seep 814). Protection within the first few days of microbial invasion is the responsibility of the "hard-wired" innate immune system. Longterm protection is the responsibility of the adaptive immune system.

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In general, disease associated with the immune system takes two forms: insuffi­ cient in1mune function causing inlmunodefi­ ciencies, manifested as increased suscepti­ bility to infections, and diseases resulting from excessive in1mune function, resulting in hypersensitivities and autoin1munity. Under certain circumstances, normally protective inlmune responses can cause significant tissue damage. In general, excessive innate immune responses do this by triggering inappropriate inflan1mation leading to collateral damage to nearby tissues, or by producing vastly excessive amounts of inflammatory cytokines. Excessive adaptive immune responses, in contrast, can cause damage by multiple mechanisms. One simple classification divides diseases due to excessive adaptive immune responses into four distinct types. Each involves the activities of different cell populations or complement. Type I is mediated by mast cells and eosinophils, Type II by complement and some mac­ rophages, Type III by neutrophils, and Type IV is T cell-mediated. Inflan1mation and limited tissue destruction are features of the normal innate and adaptive inlmune responses. Clinical disease occurs when this inflan1mation is excessive or in an inappropriate location. This may be due to external environmental factors, such as the composition of the intestinal microflora, together with genetic and hormonal influences.

IMMUNODEFICIENCY DISEASES In1munodeficiency diseases manifest clinically as a predisposition to infections. They are usually recog11ized when an animal makes multiple visits to a veterinarian for infections that would normally be relatively easy to control. Two major groups of inununodeficiency disease occur. One group is inherited as a result of mutations or other genetic disease. These p1imary or congenital in1munodeficiency diseases usually develop in very young animals (100,000 WBCs/mL) and consists predominantly of mature neutrophils. The integrin deficiency prevents blood leukocytes from leaving blood vessels and entering the tissues, so they cannot contribute to the defense of tissues against infections. Complement Deficiencies: A congeni­ tal deficiency of C3 has been described in Brittany Spaniels. These dogs developed recurrent bacterial infections, especially skin diseases and pneumonias. Although complement is necessary for opsonization and neutrophil chemotaxis, bacterial infections do not always develop in people or laboratory animals with complement deficiencies, because the existence of multiple pathways provides a way to activate the system even if one pathway is blocked. Diagnosis is based on a blood test showing reduced C3 levels. A congenital deficiency in the Cl inhibitor has been recognized in people and occurs rarely in dogs. This can lead to uncontrolled complement activation and inflammation. Affected animals have recurrent bouts of facial edema. There is no specific treatment for complement deficiencies. Vaccination and antibiotics are used to prevent and treat infection. As with all inherited diseases, subsequent breeding programs must be carefully assessed to prevent the reappear­ ance of the disease in future generations.

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Deficiencies in Adaptive Immunity Humoral Immunodeficiencies: These deficiencies may be acquired or congenital. Acquired deficiencies are seen in neonates that do not receive adequate maternal antibodies (failure of passive transfer) or in older animals due to conditions that decrease active inununoglobulin synthesis. Failure of passive transfer occurs in species that use colostrum as the major source of maternal antibodies. It is commonly associated with recurrent infections in calves, lambs, and foals. Failure of passive transfer can occur when the young animal fails to nurse properly dUiing the first several days of life or when the dam's colostrum contains low levels of specific antibodies. Defects in the absorption of in1rnunoglobulin from ingested milk may also occur. lmmunoglobulin levels ...1>osure to a dennatophyte does not ahvays result in infection. TI1e like­ lihood of infection depends on several factors, including the fungal species, host age, immunocompetence, condition of exposed skin surfaces, host grooming behavior, and nutritional status. Infection elicits specific immunity, both humoral and cellular, that confers incomplete and short-lived resistance to subsequent infection or disease. New information concerning dermatophytic virulence factors, notably secreted proteases involved in the invasion of keratin, aspects of host immune response against dermatophytes, and new . ,.- , molecular tools available for studying derma­ tophytes should hasten development of safe. and effective vaccines against dermatophy­ tosis in species without vaccination options. Under most circumstances, dermato­ phytes grow only in keratinized tissue, and advancing infection stops when reaching living cells or inflamed tissue. Infection begins in a growing hair or in the stratum corneum, where threadlike hyphae develop from the infective arthrospores or fungal hyphal elements. Hyphae can penetrate the hair shaft and weaken it, which, together With follicular inflammation, leads to a common clinical sign of patchy hair loss. As the infection matures, clusters of arthro­ �res develop on the outer surface of infected hair shafts. Broken hairs infected With spores are important sources for spread of the disease. Under experimental conditions, the housefly, Musca domestica, can 1:ransmit M canis mechanically with its 0 body surface for as long as 5 days. The � . cal relevance is yet to be determined. inflammation and host immunity d elop, further spread of infection is � . bited, although this process may take several weeks most healthy adult hosts, de. Thus, for ctions arc Self.limitin rmatophyte infe ed animals g. In young or debilitat and, to some extent in Yorkshire Terriers :d l�nghaired bre�ds of domesti� cats, ection may be persistent and widespread.

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I )pr111nl.o phytm1iH IH di:1gnosl'd hy fungal c11lt 11re, ex:unl1 1ntio11 wi t.h n Wood'H lamp, and din•cl. mkroHcopic 1�xnminat.ion of hai r or ski n sea l96 hr at temperatures 24 lu· at 20° -30° C. Survival was 30° C. Unless pigs originated from SPF colonies or after mange eradication programs, all pig herds must be considered potentially infested even if aca.ricides a.re used routinely. Lesions due to infestation with S scabiei var siiis usually start on the head, especially the ears, then spread over the body, tail, and legs. Itching can be intense and associated with a hypersensitivity reaction to the mites. As the hypersensitivity subsides, typically after several months, the thickened, rough, dry skin is covered with grayish crusts. Infestations are negatively coITela.ted with daily weight gains and feed conversion in pigs. Experimental studies of S scabiei var suis in pigs have demonstrated that infestation alters the microbial community on the skin. Comparing the microbiome of bacteria. on pigs witl10ut S scabiei var suis versus that of infested pigs showed that noninfested pigs had low relative abun­ dances of Staphylococcus, whereas the relative abundance of Staphylococcus increased significantly on pigs with S scabiei var suis during the comse of infestations. Specifically, tl1e staphylococci population shifted from S lwminis to that of the more pathogenic S chromogenes as scabies progressed. Diagnosis is best performed by combin­ ing different approaches: dermatitis score recorded at slaughter, scratching index, observation of clinical signs of mange, ear or skin scrapings for microscopic examina­ tion, and ELISA for detection of specific antibodies. The usefulness of ea.ch criterion may vary according to the group age. This global approach is particularly useful during an eradication campaign. Injectable dora.rnectin and ivennectin are labeled for use a.gainstS scabiei var suis and are considered highly effective treatments. In some instances, a second dose of macrocyclic lactone 14 days later may be necessary for complete resolution. Hot lime sulfur is labeled for use against

mange in swine. In swine, lime sulfur dips ar·e repeated at intervals of 3-7 days to treat mange, unlike in other species in which they are repeated every 12 days. Label instructions must be followed closely, because there are three possible lime sulfm dilutions for use on swine. Unlike phosmet, lime sulfur spray can be applied to suckling pigs. Certain spray formulations of pem1ethrin am labeled for use against mites on swine, but it is generally not considered the compound of choice. If pennethrin is used, animals should be wet thoroughly with the product and re-treated in 14 days. Phosmet spray is approved for sarcoptic mange in swine at the species­ specific dilution instructions on the label. A single treatment is usually effective, but a second treatment can be applied 14 days later if necessary. Phosmet should not be applied directly to suckling pigs. Cou­ ma.phos sprays are available for use on swine in the USA, but they are labeled only for control of lice.

Demodectic Mange (Swine Demodi­ cosis): Demodectic mange caused by

infestation with Demodex phylloides is possible in pigs. Clinical signs of D phyl­ loides infestation include reddening of the skin, pustules, and alopecia. Although rare in domestic pigs, D phylloides infestation car1 be common in wild boars without overt signs of clinical disease. In wild boars, the highest prevalence and greatest numbers of D phylloides were found in sebaceous glands in eyelids and cheeks. D phylloides can also be found a.round the eyes, mouth, snout, ventral neck, ventrun1, and thighs. There is no reliable treatment.

DOGS AND CATS Sarcoptic Mange (Canine Scabies):

Sarcoples scabiei var canis infestation

is a highly contagious disease of dogs found worldwide. 111e mites are fairly host specific, but anin1als (including people) that come in contact with infested dogs can also be affected. Adult mites are 0.2-0.6 mm long and roughly circular· in shape; their surface is covered with small triangular spines, and they have four pairs of sh01t legs. Females are almost twice as large as males. The entire life cycle (17-21 days) is spent on the dog. Females burrow tunnels in the stratmn comeun1 to lay eggs. Sa.rcoptic mange is readily transmitted between dogs by direct contact; transmission by indirect contact may also occur. Clinical signs may develop anytime from 10 days to 8 wk after contact with an infected animal. Asymptomatic

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MANGE carriers may exist. Intense pruritus is characteristic and probably due to hypersensitivity to mite products. Primary lesions consist of papulocrustous eruptions with thick, yellow crusts, excoriation, erythema, and alopecia. Secondary bacterial and yeast infections may develop. 'Typically, lesions start on the ventral abdomen, chest, ears, elbows, and hocks and, if w1treated, become generalized. Dogs with chronic, generalized disease develop seborrhea, severe thickening of the skin with fold fonnation and crust buildup, peripheral lymphadenopathy, and emaciation; dogs so affected may even die. "Scabies incognito" has been described in well-groomed dogs; these dogs, infested with sarcoptic mites, are prwitic, but demonstrating the mites on skin scrapings is difficult because the crusts and scales have been removed by regular bathing. Atypical, including localized, clinical forms that are probably linked to extensive use of insecticides or acaricides are being increasingly seen. Diagnosis is based on the history of severe pruritus of sudden onset, possible exposure, and involvement of other aninlals, including people. Making a definitive diagnosis is sometimes difficult because of negative skin scrapings. Concentration and flotation of several scrapings may increase chances of finding the mites, eggs, or feces. Several extensive superficial scrapings should be done of the ears, elbows, and hocks; nonexcoriated areas should be chosen. A centrifugation fecal flotation using sugar solutions may reveal mites or eggs. A specific and sensitive commercially available ELISA to detect specific antibodies has been developed and may be useful. Because mites can be difficult to detect, if Sarcoples is on the differential diagnosis list but no mites are found, a therapeutic trial is warranted. Systemic treatments of scabies are based on administration of macrocyclic lactones, some of which are FDA approved for this purpose. Among them, selan1ectin is given as a spot-on fom1ulation at 6 mg/kg. This drug appears to be safe, even in ivem1ectin­ sensitive breeds. Another is the imidaclo­ prid-moxidectin formulation, which may be used on dogs as young as 7 wk of age. In some countries, moxidectin is also registered for treatment of scabies. It is available as a spot-on fo1mulation in combination with imidacloprid and should be given in two doses of 2.5 mg/kg, 4 wk apart; additionally, oral uptake should be prevented in breeds at risk of avennectin sensitivity. Other endectocides, such as

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milbemycin oxirne and ivennecti.n, which are not registered for treatment of sarcoptic mange in dogs, have been reported to be effective depending on the dosage and route of administration. The recommended dosage for milbemycin oxi.me is 2 mg/kg, PO, weekly for 3-4 wk; potential toxicity should be considered in dogs with aver­ mectin sensitivity. Ivennectin (200 mcg/kg, PO or SC, 2-4 treatments 2 wk apart) is very effective and usually.curative. Ivermectin at this dosage is contraindicated in avermec­ tin-sensitive breeds. Additionally, the microfilaremic (Diroji.laria immilis) status of the dog should be evaluated before treatment with a macrocyclic lactone. For topical treatment, hair can be clipped, the crusts and dirt removed by soaking with an antiseborrheic shan1poo, and an acaricidal clip applied. Lime sulfur is highly effective and safe for use in young aninlals; several dips 7 days apart are reconunended. Amitraz is an effective scabicide, although it is not approved for this use. It should be applied as a 0.025% solution at 1- or 2-wk intervals for 2-6 wk. In addition, the owner must observe certain precautions to avoid self-contanlination. Fipronil spray was repo1ted to be effective but should be considered an aid in control rather than a p1irnary therapy. Treatment can be topical or systemic, and should include all dogs in contact. Notoedric Mange (Feline Scabies):

This rare, highly contagious disease of cats and kittens is caused by Notoedres cali, which can opportunistically infest other aninlals, including people. The mite and its life cycle are similar to the sarcoptic mite. Pruritus is severe. Crusts and alopecia are seen, particularly on the ears, head, and neck, and can become generalized. Mites can be found quite easily in skin scrapings. Treatment consists of both topical and systemic therapies. Nonapproved but effective and safe treatments include selarnectin (6 mg/kg, spot-on) and moxidectin (1 mg/kg, spot-on, in the imidacloprid-moxi.dectin formulation). Ivermectin (200 mcg/kg, SC) has also been used. Another effective topical therapy is lime sulfur dips at 7-day intervals. Otodectic Mange: Otodectes cynotis

mites are a common cause of otitis extema, especially in cats but also in dogs. Mites that belong to the fanilly Psoroptidae are usually found in both the vertical and horizontal ear canals but are occasionally seen on the body. Clinical signs include head shaking, continual ear scratching, and ear droop.

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Pruritus is vaiiable but may be severe. Dark brown cerurnen accumulation in the ear and suppurative otitis extema with possible perforation of the tympanic membrane may be seen in severe cases. Affected and in-contact animals should receive appro­ p1iate parasiticide treatment in the ears. Systemic therapies have been approved and include topically applied selamectin and moxidectin. Direct applications to the external ear canal of cats using approved ivermectin and milbemycin fo1mulations ai·e also effective. As a general rule, ear cleansing with an appropriate ceruminolytic agent is indicated with any therapy. Cheyletiellosis (Walking Dandruff):

Cheyletiella blakei infests cats, C yasguri infests dogs, and C parasitovorax infests rabbits, although cross-infestations are possible. This disease is very contagious, especially in animal communities. Hwnan infestation is frequent. Mite infestations ai·e rare in flea-endemic areas, probably because of the reguJai· use of insecticides. These mites have four pairs of legs and prominent hook-like mouthparts. They live on the surface of the epidermis, and their entire life cycle (3 wk) is spent on the host. Female mites can, however, survive for as long as 10 days off the host. Clinical disease is characterized by scaling, a dorsal distribu­ tion, and pruritus, which varies from none to severe. Cats can develop dorsal cmsting or generalized miliary dermatitis. Asympto­ matic carriers may exist. The mites and eggs may not be easy to find, especially in animals that are bathed often. Acetate tape preparations, superficial skin scrapings, and flea combing can be used to make the diagnosis.

Chey/etie/la sp. Courtesy of Dr. Michael W Dryden.

Both topical and systemic acaricides are effective against cheyletieUosis, although no dmgs ai·e currently licensed for this indication. In addition to treatment of the affected aitimals, it is necessary to treat aJJ in-contact anin1als. Topical dmgs include lime sulfur, fipronil spot-on and spray, permethrin, and amitraz (the latter two dmgs are contraindicated in cats). Extra-label systemic dmgs include sela.rnectin spot-on, mllbemycin oxirne (PO), and ivern1ectin (SC). Care must be taken to avoid or minimize the risks of adverse reactions as described above (see p 920). The treatment period depends on the selected drng but must be long enough to eradicate the mites from botl1 tl1e anin1als and their environment, which can be difficult in anin1al commLU1ities (eg, breeding colonies, kennels). In practice, treatment lasts 6-8 wk and should continue for a few weeks beyond din ical cure until parasitologic cure is achieved. Canine Demodicosis: Canine demodico­

sis occurs when large nLU11bers of Demodex canis mites inhabit hair folJicles and sebaceous glands. In small nwnbers, tl1ese ntites are part of the normal flora of canine skin and usually cause no clinical disease. The ntites are transmitted from dan1 to puppies during nursing within the first 72 hr after birth. The mites spend their entire life cycle on the host, and the disease is not considered to be contagious. The patho­ genesis of demodicosis is complex and not completely LU1derstood; evidence of hereditary predisposition for generalized disease is strong. In1mLU1osuppression, natural or iatrogenic, can precipitate the disease in some cases. Secondary bacterial deep folliculitis, f=culosis, or ceUulitis may occur, leading to a guarded prognosis. Three forms of demodicosis are seen in dogs: localized demodectic mange, juvenile-onset generalized demodicosis, and adult-onset generalized demodicosis. Localized demodicosis is seen in dogs usually < 1 yr old, and most of these cases resolve spontaneously. Lesions often consist of one to five well-demarcated small areas of alopecia, erythema, and scaling. Lesions are usually confined to areas aroLU1d the lips, periorbital area, and forelimbs but may be foLU1d in other locations. Pmritus is usually absent or mlld. A small percentage of these cases, especially the diffuse localized fonns, progress to a more severe generalized fom1. Juvenile-onset generalized demodicosis is the result of an inherited in1mLU1ologic defect with functional abnormality asso­ ciated with the cell-mediated inm1LU1e

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MANGE system. It is a severe disease of young dogs with generalized lesions (erythema, papules, alopecia, oily seb01Thea, edema, hyperpigmentation, and crusts) that are usually aggravated by secondary bacterial infections (pyodemodicosis). Accompany­ ing pododermatitis is common. Dogs can have systemic illness with generalized lymphadenopathy, lethargy, and fever when deep pyoderma, furunculosis, or cellu­ litis is seen. Diagnosis is not difficult; deep skin scrapings or hair plucking typically reveal mites, eggs, and larval fonns in high numbers. The third form is adult-onset generalized demodicosis and clinically appears sinillar to juvenile-onset general­ ized demodicosis but is seen in adult dogs. It is typically associated with or triggered by some neoplastic process or debilitating disease that may be producing inu11unosup­ pression, such as malignant lymphosar­ coma, malignant melanoma, hyperad­ renocorticism, hypothyroidism, diabetes mellitus, etc. However, in many cases an underlying in1rnunosuppressive condition may not be found. Localized demodicosis can generally be left untreated. The prognosis for this form is usually good, and spontaneous recovery is frequent. In contrast, treatment is required in cases of generalized demodicosis, for which prognosis is guarded. Hair clipping and body cleansing, especially with benzoyl peroxide shampoo used for its follicular flushing activity, may be required. Whole­ body amitraz dips (0.025%) applied every 2 wk remains the only approved treatment in the USA for generalized dernodicosis. Higher concentrations (0.05%) and shorter treatment intervals (1 wk) may be more efficient. A number of other protocols are commonly used for refractory generalized demodicosis. Among macrocyclic lactones, milbemycin oxime (0.5-1 mg/kg/day, PO), moxidectin, and ivermectin have all demonstrated varying degrees of effective­ ness. Moxidectin is available as a spot-on formulation in combination with a flea product (imidacloprid) and should be given at 2.5 mg/kg at 1-4 wk intervals. More frequent applications are associated with higher degrees of success. Other reportedly successful but unapproved systemic treat­ ments include mox:idectin (400 mcg/kg/day, PO) and ivermectin (300-600 mcg/kg/day, PO). For the latter, different therapeutic protocols have been proposed with a gradually increased dosage and thorough monitoring of treated anin1als to detect any potentially toxic effect. lvermectin is contraindicated in Collies and Collie

923

crosses. However, idiosyncratic toxicity may be seen in any breed. Testing for m utation in the MDRl al.lele (ABCBl) may be required before initiating therapy. Local and systemic corticosteroids are contraindicated in any animal diagnosed with demodicosis. Secondary bacterial infections must be treated aggressively with an approp1iate antibiotic. Antiparasitic therapy must be continued not only.until clinical signs abate but also until at least two consecutive negative skin scrapings are obtained at 1-mo intervals. Although some dogs respond rapidly, others may need several months of treatment. Recurrence within the first year of treatment is not uncommon. As the sole prophylactic measure, dogs developing juvenile-onset generalized demodicosis should not be used for breeding.

Feline Demodicosis: Feline demodicosis is an uncommon to rare skin disease caused by at least two species of demodectic mites. Demodex cati is thought to be a normal inhabitant of feline skin. It is a follicular mite, sintilar to but narrower than the canine mite, that can cause either localized or generalized demodicosis. One other species of Demodex (named D gatoi) is shorter, with a broad abdomen, and is found only in the stratum comeum. lt causes a contagious, transmissible, superficial demodicosis that is frequently pruritic and can be generalized. In follicular localized demodicosis, there are one or several areas of focal alopecia most conunonly on the head and neck. In generalized disease, alopecia, crusting, and potential secondary pyoderma of the whole body are seen. The generalized form is often associated with an underlying inununosuppressive or metabolic disease such as feline leukemia vims infection, feline inununodeficiency virus infection, diabetes mellitus, or neoplasia. In some cases, cemminous otitis extema is the only clinical sign. Diagnosis is made by superficial (D gatoi) and deep (D cati) skin scrapings, although mite munbers are often small, especially with D gatoi. Medical evaluation is indicated in cats with generalized disease. Dennatophyte cultures are essential, because dermatophytosis and demodicosis can be concomitant conditions. Prognosis of generalized demodicosis is unpredictable because of its potential relationship with systemic disease. Some cases spontane­ ously resolve. Weekly lime sulfur dips (2%) are safe and usually effective; an1itraz (0. 0125o/o--0.025%) has been used but is not approved for use in cats and can cause anorexia, depression, and diarrhea. The use

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MANGE

of antiparasitic macrocyclic lactones has been repo1ted but their efficacy is unclear. Trombiculosis: Trombiculosis is a common, seasonal, noncontagious acariasis caused by the parasitic larval stage of free-living mites of the fan1ily Trombiculidae (chiggers). It can affect domestic carnivores, other domestic or wild man1mals, birds, reptiles, and people. Two common species found in cats and dogs, Neotrombicula autumnalis and Eut1vmbicula alfreddugesi, are reported in Europe and in America, respectively. Adults (harvest mites) and nymphs look like small spiders and live on rotting detritus. In temperate areas from sUTI1rner to fall, dogs and cats can acquire the laivae as parasites when lying on the ground or walking in suitable habitat. In wai1.ner regions, infestation occurs throughout the year. The laivae (0.25 mm long) attach to the host, feed for a few days, and leave when engorged. At that time, they are easily identified as ovoid, 0. 7 mm long, orange to red, inlrnobile dots, usually found clustering on the head, ears, feet, or ventrum. Patho­ genicity is through traumatic and proteolytic activities. Hypersensitivity reactions are suspected in some animals, because pruritus may vary from none to severe. Lesions include erythema, papules, excoriations, hair loss, and crusts. When present, intense prmitus can persist for hours to several days even after the laivae have left the animal. Diagnosis is based on history and clinical signs. The infestation is a seasonal threat to free-ranging dogs and cats. Differential diagnoses include other p1uritic dermatoses. Diagnosis is confirmed by careful exainina­ tion of the affected areas. Microscopic exainination of sainples obtained from skin scrapings may help to identify the larvae, which have an oval-shaped body densely covered with setae, six long1egs, and curved pedipalps terminating in claws. Management is difficult. The most useful approach, if feasible, consists of keeping pets away from areas known to harbor lai·ge nun1bers of mites to prevent reinfestation during periods of 1isk. The application of pyrethroids (dogs only) with repellent-like activity to prevent infestation has yielded variable results. Fipronil and permeth1in (dogs only) can be used, both for preven­ tion and treatment of infested aninlals. Symptomatic treatment may be required in cases of severe pruritus. Straelensiosis: Canine straelensiosis is a rare, noncontagious, sporadic, but potentially emerging pai·asitic dermatitis caused by the temporary encystment in the

epidennis of the parasitic larval stage of

Straelensia cynotis. This mite belongs to

a fainily close to the family Trombiculidae. To date, the life cycle is largely unknown, and the disease has been reported only in France, Portugal, Spain, and Italy. Transmis­ sion occurs mainly in rnral and small-sized hunting dogs, probably through contact with containinated soil, litter, and other terrestrial habitat of foxes. No contagion has been reported to congeners and people. S cynotis has distinct differences from other trombidioid mites, especially in clinical presentation, histopathologic features, and response to treatment. Straelensiosis is sudden in onset and may be accompanied by systemic signs such as anorexia and prostration. Lesions are painful, variably pnuitic, and either generalized or multifocal, most often affecting the dorsal regions of the head and trunk. The characteristic erythematous papules and nodules resemble small craters. Scaling, pustules, and crusts can be seen. Differential diagnoses include bacterial folliculitis, sarcoptic mange, and gunshot. Microscopic examination of sainples obtained from deep skin scrapings may help identify the Jaivae (0.7 nun long, 0.45 mm wide), each in a thick-walled cyst. The larvae, which resembleNeotrombicula, are more easily visualized by histopathology. The prognosis is favorable; a self-cure generally occurs after several months if reinfestation is prevented. However, management of clinical signs is difficult. Arnitraz may be somewhat effective. Lynxacariasis: Feline lynxacaiiasis is a quite common but to date geographically restricted (Australia, Brazil, Hawaii, Florida, North Carolina, Texas) parasitic dem1atitis caused by the fur mite Lynxacarus radovskyi, which belongs to the fainily Listrophoridae. The life cycle remains poorly described, and this species has not been repo1ted from hosts other than cats. Infestation typically occurs by direct contact, but fomites may be important for transmission. Clinical signs include a salt-and-pepper appearance of the hair coat, variable pruritus, and alopecia. Diagnosis is based on visualization of mites (0.5 mm long) using a magnifying glass or on isolation of any parasitic stage in skin scrapings or acetate tape preparations. Treatment with acaricidal sprays, weekly lime sulfur dips, and ivennectin (300 mcg/kg, SC) are effective. The only case of contagion to people that has been reported involved a transient rash in an owner with a heavily infested cat.

TICKS

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TICKS Ticks are obligate ectoparasites of most types of terrestrial vertebrates virtually wherever these animals are found. Ticks are large mites and thus are arachnids, members of the subclass Acari. They are more closely related to spiders than to insects. The -850 described species are exclusively bloodsucking in all feeding stages. Ticks transmit a greater variety of infectious organisms than any other group of arthropods and, worldwide, are second only to mosquitoes in te1ms of their public health and veterinary importance. Some of these agents are only slightly pathogenic to livestock but may cause disease in people; others cause diseases in livestock that are of tremendous economic in1portance. In addition, ticks can harm their hosts directly by inducing toxicosis (eg, sweating sickness [seep 684], tick paralysis [seep 1314] caused by salivary fluids containing toxins), skin wounds susceptible to secondaiy bacterial infections and screwworm infestations, and anemia and death. International movement of animals infected with the tick-transmitted blood parasites Theileria, Babesia, and Anaplasma spp and Ehrlichia (Cowdria) ruminantium is widely restricted. Movement of tick-infested livestock over great distances is an in1portant factor in the extensive distribution and prevalence of many tick species and tickborne disease agents. A number of introduced tick species thrive in the vast grazing and browsing environments established during recent centuries of hun1an and livestock popula­ tion explosions. Conversely, introduction of livestock into areas with exotic tick species and tickborne agents to which they have no in1munity or innate resistance often results in significant losses. Two of the three fanlilies of ticks parasitize livestock: the Argasidae (argasids, "soft ticks") and the Ixodidae (ixodids, "hard ticks"). Although they share certain basic properties, argasids and ixodids differ in many structural, behav­ ioral, physiologic, ecologic, feeding, and reproductive patterns. Tropical and subtropical species may undergo one, two, or rai·ely three complete life cycles annually. In temperate zones, there is often one annual cycle; in northern regions and at higher elevations in temperate regions, at least 2-4 yr are required by most species.

There are four developmental stages: egg, larva, nymph, and adult. All larvae have three pairs of legs; all nymphs and adults have four. Adults have a distinctive genital and anal area on the ventral body surface. The foreleg tarsi of all ticks bear a unique sensory appai·atus-Haller's organ-to sense carbon dioxide, chemical stimuli (odor), temperature, humidity, etc. Pheromones stin1ulate group assembly, species recognition, mating, and host selection. Certain tick species that parasitize livestock can survive several months, and occasionally a few years, without food if environmental conditions pemtit. Tick host preferences are usually limited to a particular genus, fanlily, or order of vertebrates; however, certain ticks are exceptionally adaptable to a variety of hosts, so each species must be evaluated sepai·ately. The larvae and nymphs of most ixodids that pai·asitize livestock feed on small wildlife such as birds, rodents, small carnivores, or even lizards. In the Argasidae, the leathery dorsal surface lacks a hard plate (scutum). Male and female argasids appear to be much alike, except for tile larger size of the female and differences in external genitalia. The argasid capitulum (mouthparts) arises from the anterior of the body in laivae but from the ventral body surface in nymphs and adults. In the Ixodidae, the male dorsal surface is covered by a scutwn. The scutum of the ixodid female, nymph, and laiva covers only the anterior half of the dorsal surface. The ixodid capitulun1 arises from the ante1ior end of the body in each developmental stage.

Argasid Parasitism The world's argasid tick fauna comprises 185 species in four genera, nainely Argas, Carias, Ornithodoros, and Otobius, in the fainily Argasidae. The Argasidae are highly specialized for sheltering in protected niches or crevices in wood or rocks, or in host nests or roosts in burrows and caves. Some argasid species ai·e known to survive for several years between feedings. Most of these leathe1y parasites inhabit tropical or warm, temperate environments with long dry seasons. Hosts are those that

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either rest in large numbers near the argasid microhabitat or return from time to time to rest or breed there. Soft ticks can be a serious pest in poultry and pig operations in tropical and subtropical countries. Blood loss and subsequent anemia can be significant and substantially affect weight gains and egg-laying performance. Massive infestations can cause numerous fatalities. An argasid population typically parasitizes only a single kind of vertebrate and inhabits its shelter area. Argasids use multiple hosts, ie, the larvae feed on one host and drop to the substrate to molt; the several nymphal instars each feed separately, drop, and molt; adults feed several times (but do not molt). Argasid nymphs and adults feed rapidly (usually 30-60 min). Larvae of some argasids also feed rapidly; others require several days to engorge fully. Adult argasids mate off the host several times; afterward, females deposit a few hundred eggs in several batches and feed between ovipositions. Most of the 57 describedArgas spp parasitize birds that breed in colonies in trees or against rock ledges; others parasitize cave-dwelling bats. Few feed on reptiles or wild manUTials, and none on livestock. Several species have become important pests of domestic fowl and pigeons; among these are the vectors of Barrelia anserina (avian spirochetosis) and the rickettsia

Anaplasma (Aegyptianella) pullarum (aegyptianellosis). Argas spp also cause tick paralysis and transmitPasteurella multacida (agent of fowl cholera), and

many are vectors of a variety of a.rboviruses, some of which infect people. Genus Carias includes 88 species, most of which are parasites of mammals, especially bats and rodents. Depending on the species, they inhabit de'hs or roosts of bats located in caves or tree holes or rodent burrows. Several species parasitize colonial nesting birds and dwell in the substrate or under stones and debris in ground-level bird colonies. Many of these ticks parasitize only a single host species or a group of closely related hosts. However, some Carias ticks will feed on people and domestic animals if the p!irnary host is not available. C kelleyi, a tick associated with bats and bat habitats, has been reported to can-y a novel spotted fever group Rickettsia and a relapsing fever spirochete closely related to Barrelia turicatae. The seabird tick C capensis has been shown to transmit West Nile virus to ducklings. The American C puert01icensis and C talaje are potential vectors of Afiican swine fever virus.

The majority of nearly 37 species belonging to the genus Ornitlwdaros inhabit animal burrows and lairs in hot, arid climates and feed on most any potential hosts that enter their habitat. Larvae in this nidicolous genus do not feed, which may be related to the fact that these ticks dwell in btuTows that may house hosts irregularly. A few species have adapted to living in crevices of walls and under fences where livestock are confined and also are pests of people. Certain species are vectors of relapsing fever spirochetes (Barrelia spp) and African swine fever virus; some species cause toxicosis, and one species (0 caria­ ceus) transmits a spirochete causing epizootic bovine abortion in the western USA. Ntunerous Ornithadaras-transmitted salivary toxins or arboviruses cause irritation or febrile illnesses in people. The unique argasid genus Otabius (see p 939) has ttu·ee species, which do not feed in the adult stage. 0 megnini (spinose ear tick) is exceedingly specialized biologically and structurally. It infests the ear canals of pronghorn antelope, mountain sheep, and Virginia and mule deer in low rainfall biotopes of the western USA, Mexico, and western Canada. Cattle, horses, goats, sheep, dogs, various zoo animals, and people are sinlilarly infested. This well-concealed parasite has been trans­ ported with livestock to western South America, Galapagos, Cuba, Hawaii, India, Madagascar, and southeastern Africa. Notably, adults have nonfunctional mouthparts and remain nonfeeding on the ground but may survive for almost 2 yr. Females can deposit as many as 1,500 eggs in a 2-wk period. Laivae and two nymphal instars feed for 2-4 mo, mostly in winter and spring. There can be two or more genera­ tions per year. People and other animals may have severe irritation from ear canal infestations, and heavily infested livestock lose condition during winter. Tick paralysis of hosts and secondary infections by laival screwworms are reported. 0 megnini is infected by the agents of coxiellosis/Q fever, tularemia, Colorado tick fever, and Rocky Mountain spotted fever. Another species, 0 lagaphilus, feeds on the heads of jackrab­ bits (hares) and rabbits in western USA.

lxodid Parasitism The Ixodidae number >600 species, occupy many more habitats and niches than do ai·gasids, ai1d parasitize a greater nun1ber of vertebrates in a wider vai'iety of environ­ ments. Most ixodid species have a three-host life cycle, others have a two-host

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TICKS cycle, and a few have a one-host cycle. Each ixodid postembryonic developmental stage (larva, nymph, adult) feeds only once but for a period of several days. Males and females of most species that parasitize livestock mate while on the host, although some mate off the host on the ground or in burrows. Males take less food than females but remain longer on the host and can mate with several females. During inactive seasons, few or no females are found feeding, even though males may remain attached to the hosts. Such males may contribute to transmission of pathogens to new susceptible animals by serial interhost transfer. Larval and nymphal population activity generally peaks during the "off seasons" of adults, although in some species there is overlap in the seasonal dynamics of immatures and adults. The ixodid males, except those in the genus Ixodes, become sexually mature only after beginning to feed, after which they mate with a feeding female. Only after mating does the female become replete and proceed to develop eggs. She then detaches, drops from the host, and over a period of several days deposits a single batch of many eggs on or near the ground, usuaJly in crevices or w1der stones, leaf litter, or debris. Depending on species and quantity of female nourishment, the egg batch usually numbers 1,000-4,000 but may be > 12,000. The female dies after ovipositing. Notably, ixodids (except one- and two-host species, which use vertebrate host anin1als as habitat for much of their life cycle) spend >90"A, of their lifetin1e off the host, a fact of utmost significance in planning control measures. The several-day feeding process progresses slowly; the baJloon shape characte1istic of engorged lruvae, nymphs, and females develops only during the final half day of feeding and is followed by detaching. The dropping tin1e at certain hours of the day or night is governed by a circadian rhythm closely associated with the activity cycle of the principal host. It is also important, especially in understanding the epidemiology of tickbome pathogens, to know whether in1matures of an ixodid species feed on the same host species as do the adults, or on smaJler vertebrates. Where acceptable smaller-sized hosts are scarce, immatures of some ixodid species can feed on the san1e livestock hosts as adults; immatures of other species seldom or never do so. The proximity of acceptable hosts, air temperature gradients, and atmospheric hw11idity during resting and questing periods are among the factors that regulate

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the development of each stage and, in the case of females, oviposition.

Three-host lxodids: Most ixodids have a three-host cycle. The recently hatched lruvae quest for a suitable host, usuaJly from vegetation, feed for several days, drop, and molt to nymphs, which repeat these activities and molt to adults. Of the tlu·ee-host species that parasitize livestock or dogs, a few have immatures and adults tl1at parasitize the san1e kind of host; these often develop tremendous population densi­ ties. The success of ixodid species that require smaJle1°size hosts for inunatures depends on the availability of those hosts in the livestock browsing and grazing grounds. The natural hazards inherent in the three-host cycle have been compensated for by the benefits afforded adaptable tick species by a.i1in1al husbandry practices. Only certain ixodids specific for herbivores have adapted to coexistence with livestock, and therein lies the answer to nun1erous livestock tick problems in Africa, where hosts for adults and in1matures ru·e abundant. Two-host lxodids: Some ixoclids,

especiaJly those tl1at parasitize wandering ma.i11mals (and also birds in certain cases) in inclement envirorunents of the Old World, have developed a two-host cycle in which lruvae and nymphs feed on one host, and adults on another. As in three-host species, both hosts may be different or may be the sa.ine species. Two-host parasites of livestock thrive in both inclement and clement envirorunents and are difficult to control. This is especially true of two-host species that feed in the ears and anal areas of livestock.

One-host lxodids: Among the most

economically important ticks ru·e several one-host species. These parasites evolved together with herbivores that wandered in extensive ranges in the tropics (Rhipiceph­ alus [Boophilus] spp, Dermacentor nitens, etc) or in temperate zones (D albipictus, Hyalomma scupense). Larvae, nymphs, and adults feed on a single animal until the mated, replete females drop to the ground to oviposit.

Feeding Sites: Each species has one or more favored feeding sites on the host, although in dense infestations, other areas of the host may be used. Some feed chiefly on the head, neck, shoulders, and escutch­ eon; others in the ears; others around the anus and under tl1e tail; and some in the

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nasal passages. Other common feeding sites are the axillae, udder, male genitalia, and tail brush. Immatures and adults often have different preferred feeding sites. Attach­ ment of the large, irritatingAmblyomma spp is regulated by a male-produced aggregation-attachment pheromone, which ensures that the ticks attach at sites least vulnerable to grooming.

IMPORTANT IXODID TICKS The important ixodid ticks include

Amblyomma spp, Anomalohimalaya spp, Both1iocroton spp, Cosmiomma sp, Dermacentor spp, Haemaphysalis spp, Hyalomma spp, Ixodes spp, Margaropits spp, Nosomma sp, Rhipicentor spp, and Rhipicephalus spp.

AMBLYOMMA SPP More than half of the -140 knownAmbly­ omma species are endemic to the New World. Amblyomma ticks are large, three-host parasites. They have eyes and long, robust mouthparts. They are more or less brightly ornamented and generally confined to the tropics and subtropics. Adults and immatures of37 species in this genus parasitize reptiles, which together with ground-feeding birds, are often hosts of inunature Amblyomma ticks that have adapted, in the adult stage, to parasitizing manunals. Their long mouthparts make Amblyomma ticks especially difficult to remove manually and frequently cause serious wounds that may become secondai� ily infected by bacteria or screwworms and other myiasis flies. Several Af1icanAmblyomma that infest livestock are vectors of Ehrlichia (Cowdria) ruminantium, the rickettsial agent that causes herutwater (seep 751), whereas New WorldAmblyomma spp cariy agents of monocytic and granulocytic ehrlichioses as well as several Rickettsia spp, includingR rickettsii, the agent of Rocky Mountain spotted fever. A ammicanum, the lone-stat· tick, is abundant in the southern USA from Texas and Missouri to the Atlantic Coast and ranges northward into Maine. Southward, its distribution extends into no1thern Mexico. Because of the changing climate, the geographic range of this species continues to expand. The scutum is distinctive because of pale ornainentation in males and a conspicuous, silvery spot ("star") near the posterior margin in females. Larvae, nymphs, and adults are indiscriminate in host choice and

parasitize a variety of livestock, pets, and wildlife as well as people. Activity in the USA continues from early spring to late fall. Feeding sites on domestic and wild mainmals are usually skin areas with sparse hair; wounds at these sites predispose livestock to attack by the screwworn1 fly

Cochliomyia hominivorax. A ammicanum is a vector of Prancisella tularmisis, the etiologic agent of tularemia; Ehrlichia chaffeensis, which causes mono­ cytic ehrlichiosis in people; E ewingii,

which causes granulocytic ehrlichiosis in dogs and people; and a recently described Panola Mountain Ehrlichia closely related to the agent of heaitwater, which is patho­ genic to at least goats and people. This tick also transmitsRickettsia amblyommii, Borrelia lonesta1i, and the Heartland virus pathogenic to people. A Coxiella sp symbiontic bacteria, closely related to the agent of Q fever, can be present in tl1e majority of ticks in a population but is unknown to cause infections in people or otl1er animals. A ammicanum may cause tick paralysis in people and dogs. In addition, Lone star virus (Bunyaviridae) has been isolated from a single A ame1icanum nymphal tick that had been removed from a woodchuck (Ma1mota monax) in Kentucky. A cajennense, tl1e Cayenne tick, ranges from South America into southern Texas. This species is found most conunonly in dry tropical habitats and lower elevations of subtropical highlands. As with A ameiica­ num, each active stage is indiscriminate in host choice: livestock and a large variety of avian and man1malian wildlife serve as hosts. People are severely irritated by clusters of A cajennense larvae ("seed ticks") in wooded and high-grass areas. Most adults attach on the lower body surface, especially between the legs; some feed elsewhere on the body. Activity continues throughout the year. A cajenn­ ense is a vector o(R rickettsii in Central and South America from Panaina to Argentina and has been expe1imentally shown to transmit Ehrlichia ruminan­ tium. Wad Medani virus (an Orbivirus, Reoviridae), an African virus transported to Caribbean islands by A variegatum­ infested cattle from Senegal, has been isolated from A cajennmise inJainaica. A maculatum, the Gulf Coast tick, is an important pest of livestock, particularly cattle, from South America to southern USA. Optimal habitats are warm areas with high rainfall, near seacoasts. Immatures usually parasitize birds and small mainmals; adults parasitize deer, cattle,

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TICKS horses, sheep, pigs, and dogs. Adult feeding activity is chiefly in late summer and early fall but may begin later after a dry summer. Most adults infest the ears, where the feeding wounds are initial sites of screw­ worn1 infestations. Clustered feeding adults also cause much irritation to the upper parts of the neck of cattle and to the hun1ps of Brahman cattle. A maculatum is the primary vector of R parkeri,, and in some tick populations as many as 500;6 of individual ticks may be infected with this pathogen. A imitator parasitizes livestock from Central America to southern Texas; it has been shown to transmitR rickettsii in Mexico. Occasional pests of livestock in tropical America are A neumanni (Argentina), A ovale and A parvum (Argentina to Mexico),A tigrinum (much of South America), and A lapirellum (Colombia to Mexico). A testudinarium inhabits Asian tropical wooded environments from Sri Lanka and India to Malaysia and Vietnam, Indonesia, Borneo, Philippines, Taiwan, and southern Japan. Adults are particularly abundant on wild and domestic pigs and also infest deer, cattle, other livestock, and people. lnlrnatures parasitize birds and small man1mals as well as people. In India and Sri Lanka, adultA integrum and A mudlairi also parasitize livestock, wild ungulates, and people. A hebraeum, the southern Africa bont tick, inhabits warm, moderately hwnid savannas of South Africa, Namibia, Botswana, Zimbabwe, Malawi, Mozam­ bique, and Angola In1matures feed on various small mai11mals, ground-feeding birds, and reptiles. Adults infest livestock, antelope, and other wildlife. Adults, attached chiefly to body areas with relatively little hair, cause se1ious wounds that become secondarily infected by bacteria and the screwworm Ch1ysomya bezziana. Like other AfricanAmblyomma ticks (bont ticks) that pai·asitize livestock, A hebraemn is an in1portant vector of Ehrli­ chia ruminantium and the principal vector of Rickettsia africae, the agent of African tick bite fever, in southern Africa. A va.riegatum, the tropical African bont tick, is an easily visible, brightly colored parasite found throughout sub-Sallai·an savaimas southward to the range of A hebraemn, and also in southern Arabia and several islands in the Indian and Atlantic Oceans and tlle Caribbean. An eradication program is in progress in the Caribbean; St. Kitts, St. Lucia, Montserrat, Anguilla, Barbados, and Dominica qua.lilied

· 929

for "provisionally free" certiiication by 200� altl1ough St. Kitts was reinfested in 2004. Host preferences are sinillar to those of A hebraeum but also include can1els. The bites of the tropical bont tick are severe. They may result in septic wounds and abscesses, inflanm1ation of tlle teats of cows, and considerable damage to hides and skins. Adults feed chiefly during rainy seasons, inm1atures during dry seasons. Most adults attach to tlle underside of the host body, on the genitalia, and under tlle tail. A variegatum injuries to hosts and transmission of E ruminantium are simila to those of A hebraeum but also include the spread of acute bovine dern1atophilosis (se( p 858). This tick is not considered to be an effective vector of Nai.robi sheep disease virus but is a secondary vector of Crimean­ Congo hemorrhagic fever virus. Dugbe virui has been isolated from A variegatum in six countries north of the equator; the Thogoto and Bhartja viruses are also associated with this tick in vaiious areas north of tlle equator. Notably, yellow fever virus has been isolated from A variegatum collected from cattle in the Central African Republic and has been demonstrated to be transovarially transmitted to the progeny of infected females. Jos virus infects A varie­ gatum from Ethiopia to Senegal and has been tra.I1Sported in this tick to Jainaica. A lepidum, the East African bont tick, inhabits xeric savanna environments from northern Tanzania to central Sudan. A gemma, the gem-like bont tick, occurs in similar environments of Tanzania, Somalia, Kenya, and Ethiopia. A small variety of tlle buffalo bont tick, A cohaerens,'is abundant on cattle in Ethiopian highlands, but from Zaire to Tanzania tlle larger variety of A co­ haerens parasitizes chiefly Cape buffalo. Other African Amblyomma ticks of Cape buffalo and various other large man1mals, including livestock, are A pomposum of hwnid highland forests in Angola, Zaire, Uganda, southern Sudan, Kenya, and Zimbabwe, and A astrion of West Africa and Zaire. In Central and South America, nwnerous Amblyomma spp parasitize livestock and dogs, often in lai·ge nwnbers. Among tllose, Amblyomma and A ovale adults feed primai·ily on cainivores and A parvum on carnivores ai1d armadillos. A awicularium has been found on wild hosts of tlle families Mynnecophagidae and occasionally Didelphidae, Caviidae, Chinchillidae, Hyclrochaeridae, Muridae, Canidae, Mustelidae, and Procyonidae; it tra.I1Srnits R rickettsii in Brazil. A pseudoconcolor has

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been found occasionally on wild hosts of the family Didelphidae. A naponense is common on peccaries, and A oblongogut­ tatiim has been found on a variety of hosts in several South and Central Ame1ican countries. The South American tapir (Tapirus lerrestris) seems to be the primary host for the adult stage of A la.tepunctatum, A scalpturatum, and A incisum. A dissimile is a common parasite of reptiles and true toads of the genus Bufo, from Argentina northward to southern Mexico, the Caribbean islands, and southern Florida.

ANOMALOHIMALAYA SPP The three Anomalohimalaya spp are found in mountains of Central Asia-Panlir, Tian Shan, Tibet, and Himalayas. All stages of these three-host ticks parasitize rodents, shrews, and less frequently hares.

BOTHRIOCROTON SPP Genus Bothriocroton (formerly Aponomma) includes seven species of ticks indigenous to Australia and Papua New Guinea (B oudemansi). Bothriocroton spp resemble Amblyomma spp except they have no eyes. In this group, B aruginans is a parasite of wombats; B concolor and B oudemansi are ectoparasites of echidnas in Australia and Papua New Guinea, respectively. The other four species in this genus parasitize reptiles almost exclusively. B hydrosauri, the blue-tongued lizard tick, is the reservoir of Rickettsia honei on Flinders Island, Australia.

COSMIOMMA SP Genus Cosmiomma contains a single species, C hippopotamensis,.which is found in southwestern and eastern Africa. It feeds primarily on white and black rhinocer­ oses and less frequently on antelopes.

DERMACENTOR SPP Of the 36Dermacentorspp , 19 inhabit temperate zones. Of the tropical species, D (Anocenter) nitens is of major veterinary in1portance, although others may transmit zoonotic infections, and adults may be common on wildlife such as pigs, deer, and antelope. Inunatmes infest chiefly rodents and lagomorphs. De1macentor spp in cold areas and D nitens in tropical America have specialized life cycles and seasonal dynan1ics of activity, each of which must be considered separately. Except for D nitens,

D albipictus, and D dissimitis, the De1macentor life cycle is of the typical three-host pattern. D nite11S, the one-host tropical horse tick, is of considerable veterinary importance. It originally parasitized deer (Mazama) in the forests of northern South America. With the introduction of Equidae and other livestock into its habitat, it adapted to these anin1als. Spending its entire parasitic life deep in the hosts' ears, this parasite was easily spread by human activities to other areas of the Americas, including Florida and Texas. In addition to ear cavities, each active stage may infest nasal passages and the mane, ventral abdomen, and perianal area. D nitens transmits Babesia. cab. atli transovarially to successive generations and is important in the horse-racing industry. It also is an experimental vector of Anaptasma marginale to cattle. Another American one-host species, D albipictus, the winter or moose tick, ranges from Canada and nmthern USA into western USA and Mexico. A brownish form, sometimes called D nigrolineatus, is distributed from New Mexico to southern and eastern USA and may merit subspe­ cies, if not full-species, rank. The larval­ nymphal-adult feeding period on a single host (moose, deer, elk, or domestic cattle or horses) extends from fall to spring. Heavily infested hosts may die. D albipictus causes the often fatal "phantom moose disease" of Canada, is a secondary vector of Colorado tick fever virus, and is an experimental vector of B cabatli; it is a natural vector of A marginale in OkJal10ma. In Mexico and central America, D dissimilis parasitizes a variety of equine and ruminant hosts and may be a one-host tick on horses. The Rocky Mountain wood tick, D andersoni, is found from Nebraska westward to the western mountains (Cascades and Sierra Nevadas), in northern New Mexico and Alizona, and in western Canada. The American dog tick, D variabilis, is found west of the Cascades and Sierra Nevadas, in Mexico, from Montana to Texas and east to the Atlantic, and in eastern Canada. Both species may cause tick paralysis in livestock, wildlife, and people. They are the primary vectors of Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (seep 806). D ande1·soni is also the chief vector of Colorado tick fever virus and transmits Powassan virus, A marginale, A ovis, and the agents of tularemia and coxiellosis/Q fever. D variabilis is an experin1ental vector of A

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marginme, B caballi, and B equi. In addition, sawgrass virus, Ehrlichia cha.ffeensis, and E ewingii have been detected in questing D variabilis adults. Adults of both species

parasitize livestock and wildlife, including deer, bison, and elk, but those of D variabilis prefer skunk, raccoon, puma, etc, and domestic dogs. Immatures feed on rodents and other small wild manunals. A related, biologically similar species, D occidentalis, is restricted to the Pacific lowlands and foothills from Oregon to Baja California and is a natural vector of A marginale. In western USA and Mexico, D paru­ mapterus, D hunteri, and D halli parasitize various hares and rabbits, mountain sheep, and peccaries, respectively. These ticks seldom make contact with livestock. D hunteri is an experimental vector of A mmginale and A ovis. In Costa Rica and Panama, D latus infests tapirs. In Eurasian steppes, forests, and mountains, D marginatus, D reticulatus, and D silvarum, collectively, are vectors of Rickettsia slovaca and R ramtltii (the causative agents of tickborne lymphadenopa­ thy), R sibiiica (the agent of Siberian tick typhus), Babesia bovis, B caballi, B equi, B canis, Theileria ovis, and A ovis, together with the agents of tularemia and coxiellosis/Q fever, and Russian sprin g -summer encepha­ litis. D marginatus is found in forests, marshes, semideserts, and alpine zones from France to southwestern Siberia, Kazakhstan, Xirtjiang Uygur Autonomous Region of China, I.ran, and northern Afghanistan. D reticulatus ranges from Ireland and Britain to northwest­ ern Siberia and Xirtjiang, China, in meadows, floodplains, and deciduous and deciduous­ conifer forests. D silvarum ranges from central Siberia and northeastern China to Japan in marshes, meadows, shrubby and secondary forests, and farmlands in taiga forest areas. Some males in populations of each of these three species remain attached to the host during winter. Adults and immatures may overwinter on the ground. Greatest adult activity is from early spring to summer with a lower peak in fall. Larvae and nymphs are active from spring through fall. The life cycle may be completed in 1 yr or extended by one or more swnmer or winter diapauses to 2-4 yr. About 12 other Dermacentor spp inhabit certain lowland, mountain steppe, and semidesert areas of temperate Asia. Their adults are commonly taken from camels, cattle, horses, sheep, and goats. In tropical Asia, the several species of the Dermacen­ tor subgenus Indocentor are parasites of wild pigs; they also infest larger wildlife but seldom if ever feed on livestock.

931

HAEMAPHYSALIS SPP Few of the 166 species of Haemaphysalis parasitize livestock, but those that do are economically in1portant in Eurasia, Africa, Australia, and New Zealand. Some haemaphysaline parasites of wild deer, antelope, and cattle have adapted to domestic cattle and, to a lesser extent, to sheep and goats. Others, originally specific for various wild sheep.and goats, have adapted chiefly to the domestic breeds of these aninlals. A few African species that evolved together with carnivores now parasitize domestic dogs. In1111atures of species that parasitize livestock generally feed on small vertebrates, but there are a few notable exceptions. All Haemaphysalis spp have a three-host life cycle. They are small (unfed adults 10 yr old) cats and may be associated with in1mW1osuppres­ sion. There is no defined breed or sex predilection. Clinically, lesions appear as multiple discrete, erythematous, black or brown hyperkeratotic plaques and papules. Lesions are nonpruritic, and ulceration is W1c01mnon. Their development is

947

associated witl1 the presence of a papilloma virus. The tem1 in situ refers to a malignant proliferation of epidem1al and follicular outer sheath cells that are not invasive into the W1derlying dennis. UnfortW1ately, lesions may progress over time into a,_1 invasive carcinoma. Metastasis is extremely W1conrn1on. These lesions usually develop in systemically ill or immW1osuppressed cats ru1d are believed to be virally induced. They have not been an1enable to therapy; however, cryotherapy of local lesions and topical imiquin1od as described above may increase tin1e to progression.

Keratinized Cutaneous Cysts Most keratinized cuta.J.1eous cysts are malformations of the hair follicle. They a,_·e common in dogs; occasionally identified in cats, horses, goats, and sheep; and rare in cattle and pigs. Excision is the treatment of choice. Vigorous squeezing of these lesions is contraindicated, because it often incites a severe foreign body infla,_mnatory response due to the release of keratin into surroW1d­ ing tissues. Infundibular follicular cysts (epidem1oid cysts, epidennal inclusion cysts, erroneously called sebaceous cysts) a,_·e the most common. They are a cystic dilatation of the upper portion of the outer sheath of the hair follicle (the infundibu­ lum) lined by a layer of stratified cornifying epithelial cells indistinguishable from the epidennis. These cysts vary in size from 2 mm to >5 cm (lesions 5 cm in diameter and contain white to brown laminated keratin, often with a necrotic center associated with secondary inflan1mation. When Jan1eness is present, surgical excision and curettage of the underlying bone, if affected, is the treatment of choice. Dilated pores ofWmer are rare, hair-follicle neoplasms recognized only in aged cats. Males may be predisposed. These lesions most often develop on-the head. Clinically, they appear as solitary, dome­ shaped lesions with the appearance of a giant comedo. Compact keratin may protrude through (above) the surface, giving them the appearance of a cutaneous horn. These lesions are benign, and complete excision is curative.

Tumors of the Hair Follicle The hair follicle is a complex structure composed of eight different epithelial layers. Hair-follicle tun1ors display a similar complexity, and much work needs to be done to characterize them further. They are most common in dogs, less frequent in cats, and rare in other domestic animals. Tricholemmomas are rare, benign, hair-follicle neoplasms of dogs, most

commonly found on the head. Poodles may be predisposed. These tumors are derived from the lower portion of the outer root sheath and often have areas of transition into basal cell tumors. They have little in common with a tumor of the same name in people that represents an old wart. They appear as firm, ovoid masses, 1-7 cm in diameter, that are encapsulated but expand over time. Excision is curative. Trichofolliculomas are extremely rare follicular tumors of dogs composed of the inferior and isthmic regions of multiple abortive follicles that extrude their lumenal contents into a dilated abnom1al cystic infundibulum. Too few have been recog­ nized to detemiine age, breed, or sex predilection. Considered by some to be more a hamartoma than a true neoplasm, these tumors are benign, and complete surgical excision is curative. Trichoepitheliomas are cystic hair follicle neoplasms of dogs and, less commonly, cats, in which all elements of the hair follicle (infundibulum, isthmus, and inferior portions) and the patterns of comification they produce are represented. The epithelium and comification of the infundibular and isthmic portions predo­ minate. Benign and malignant fom1S are recognized. In dogs, these lesions can be seen at any age but are fotmd most commonly during late middle age. Many breeds are predisposed, including Basset Hounds, Bull Mastiffs, Irish Setters, Standard Poodles, English Springer Spaniels, and Golden Retrievers. There is no defined sex predilection. Tumors can develop anywhere on the body but are most common on the trunk in dogs and on the head, tail, and extremities in cats. Benign foffi1S appear as palpably encapsulated cystic nodules ( 1-5 cm in diameter) in the dermis and subcuta­ neous fat. Expansion of cysts or self-trauma may induce ulceration associated with extrusion of lumenal keratin that appears as a condensed, yellow, granular, "cheesy" material. Excision is curative; however, aninlals that develop one such tun1or are prone to develop additional lesions at other sites. This is especially true for Basset Hounds and English Springer Spaniels. Malignant trichoepitheliomas are much less common than benign trichoepi­ theliomas and are differentiated by their local invasiveness; continuity with the epidemtis; and association with extensive inflan1mation, necrosis, and fibrosis. Metastasis is uncommon. Wide surgical exci­ sion is the treatment of choice and is often curative in those tumors that are invasive but have minin1al metastatic potential.

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TUMORS OF THE SKIN AND SOFT TISSUES

Pilomatricomas (hair matrix tumors, calcifying epitheliomas of Malherbe) are cystic hair-follicle neoplasms recognized almost exclusively in dogs. Unlike tricho­ epitheliomas, in which all elements of the follicle are represented, in pilomatricomas only the cells of the matrix region of the inferior part of the hair follicle and the cornification patterns they produce (hair shaft and inner root sheath) are present. Benign and malignant fonns are recognized. Benign tumors are most common on the trunk of middle-aged dogs. Ken-y Blue and Wheaten Terriers, Bouviers des Flandres, Bichons Frises, and Standard Poodles are most at risk. Grossly, these tumors are indistinguishable from trichoepitheliomas, but their cystic contents are often gritty because of mineralization. Excision is the treatment of choice. As in trichoepithelio­ mas, when one such lesion develops, additional lesions often develop over time. Malignant pilomatricomas (malignant hair matrix tumor, matrical carcinoma) are rare and have been identified most often in dogs. They are a tumor of old dogs and grossly characterized as solitary or multinodular, vaiiably cystic tumors that are often firmly attached to subjacent soft tissues. Because they ai·e invasive, they are difficult to excise, and recurrence is common after attempts at surgical excision. They often metastasize to draining lymph nodes and internal organs, especially the lungs. Aggressive surgery is recommended. It is unknown whether they respond to radiation or chemotherapy. Cutaneous Apocrine Gland Tumors Sweat glands are of two types: apocrine and eccrine. Apocrine glands ai·e tubular glands with a coiled secretory portion and a long,

Ceruminous gland carcinoma, right ear of a cat. Courtesy of Or. Alice Villalobos.

949

straight duct that flows into the folliculai· infundibulun1. In domestic animals, all hair follicles have apocrine glands. Apocrine glands in dogs and cats are also present in association with the anal sac, and modified apocrine glands, known as cerunlinous glands, are present in the external auditory meatus. In most mainmals, apocrine glands produce an odiferous, oily compound that is a sexual attractant, a territorial marker, ai1d a warning signal. In horses and cattle, these glands play a role in thennoregulation by producing sweat. Apocrine gland tumors and malfonna­ tions are most common in dogs and cats. Three diseases of apocrine glands of haired skin have been characterized. Cystic apocrine gland dilations (apocrine gland cysts, cystic apocrine gland hyperplasia, apocrine cystomatosis) are best characterized as hainartomas. Two forms exist: a cystic form in which one or more cysts develop in the mid to upper dermis with a poor association with hair follicles, and a more diffuse form character­ ized by cystically dilated apocrine glands associated with multiple hair follicles in nontraun1atized skin. Both ai·e found in middle-age or older dogs and, less commonly, cats. The head and neck are the most conunon sites where these lesions develop. In both species, lesions appear as fluctuant detmal cysts or as translucent bullae. Complete excision is curative; however, this may be difficult to accomplish in the more diffuse forn1. Apocrine gland adenomas are diagnosed almost exclusively in clogs, cats, and rarely horses. Two types are recognized based on whether their histologic appear­ ance primarily resembles the secretory or cluctular portion of tl1e apocrine gland. Apocrine adenomas resemble the secretory region of the apocrine glands. They ai·e fow1cl in older dogs and cats. Great Pyrenees, Chow Chows, and Alaskan Malainutes are the most commonly affected breeds. The head, neck, and extremities are the most frequent sites of development. In cats, apoc1ine aclenomas are more likely to be seen in males, and no breed appears at greater risk than any other. The vast majority of apocrine aclenomas occur on the head, especially the pinnae. In horses, no age, sex, or breed association is known. The pinnae and vulva are the most likely regions to develop these tumors. In all species, these tumors appear as firm to fluctuant cysts, seldom >4 cm in diaineter. They contain varying an1ounts of clear to brownish fluid. In cats, the luminal fluid may be darkly pigmented, and apocrine cysts can be

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TUMORS OF THE SKIN AND SOFT TISSUES

confused clinically with melanocytomas, especially when present on the inner aspect of the ears. Apocrine ductular adenomas are less conunon. They are found in older dogs and cats and are putatively derived from or show differentiation toward apocrine ducts. In dogs, these tumors are most commonly recognized in Peekapoos, Old English Sheepdogs, and English Springer Spaniels. They are often smaller, fumer, and less cystic than apocrine adenomas. Because they often consist of a large population of basal cells and because evidence of ductula.r differentiation can be extremely subtle, these tumors are often diagnosed histologically as basal cell tun10rs (seep 944). Apocrine adenomas and apocrine ductular aclenomas are benign, and complete surgical excision is curative. Apocrine gland adenocarcinomas of haired skin are rare in all domestic animals but most frequently identified in older dogs and cats. In clogs, Treeing Walker Coon­ houncls, Norwegian Elkhouncls, German Shepherds, and mixed-breed dogs are most at risk; in cats, Siamese may be predisposed. In botl1 species, this tumor most commonly arises in axillary and inguinal regions-sites that allow it to be easily confused clinically and histologically with manunary gland ductular adenocarcinomas. Apocrine gland adenocarcinomas generally are larger than adenomas and have a variable clinical appearance ranging from fibrotic dermal nodules to ulcerated plaques. They are locally invasive and frequently metastasize to draining lymph nodes. Less conunonly, skin and lung metastasis may occur. Complete surgical €Xcision is the treatment of choice. Little is known about response to adjunct chemotherapy. Apocrine Gland Tumors of Anal Sac Origin Apocrine gland tumors of anal sac origin have been definitively identified only in clogs, although anecdotal reports suggest they may also be seen in cats. Older English Cocker and Springer Spaniels, Dachshm1ds, Alaskan Malanmtes, Gem1an Shepherds, and mixed-breed dogs are most at risk. Unlike hepatoid gland tumors (seep 951), these apocrine gland tun1ors have no sex predilection. They most commonly appear as deep, firm, nodular masses near tl1e anal sac. As these lesions grow, they may compress the rectum and induce constipa­ tion. Some of tl1ese tun1ors are associated with paraneoplastic hypercalcemia, which causes anorexia, weight loss, polyuria and polydipsia, and mineralization of renal

tissue with increased BUN and creatinine values. These tumors are often highly infiltra­ tive into the pelvic canal and conunonly (90%) metastasize to the sublmnba.r lymph nodes or to distant internal organs (400Ai). Wide surgical excision, including involved lymph nodes, is the treatment of choice. Even if the tumor cannot be totally resected, debulking can be of value in dogs with pseudohyperpa.rathyroiclism, because the hypercalcemia is related to the production of paratl1om1one-like hormone from the total twnor volume. Adjunct chemotl1erapy along with tyrosine kinase inhibitors, metronomic chemotherapy, and radiation therapy may also be of benefit to increase time to progression, but few clogs are reported to live > l YT after the tun1or has been recognized. Eccrine Gland Tumors Eccrine glands are the coiled, tubular, sweat glands present on the footpads of carni­ vores, the frog of ungulates, the carpus of pigs, and the nasolabial region of run1inants. Ttunors derived from these glands are extremely rare and have been identified only on the footpads of dogs and cats. Most are malignant and invasive. These tumors are reported to have a high potential to metastasize to draining lymph nodes. Sebaceous Gland Tumors Tumors and tumor-like conditions of sebaceous glands are conunon in clogs, infrequent in cats, and rare in other domestic animals. Based on morphologic more tllan on behavioral features, four categories of benign sebaceous gland proliferations have been described. In people, in which a roughly sintilar clas­ sification scheme is traditionally used, it has been proposed that all benign sebaceous gland tumors be called sebaceomas. Sebaceous gland hamartomas are solitary lesions reported only in dogs. These lesions are distinguished from sebaceous gland hyperplasias and adenomas because they are linear or circumscribed, several centimeters in length or diameter, and usually identified shortly after birtll. Sebaceous gland hyperplasias (senile sebaceous hyperplasias) represent a senile change in dogs and cats. In dogs, Manchester, Wheaten, and Welsh Terriers are at greatest risk. In cats, there is no breed predilection, but females develop these lesions more frequently than males. In both species, the skin of the head and abdomen are affected most conunonly. Sebaceous hyperplasias conunonly appear as papillated

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TUMORS OF THE SKIN AND SOFT TISSUES masses seldom >1 cm in diameter, often with a shiny, keratotic surlace. Sebaceous gland adenomas are seen in all domestic animals but are so common in older dogs and cats they can be considered primarily a small animal neoplasm. Coonhounds, English Cocker Spaniels, Cocker Spaniels, Huskies, Samoyeds, and Alaskan Malamutes are the canine breeds most likely to develop these tumors; Persians are the feline breed most predisposed. In dogs, these tumors frequently are clinically indistin­ guishable from sebaceous hyperplasias, but they tend to be larger (typically >l cm). They are often multiple and may develop anywhere on the body but are commonly found on the head. Sebaceous adenomas may be covered with a serocellular crust and exhibit pleocellular inflammation and superficial pyoderma. Sebaceous gland epitheliomas are a variant of sebaceous adenoma distin­ guished by lobules composed primarily of basal progenitor cells rather than mature sebocytes. Because they often have irregular lobules that extend into the deep dermis, they can occasionally be confused with sebaceous carcinomas. These tumors are found in older dogs and rarely in cats. They appear as ulcerated nodules that may be several centimeters in diameter. A papillated epidermal surface and pigmentation are variable findings. Sebaceous gland adenocarcinomas are rare in domestic animals. They ru·e recognized almost exclusively in dogs and cats, generally in middle-aged or older animals. Cavalier King Charles Spaniels; Cocker Spaniels; and Scottish, Cairn, and West Highland White Terriers are most at risk Male dogs and female cats may be predisposed. These lesions are often ulcerated and may be indistinguishable from sebaceous epitheliomas or other cutaneous carcinomas. They are locally infiltrative and may metastasize to regional lymph nodes late in the disease. Once a diagnosis is established, treatment is optional for benign sebaceous gland tumors unless they are secondarily inflamed and infected. For malignant adenocarcino­ mas, excision is the treatment of choice, but complete removal can be difficult because of the infiltrative nature of this tumor; adjunct radiotherapy may be required. Even benign sebaceous gland growths recur if remnants are left at the surgical site. In addition, animals that develop one sebaceous gland hyperplasia or adenoma often develop new lesions at other sites over time. No established protocol of

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chemotherapy for any of these lesions has been defined. Oral retinoids may prevent recurrence of sebaceous hyperplasia, but their use remains poorly defined, and consultation with a vete1inary oncologist or dem1atologist is strongly recommended.

Hepatoid Gland Tumors (Perianal gland tumors, Circumanal gland tumors)

These common neoplasms arise from modified sebaceous glands that are most abundant in the cutaneous tissues around the anus but may also be present along the ventral midline from the perineun1 to the base of the skull, the dorsal and ventral tail, and in the skin of the lumbar and sacral regions. Because androgens stin1ulate the development of hepatoid glands, the incidence of proliferative lesions of hepatoid glands in intact, male dogs is three times that in females. Benign hepatoid gland tumors are divided into hepatoid gland hyperplasias and adenomas; however, as with benign sebaceous gland tumors, there is a continuun1 from hyperplasia to adenoma. Here, they will be considered as a single entity. Hepatoid gland adenomas are most common in aged dogs. Siberian Huskies, Samoyeds, Pekingese, and Cocker Spaniels are most commonly affected. Tumors may develop at any site where hepatoid glands are present, but 9096 are found in the perianal region. Grossly, they appear as one or (more commonly) multiple intraderrnal nodules 0.5--10 cm in diruneter. Larger lesions commonly ulcerate, and hemorrhagic, proteinacious material can often be extruded with local pressure. Large tumors cru1 compress the anal canal and make defecation difficult. Up to 95% of male dogs respond completely to castration; in those that do not, the pituitary-adrenal axis should be evaluated and, ifno abnormality is detected, the dog should be reevaluated for the presence of a low-grade hepatoid gland adenocarcinoma. Excision may be used concun·ently to remove extremely large or ulcerated tumors that have become secondarily infected. Surgery is the treatment of choice for females with hepatoid gland adenomas but may need to be repeated, because recurrence is common. Radiation therapy is also an option and has a 2-yr cure rate of 69% for benign tun1ors. Cryosurgery is another therapeutic alternative, but because of the complication of fecal incontinence, should be used only when tumors are not amenable to surgical intervention. Diethylstilbestrol has been

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TUMORS OF THE SKIN AND SOFT TISSUES

used in the past as an alternative to castration, but because of severe adverse effects, including aplastic anemia and cystic prostatic hyperplasia, it should be used with extreme caution, if at all. Antiandrogens may have a role as an alternative to castration. Hepatoid gland adenocarcinomas are uncommon canine neoplasms that generally appear as nodular lesions affecting the perianal region. These tun1ors are found in male dogs 10 times more commonly than in females. Siberian Huskies, Alaskan Malamutes, and Bulldogs are most likely to develop this tun1or. Histologic evaluation is the best means of diagnosis; however, there is debate about how to distinguish low-grade malignant tun1ors from hepatoid adenomas, because well-differentiated fom1s can be confused with adenomas, and anaplastic fonns can be confused with apocrine gland adenocarcinomas of anal sac origin. These tun1ors have metastatic potential and often spread to regional lymph nodes. Treatment consists of wide surgical excision including involved lymph nodes and, possibly, subsequent radiation. These tun1ors are generally not responsive to castration or to estrogen therapy; however, some studies show that the use of masitinib and other tyrosine kinase inhibitors may overcome chemoresistance, inhibit the proliferation of tun1or cells, and prevent the emergence of metastasis. These findings may increase the benefit of combining targeted agents with various fom15 of chemotherapy such as oral piroxicam and capecitabine or with metronomic chemotherapy to prevent or treat local recwTence and metastatic disease. The overall prognosis is guarded. Primary Cutaneous Neuroendocrine Tumors (Merkel cell tumors, Atypical histiocytomas, Trabecular carcinomas, Extramedullary plasmacytomas)

In veterinary medicine, the diagnosis of tun1ors derived from Merkel cells (tactile, neurosecretory cells of epithelial derivation present in the basal cell layer of the epidennis) has fallen in disfavor, and most pathologists consider this tumor to be an extramedullary plasmacytoma. Merkel cell tumors most likely develop in animals but are not recognized as such. Papillomas (Warts)

Papilloma viruses are small, double­ stranded DNA viruses of the Papovaviridae family. Some manm1als have several distinct

papilloma viruses: people have >20; cattle, 6; dogs, 3; and rabbits, 2. Different papilloma viruses often have considerable species, site, and histologic specificity. The virus is transmitted by direct contact, fomites, and possibly by insects. Papillomas have been reported in all domestic animals, birds, and fish. Multiple papillomas (papillomatosis) of skin or mucosa! smfaces generally are seen in younger anin1als and are usually caused by viruses. Papillomatosis is most common in cattle, horses, and dogs. Single papillomas are more frequent in older animals, but they may not always be caused by viral infection. When lesions are multiple, they may be sufficiently characteristic to confinn the diagnosis; however, there are many simulants of warts, and a definitive diagnosis requires identification of the virus or its cytopathic effects on individual cells-a change known as koilocytic atypia or koilocytosis. In cattle, warts commonly are found on the head, neck, and shoulders, and occasionally on the back and abdomen. The extent and duration ofilie lesions depend on ilie type of virus, area affected, and degree of susceptibility. Warts appear -2 mo after exposure and may last �l yr. Papillo­ matosis becomes a herd problem when a large group of young, susceptible cattle becomes infected. Immwuty usually develops 3--4 wk after initial infection, but papillomatosis occasionally recurs, probably due to loss of immwuty. Aliliough most warts appear as epidermal proliferations iliat have a keratotic surface resembling a cauliflower (verruca vulgaris), some bovine papilloma viruses (bovine papilloma types 1 and 2) involve dermal fibroblasts and keratinocytes and appear as a papulonodule with a warty surface. Such fibropapillomas may involve ilie venereal regions, where they can cause pain, disfigurement, infection of the penis of young bulls, and dystocia when ilie vaginal mucosa of heifers is affected. A form of persistent cutaneous papillo­ matosis with smaller nwnbers of papillomas may be seen in herds of older cattle. A bovine papilloma virus has been demon­ strated in bladder tumors associated wiili bracken fem ingestion (seep 3089) and in upper GI tract papillomas of cattle in Scotland. It is believed that ilie papilloma virus acts as a co-carcinogen. When bovine papilloma virus type 1 or 2 is injected into the skin of horses, a dermal tmnor similar to equine sarcoid develops. In horses, small, scattered papillomas develop on ilie nose, lips, eyelids, distal legs,

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penis, vulva, mammary glands, and inner surfaces of the pirmae, often secondary to mild abrasions. They can be a herd problem, especially when young horses are kept together, but regress in a few months, as a foal's immune system matures. When they develop in older horses, they often persist for> 1 yr. So-called aural plaques are also thought to be a flat form of papilloma (vem1ca planum). Equine papillomas are disfiguring but benign. They should be distinguished from verrucous equine sarcoid (seep 954). ln dogs, three clinical presentations of canine papilloma virus infection have been described. The first is canine mucous membrane papillomatosis, which primarily affects young dogs. It is character­ ized by the presence of multiple warts on oral mucous membranes from lips to (occasionally) the esophagus and on the conjunctiva! mucous membranes and acljacent haired skin. When the oral cavity is severely affected, there is interference with mastication and swallowing. A viral etiology has been clearly established for these lesions. Azithromycin therapy has been shown to speed up regression in dogs. The second presentation is cutaneous papillomas, which are indistinguishable from the warts that develop on or around mucous membranes. However, they are more frequently solitary and develop on older dogs. Cocker Spaniels and Kerry Blue Terriers may be predisposed. A definitive viral etiology has not been established, and lesions may be confused with cutaneous tags. A syndrome characterized by papi­ llomatosis of one or more footpads has also been described. Clinically, lesions appear as multiple, raised keratin horns. A viral etiology has been suggested but not proved. The third presentation is cutane­ ous inverted papillomas, which have more in common clinically with intracuta­ neous comifying epitheliomas. ln this disease of young, mature dogs, lesions most commonly develop on the ventral abdomen, where they appear as raised papulonodules with a keratotic center. Infrequently, viral papillomas in dogs may progress to invasive squamous cell carcinomas. ln cats, papilloma virus infection appears most commonly as a multicentric squamous cell carcinoma (seep 945). The typical warty lesions associated with papilloma virus infection in most species are not present. Papillomas may affect the skin of goats, and infection on the teats has been reported to induce malignant transfonna­ tion. ln sheep, papillomas a.re rare and most commonly appear as fibropapillomas. In

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pigs, they are very rare and when present a.re identified as solitary or multiple lesions on the face or genitalia. (For discussion of papillomatosis in rabbits, seep 1950.) A cutaneous fibroma occurs in white­ tailed, black-tailed, and mule deer, and in antelope, moose, and caribou. It is ca.used by a papilloma vims that resembles a bovine papilloma virus and is found only in the epitl1eliun1 that cove� the tumors. Infectious papillomatosis is a self-limiting disease, although the duration of warts varies considerably. A variety of treatments have been advocated without agreement on efficacy. Surgical removal is recommended if the warts a.re sufficiently objectionable. However, because surgery in the early growing stage of warts may lead to rec­ urrence and stimulation of growth, the warts should be removed when near their maximum size or when regressing. Affected animals may be isolated from susceptible ones, but with the long incubation period, many are likely to have been exposed before the problem is recognized. Vaccines are of some value as a preven­ tive but are of little value in treating cattle that already have lesions. Because wart viruses are mostly species-specific, there is no merit in using a vaccine de1ived from one species in another. An intralesional lymphocyte T-cell inlmunomodulator, which stimulates T cells and endogenous interleukin 2 levels, may benefit individual animals that develop multiple or persistent warts. ln addition to azithromycin, topical imiquirnod cream may also help the immune system to resolve these warts in dogs. When the disease is a herd problem, it can be controlled by vaccination with a suspension of ground wart tissue in which the virus has been killed with formalin. Autogenous vaccines may be more effective than those commercially available. It may be necessary to begin vaccination in calves as early as 4-6 wk of age with a dose of -0.4 mL intradermally given at two sites. The vaccination is repeated in 4-6 wk and at 1 yr of age. Immunity develops in a few weeks but is unrelated to whatever mechanism is involved in spontaneous regression. If the animal was exposed to the virus before vaccination, immunity may develop too late to prevent warts. A vaccination program must be in effect for -3---6 mo before its preventive value will be evident. Vaccination should be continued for �l yr after the last wart disappears, because the premises may still be contami­ nated. Stalls, stanchions, and other inert materials can be disinfected by fumigating with formaldehyde.

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TUMORS OF THE SKIN AND SOFT TISSUES

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EQUINE SARCOIDS Equine sarcoids are the most commonly diagnosed tumor of equids, representing 200A, of all equine neoplasms and 36% of all skin tumors in horses. Studies suggest there is no significant gender or age predisposi­ tion. Equine sarcoids are rarely life threaten­ ing but can compromise function and be a major economic concern. Sa.rcoids may also cause significant welfare dilemmas, particularly in developing countries where equids, principally donkeys, are widely used as work anin1als (eg, brick-carrying donkeys in India). Sarcoids can occur as single or multiple lesions in different forms, ranging from small, wart-like lesions to large, ulcerated, fibrous growths. Six distinct clinical entities are recognized: 1) Occult-flat, gray, hairless, and persistent; often circular or roughly circular. 2) Vemicose-gray, scabby, or warty in appearance and may contain small, solid nodules; possible sur­ face ulceration; well-defined or cover large, ill-defined areas. 3) Nodular-multiple, discrete, solid nodules of variable size; may ulcerate and bleed. 4) Fibroblastic-fleshy masses, either with a thin pedicle or a wide, flat base that commonly bleed easily; may have a wet, hemorrhagic surface. 5) Mixed­ variable mixtures of two or more types. 6) Malevolent-an extremely rare, aggressive tumor that spreads extensively th.rough the skin; cords of tumor tissue intersperse with nodules and ulcerating fibroblastic lesions. Lesions can develop anywhere on the body but are most common in the para.geni­ tal region, the ventral thorax and abdomen, and the head. They frequently are seen at sites of previous injury and scarpng. Equine sarcoids can resemble other skin tun10rs such as benign fibropapillomas and also other cutaneous conditions such as exuberant granulation tissue (proud flesh). An individual lesion on a horse can be difficult to diagnose, but multiple tumors (often of more than one type) with characteristic features on an individual horse make the clinical diagnosis reason­ ably straightforward. A definitive diagnosis can be made by biopsy; however, acquiring the sample carries the risk of triggering a considerable and uncontrollable expansion of the lesion. Bovine papillomavirus (BPV), primarily types 1 and 2, is now considered the main etiologic agent of equine sarcoids. There may also be a genetic predisposition associated with equine leukocyte antigens;

particular breeds and bloodlines appear to be more susceptible to the disease. The mode of transmission has not been confirmed. BPV-1 has recently been detected in several conunon fly species (eg, house fly and stable fly), and because there is an apparent predilection for sarcoid development at wound sites, it has been proposed that flies may act as vectors as they move between wound sites on different horses. Alternatively, BPV infection may be transmitted via stable management practices, such as the sharing of contan1i­ nated tack, or be passed into existing wounds from contaminated pasture. There is a wide range of therapies for sarcoids, and many tumors recur. Peduncu­ lated sarcoids with a discernible neck are ideally suited to ligation with mbber bands or elasticized suture material, usually in combination with a topical preparation once the twnor is detached. Other conunonly used treatments include cryotl1erapy, surgical or laser excision, and local inunune modulation (Bacillus Cal.rnette-Guerin [BCG] therapy). Surgical excision with margins of at least 0.5-1 cm is reconunended. Preplaced sutures or releasing incisions are often needed for primary closure. Local radiotherapy (interstitial brachytherapy), using pennanently in1planted radon-222 or gold-198 seeds or removable needles of radiun1-226, cobalt-60 or, more often, iridium-192 (192Ir) implants, is a highly effective treatment for tun10rs less amenable to traditional therapy (eg, those on the limbs or around the eye). However, 1921.r implants and other radioisotopes are expensive and not widely available but may be the best option for recurrent aggressive lesions. Sarcoids have a 15%--82% recw� rence rate if treated by surgical excision alone. Excised sarcoids often regrow more aggressively within 6 mo, which may be due to activation of latent BPV in apparently normal tissue surrouncling the lesion. Larger tun1ors may require a combination of th.era.pies (eg, surgical debulking or C02 laser vaporization followed by topical or intracavitary chemotherapy or local electrochemotherapy). Several pron1ising treatments now available or in the final stages of clinical trials include the use of intra-tun10ral bioabsorbable cisplatin beads/emulsion (9% recurrence rate), the application of topical in1iquirnod every other day for 32 wk or until resolution (600Ai), autologous in1plantation, and topical acyclovir crean1s for treatment of flat, occult sarcoids (68% response rate) or applied to the wound bed of larger

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TUMORS OF THE SKIN AND SOFT TISSUES tumors removed by surgical excision. Acyclovir is relatively inexpensive and has a wide safety margin, but its method of action is w1known. Other products used to treat sarcoids are topical ointments that contain heavy metals, thiouracils, and 5-fluoroura­ cil; an escharotic salve containing bloodroot powder extract and zinc chloride; and an IV immw10stimulant of nonviable Propioni­ ba.cterium acnes and BCG. The develop­ ment of preventive and/or therapeutic vaccines may fom1 a significant pa.it of disease control strategies in the future, but trials so far have shown limited success. A novel therapeutic approach using small interfering RNA molecules to target viral gene expression is being investigated. This technique has been shown to selectively destroy BPV-1-infected equine skin cells in vitro.

CONNECTIVE TISSUE TUMORS Benign Fibroblastic Tumors Collagenous nevi are benign, focal, developmental defects associated with increased deposition of dennal collagen. They are common in dogs, W1common in cats, and rare in large animals. They generally are fow1d in middle-aged or older anin1als, most frequently on the proxin1al and distal extremities, head, neck, and areas prone to trauma. They are sessile to raised, dennal nodules, often with a papillated surface. 1\vo fom1s are seen: one develops in the interfollicular dermis or subcutat1e­ ous fat that is not accompanied by adnexal involvement, and one incorporates adnexa and induces enlai·ged, often malformed follicles, sebaceous glands, and apocrine gla.11ds. This latter form has been called focal adnexal dysplasia. Excision of both fom1s is generally curative although, infrequently, expansive fom1s have been identified that may grow too large to be surgically removed. Generalized nodular dermatofibrosis ( dermatofibromas ), recognized rai·eJy in German Shepherds (believed to be a.11 inhe1ited, autosomal dominant trait) and even less commonly in other canine breeds, is a syndrome in which multiple collagenous nevi are associated with renal cystadeno­ carcinomas and, in females, multiple uterine leiomyomas. Skin lesions, first recognized when animals are 3--5 yr old, are characte1° ized by the development of multiple collagenous nevi varying from barely palpable to large and nodular, generally on the lin1bs, feet, head, and trunk They may be symmetrically distributed. Renal disease

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develops -3--5 yr after t11e skin lesions are recognized. No known therapy can prevent development of tl1e renal and ute1ine neoplasms. Acrochordons (cutaneous tags, soft fibromas, fibrovascular papillomas) ai·e distinctive, benign, cutaneous lesions of older dogs. These lesions ai·e common, may be single or multiple, and can develop in any breed, although large breeds may be at increased risk Most commonly, they appear as pedW1culated exophytic growths, often covered by a verrucous epidem1al surface. Treatment is optional, but a biopsy is recommended to confinn the diagnosis. Acrochordons are an1enable to excision, electrosurgery, and cryosurgery, but dogs that develop one are prone to develop others over time. Fibromas are discrete, generally cellu­ lar proliferations of dermal fibroblasts. Histologically, they resemble collagenous nevi or cutaneous tags. Fibromas occur in all domestic species but are primarily a tw11or of aged dogs. Dobem1an Pinschers, Boxers (predisposed to developing multiple ttm10rs), and Golden Retrievers are most at risk. The head and extremities are tl1e most likely sites. Clinically, the lesions appeai· as discrete, generally raised, often hairless nodules originating in the dermis or subcutaneous fat. They palpate as either firm and rubbery (fibroma durum) or soft and fluctuant (fibroma molle). These lesions are benign, but complete excision is recommended if they change appearance or grow large.

Soft-tissue Sarcomas Th.is group of malignancies includes equine sarcoids, fibromatoses, fibrosarcomas, malignant fibrous h.istiocytomas, neurofi­ brosai·comas, leiomyosarcomas, rhabdo­ myosarcomas, and vaiiants of liposai·co­ mas, angiosarcomas, synovial cell sarcomas, mesotheliomas, and meningi­ omas. As a group, sarcomas ai·e widely recognized, yet poorly characterized neoplasms. The confusion stems in part from tl1e fact tl1at spindle-cell sai·comas demonstrate much greater morphologic heterogeneity than carcinomas; often, features of one sarcoma are intermixed with features of another. Consequently, it is widely accepted that the cell of origin of all soft-tissue sarcomas is a primitive mesenchyn1al cell tl1at can differentiate in many different directions. Th.is makes it difficult to define histopatl10logic c1iteria necessaiy for making an unequivocal diagnosis of specific spindle-cell sarcomas.

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In addition, comparing neoplastic mesenchymaJ cells with the nom1aJ cell they most closely resemble does not imply origin from those cells. A second cause for the confusion stems from the difficulty in deteffilining whether these are benign or malignant or what their biologic behavior will be in certain locations or breeds. Most spindle-cell sarcomas of domestic aninlals are locally infiltrative, difficult to excise, and yet seldom metasta­ size. Because, by definition, only malignant tumors have metastatic potential, these tumors should be considered benign; however, again by definition, benign neoplasms are not infiltrative, and those tumors should be considered malignant and treated aggressively from the start. In human pathology, infiltrative but nonmetas­ tasizing mesenchymaJ spindle-cell tumors have been defined as sarcomas of intermedi­ ate malignancy, a concept used below. Clinically, four general principles relate to spindle-cell sarcomas and soft-tissue sarcomas: The more superficial the location, the more likely the tumor is to be benign ( deep tumors tend to be malignant). The larger the tumor, the more likely it is to be malignant. A rapidly growing tumor is more likely to be malignant than one that develops slowly. Benign tumors are relatively avascular, whereas most mali­ gnancies are hypervascular. The type of sarcoma, its size, location, stage and histologic grade (low, intermediate, high [or I, II, ill]), which depends on the degree of differentiation, the number of mitotic figures per 10 high-power fields, and percent that is necrotic, will help guide treatment planning. Surgical excision is the treatment of choice. Wide excision or an1putation should be performed when anatomically.feasible because spindle-cell sarcomas often infiltrate along fascia] planes, making it difficult to determine from gross exanlina­ tion the peripheral margins of the tumor. The best, if not only, opportunity to completely remove a spindle-cell sarcoma is during the first surgical attempt. A presurgical biopsy should be performed and, if possible, tumor imaging with CT or MRI or ultrasound to provide a clear surgical plan that includes the intention of complete removal, with biopsy samples submitted for margin determinations. Those sarcomas that recur have a greater potential for metastasis, and the time to recurrence often shortens with each subsequent attempt at excision. In addition, many soft-tissue tumors have a pseudocapsule, which on gross examination gives the

in1pression of complete encapsulation; these tumors should not be "shelled out," because neoplastic cells are usually present in the pericapsular connective tissues. Many sarcomas are shaped like an octopus, with tentacles that extend deeply into the tumor bed. Except for equine sarcoids, cryosur­ gery is usually not used for these tumors because some types, most notably fibrosarcomas, are resistant to freezing. Spindle-cell sarcomas generally do not respond well to conventional doses of radiation; however, higher doses have been reported to control -50% of them for 1 yr. Surgical debulking followed by intraopera­ tive placement of carboplatinum-containing biodegradable beads, intracavitary chemotherapy with follow-up intratumor bed chemotherapy, and/or follow-up radiation therapy are options to enhance local control. Chemotherapeutic protocols for sarcomas that include targeted therapy agents such as tyrosine kinase (T-K) inl1ibitors have become more accepted as a means of treatment. Most older protocols involve the use of adriamycin often in combination with other agents, including cyclophosphanlide, vincristine, dacar­ bazine, and methotrexate. Some clinicians prefer to use a combination of carboplatin, T -K inhibitors, and metronomic chemothe1" apy, whereas others rotate carboplatin with adriamycin. Although chemotherapy may cause temporary adverse events, it can improve the length and overall quality of life; it is seldom curative. Fibromatosis (aggressive fibromatosis, extra-abdominal desmoids, desmoid tumors, low-grade fibrosarcomas, nodular fasciitis) is a sclerosing and infiltrative proliferation of well-differentiated fibroblasts derived from aponeuroses and tendon sheaths. They are generally seen on the heads of dogs, especially Doberman Pinschers and Golden Retrievers, where they are commonly diagnosed as nodular fasciitis. In veterinary medicine, the term nodular fasciitis is applied to two different diseases: one that behaves as a fibroma­ tosis and one that commonly affects the periocular tissues (known as canine fibrous histiocytoma [seep 957]). Fibromatoses are infrequently diagnosed in cats and horses. Grossly, fibromatoses are generally indistinguishable from infiltrative fibrosar­ comas; however, they can be differentiated on histologic exanlination. Focal lymphoid nodules are scattered throughout the tissues. The fibromatoses are locally infiltrative, with essentially no metastatic potential. If feasible, wide, complete

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TUMORS OF THE SKIN AND SOFT TISSUES

excision with local control techniques as described above is the treatment of choice at diagnosis. Recurrence is common, and radiation therapy may be of value for local control. Fibrosarcomas are aggressive mesenchymal tumors in which fibroblasts are the predominant cell type. They are the most common soft-tissue tumors in cats and are also common in dogs but rare in other domestic anin1als. In dogs, these tumors are most conunon on the trunk and extremities. Gordon Setters, Irish Wolthounds, Brittany Spaniels, Golden Ret1ievers, and Doberman Pinschers may be predisposed. Fibrosarco­ mas vary markedly in their appearance and size. Neoplasms arising in the dermis may appear nodular. Those arising in the subcutaneous fat or subjacent soft tissues may require palpation to identify. They appear as firm, fleshy lesions involving the dermis and subcutaneous fat and often invade musculature along fascial planes. When tumors are multiple, they are usually found within the san1e anatomic region. Fibrosarcomas with abundant interstitial proteoglycans (connective tissue mucins) are called myxosarcomas or myxofibro­ sarcomas. Myxosarcomas remain poorly defined in veterinary medicine, and many of them could be characterized as variants of liposarcomas or malignant fibrous histiocytomas. Fibrosarcomas in dogs are invasive tun10rs; -1 OOAimetastasize. Factors that affect whether a fibrosarcoma can be completely excised include the skill of the surgeon; rate of growth (as defined by the mitotic index and quantity of necrosis); degree of cellular atypia; and the tumor's infiltrative nature, size, and location (which may require imaging to define properly). Three forms of fibrosarcoma are recognized in cats: a multicentric form in the young (generally 700Aiwithin 1 yr of the initial surgery). The rate of recurrence is >90%for vaccine-associated sarcomas. Even when surgical excision is clinically and histologi­ cally complete, recurrence is still the rule. Therefore, multimodal therapy combining presurgical imaging, aggressive surgery, intracavitary chemotherapy with carbo­ platin, followed by radiation therapy and IV carboplatin every 21 days for 4---0 treatments with tyrosine kinase (T-K) inhibitors as adjunctive therapy may yield the best results. Chemotherapy with carboplatin, doxorubicin and cyclophosphamide, or dacarbazine, along with T-K inhibitors, has been recommended for nonresectable tumors. Initial results using a biologic response modifier (used intratun1orally before excision and followed by radiation therapy) appear promising. Further work suggests that its effectiveness as an adjunct to surgery and radiation may increase tun10r-free intervals up to 200Aicompared with historical controls. Fibrohistiocytic Tumors These pleomorphic, mesenchymal tumors· composed of fibroblasts and histiocytic cells (often present as multinucleated giant cells) remain poorly defined in veterinary medicine. A lesion called canine fibrous histiocytoma (nodular granulomatous episclerokeratitis, nodular fasciitis, proliferative keratoconjunctivitis, cortjunctival granuloma, Collie granuloma) is recognized at the episcleral junction and cornea primarily in young to middle-aged (2-4 yr old) Collies, but the histologic features are more suggestive of a granu­ lomatous inflan1.111atory response than a neoplasm. As might be expected for a nonin­ fectious inflammatory process, these are generally responsive to sublesional injections of 10-40 mg of methylpred.niso­ lone. Malignant fibrous histiocytomas (extraskeletal giant cell tumors, giant cell tun1ors of soft parts, dem1atofibrosarco­ mas) are most frequently found in the skin and soft tissues of cats, occasionally found

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TUMORS OF THE SKIN AND SOFT TISSUES

in horses and mules, and rarely in the skin of other domestic species, including dogs. In cats, malignant fibrous histiocytomas are most common on the distal extremities or ventral cervical regions of the aged but may also be diagnosed at vaccination sites. In horses and mules, these have been described as giant cell tumors of soft parts. Seen in young adult to middle-aged Equidae, they are firm, nodular to diffuse swellings that are white on cut surface, with variable hemorrhage. Malignant fibrous histio­ cytomas are sarcomas of intermediate malignancy. They are locally invasive and tend to recur after attempts at complete excision but seldom metastasize. Radical excision is reconunended.

Peripheral Nerve Sheath Tumors Amputation neuromas (traun1atic neuromas) are non-neoplastic, disorganized proliferations of pe1ipheral nerve paren­ chyma and stroma that form in response to amputation or traun1atic irtjury. They are most conunonly identified after tail docking in dogs or neurectomy in the distal extremities of horses. The most common clinical presentation is a yotmg dog that continuously traumatizes its docked tail. In horses, such a lesion appears as a firm, often painful swelling at a neurectomy surgery site. Excision is curative. Neurofibromas and neurofibrosar­ comas (perineuromas, neurilenunomas, nerve sheath tunlors, hemangiopericyto­ mas, neurothekomas, schwannomas) are spindle-cell twnors that arise from the connective tissue components of the pe1ipheral nerve. They are believed to aiise from Schwarm cells, but they could also arise from mesenchyrnal cells, which produce the nonmyelinat�d connective tissues that surround the myelinated ne1ve fiber. In dogs, forms of this twnor cai1 be virtually indistinguishable from hemangio­ pericytomas and may be the san1e tunlor. In dogs and cats, peripheral nerve sheath tun1ors of the skin ai·e found in older a.Ilin1als. In cattle, they have a suspected genetic basis, may be multiple, can develop in both the young and old, and are generally an incidental finding at slaughter; they arise from the deep nerves of the thoracic wall and viscera, and cutaneous involvement is rare. Regai·dJess of the species, these tun1ors appear as white, finn, nodules. Attachment to a peripheral nerve may occasionally be noted. Both benign and intermediate-grade malignant variants ai·e recognized. Benign tun10rs are most conunon in cattle in which, because of their

indolent nature, treatment is optional; also, additional tun1ors often develop spontane­ ously at other sites over ti.me. In dogs, cats, and horses, most are locally infiltrative but do not metastasize. Complete excision is the treatment of choice. When mai·gins are nanow or insufficient, followup radiation therapy, postoperative intralesional tumor bed chemotherapy (using the patient's serum mixed with the chemotherapy agent), electrochemotherapy, or systemic chemotherapy with carboplatin or metronomic chemotherapy may increase the tun1or-free interval.

Adipose Tissue Tumors Lipomas are benign tun1ors of adipose tissue, perhaps more accurately characte1� ized as hainartomas. They are conunon in dogs, occasionally identified in cats and horses, and rare in other domestic species. In dogs, they generally develop in older, obese females, mosL conunonly on U1e Lrunk and proxin1al limbs. The breeds most at risk are Doberman Pinschers, Labrador Retrievers, Miniature Schnauzers, and mixed-breed dogs. Older, neutered male Siainese cats ai·e predisposed, and tun10rs are most commonly found on the ventral abdomen. Obesity does not appear to be a factor in the development of lipomas in cats. Affected horses are generally 5% ai·e multiple. In general, these tunlors float when placed in fom1alin. A rare variant of this twnor, diffuse lipomatosis, has been identified in Dachshunds. Virtually the entire skin is affected, resulting in prominent folds on the neck and truncal skin. Many lipomas merge imperceptibly with the adjacent non­ neoplastic adipose tissue, making it difficult to detennine when the entire lesion is excised. Lipomas with-an abundant connective tissue stroma (fibrolipomas), cartilaginous stroma (chondrolipomas), or a prominent vascular component (angiolipo­ mas) are also recognized. Despite their benign nature, lipomas should not be ignored because they tend to enlarge over tin1e, and their gross presentation may be indistin­ guishable from that of infiltrative Jipomas or liposarcomas (see below). Excision is curative. In dogs, dietaiy restiiction to 7ff'/o of nonnal intake for several weeks before surgery may allow for better definition of the surgical mai·gins of the tumor. Infiltrative lipomas (intra- and inter­ muscular lipomas) are rare in dogs and

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TUMORS OF THE SKIN AND SOFT TISSUES even less common in cats and horses. In dogs, they are most conunon in middle-aged females, usually on the thorax and limbs. The breeds (dogs) most at risk are the same as those for lipomas. These tumors are poorly confined, soft, nodular to diffuse swellings that typically involve the subcutaneous fat and nnderlying muscle and connective tissue stroma. Infiltrative lipomas, which dissect along fascia! planes and between skeletal muscle bnndles, are considered sarcomas ofintennediate malignancy. They rarely metastasize. Aggressive excision is recommended, and amputation may be necessary. Liposarcomas are rare neoplasms in all domestic animals. Most are recognized in older male dogs in which they usually develop on the trunk and extremities; Shetland Sheepdogs and Beagles may be predisposed. In cats, feline leukemia virus infection has been infrequently associated with their development; whetl1er this is a coincidence or such infections play a causative role remains unclear. Liposarco­ mas are nodular and soft to finn. They may exude a mucinous fluid when sectioned. Many have palpable, partially encapsulated areas, but these zones should not be construed as evidence of a benign tumor. Liposa.rcomas are malignant neoplasms that have a low metastatic potential but are frequently pseudoencapsulated. Wide excision is reconunended. Recurrence is conunon, so followup radiation therapy is indicated in cases with insufficient margins. Vascular Tumors Hemangiomas ofthe skin and soft tis­ sues are benign proliferations that closely resemble blood vessels. Whether these are neoplasms, hamartomas, or vascular malfom1ations remains w1defined, and no clear criteria exist that allow for their separation. They are most commonly identified in dogs, occasionally in cats and horses, and rarely in cattle and pigs; they are an exceptional finding in other domestic anin1als. In dogs, they are tumors of adult clogs and most corrunonly develop on the tflll1k and extremities. Many canine breeds (including Gordon Setters; Boxers; and Airedale, Scottish, and Kerry Blue Terriers) are considered to be at risk. Cats most frequently develop hemangiomas when they are adults. Lesions are most corru11on on the head, extremities, and abdomen. In horses, they are most common on tl1e distal extremities of young ( 23/grid; proliferating cell nuclear antigen, Agnor count >54; mutations in exon 8 and exon 11 of c-Kit gene; and increased PCNA levels are prognostic for local recurrence and a poor prognosis. Correlation of test results with survival times can be useful but is not always a reliable predictor of the outcome. There is agreement on cytologic features for high-grade mast cell tumors: seven or more mitotic figures/IO high-power fields (hpf),

three multinucleated cells/10 hpf, three bizarre nuclei/IO hpf, and karyomegaly in J()OA, of the cells. These high-grade features confer a prognosis of a 4-mo survival time vs >2 yr for low-grade mast cell tumors. Because of the difficulty of subcategorizing canine mast cell tumors, all should be treated as at least potential malignancies. The Mast Cell Tun10r Panel to detemline prognosis and treatment guidance can be requested for grade II tumors at the Diagnostic Center for Population and Animal Health at Michigan State University. Treatment depends on the clinical stage of the disease and the predicted aggressive biologic behavior. For Stage I tumors (a solitary tumor confined to the dennis without nodal involvement), the preferred treatment is complete excision with a wide margin; at least 3 cm of healthy tissue surrounding all palpable borders should be removed in an attempt to excise both the nodule and its surrouncling halo of neoplastic cells. Intraoperative cytology (examination of impression smears at the excised tissue margins) can guide the surgeon, who should continue to remove tissue until the margins are adequate and free of mast cells. If histologic evaluation suggests that tl1e tumor extends beyond the surgical margins, reexcision or tun1or bed excision should be attempted. Because mast cells are sensitive to radiation, intra­ operative radiation therapy is an option along with followup external beam radiation therapy, which may be curative if the remaining tumor is small or micro­ scopic. Combination or multimodal treatments using radiation therapy (if affordable), with intralesional chemother­ apy and or local hyperthemlia or electro­ chemotherapy along with systemic chemotherapy including tyrosine-kinase inhibitors, may be more effective than radiation alone to control biologically and locally aggressive mast cell tumors. There is no agreed upon mode of therapy for Stage II-IV mast cell tumors; however, the advent of multikinase inllibitors represents a new option, which when used in combination with cytotoxic chemother­ apy, requires dose reduction to avoid adverse events. Standard care options for Stage II tumors (a solitary tumor with regional lymph node involvement) include excision of the mass and the affected regional node (if feasible), prednisolone, and radiotherapy, used either singly or in combination. Tl.iamcinolone or dexametha­ sone sodium phosphate, nlixed with the patient's serun1 and irtjected evenly into the tissues of tl1e tun10r bed at the time of

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TUMORS OF THE SKIN AND SOFT TISSUES

surgery or postoperatively as a followup series, may also help reduce recurrence. Intraoperative radiation therapy and/or followup external beam therapy is still considered the highest standard of care but is often declined because of cost. Injections into the tumor bed after incomplete excision using hypotonic, deionized, or distilled water has been debated. Treatment of Stage m (multiple dermal tumors with or without lymph node involvement) or Stage IV (any twnor with distant metastasis or recurrence with metastasis) tumors is generally considered palliative. One recommended therapy is prednisolone (2 mg/kg, PO, for 5 days, followed by a maintenance dose of 0.5 mg/kg/day) or intralesional injections of triamcinolone ( l mg/cm diameter of tumor, every 2 wk). Treatment with H1- and Hz-receptor antagonists for the peripheral and gastric effects of histamine, respectively, may be indicated for animals with systemic disease or clinical signs referable to histamine release. Chemotherapy with vinca alkaloids (vincristine, vinblastine), L-asparaginase, and cyclophosphanude has also been used with some effectiveness. Prednisone and vinblastine used as adjuvant chemotherapy to incomplete surgical resection conferred an apparent improvement over historical survival data using surgery alone, yielding a 57% 1- and 2-yr disease-free state and a 45% survival at 1 and 2 yr for dogs with grade m tumors. In 19 dogs on a high dose of lomustine given every 21 days, 42% of mast cell tumors showed measurable responses, ranging from stable to partial with one complete response. Neutropenia appears 7 days after treatment, with neutrophil counts of 1,500 cells/µL. Vinc1istine doses must be lowered if used in combination with multi­ kinase inhibitors. Lomustine at metrononuc doses given daily along with multikinase inhibitors may be helpful and may avoid the adverse events associated with high-dose lomustine. Novel small molecule multikinase inhibitors such as masitinib mesylate and toceranib phosphate are available to treat mast cell tumors and have been shown to be very helpful in management of difficult cases. They inhibit the c-Kit tyrosine kinase receptor, an activated or mutated proto­ oncogene associated with the development of mast cell tumors. Tissue sampling to detemune the biologic aggressiveness of mast cell tmnors and to look for the presence of the mutated tyrosine kinase c-Kit receptor has been recommended before starting treatment, although evidence shows that many mast cell tumors

965.

respond regardless of their c-Kit status. A study of 202 client-owned dogs with or without prior treatment, having measurable cutaneous grade II or III mast cell tumors without nodal or visceral metastasis, found that masitinib (12.5 mg/kg/day, PO) was a relatively safe and beneficial treatment option. Another clinical trial fow1d that toceranib (3.25 mg/kg, PO, every 48 hr), a receptor tyrosine kinase inhibitor, results in inhibition of Kit phosphorylation in canine mast cell twnors and was of clinical benefit with continued use. Note that the toceranib dosage stated on the package insert may lead to unacceptable toxicity. Veterinary oncologists are the most informed sources for clinical application using these novel tyrosine kinase inhibitor drugs against mast cell twnors, which may also benefit other malignancies. In cats, cutaneous mast cell tumors are the second most common skin tun1or; however, the disease is seen only occasion­ ally in practice. In addition to cutaneous tumors, primary splenic, systenuc, leukenuc, and GI fom1s have been recognized. Two distinct variants of the cutaneous form occur-a mast cell type analogous to, but not identical with, cutaneous mast cell tumors in dogs, and a histiocytic type unique to cats. Feline cutaneous mast cell tumors may be either solitary or multiple. Piin1ary splenic, systenuc, recurrent, and multiple tun10rs (five or more) are associated with a guarded prognosis. The mast cell type is most common. It is found primarily in cats >4 yr old and may develop anywhere on the body butmost commonly on the head and neck. The tumors are single, alopecic nodules, generally 2-3 cm in diameter, that occasion­ ally extend into the subcutaneous fat. Lymphoid nodules are common; eosinophils are rare. Unlike mast cell tumors in dogs, those in cats are generally benign; atypia and clinical behavior are poorly correlated. Surgical excision is the treatment of choice; 3096 of tun10rs recur after surgery and some metastasize. Cryotherapy may be a good option to treat multiple recurrent small lesions to avoid anesthesia. Recurrent tumors may respond to chemotherapy, radiation therapy, and novel small molecule targeted therapy (see above). The histiocytic type of cutaneous mast cell tun10r in cats is recognized primarily in Siamese cats 1.5:1) and ensure total calciwn in the diet meets NRC requirements (see TABLE 1),

as well as vitamin D levels, may help to prevent further cases in pregnant animals. Sudden dietary changes or other stressors should be avoided during late gestation, and risk factors for pregnancy toxemia investigated.

PUERPERAL HYPOCALCEMIA IN SMALL ANIMALS (Postpartum hypocalcemia, Periparturient hypocalcemia, Puerperal tetany, Eclampsia) Puerperal hypocalcem.ia is an acute, life-threatening condition usually seen at peak lactation, 2-3 wk after whelping. Small-breed bitches with large litters are most often affected. Hypocalcemia may also occw· during parturition and may precipi­ tate dystocia. Etiology and Pathogenesis: Hypocal­ cemia most likely results from loss of calcium into the milk and from inadequate dietary calciwn intake. This imbalance in calcium metabolism occurs because calcium mobilization from bone into the serwn pool is insufficient to maintain the efflux of calcium leaving through the manunary glands. Heavy lactational demands from large puppies or a large litter are often noted. The incidence is increased in small breeds of dogs, although puerperal hypocalcemia can occur in any breed, with any size litter, and at any time during lactation. Rarely, it occurs during late gestation in bitches. Although uncommon in queens, it may occur during early lactation. In dogs, supplementation with oral calcium during pregnancy may predispose to eclarnpsia during peak lactation, because excessive calcim11 intake during pregnancy causes downregu­ lation of the calcium regulatory system and subsequent clinical hypocalcemia when calciun1 demand is high.

CALCIUM REQUIREMENTS OF A MEAT EWE AND DAIRY DOE DURING GESTATION AND LACTATION 70-kg adult with twins

Calcium Requirements (g/day) Early gestation Late gestation

Early lactation Mid lactation

Ewe (meat)

6.5

8.8

7.9

6.5

Doe (parlour milked)

6.6

6.6

20.7

21.4

Adapted, with pennission, from Nutrient Requirements of Small Ruminants, Animal Nutrition Seties, 2007. National Academy of Sciences, National Academy Press, Washington DC.

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DISORDERS OF CALCIUM METABOLISM Inadequate production of parathyroid hormone (PTH) during the hypocalcemic crisis is not responsible for eclampsia in dogs. In dairy cows with a similar condition (seep 988), production of PTH is adequate, but the pool of osteoclasts for PTH to stimulate is not. The small osteoclast pool results from feeding a high level of dietary calcium during the nonlactating period, which suppresses parathyroid gland secretion of PTH and stimulates parafollicu­ lar C-cell secretion of calcitonin. Hypocalce­ mia at partwition interferes with the release of acetylcholine at the neuromuscular junction, which is nonnally mediated by extracellular calciwn entering presynaptic nerve terminals through voltage-gated calcium channels and triggering the fusion of acetylcholine-filled synaptic vesicles with the presynaptic nerve terminus. The paresis seen in cattle, rather than the tetany seen in dogs, is probably the result of a combination of factors. Cows often have concurrent mild hypermagnesemia. Magnesium is a calcium-channel antagonist and plays a key role in modulating any activity governed by intracellular calcium fluxes. Cows also have increased volatile fatty acids (which are inhibitory at neuromuscular synapses), and cows have a higher threshold potential at new·omuscularjw1ctions than do dogs. In dogs with hypocalcemia, unlike cows, excitation-secretion coupling is maintained at the neuromuscular junction. The low concentration of calcium in the extracellu­ lar fluid has an excitatory effect on nerve and muscle cells, because it lowers the threshold potential (voltage level at which sodiun1 channels become activated) so it is closer to the resting membrane potential. With hypocalcemia, sodiun1 channels become activated (opened) by very little increase in membrane potential from their normal, negative level. Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without provoca­ tion rather than remaining in the resting state. The probable way that calcium ions affect the sodium channels are that calciw11 ions bind to the exterior surfaces of sodium channels. The positive charge of these calciun1 ions alters the electlical state of the sodiun1 channel protein, thus altering the voltage level required to open the sodium channel. Because of the loss of stabilizing membrane-bound calciwn ions, nerve membranes become more permeable to sodium ions and require a stimulus of lesser magnitude to depolarize. Tetany occurs as a result of spontaneous repetitive firing of motor nerve fibers. Hypoglycemia can occur concurrently.

993

Clinical Findings: Panting and restless­ ness are early clinical signs. Mild tremors, twitching, muscle spasms, and gait changes (stiffness and ataxia) result from increased neuromuscular excitability. Behavioral changes such as aggression, whining, salivation, pacing, hypersensitivity to stimuli, and disorientation are frequent. Severe tremors, tetany, generalized seizure activity, and finally coma and deatl1 may be seen. Hyperthermia may occur in severe cases. Prolonged seizure activity may cause cerebral edema. Tachycardia, hypertl1em1ia, polyuria, polydipsia, and vomiting are sometimes seen. Historically, the bitch has been otherwise healthy and the neonates have been thriving. Although hypocalcemia usually occurs postpartwn, clinical signs can appear prepartum or at parturition. Mild hypocalce­ mia (serum calcium concentration >7 mg/dL but below the normal reference range) may contribute to ineffective myometrial contractions and slow the progression of labor without causing any other clinical signs. Heavy panting may produce a respiratory alkalosis. Ionized calciwn is the physiologi­ cally available fraction; it is affected by protein concentration, acid-base status (aJkalosis favors protein binding of serum calciwn and will decrease blood levels of the biologically important ionized calcium, thus exacerbating hypocalcemia), and other electrolyte imbalances. Thus, the severity of clinical signs may not correlate with total calcium concentration. Diagnosis: Diagnosis is often made from the signalment, history, clinical signs, and response to treatinent. A pretreatinent total serum calciun1 concentration 400 m long. However, there may be an ergogenic effect when sodilll11 bicarbonate is administered at high dosages. Sodium bicarbonate at a dosage rate of 1 g/kg (by nasogastric tube) increased the time to fatigue in horses nmning on a treadmill, and it was concluded that treatment at this dose affected perfonnance. Energy supply and hydration are frequently manipulated in hU111an athletes to lirnit fatigue during endtrrance exercise. Dehydration before exercise results in higher core temperatures dttring exercise in horses. It would be inappropriate for an anin1aJ to begin an endurance exercise with subopti­ mal hydration. Horses are more susceptible to hypertl1em1ia during prolonged exercise than people because of tl1eir high body mass to swface area ratio, which inhibits heat loss. Equine them1oregulation also results in extreme changes to total body fluid status, and there is increasing interest in the way of linuting these excessive responses to exercise by preexercise fluid administration. Hyperhydration by administration of electrolytes or saline solutions orally before exercise will result in expansion of the blood volLU11e during the event. Studies suggest that hyperhydration before prolonged exercise helps conserve plasma volm11e during exercise but does not lower body temperature or improve arterial hypoxemia. Maintenance of euhydration with water or a carbohydrate-electrolyte solution during exercise improves perfusion parameters and sweating rates and reduces heat storage. Horses should be acclimated to hot environments before competition. Horses should not be given large meals (equal to half the ration) 1-2 hr before intense exercise, because plasma volume is decreased for at least 1 hr after a large meal. Large meals may also shift fluid to the GI tract, reducing cardiovascular and tl1ermoregulatory function dming exercise. Feeding smaller rations every 4 hr does not result in changes in plasma volLU11e. A sho1t-tenn reduction in fiber intake before high-intensity racing (fed as -1% of body wt in hay for 3 days before high-intensity exercise) is a strategy to reduce GI water volume and, hence, body weight. For endurance exercise, feeding before exercise, especially high-fiber feeds, is likely

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1014

FATIGUE AND EXERCISE

to be beneficial, because the increased water in the GI tract can be an important reservoir for water and electrolytes to replace sweat losses. Feeding high-fiber feeds also increases voluntary water intake. Glucose supplementation may be important in lintiting fatigue in endurance exercise in horses. Endurance time during treadmill running was prolonged by the IV infusion of a glucose solution during exercise. Plasma glucose was higher than controls, and plasma lactate and body temperature were lower at the point of fatigue. These results suggest that supplemental glucose during exercise prolongs performance time in horses. This increase may be due to increased glucose availability, reduced reliance on anaerobic energy production, lower core temperature, and better maintenance of plasma volun1e. In endurance horses, hydrolyzable starches and sugars fed within 3 hr of a race may increase glucose utilization in the short tem1 but inhibit lipid oxidation, which could be detrin1ental for energy production. Glycogen concentration in skeletal muscle before perfom1a.nce is relevant to fatigue during both short-tennlintense and prolonged endurance exercise. Depletion of muscle glycogen before exercise causes a decrease in anaerobic power generation and capacity for high-intensity work. Intense or prolonged exercise depletes the muscle glycogen stores, and it may take 48 hr for glycogen to be replenished in the horse. Although modest increases in glycogen stores may be obtained using high-starch diets in the horse, no benefit on performance has been shown. On the contrary, high­ carbohydrate diets have increased heart rates and blood lactate concentrations during intense exercise. Use of glucose or other carbohydrate solutions before racing to promote perfonnance in Standardbred and Thoroughbred racehorses has no scientific basis. Fat supplementation is now a widespread practice in diets for athletic horses and can increase perfom1ance during endurance exercise. Increased free fatty acid concentra­ tions in the bloodstream before prolonged exercise results in an increased use of fat as an energy source and in higher blood glucose and muscle glycogen concentrations during exercise. The shift to increased use of fat as a fuel results in lower respiratory demands for exercise, because less carbon dioxide must be expired when more fat is used for energy. Fat adaptation appears to facilitate the metabolic regulation of glycolysis by sparing glucose and glycogen at low-intensity work and by promoting glycolysis when power is

needed for high-intensity exercise. Adding fat to the diet also affects the metabolic and thermoregulatory response to exercise. Feeding vegetable oil at a rate of 100/o-12% of the total diet on a dry-matter basis has been suggested, but horses must be acclimated to !ugh-fat diets. In horses not acclimated, fat supplementation can slow the rate of muscle glycogen repletion. Creatine has been used in horses as an ergogenic aid, but there is no evidence of its efficacy. Horses receiving 25 g of creatine monohydrate bid for 6.5 days did not have significantly different run times until fatigue on a treadmill than control horses. Supplementation with creatine also had no significant effect on muscle or blood creatine concentrations at rest or after exercise until fatigue. An association between plasma vita.min E concentration and performance has been described in sled dogs. Dogs with a higher prerace vita.min E concentration were more likely to finish the race and were less likely to be withdrawn during tl1e race for poor health, fatigue, or other reasons. Vita.min E concentrations for the dog team overall were not associated with speed during the race. Additional studies are needed to investigate whether tl1e reduced signs of fatigue are directly linked to higher vita.min E concentrations in the bloodstream. Recovery: Recovery of horses after endurance exercise is influenced by tl1e rehydration strategy used. After prolonged treadmill exercise and furosemide-induced dehydration, horses offered a saline solution (0.9% NaCl) as the initial rehydra­ tion fluid maintained a plasma sodium concentration higher than that of control horses. The recovery of body weight was more rapid than in horses offered plain water. A similar study noted ambient temperature fluids were more palatable (20°C [68° F]) and increased voluntary intake. Water intake can also be increased by providing a saline solution (0.9% NaCl) both during and after endurance exercise. Sodiun1 chloride solutions may increase plasma chloride and accentuate a metabolic acidosis; as a result, isotonic polyionic electrolyte solutions fom1ulated specifically for horses should be selected. When providing electrolyte solutions, horses may need to be trained to drink these fluids, and plain water should always be available. However, use of electrolyte solutions should be encouraged, especially in horses required to compete on consecu­ tive days, such as in endurance rides and 3-day events.

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FEVER OF UNKNOWN ORIGIN

1015

FEVER OF UNKNOWN ORIGIN In both veterinary and human patients, fever may indicate infectious, inflamma­ tory, immune-mediated, or neoplastic disease. In most cases, the history and physical examination reveal the cause of the fever, or the fever resolves spontane­ ously or in response to antibiotic therapy. However, in a small percentage of patients, the cause of fever is not readily apparent, and the problem becomes persistent or recurrent.These patients are said to have fever of unknown origin (FUO). In human medicine, classic FUO is defined as fever >101° F (38.3° C) on several occasions over a period >2-3 wk with no diagnosis established after 3 outpatient visits or 3 days in the hospital. There is no recognized definition of this syndrome in veterinary medicine, making it difficult to determine its true preva­ lence. FUO is probably less prevalent now than in the past because of improved diagnostic technology (eg, imaging, molecular diagnostic tests). Body Temperature Regulation: Body temperature is regulated by the hypothala­ mus.This area of the brain acts as a thermostat to maintain temperature as close as possible to a normal set-point.The hypothalamus receives input from internal and external thermoreceptors, and it activates physiologic and behavioral activities that influence heat production, heat loss, and heat gain. Hyperthermia refers to any increase in body temperature above the normal range. Fever is a particular form of hyperthermia in which the heat loss and heat gain mechanisms are adjusted to maintain body temperature at a higher hypothalamic set-point; thus, fever is essentially a regulated hyperthermia. In nonfebrile cases of hyperthermia (eg, heat stroke, exercise-induced hyperthermia, malignant hyperthermia, seizure), body temperature is increased by abnormal and unregulated heat loss, heat gain, or heat production, and the hypothalamic set-point is not altered. Depending on their severity, these conditions can potentially result in body temperatures ;,cl06 ° F (41.1° C). In comparison, most patients with true fever have body

temperatures in the range of 103° - l06°F (39.5° -41.l ° C). An increase in the hypothalamic set-point may be initiated by exogenous pyrogens, which include drugs, toxins, and viral or bacterial products (eg, endotoxin).These pyrogenic stimuli lead to the release of cytokines, termed endogenous pyrogens, from inflammatory cells.Ultimately, locally synthesized prostaglandin E2 in the hypothalamus is responsible for increasing the set-point, resulting in fever. Etiology and Pathogenesis: FUO may be defined as fever that does not resolve spontaneously in the period expected for self-limited infection and for which a cause cannot be found despite considerable diagnostic effort. This excludes patients that respond to antibiotic therapy (and do not relapse) and patients in which the cause of fever is determined from initial history, physical examination, or laboratory tests, or in which fever resolves spontaneously. Infectious, immune-mediated, and neoplastic disease are the most common causes of FUO in dogs. In a study of 101 dogs with fever, 22% had immune-mediated diseases, 22% primary bone marrow abnormalities, 16% infectious diseases, 11.5% miscellaneous conditions, 9.5% neoplasia, and 19% genuine FUO. In cats, the cause is more likely to be infectious, but there are fewer published data on feline cases than on canine cases. In a case series of horses with FUO, 43% had infectious disease, 22% neoplasia, 6.5% immune-mediated disease, 19% miscella­ neous causes, and in 9.5% the cause was not determined. In farm animals, the most likely causes of FUO are infectious or inflammatory diseases such as pneumonia, peritonitis, abscesses, endocarditis, metritis, mastitis, polyarthritis, and pyelonephritis. Diagnosis: The key to diagnosis of FUO is to develop and follow a systematic plan that allows for the detection of both common and uncommon causes of fever. The plan should always include repetition of relevant tests, because findings can change over time. Owners should be informed that diagnosis of FUO may require considerable time and patience

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FEVER OF UNKNOWN ORIGIN

and may demand more advanced or expensive diagnostic tests. Nevertheless, simple and inexpensive tests may also reveal diagnostic clues that eventually point to the cause of the fever. In one retrospective study of fever in dogs, radiography, cytology, and bacterial or fungal cultures of tissues or fluids were found to be the most useful diagnostic tests. A staged or tiered approach to diagnosis can assist in choosing appropriate tests. The first stage should include history, physical examination, ophthalmic and neurologic examinations, CBC, fibrinogen, serum chemistry profile, urinalysis and urine culture, feline leukemia virus and feline immunodeficiency virus tests (cats), and usually thoracic and abdominal radiographs in small animals. Any medications that could induce fever should be discontinued. In the second stage, some first-stage tests may be repeated (particularly the physical examination), and additional specialized tests are performed. These may be dictated by abnormal findings in the first stage of testing or may be determined by consideration of the most common known causes of FUO. Tests included in this stage include blood cultures, arthrocentesis, abdominal ultrasonography, lymph node aspiration, aspiration of other organs or masses, analysis of body fluids (eg, fluid from body cavities, milk samples, reproductive tract secretions), rectal cytology, fecal culture, echocardiography (in the presence of a murmur), long-bone and joint radiographs, contrast radio­ graphs, serology, and molecular diagnos­ tic tests. In the third stage, earlier tests may be repeated again, as well as additional specialized proceck!res. These procedures are most likely to be chosen on the basis of previous findings but may also be considered when all previous testing has been unrewarding. Examples include echocardiography (in the absence of a murmur), dental radiographs, bone marrow aspiration, bronchoscopy and bronchoalveolar lavage, CSF analysis, CT, MRI, laparoscopy, thoracoscopy, biopsies, exploratory surgery, or trial therapy. History and Physical Examination:

Epidemiologic characteristics such as vaccination, parasite control, exposure to vectors, and travel history should always be reviewed. The response to previous medications should be determined, as well as the presence of illness in other animals or people. Owners should be questioned

carefully about specific clinical signs, because these may help localize the source of the fever. The physical exan1ination should be detailed; always include fundic, neurologic, and rectal exan1inations; and repeated frequently. CBC and Serum Chemistry Profile: The CBC and chemistry changes in animals with FUO are often nonspecific but may suggest further diagnostic tests. For example, bile acids assay may be indicated in an animal with changes suggestive of hepatic dysfunction. The CBC should always be accompanied by blood smear evaluation to detect parasites or morphologic changes. Urine Culture: This test is always indicated to evaluate FUO in small animals, regardless of the appearance of tl1e urine sediment. Radiography and Advanced Imaging:

Thoracic and abdominal radiographs are useful screening tools for the early localization of fever. Skeletal radiographs and contrast radiographs may subsequently be considered, depending on initial findings. For exan1ple, myelography may be used to investigate back pain. The use of techniques such as CT or MRI is determined by the results of initial diagnostic testing or by consideration of the body system of interest, eg, MRI is particularly useful to evaluate the CNS. Advanced imaging with nuclear scintigraphy or positron emission tomography is used in human patients with FUO but is not yet widely reported in veterinary medicine. Ultrasonography and Echocardiogra­ phy: Abdominal ultrasonography may

reveal a source of fever in the abdomen, such as neoplasia, peritonitis, pancreatitis, or abscesses. The thoracic cavity, limbs, and retrobulbar areas may also be exan1ined by ultrasound. Echocardiography is indicated at the early stages of evaluation of the FUO patient with a murmur. This may aid in the detection of endocarditis, although this diagnosis should also be based on signalrnent, characteristics of the heart murmur, and blood culture results. Bone Marrow Evaluation: Bone marrow cytology and histology should be evaluated in any animal with unexplained CBC abnormalities. Bone marrow disease is a common cause of FUO in small animals; therefore, bone marrow aspiration and biopsy, if possible, should also be included in the second stage of diagnostic testing in these patients. When obtaining bone marrow aspirates from

FEVER OF UNKNOWN ORIGIN

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cats, a sample should be saved for possible molecular diagnostic testing for feline leukemia virns. Arthrocentesis: Because immune­ mediated polyartlu·itis is a common cause of FUO in dogs, aithrocentesis of multiple joints is included in the second stage of diagnostic testing in this species, even if the joints are nom1al on palpation. Some dogs with steroid-responsive meningitis-arteritis also have concurrent inunune-mediated polyarthritis; therefore, arthrocentesis should be performed in dogs with spinal pain. Infectious polyarthritis is more commonly recognized in large ai1imals, in which arthrocentesis is ai1 importai1t diagnostic test. CSF Analysis: CSF sainpling is recom­ mended for dogs with FUO if less invasive tests do not reveal the cause of the fever. Fluid should be submitted for cytology, protein measurement, ai1d culture. Blood Culture: Blood cultures are recommended in all animals with unex­ plained fever. The techniques used should allow the collection of adequately large volun1es of blood under aseptic conditions. If the size of the ai1imal allows collecting more thai.1 one set of sainples for blood culture, using appropriately sized aerobic ai1d ai1aerobic bottles increases the sensitivity ai1d specificity of the test. Special enrichment culture methods may be considered for certain organisms, eg, Barlonella spp. Infectious Disease Testing: Tests available for the diagnosis of infectious diseases include assays for detection of ai1tibodies or ai1tigen in blood, body fluids, or tissues. Molecular diagnostic tests detect nucleic acid, with PCR being the most common in this category. Selection of these tests should be based on the signalrnent, clinical signs, ai1d epidemiologic character­ istics of the animal. Interpretation of test results requires aJ.1 understanding of disease prevalence, vaccination history, ai1d sensitivity ai1d specificity of the test. When requesting PCR-based assays, it is in1porta.J.1t to use laboratories that have quality mai1agement prograins that address test perfo1mai1ce ai1d consistency, ai1d control for sainple contan1ination. Other Serologic Tests: The value of immune pai1els or autoai1tibody screens in small ai1imal patients with FUO is unclear. Neither ai1tinuclear ai1tibody nor rheun1a­ toid factor titers alone should be used to

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diagnose systemic lupus erytl1ematosus or rheun1atoid arthritis, respectively. Microbiology, Cytology, and Histology: Fine-needle aspirates are safe ai1d simple to obtain from effusions, masses, nodules, orgai1s, tissues, ai1d body fluids. Fluids should be exainined cytologi­ cally ai1d also submitted for microbiologic or molecular diagnostic testing. Tissue biopsies are generally obtained in the second or third stages of diagnostic testing, after clinical signs or initial diagnostic tests have localized the fever. When biopsies are obtained, sufficient samples should be submitted for histopa­ thology, appropriate culture (aerobic ai1d ai1aerobic, fungal, mycoplasmal, mycobac­ terial, etc), moleculai· diagnostics, ai1d special stains. If exploratory surgery is perfom1ed, biopsies should be obtained from several sites. Treatment: In some FUO cases a specific

diagnosis is not reached, or diagnostic testing is discontinued, leading to consideration of therapy in the absence of a diagnosis. Options include ai1tibiotics, ai1tifungal agents, ai1d anti-inflammatory or immunosuppressive therapy (usually with corticosteroids). Trial therapy may resolve the clinical signs or confirm a presumptive diagnosis, but it is also associated with significai1t risk. Before pursuing a therapeutic trial, the owner should be informed of the potential risks ai1d should be committed to careful monitoring of the ai1imal for aJ.1 appropri­ ate length of time. The therapeutic trial should be based on a tentative diagnosis ai1d should define the parai11eters to be followed ai1d the criteria used to deter­ mine treatment success or failure. If aJ.1 ai1imal is likely to be referred for in-depth investigation of FUO, trial therapy should not be started because it may affect the results of further testing. In true fever, the increase in body temperature is regulated; therefore, cooling methods such as water baths work against the body's own regulatory mecha.J.1isms. It is also likely that fever itself has some beneficial effects, particulai·ly in infectious diseases. However, fever cai.1 lead to ai1orexia, lethargy, ai1d dehydration. Thus, a.J.1imals with FUO may benefit from IV fluid therapy or ai1tipyretic medications. Exainples include NSAIDs such as aspirin, carprofen, ketoprofen, ai1d meloxican1 in small a.J.1imals, and flunixin meglumine or phenylbutazone in large animals.

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HEPATIC LIPIDOSIS

HEPATIC LIPIDOSIS FATTY LIVER DISEASE OF CATTLE Fatty liver results from a state of negative energy balance and is one of the important metabolic diseases of postparturient dairy cows. Although often considered a postpartum disorder, it usually develops before and during parturition. Periparturi­ ent depression of feed intake, and endocrine changes associated with parturition and lactogenesis contribute to development of fatty liver. Cows that are overconditioned at calving are at highest risk. Fatty liver can develop whenever there is a decrease in feed intake and may occur secondary to the onset of another disorder. Fatty liver at calving is commonly associated with ketosis (seep 1024). Etiology: Mobilization of body fat reserves that is triggered by hom1onal cues in states of negative energy balance results in the release of nonesterified fatty acids (NEFAs) from adipose tissue. The liver retains -15%-200/o of the NEFAs circulating in blood and thus accumulates increased amounts du1ing periods when blood NEFA concentrations are increased. The most dramatic increase occurs at calving, when plasma concentrations are often >1,000 µEq/1. Concentrations can reach that level if the animal goes off feed. NEFAs taken up by the liver can either be oxidized or esterified. The primary esterification product is triglyceride, which can either be exported as part of a very low density lipoprotein (VLDL) or be stored iu liver cells. In ruminants, export occurs at a very slow rate relative to many other species because of impaired VLDL synthesis. Therefore, under conditions of increased hepatic NEFA uptake and esterification, triglycerides accumulate. Oxidation of NEFAs leads either to the production of ATP in the tricarboxylic acid cycle or to the formation of ketones through peroxisomal or !3-oxidation. Ketone formation is favored when blood glucose concentrations are low. Conditions that lead to low blood glucose and insulin concentrations also contribute to fatty liver, because insulin suppresses fat mobilization from adipose tissue. The greatest increase in liver triglycer­ ide typically occurs at calving. The extent of feed intake depression before and after calving or during disease in combination

with the amount of available body fat reserves moderates the degree of triglyceride accumulation. Excessive intracellular triglyceride accumulation in liver cells results in disturbed liver function and cell damage. Fatty liver can develop within 24 hr of an animal going off feed. Although lipid accumulation in the liver is a reversible process, the slow rate of triglyceride export as lipoprotein causes the disorder to persist for an extended period. Depletion of the liver lipid content usually begins when the cow reaches positive energy balance and may take several weeks to fully subside. Fatty liver is not a consequence of positive energy balance or overfeeding. Energy consumption above requirements for maintenance and productive purposes will not directly result in deposition of triglyceride in hepatic tissue. Triglyceride deposition will occur only if the animal becomes overconditioned and consequently reduces feed intake. Clinical Findings: There are no pathogno­ monic clinical signs of fatty liver disease in cattle. The condition is often associated with feed intake depression, decreased milk production, and ketosis. Increased blood NEFA concentration has been associated with impaired immune function and a proinflammatory effect, presumably reflecting in increased incidence of clinical mastitis, metritis, and other periparturient infectious diseases. However, cause and effect has not been established. Metabolic consequences of triglyceride accun1ulation in the liver include reduced gluconeogen­ esis, ureagenesis, hormone clearance, and hormone responsiveness. Consequently, hypoglycemia, hyperammonemia, and altered endocrine profiles may accompany fatty liver. Fatty liver is likely to develop concur­ rently with another disease, typically disorders that are seen at or shortly after calving. These include metritis, mastitis, abomasal displacement, or hypocalcemia. Field observations suggest that response to treatment of concurrent disorders is poor if cows have extensive triglyceride infiltration of the liver. Cows slow to increase in milk production and feed intake after calving are likely to have fatty liver. However, fatty liver is probably the result rather than the cause

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HEPATIC LIPIDOSIS

of poor feed intake. Fatty liver is often associated with obese cows and downer cows (seep 1188) but is unlikely to be a direct cause of the downer cow syndrome. Overconditioned cows exhibit more pronounced feed intake depression before and after calving than nonobese cows and, therefore, are susceptible to fatty liver. Although obesity predisposes to fatty liver disease, it is not restricted to obese cows. Similarly, obese cows do not necessarily have fatty liver.

Diagnosis: Diagnostic tools for fatty liver are of limited value. Fa.tty liver is usually diagnosed after the animal has been off feed or has died because of another disease. A positive diagnosis does not mean that clinical signs of illness are the result of fatty liver, and misinterpretation of a positive diagnosis is common. Liver biopsy is a minimally invasive procedure that is the only direct and most reliable method to determine severity of fatty liver in dairy cattle. Measurement of total lipid or triglyceride content by gravin1etric or chemical methods after extraction from tissue by organic solvents is necessary for quantitative assessment; however, these assays are not routinely conducted in commercial laboratories. Estimation of triglyceride content by flotation characteristics of the tissue in copper sulfate solutions of varying specific gravity is rapid, easy, and available for use under field conditions. Blood and urine metabolites or blood enzyme activity have been proposed as indirect diagnostic para.meters. Blood glucose concentrations are low and blood NEFA and 13-hydroxybutyra.te concentra­ tions are high when conditions are conducive to the development of fatty liver. Blood cholesterol concentration is usually low when fatty liver occurs, which may reflect an impaired ability of the liver to secrete lipoproteins. AST, ornithine decarboxylase, and sorbitol dehydrogenase are hepatic enzyn1es that may be positively associated with liver triglyceride and liver damage. The total bilirubin concentration in blood is often positively associated with the NEFA concentration in blood. Blood metabolites or enzyn1es are unreliable indices of the degree of fatty liver, because nom1al concentrations vary widely an1ong animals. The same problem exists when attempting to detem1ine liver function by measuring sulfobromophthalein clearance from blood. With the availability of handheld devices allowing cowside testing, measuring

1019

13-hydroxybutyra.te concentration in blood has become a popular way to identify herds that may be at risk of developing fatty liver. Measurement of plasma NEFA concentration is more expensive and requires submission of blood samples to a diagnostic laboratory. In addition to extreme variations in plasma NEFA concentrations among animals, there is extreme variation in a single individual, because concentrations increase dramatically immediately before and after calving. Therefore, a large number of animals must be san1pled at a consistent time relative to calving. Ca.re must be taken not to excite animals before sampling blood, because NEFAs increase rapidly in response to stress; samples should be drawn at standru·dized times using standardized procedures. The plasma NEFA concentrations at which triglyceride accun1Ula.tes in the liver have not been established but are probably -600 µEq/L and higher. These concentrations are common within 24-48 hr of parturition. However, prolonged exposure of the liver to concentrations >600 µEq/L will likely lead to fatty liver. Primiparous cows are less susceptible to fa.tty liver during peri­ ods of increased plasma NEFAs. There­ fore, mature animals should be sampled when using plasma NEFAs as a predictor of fatty liver. To screen a herd for the prevalence and severity of hepatic lipidosis, detem1ination of plasma NEFAs not eru·lier than 1 wk antepartum is recommended. Even though plasma NEFA concentration is a direct para.meter for the lipid mobilization and thus the liver lipid accumulation, after parturition the plasma 13-hydroxybutyra.te concentration has been found to more accurately reflect the severity of hepatic lipidosis. Microscopic evaluation can be used to estimate the volwne of the tissue occupied by fat. Estimates obtained by this method agree fairly well with chemical detennina­ tion of triglyceride when expressed as a percentage of tissue dry weight. Mild, moderate, and severe fatty liver are often defined as 30,000 WBC/mm3 and a total protein level of>4g/dL. In foals,hematogenous osteomyelitis often accomparues septic arthtitis. Septic arthritis in foals has been classified into type S (septic joint only), type P (involving osteomyelitis of the adjacent growth plate as well), or type E (involving osteomyelitis of the epiphyseal and subchondral bone). Vaiious organisms may be involved. In young lainbs,Actinobacillus seminis causes polyartht·itis, as do Chlamydia psittaci and E1ysipelothrix insidiosa. The latter can follow docking, castration, or navel infection. Viruses and mycoplasma may also be etiologic agents in food-produc­ ing anin1als. In mature goats, caprine arthritis and encephalitis virus (see p 7 47) is an inlportant cause of infective arthritis. In young goats, C psittaci and Mycoplasma mycoides are frequent causes. Bacte1ial (includingMycoplasma) arthritides are seen in young pigs. In newborn pigs, septic artluitis usually is due to intraute1ine or navel infection with Escherichia coli, ConJnebacterium, Stre'[J­ tococcus, or Staphylococcus spp. Control is

best directed toward reducing the possibility of infection from the environment. Older pigs sometimes develop arthritis as a sequela of infection with Haemophilus, Erysipelothrix, or Mycoplasma spp. Although diagnosis in the early stages is not difficult, the more chronic stages can be confused with articulai· lesions produced by dietaiy hypervitarninosis A Trawnatic injury to joints with contami­ nation and progression to infection is common in horses, and various species of bacteria are involved. Infection associated with intra-articulai· injection or smgery occms in horses and is usually associated with Staphylococcus aureus or S e'[Jider­

midis.

1063

Treatment: Septic arthritis requires

prompt treatment to avoid irreparable dan1age. Systemic broad-spectrwn antibiotics are indicated; the initial choice is based on the most likely pathogen but is subject to change based on cultme and sensitivity tests. Systemic antibiotic treatment is often combined with intra­ articular antibiotics (to achieve more effective sterilization of the joint) and other local therapy, including joint lavage (initially) ai.1d arthroscopic debridement and drainage. Adjunctive treabnent with NSAIDs (eg, phenylbutazone) is also done. The effectiveness of treab11ent is monitored carefully with clinical signs and repeat synovial fluid analyses.

Osteoarthritis (Degenerative joint disease)

Etiology and Epidemiology: Osteo­ arthritis is a progressive degradation of articulai· caitilage and represents the end stage of most of the other diseases discussed above if treatment is ineffective or the initial problem is too severe. For this reason, prompt diagnosis ai.1d correct management of traun1atic synovitis and capsulitis, intra-aiticulai· fractmes or traw11atic cartilage damage, osteochond1itis dissecans, subchondral cystic lesions,and septic arthritis are critical. Clinical Findings and Diagnosis: Lame­

ness can be localized with analgesia to.the affected joint. There ai·e varying degrees of synovial effusion,joint capsule fibrosis, and restricted motion (decreased flexion). Radiographic signs of osteoarthritis include decreased joint space, osteophytosis, enthesitis, ai.1d subchondral sclerosis. In less severe cases, articular degradation requires definition with arthroscopy.

Treatment: Treatment of osteoarthritis is

most commonly palliative and includes the use ofNSAIDs, polysulfated intra-aiticular glycosaniinoglycans, intra-articulai· corticosteroids, IV hyaluronic acid, and IM pentosan polysulfate. The use of intra­ articular autologous conditioned serwn has also been validated. Physical therapy regin1ens may prove useful. Artht·oscopy is conunonly performed to diagnose the extent of articular cartilage loss, as well as to treat p1irnary conditions such as articulai· cartilage separation,meniscal tears, and ligan1entous injury. In advanced cases of osteoarthritis, smgical fusion (arthrodesis) may be performed on selected joints.

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ARTHROPATHIES IN LARGE ANIMALS

Surgical fusion of the proximal interphalan­ geal joint (pastern) or distal tarsal joints can effect athletic soundness. Fetlock arthro­ desis is also done in valuable animals and makes them comfortable and capable of breeding. Treatment is usually unsuccessful in chronic cases in bulls and cows, but restricted exercise and careful feeding and nursing prolong the life of and can be worthwhile for valuable breeding animals.

BURSITIS Bursitis is an inflanm1at01y reaction within a bw-sa that can range from mild inflamma­ tion to sepsis. It is more common and in1portant in horses. It can be classified as true or acquired. True bursitis is inflamma­ tion in a congenital or natural bursa (deeper than the deep fascia), eg, trochanteric bursitis and supraspinous bursitis (fistulous withers, see below). Acquired bursitis is development of a subcutaneous bursa where one was not previously present or inflammation of that bursa, eg, capped elbow over the olecranon process, shoe boil over the point of the elbow, and capped hock over the tuber calcaneus. Bursitis may manifest as an acute or chronic inflanunation. Examples of acute bursitis include bicipital bursitis and trochanteric bursitis in the early stages. It is generally characterized by swelling, local heat, and pain. Chronic bursitis usually develops in association with repeated traun1a, fibrosis, and other chronic changes (eg, capped elbow, capped hock, and carpal hygroma). Excess bursa! fluid accumulates, and the wall of the bursa is thickened by fibrous tissue. Fibrous bands or a septun1 may form within the bursa! cavity, and generalized subcutaneous thickening usually develops. These bursa! enlarge­ ments develop as cold, painless swellings and, unless greatly enlarged, do not severely interfere with function. Septic bursitis is more serious and is associated with pain and lan1eness. Infection of a bw-sa may be hematogenous or follow direct penetration. The pain in acute bursitis may be relieved by application of cold packs, aspiration of the contents, and intrabursal medication. Repeated ir\jections may result in infection. Treatment of chronic bmsitis is sw-gical (and is done arthroscopically (bursoscopy). In infected bursitis, systemic antibiotics as well as local drainage are required.

Capped Elbow and Hock Capped elbow and hock are inflanm1atory swellings of the subcutaneous bursae

(acquired bursitis) located over the olecranon process and tuber calcaneus, respectively, of horses. Frequent causes include trauma from lying on poorly bedded hard floors, kicks, falls, riding the tailgate of trailers, iron shoes projecting beyond the heels, and prolonged recumbency.

Clinical Findings and Diagnosis: Cir­ cw11scribed edematous swelling develops over and around the affected bursa. Lame­ ness is rare in either case. The affected bursa may be fluctuating and soft at first but, in a short tin1e, a fim1 fibrous capsule forms, especially if there is a recmTence of an old injmy. Initial bursa! swellings may be hardly noticeable or quite sizable. Chronic cases may progress to abscessation. Treatment: Acute early cases may

respond well to applications of cold water, followed in a few days by aseptic aspiration and injection of a corticosteroid. The bursa may also be reduced in size by application of a counterirritant or by ultrasonic or radiation therapy. Older encapsulated bursae are more refractory. Surgical treatment (usually cmettage and drainage) is reconm1ended for advanced chronic cases or for tl1ose that become infected. A shoe-boil roll should be used to prevent recmTence of a capped elbow if the condition has been caused by the heel or the shoe. With capped hock, behavioral modification so the horse does not kick the stall offers the only hope of pem1anently resolving the problem.

Fistulous Withers and Poll Evil Fistulous withers and poll evil are rare, inflammato1y conditions of horses that differ essentially only in their location in the respective supraspinous or supra-atlantal bursae. Th.is discussion is of fistulous witl1ers but, except for anatomic details, also applies to poll evil. In the early stage of the disease, a fistula is not present. When the bursa! sac ruptures or when it is opened for surgical drainage, and secondary infection with pyogenic bacteria occurs, it usually assumes a true fistulous character.

Etiology: The condition may be t.rawnatic or infectious in origin. Agglutination titers suppmt an infectious etiology. Brucella abortus can sometimes be isolated from the fluid aspirated from the unopened bursa. Clinical Findings: The inflanm1ation

leads to considerable thickening of the bursa wall. The bursa! sacs are distended

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ARTHROPATHIES IN LARGE ANIMALS

and may rupture when the sac has little covering support. In more chronic, advanced cases, the ligament and the dorsal ve1tebral spines are affected, an.ct occasion­ ally these structures necrose. In the early stage, the supraspinous bursa distends with a clear, straw-colored, viscid exudate. The swelling may be dorsal, unilateral, or bilateral, depending on the arrangement of the bmsal sacs between the tissue layers. It is an exudative process from the beginning, but no true suppmation or secondary infection occurs until the bursa ruptures or is opened.

Treatment and Prevention: The earlier treatment is instituted, the better the prognosis. The most successful treatment is complete dissection and removal of the infected bursa. The expense of the protracted treatment required in chronic cases often exceeds the value of the animal. Brucella vaccines have not proved helpful. Sodium iodide therapy is of limited value.

CHLAMYDIAL POLYARTHRITIS­ SEROSITIS (Transmissible serositis)

Chlamydia! polyarthritis-serositis is an infectious disease that affects sheep, calves, goats, and pigs. Chlan1ydial polyarthritis of sheep was first described in Wisconsin and has since been recognized in the western USA, Australia., and New Zealand. The disease was identified in calves from the USA, Australia., and Austria, and in pigs from Austria, Bulgaria., and the USA.

Etiology and Epidemiology: Strains of the causal a.gent, Chlamydia psitlaci, isolated from affected joints of sheep and calves, are identical, but strain-specific antigens in their cell walls distinguish them from those that ca.use abortions in sheep and cattle (seep 1332). The GI tract is of prime importance in the pathogenesis of chlan1ydial polyarthritis (seep 598). The disease has been repro­ duced experimentally by oral inoculation. Because chlan1ydia.e can be recovered from the feces of clinically healthy calves and lambs, it is most likely the GI tract wherein the host and parasite stay frequently in balance. If there is a shift in favor of the chlan1ydia.e, then a systemic infection and chlamydemia. ensues; the ultimate site of replication is the synovial membrane. The GI tract also has been infected after experimental intra-articular inoculations. Chlamydiae are excreted in the feces and

1065

urine and transmitted via ingestion or, in some cases, inhalation.

Clinical Findings: Chlamydia! polyarthri­ tis is seen in lambs on range, on fa.nns, and in feedlots. Morbidity may be 5%---75%. Rectal temperatures are 102°-107°F (39°-41.5°C). Varying degrees of stiffness, lameness, anorexia., and a concurrent conjunctivitis (see p 506) mity be seen. Affected sheep are depressed, reluctant to move, and often hesitate to stand and bear weight on one or more limbs, but they may "warm out" of stiffness and lameness after forced exercise. Incidence of the disease in sheep on range is highest between late swnmer and early winter. The disease affects cattle of all ages, but calves 4----30 days old a.re affected more severely. Calves may have fever, are moderately alert, and usually nurse if carried to the dam and supported while sucking. They invariably also have diarrhea., which can be severe. Affected calves a.sswne a hunched position while standing; theirjoints usually are swollen, and palpation ca.uses pain. Navel involvement and nervous signs are not seen. Chlamydia] polyarthritis has been recognized in older pigs as well as in young piglets. The affected piglets become febrile and anorectic and may develop nasal cata.n·h, difficulties in breathing, and conjunctivitis. This condition has not been clearly differentiated from other infections that lea.cl to polyserositis and arthritis in pigs. Lesions: The most striking tissue changes are in the joints. In lambs, enlargement of the joints is not often noticed, but in chronic· advanced cases, the stifle, hock, and elbow may be slightly enlarged. In calves, peliarticular subcutaneous edema along tendon shea.tl1s and fluid-filled, fluctuating synovial sacs contribute to enlargement of thejoints. Most affected joints of lambs or calves contain excessive, grayish yellow, turbid synovial fluid. Fibrin flakes and plaques in the recesses of the affected joints may adhere firmly to the synovial mem­ branes. Joint capsules a.re thickened. Articular cartilage is smooth, and erosions or evidence of marginal compensatory changes are not present. Tendon sheaths of severely affected lambs and calves may be distended and contain creamy, grayish yellow exudate. Surrotmding muscles are hyperemic and edematous, with petechia.e in their associated fascia! planes. Diagnosis: The history and careful exanlination of the pathologic changes in the joints and other organs can be of

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ARTHROPATHIES IN LARGE ANIMALS

diagnostic value. Cytologic examination of synovial fluids or tissues may reveal chlamydia! elementary bodies or cytoplas­ mic inclusions. Isolation and identification of the causative agent from affected joints confirms the diagnosis. Bacteriologic cultmes of affected joints a.re usually negative, but Escherichia coli or strepto­ cocci occasionally may be isolated. If the joints of young calves a.re arthritic, and if navel lesions are absent, chlamydia! polya.rthritis should be considered. Clinical and pathologic features distin­ guish chlamydia! polyaithritis from most other conditions that cause stiffness and lai11eness in lambs. Lambs with mineral deficiency or osteomalacia usually a.re not febrile. The abnormal osteogenesis in these two conditions ai1d the distinct lesions of white muscle disease a.re virtually pathogno­ monic. In arthritis ca.used by E1ysipelothri..'"C rhusiopa.thiae, there a.re deposits on and pitting of articular surfaces, peria.rticula.r fibrosis, and osteophyte fonnation. Larninitis due to bluetongue virus infection (seep 738) can be differentiated clinically and etiologi­ cally. Detailed microbiologic investigations a.re required to differentiate chlamydia! arthritis from mycoplasmal artluitis.

Treatment and Prevention: If begun

early, therapy with long-acting penicillin, tetracyclines, or tylosin appears to be beneficial. More advanced lesions do not respond satisfactorily. Feeding chlortetra­ cycline at 150-200 mg/day to affected lai11bs in feedlots reduces the incidence of chlamydia! polyarthtitis. No approved vaccines a.re available.

TENOSYNOVITIS Tenosynovitis, an inflanl.lllation of the synovial membrane and usually the fibrous

layer of the tendon sheath, is characterized by distention of the tendon sheath due to synovial effusion. It has a mUTiber of possible causes and clinical manifestations. The various types of tenosynovitis include idiopathic, acute, chronic, and septic (infectious). Idiopathic synovitis refers to synovial distention of tendon sheaths in yow1g ailin1als, in which the cause is uncertain. Acute and chronic tenosynovitis a.re due to trawna. Septic tenosynovitis may be associated with penetrating wounds, local extension of infection, or a hematog­ enous infection.

Clinical Findings and Diagnosis: There

a.re varying degrees of synovial distention of the tendon sheath ai1d laineness, depending on the severity. Horses are markedly Jaine in septic tenosynovitis. Chronic tenosynovitis is common in horses in the tai·saJ sheath of the hock (thoroughpin) and in the digital sheath (tendinous windpuffs). These two entities must be differentiated from synovial effusion of the tarsocnrral ai1d fetlock joints, respectively.

Treatment: In idiopathic cases, no

treatment is initially recommended. Acute cases with clinical signs may be treated symptomatically with cold packs, NSAIDs, and rest. Tenoscopic surgery is often used to treat specific conditions within the tendon sheath that give rise to tenosynovitis symptoms. Application of counterirritants ai1d bandaging has been used in more chronic cases. Septic tenosynovitis requires systemic antibiot­ ics and drainage. If adhesions develop between the tendon sheath and the tendon, persistent effusion and lameness is the rule.

LAMENESS IN CATTLE The lesions that cause lameness in dairy cows result in intense pain and a.re a major aninlal welfare issue. Lameness also causes stress, which debilitates and reduces productivity. The financial impact of lan1eness includes losses from decreased production, cost of treatment, prolonged calving interval, ai1d possibly nmsing labor.

Loss of milk of 1. 7-3 Uday for up to 1 mo before and 1 mo after treatment (because of pain) plus milk discarded because of antibiotic therapy must also be considered. Lame cows a.re more reluctai1t to use automatic milking systems and show visible signs of stress when forced to do so. At least 10% of cows in a herd are culled for reasons related to lan1eness. Rea.ring replacement heifers is expensive, and

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LAMENESS IN CATILE replacement animals are not initially as productive as mature cows. Cows in poor condition have a greater predisposition to lameness. Cows that are lame before breeding have a reduced ability to conceive, and cystic ovaries are much more common in lame cows. Lame cows are less aggres­ sive in their struggle for feed and are more likely to die early or be culled. Considerable funds are being invested in bovine lameness research; within the next decade, national databases detailing bovine lameness are expected to become increasingly available as a management tool. Although the lameness data are being collected primarily by hoof tlimmers, veterinruians should be familiar with this information to continue to play a leading role in management of bovine lru11eness.

PHYSICAL EXAMINATION OF A LAME COW Visual Appearance of the Standing Animal: Abrasions or swellings on the

limbs suggest a prior traumatic event. Decubital lesions (to the knee or more often the hock) might indicate prolonged periods of recwnbency or difficulty when rising. Cubicle design should be reviewed. Muscular atrophy, particularly noticeable in the gluteal region, can be associated with a painful condition such as arthritis. Cows experiencing exti·eme pain can Jose body condition rapidly. Stance or posture can change as the bearing surface of the claw wears or there is a painful lesion in the foot. In a nom1al stance, the point of the hock (tuber calcanei) lies directly beneath the pin bone (ischial tuber) when viewed either from tl1e side or from behind. Approximately 6096 of the body weight is borne by the forelimbs. A Jame anin1al adjusts its posture to relieve pain. The following principles illustrate specific exru11ples of changes in stance or posture related to lameness: 1) A painful abscess in a lateral hind claw causes the cow to abduct that limb. 2) Pain in the heel of the hind foot forces the cow to hold its foot to tl1e rear, a posture known as "camping back" or retraction. 3) After a cow has spent much time walking on concrete, the lateral hind claw may become overbur­ dened (excessive buildup of solear horn). This forces the hock to tum inwru·d, a posture referred to as "cow hocked." 4) Pain in the toe, which occurs in laminitis, causes the cow to hold its hind feet further forward than nom1al, a posture referred to as "camping forward" or protraction. This

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posture cru1 be confused witl1 a conforma­ tional defect referred to as "sickle hock," in which the angle of the hock is 4 yr old. Although corkscrew claws are rarely seen in bulls, many believe there is a heritable component.

Pathogenesis: Bone molding is seen in the

distal phalanx, but it is not known whether this is a matter of cause or effect. Periarticu­ lar exostoses develop around the distal interphalangeal joint, possibly resulting

corkscrew claw requires much skill. The horn forn1ation is extremely hard and difficult to cut. The abnonnally naiTow shape of the distal phalanx makes it difficult to pare the claw without causing bleeding at the toe. The strategy is to sho1ten the claw as much as possible without causing bleeding. Next, the horn wall that is displaced beneath the claw is cut away. Then, so fai· as is possible, the horn is shaped to approxin1ate norn1al. Trinuning helps the anin1al get around for a while but does not "cure" the condition. Affected animals should ultimately be culled.

SLIPP ER FOOT A slipper foot is nained for its alleged likeness to a Persian slipper. The claw is flat and curled upward to fonn a squai·e end. The horn is heavily ridged and has lost its shine, and the coronary bai1d is rougher and dai·ker than normal. Although tl1ere is no objective evidence to suppmt the theory, the slipper foot is probably synonymous with chronic laininitis and may be a sequela of either acute or subclinical larninitis. Treatment is always disappointing. The claw can be shaped to approximate nonnal, but invaiiably it collapses and serious sequelae follow. Animals with slipper foot should be culled as soon as economically appropriate.

ANKYLOSING SPONDYLOSIS In ankylosing spondylosis, exostoses develop on the ligan1ent of the ventral aspect of the lumbar vertebrae, primarily in older bulls. Fracture of the exostosis and associated ve1tebrae causes pressure on the spinal cord, which results in severe ataxia or paralysis. There is no treatment.

DEGENERATIVE ARTHROPATHY

Corkscrew claw. Courtesy of Dr. Paul Greenough.

This nonspecific condition affecting mainly the hip and stifle is characterized by degeneration of articular cartilage and ebumation of subchondral bone,joint effusion, and fibrosis with calcification of tl1e joint capsule.

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LAMENESS IN CATILE

Etiology: Many causes and predisposing factors influence the development of degenerative joint lesions. There is almost certainly an inherited predisposition to the condition. Certain confonnations, eg, straight hocks in beef bulls, are also incriminated. Joint instability after trauma is a common cause. Nutritional factors involved in some cases, such as rations high in phosphorus and low in calcium, influence the strength of subchondral bone. Copper deficiency or fluoride poisoning also may act sinillarly. Forced traction of a calf in breech presentation can impede the blood supply to the hip joint, and arthritis may result. The role of infection is unclear. Infectious arthritis in calves usually produces severe changes in the hock, but degenerative arthropathy rarely involves this joint. Bulls fed high-grain diets for show may become lame when as young as 6-12 mo, but most cases are first noticed at 1-2 yr. Clinical Findings: Onset is gradual (later in bulls), and both hip joints are usually affected; stifle involvement is rare. Lameness to the point of incapacitation, with crepitation of degenerate joints, may develop in a few months; however, correlation between pathologic changes and clinical signs is poor. The earliest changes occur in the acetabulum and on the dorsomedial surface of the femoral head. In the stifle, the medial condyle of the femur shows the earliest changes. Because degenerative arthropathy may result from any of several initiating factors, a specific diagnosis may be difficult. Radiographic, cytologic, and microbio­ logic evaluation of the synovial fluid are useful diagnostic aids. Arthroscopy of articular surfaces and ligan1ents may help attain a definitive diagnosis and prognosis. Treatment: Changes in the joints are

usually irreversible by the time of diagnosis. Palliative treatment of valuable breeding anin1als should be undertaken with the knowledge that the condition or predispos­ ing factors may be inherited. The diet should be carefully analyzed and, if necessary, corrected. This is especially important in fast-growing anin1als, in which adequate exercise is indicated and overfinishing should be avoided.

COXOFEMORAL LUXATION Luxation of the coxofemoral joint is usually upward. It is seen in cows riding each other. The affected limb appears shorter than the contralateral limb. The hock is turned inward

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and, when trying to walk, the anin1al appears to be dragging one foot behind the other.

Treatment: Resolution is possible,

provided that the head of the femur or the rim of the acetabulum has not been fractured. The animal should be deeply sedated to the level of recumbency. A rope should be looped around the groin of the affected limb, which should be uppennost. The free ends of the rope should be tied arotmd a tree or some other fixed object, and traction should be applied to forcibly extend the limb. Downward pressure should then be applied to the hock, which should be strongly rotated outward (upward) until the head of the femur slips back into the acetabulun1. Traction should be applied at several angles until the head of the femur clicks back into the acetabulum. If the head of the femur or the rim of the acetabultm1 is fractured, there will be considerable crepitation, and the head of the great trocanter will displace as soon as traction is stopped.

PATELLAR LUXATION lntennittent fixation of the patella on the upper part of the femoral trochlea results in a characteristic jerky action of one or both hindlimbs. The limb remains in caudal extension for a longer period than normal and may even be dragged for a few steps before clicking forward to a normal posture. In young anin1als, the condition may resolve spontaneously. For luxations that do not. resolve, medial patellar desmotomy should be performed.

FETLOCK DISLOCATION Fetlock dislocation is seen in young cattle when they cross cattle guards (grillwork laid over a pit as a gate substitute). T.ranquiliza­ tion or light anesthesia facilitates replace­ ment of dislocated structures. A padded, fiberglass cast maintained in place for 3 wk usually promotes a satisfactory recovery.

HIP DYSPLASIA Hip dysplasia, a bilateral malformation of the hip joint, is often associated with secondary osteoarthritis. It may be present at bi.1th. However, abnonnal gait may develop in rapidly growing animals. Usually, it is possible to rock the hindquarter to produce a click as the head of the femur pops in or out. Radiography may confinn the diagnosis in young anin1als. There is no treatment.

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FRACTURES Bone fractures occur in cattle of all ages, but they are most common in those 3 ft (1 m) apart.

FEMORAL PARALYSIS In femoral paralysis, paralysis of the quadriceps muscles, which extend the stifle, and partial paralysis of the psoas major muscle, which flexes the hip, are seen. Clinical Findings and Diagnosis: Femoral neIVe paralysis is seen in large, newborn calves (eg, Charolais, Sinunental) after the use of mechanical force dming an assisted birth. Reduced quadriceps tonicity

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reduces tension on the patella, with the result that a lateral patellar luxation may develop. Atrophy of the quadriceps soon becomes obvious and, although the patella can be replaced easily, the animal has extreme difficulty walking. The condition may affect one or both limbs. Prognosis is related to the severity of the clinical signs. Treatment: Despite a fair or good prognosis, the animal may be unable to suckle unaided. The animal should be maintained in a well-bedded area, and colostrnm given as soon as possible after birth. A radiographic study should be done to exclude fractures. The administration of anti-inflanunatory drugs may be useful.

PERONEAL PARALYSIS Peroneal paralysis results in paralysis of the muscles that flex the hock and extend the digits. Clinical Findings: The peroneal nerve is the cranial division of the ischiatic nerve. It passes superficially over the lateral femoral condyle and the head of the fibula, which makes it vulnerable to external trauma or pressure from recumbency. An affected animal stands with the digit knuckled over onto the dorsal swiace of the pastern and fetlock. The hock may appear to be overextended. In mild cases, the fetlock tends to knuckle over intermittently during ambulation; however, this may also occur if the animal is expe1ienci,ng pain in the heels. In severe cases, the dorsal swiace of the hoof may be dragged along the ground, and sensation to the dorsun1 of the fetlock is often decreased. Testing of reflexes may demonstrate that hock flexiori is absent, but stifle and hip flexion are norn1al. This would not be the case if the ischiatic nerve was involved. Treatment: Most cases resolve naturally. However, if the condition is associated with long periods of recumbency, care must be taken to avoid exacerbation of the initial injury.

TIBIAL PARALYSIS In tibial paralysis, there is paralysis of the extensors of the hock and flexors of the digits. Etiology: The tibial nerve is the caudal branch of the ischiatic nerve, which, in its proximal course, is well protected by the gluteal muscles. Distally, it progresses

beneath the tendon of the gastrocnemius muscle and can be damaged when the tendon is traun1atized. Clinical Findings: The hock joint is overflexed (dropped hock syndrome) and the fetlock is partially flexed. The gastrocne­ nlius appears to be longer than normal and gives the inlpression that it or its tendon could be ruptured. The fetlock tends to be buckled, but the animal can walk and bear weight, although its attempts to do so are awkward. Compared with that seen in peroneal nerve injury, tl1e gait disturbance is mild, but the postural disturbance could be pern1anent. Treatment: The use of anti-inflammatory drugs may be of value in the early stages. However, the prinlary efforts should be directed toward ensuring tl1at the animal does not injure itself further, by maintaining it on swiaces witl1 good footing.

SPASTIC SYNDROME Episodic, involuntary muscle contractions or spasms involving the hindlimbs are associated with postural and locomotor disturbances as well as spasticity. The condition may progress to posterior paresis or hindlimb paralysis. It is seen most frequently in Holstein and Guernsey cattle 3-7 yr old. Spastic syndrome is regarded as a genetic disease, possibly due to an autosomal donlinant gene with incomplete penetrance. The pathology and pathophysi­ ology remain obscure. Clinical Findings: Clinical signs may vary in severity, duration, and frequency. Usually, some stinmlus provokes the onset of clinical signs, such as the effort associated with rising or any factor that induces a significant emotional reaction. Pain, particularly in the feet or joints, may precipi­ tate an attack. During an attack, the animal may be unable to move forward, stands trembling, and characteristically extends its hindlimbs backward. Between episodes, the animal can ambulate nom1ally. Treatment: Spastic syndrome is progressive, and because of the possibility of genetic transmission, rulimals (pruticularly bulls used for artificial insenlination) are best eliminated as soon as a positive diagnosis is made. Palliative treatment for animals in the peak of production may be helpful. Mephenesin (30-40 mg/kg, PO, for 2-3 days) may be given during an episode. Phenylbuta­ zone may also have beneficial effects.

LAMENESS IN CATILE

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SPASTIC PARESIS (Elso heel)

Spastic paresis is a progtessive unilateral or bilateral hyperextension of the hindlirnb(s). It is seen sporadically in most breeds of cattle. Post-legged cattle are most frequently aff ected. Attempts to move are believed to simultan�ously trigger contractions of both ext�nsors and flexors of the limb. Spastic pare�is is currently considered to be inhelitl!d via a recessive gene( s) witl 1 incomplete penetrance. Clinical Findings: Th e disease may be

seen within the first 6 111() of life. As the animal ages, the gastroctiemius muscles gradually contract. The l\ock and stifle become increasingly extended. Over a period of months, tl1e hutdlimbs become so stiff that the anin1al Walks with short, pendulum-like steps. If On]y one limb is affected, the animal stands with the affected limb camped back and tl\e sound limb held toward the midline to 1113 mL) is injected. If the horse's gait does not improve after a PDN block, some clinicians next administer a semi-ring block at the pastern to anesthetize the dorsal branches of the digital nerve that supply the foot. Because the dorsal branches of the digital nerve contribute little to sensation within the foot, a semi-ring block at the pastern is unlikely to improve tl1e gait if aPDN block failed to improve it. Most clinicians proceed to a basisesa­ moid nerve block if the horse's lameness is not reduced with a PDN block. With this regional nerve block, the palrnar nerves are anestl1etized at the level of the base of the proximal sesan1oid bones, before tl1e nerve branches into the dorsal and palmar digital nerves. When performing an abaxial sesan1oid nerve block, 2.5--3 mL of local anesthetic solution is deposited at the base of the proximal sesamoid bones over the neurovascular bundle, which is easily palpated at this location. More proxin1al deposition of local anesthetic solution may

anesthetize a portion of the fetlock joint. Positive response to a basisesamoid nerve block, perforn1ed after aPDN block has failed to ameliorate lameness, localizes the site of pain causing lameness to the pastern. The low palmar nerve block, or low 4-point block, is performed after a negative response to the abaxial sesarnoid nerve block. TI1is nerve block is usually performed with the horse bearing weight on the limb, but it can also be pe1fo1med with the limb held. The medial and lateral palmar nerves are anesllietized, using a 25-gauge, 5/8-in. needle, by depositing 2 mL of local anesthetic solution over each palrnar nerve where it lies subcutaneously at the dorsal border of the deep digital flexor tendon. The palmar ne1ves should be blocked at llie level of the metacarpus to avoid the possibility of misdirecting a needle into the digital flexor sheath, which often extends proximally to the level of the end of llie splint bones. When fue palrnar nerves are blocked at tl1e level of the middle of fue metacarpus, tl1e communi­ cating branch lliat connects fuem, fue ramus conununicans, should also be blocked witl1 1 mL of local anesthetic solution. Blocking one palmar nerve proxin1al to fue ran1us comrnunicans and the other distal to it allows sensory impulses to propagate tJu·oughfue ran1us from fue side blocked proximal to the ramus andfuen proximally tl1rough fue pal.mar ne1ve blocked distal to llie ramus. Though easily palpated onfue forelimb, tl1e ramus comrnunicans is often nonexistent or impossible to palpate onfue pelvic limb. To complete the 4-point block, 1-2 mL of local anesllietic solution is deposited SC at the distal end of each splint bone, where llie palmar metacarpal ne1ve lies next to tl1e periosteurn offue third metacarpal bone. A positive response to a low 4-point block, perforn1ed after a negative response to an abaxial sesamoid nerve block, localizesfue site of pain causing lameness to the fetlock. The high palmar nerve block, or high 4-point block, can be pe1fonned when tl1e low 4-point block fails to improve lan1eness. Willifue limb bearing weight,fue medial and lateral palmar and palmar metacarpal nerves are anesfuetized slightly distal to llie level of the carpometacarpaljoint. To anesthetize a palrnar ne1ve, a 25-gauge, 5/8-in. needle is inse1ted tJu·ough fascia to wherefue nerve lies near the dorsal border offue deep digital flexor tendon, and 3-5 mL of anesfuetic solution is deposited over tl1e nerve. Anesthetizing the medial and lateral palrnar nerves alone desensitizes llie flexor tendons and inferior check ligament. Willi tl1e limb held or bearing weight, the palmar metacarpal nerves are anesthetized slightly

1105

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LAMENESS IN HORSES

ulnar n.

\ r

L--- caudal cutaneous antebrachial n.

I

Y

deep ' br. of palmar br. of � ulnar ll.

dorsal br. of ulnar n.

paln1ar m1. lateral medial

�neti�ru;� 1111. medial lateral

median n., distal approach

0mar digital � lateral medial ;-------\ paln1ar br. of palmar digital nn. � / lateral medial Thoracic limb, lateral aspect

Thoracic limb, medial aspect

Landmarks for nerve block of the forelimb, horse. Illustration by Dr. Gheorghe Constantinescu.

distal to the level of the carpometacarpal joint by inserting a 20- to 22-gauge, l \.2-in. needle into the angle formed by the junction of the third metacarpal bone and the second or fourth metacarpal bone. Anesthetizing the medial and lateral palmar metacarpal nerves alone desensitizes the splint bones and their interosseous ligan1ents and the proximal aspect of the suspensory ligament. An easier alternative to the high palmar nerve block, when the site of pain causing lameness is suspected to be in the proxinlal pmtion of suspensory ligan1ent, is the lateral palmar nerve block, which is performed, with the limb bearing weight, by inserting a 25-gauge, 5/8-in. needle over the lateral palmar nerve where it courses over the medial aspect of the accessory carpal bone. The needle is inserted in a medial to lateral direction at the distal third of a palpable groove, and 2 mL of local anesthetic solution is deposited. Because the medial and lateral palmar metacarpal nerves arise from the deep branch of the

lateral palmar nerve distal to this site, the structures they innervate, such as the proxinlal aspect of the suspensory liga­ ment, are desensitized. If the site of pain causing lan1eness cannot be localized by performing the previously discussed nerve blocks, most clinicians perform joint blocks of the carpus, elbow, or shoulder. The order in which these synovial structures are desensitized is not important. The median and ulnar nerves are sometimes anesthetized simultaneously as part of a lan1eness evaluation to exclude pain below the elbow as the cause of lameness, but more commonly, they are anesthetized along with the medial cutaneous a.ntebra­ cheal nerve to allow surgery of the limb without the need for general anesthesia.

Regional Anesthesia of the Pelvic Limb Techniques to ad.minister regional anesthe­ sia of the distal portion of the pelvic limb are

LAMENESS IN HORSES

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v

common fibular (peroneal) n.

,

\

saphenous n. ,,4 mm thick, has rounded distal margins, or

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LAMENESS IN HORSES if hyperechoic regions are found within the pad. Treatment is surgical excision via arthroscopy.

DIGITAL SHEATH TENOSYNOVITIS Tenosynovitis of the digital flexor tendon sheath is conunon in all types of working horses. Chronic digital sheath tenosynovitis may be bilaterally synunetiic in the hindlimbs in horses witl1 minimal clinical significance ("windpuffs"). The digital sheatl1 encom­ passes ilie superficial and deep digital flexor tendons and extends from tl1e distal one-iliird of ilie metacarpus/metatarsus distally to just proxin1al to ilie navicular bursa. Asynm1etric tendon sheatl1 effusion typically indicates a problem. Lameness degree is vruiable, depending on ilie structure(s) involved, and may increase witl1 exercise. Horses are typically sore on finn flexion of tl1e distal limb. Aliliough some cases of tenosynovitis are prin1ary and respond to conservative ilierapy witl1 or without treatment of ilie sheatl1 witl1 corticosteroids and/or hyal­ uronic acid, otl1ers are secondruy to lesions of structures contained wiiliin ilie sheath. Ultrasonographic exrunination of ilie entire digital flexor tendon sheath, including the intersesrunoidean ligament and distal sesrunoidean ligan1ents, is recommended and typically leads to a diagnosis. However, marginal tears of ilie deep digital flexor tendon (typically dorsolateral in the pastern) and tears of ilie manica flexoria can be difficult to diagnose via ultrasound but are confirmed ilirough tenoscopic examination of ilie sheatl1. Verification of site of lan1eness should be confirmed via intrailiecal injection of analgesia Palmar/plantar armulru· ligament constriction can be primal)' due to desmitis of the ligrunent or secondruy to longstanding tenosynovitis or enlargement of ilie flexor tendons contained wiiliin ilie fetlock canal. Clinical signs are sin1ilar to iliose of oilier causes of tenosynovitis and include pain on palpation, swelling, and lruneness, especially after forced flexion of ilie distal limb. Careful ultrasonographic exan1ination is recom­ mended to assess accompanying pailiology. Treatment can be eiilier conservative (ie, steroids) or surgical (pal.mar/plantar armula.r ligrunent desmotomy). Surgery is best pe.rfonned tenoscopically, which allows visualization of ilie remainder of ilie sheatl1 for prirnruy pathology and assessment of the degree of constiiction. Other common causes of tendon or ligrunent pathology distal to ilie fetlock include desmitis of the distal sesrunoidean ligrunents (oblique and straight), deep

1121

digital flexor tendon, superficial digital flexor tendon, and the distal digital armular ligrunent. Any of these conditions can result in tenosynovitis of the digital sheath and can typically be diagnosed using ultra­ sonography or MRI.

TENDINITIS (Bowed tendon)

Inflan1mation of a tendon can be acute or chronic, with varying degrees of tendon fibril disrnption. Tendinitis is most conunon in horses used at fast work, particulru·ly racehorses. The problem is seen in ilie digital flexor tendons and is more common in ilie forelimb ilian in ilie hindlimb. In racehorses, the superficial digital flexor is involved most frequently. The primruy lesion is a central rnpture of tendon fibers with associated hemorrhage and edema.

Etiology: Tendinitis usually appears after fast exercise and is associated with overextension and poor conditioning, fatigue, poor raceti·ack conditions, and persistent training when inflanm1atory prob­ lems in ilie tendon al.ready exist. Improper shoeing may also predispose to tendinitis. Poor conformation and poor training also have been implicated. Clinical Findings and Diagnosis: D1w ing the acute stage, ilie horse is severely lan1e and ilie involved strnctures are hot, painful, and swollen. In chronic cases, iliere is fibrosis with thickening and adhesions in ilie peritendinous area. The horse witl1 chronic tendinitis may go sound while walking or trotting, but lruneness may recur under hard work. Ultrasonography delineates the cross-sectional and longitudinal extent of the tendinitis. Treatment: Tendinitis is best treated in

ilie early, acute stage. The horse should be stall-rested, and the swelling and inflrunma­ tion treated aggressively witl1 cold packs and systemic anti-inflanunato1y agents. Some degree of support or immobilization should be used, depending on ilie runount of drunage to ilie tendon. Inti·atendinous corticosteroid injections are contraindi­ cated. When a distinct hypoechoic or anechoic core lesion is present on ultra­ sound exrunination, tendon splitting has been recommended (ilie rationale is to decrease intratendinous pressure due to

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sernrn or hemorrhage). Cases also have been treated with shock wave therapy, intra­ lesional irtjection offat-derived strornal cells or cultured bone rnarrow-de1ived rnesen­ chyrnal stern cells, or platelet-rich plasma products. The levels ofevidence for these modalities are variable. TI1e horse should be rehabilitated using a regimen ofincreasing exercise. Supe1ior check ligament desrnot­ orny has been used as an acljunctive treatment to rninintize recurrence ofthe problem before the horse is returned to training. Other treatments for chronic tendinitis have included superficial point firing (ofques­ tionable benefit) and percutaneous tendon splitting. Annular ligament desrnotomy is also used when tendinitis occurs within the confines ofthe digital tendon sheath. The prognosis for a flat-racing Thorough­ bred racehorse to return to racing after a bowed tendon is guarded, regardless of treatment. However, increasing success is seen with eventers, show jumpers and show hunters, and dressage horses, respectively. SUSPENSORY DESMITIS l.ajuries ofthe suspensory ligan1ent (interos­ seous muscle) are common in forelin1bs and hindlimbs ofhorses. Lesions are typically classified as affecting the proxinlal, body, or branches ofLl1e suspensory ligan1ent. Proximal Suspensory Desmitis: The te1111 proxin1al suspensory desmitis (PSD) is restricted to lesions confined Lo the proxinlal one-third ofthe metacarpus. PSD can occur unilaterally orbilaterally and is a common irtjwy in all types ofathletic horses. l.ajwy to the proxinlal suspensory ligan1ent and/or its attachment to Ll1e proxinlal palmar aspect ofthe third metacarpal bone typically results in sudden onset lameness that seems to improve within a few days. Lameness varies from mild to moderate and is typically not severe unless there is substantial involvement oftl1e ligament and its attachment (avulsion ofthe palmar cmtex). IfLl1e horse has bilateral PSD, there may be less overt lameness but more loss ofaction ofthe horse. Lameness is typically more noticeable on soft ground and with the affected leg on the outside ofthe circle. Response to distal limb and/or carpal Hexion tests is variable. Pressure applied to the proximal palmar metacarpal region may elicit pain; however, this response/reaction should be compared with that ofthe other limb to detemune significance. Diagnosis ofPSD usually requires localization with diagnostic analgesia, because typically horses do not have clinical signs (eg, heat, pain, swelling) that allow

lameness to be localized to Lllis region. There are multiple techniques to desensitize the proximal aspect ofthe palrnar metacarpus. However, there is confusion interpreting the results ofsubcarpal analgesia because of the lack ofspecificity oflocal analgesic teclmiques. After lameness has been localized, radiographs as well as ultrasono­ graphic examination ofthe region should be pe1formed. Ultrasow1d ofthe proximal suspensory should be critically compared with that ofthe other limb, remembering that bilateral lesions do exist. Nuclear scintigraphy can help detect osseous injwy at the proximal suspensory attachment, but negative scintigraphic images do not exclude the presence ofPSD. MRI is also extremely useful to detect subtle changes in the proxinlal suspensory ligament that may not be visible or conclusive with ultrasonog­ raphy. In addition, MRI allows accurate examination ofthe osseous structures acljacent to the suspensory ligament (metacarpal bones and distal carpal bones). In contrast to hindlimb PSD, most horses with acute forelimb PSD respond well to rest and a controlled exercise program for 3-6 mo ( -900/o retwn to function). Prema­ ture return to work typically results in recurrence/persistence oflan1eness. Horses with chronic PSD may require a longer rehabilitation program or acljunct therapy (NSAIDs, shockwave, regenerative therapies) to return to consistent work. Desmitis of the Body of the Suspen­ sory Ligament: This is principally an irtjwy ofracehorses. l.ajtuies usually affect the f orelimbs ofThoroughbreds and the forelimbs and hindlimbs in Standardbreds. Soreness on palpation ofthe forelimb suspensory ligament is quite common in horses with lameness associated with a more distal limb problem; however, strnctural abnormality of the ligaments is only rarely identifiable ultrisonographically. Clinical signs vary and involve enlargement ofthe ligan1ent, local heat, swelling, and pain. Diagnosis is usually based on clinical sigrts and can be confumed ultrasonograph­ ically. Treatment is aimed at reducing inflammation by systemic SA.IDs, hydrotherapy, and controlled exercise. Shockwave therapy, platelet-rich plasma, and stem-cell Ll1erapy have also been used for suspensory body lesions. Desmitis of the Branches of the Suspensory Ligament: This relatively common injury is seen in all types ofhorses in forelimbs and hindlimbs. Usually only a single branch in a single lin1b is affected, although both branches may be affected,

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LAMENESS IN HORSES especially in hindlimbs. Foot imbalance is often recognized in affected horses, and this may be a predisposing factor. Clinical signs depend on the degree of damage and the chronicity of the lesion(s) and include localized heat and swelling. Swelling is often due to local edema of the affected branch. Effusion can be present in the acljacent palmar/plantar fetlock joint and/or the iligital flexor tendon sheath. Pain is usually elicited either by direct pressure applied to the i.rtjured branch or by flexion of the fetlock. Lameness is variable and may be absent. Diagnosis is based on clinical signs and ultrasonographic examination. Radio­ graphic examination should also be performed to evaluate the attachment of the suspensory branch on the proximal sesamoid bones. Low 4-point iliagnostic analgesia as well as intra-articular analgesia of the fetlockjoint (varying degrees based on the location of tl1e branch irtjury) improves lameness. Ultrasonography can detect a range of abnormalities, including enlargement, alteration of shape, and alterations in echodensity. Management depends on the severity of the signs and on the breed and use of the horse. Shockwave therapy, local anti-inflan1matories, ligament splitting, and regenera­ tive therapy have all been used with varying results. Strict attention to foot balance is also critical in management of these lesions. Clinical signs may take �6 mo to improve, and the condition may recur. Prognosis for reirtjury or persistence of lameness is worse in horses that are hyperextended in their fetlocks at rest or in horses with marked periligan1entous fibrosis around the branch on ultrasound.

INFERIOR CHECK DESMITIS The accessory ligament of the deep iligital flexor tendon (inferior check ligament [ICL]) is a strong fibrous band that is the direct continuation of the common palmar ligament of the carpus. Desmitis of the ICL may be seen alone or develop secondarily to irtjury to the superficial digital flexor tendon. In horses with severe ICL damage, the deep flexor tendon may also be affected. lr\jury to the ICL appears to be more common in adult or aged horses, affinning that degenerative aging changes may predispose the ligament to injury. Ir\jury is relatively uncommon in racehorses and is common in ponies and Warmbloods (showjumpers and dressage). lr\jury of the ICL is usually unilateral. Diag­ nosis is typically from clinical examina­ tion, with swelling in the proximal

1123

one-third of tl1e metacarpus dorsal to the superficial digital flexor tendon. Ultrasono­ graphic examination is typically confinna­ tory, with areas of enlargement, fiber pattern ilisruption, and loss of the normal border of the ligament. lr\jury to the ICL is usually treated witl1 rest and controlled exercise, along with possible shockwave and/or intralesional irtjection of platelet-rich plasma or stern cells. Desmatomy of tl1e ICL has also been perfonned in horses that have not responded to conservative therapy.

BUCKED SHINS "Bucked shins" are pa.it of tl1e clisease complex known as dorsal metacat1)al disease. Bucked shins is a painful, acute periostitis on the dorsal surface of the third metacarpal bone. It is seen most often in the forelimbs of young Thoroughbreds (2-yr-olds) in training and racing, and less commonly in Standai·dbreds and Quatter horses. This ir\jury can occw- bilaterally and usually occurs sequentially, with the left leg being affected first because horses are trained at1d raced in North America in a cow1terclockwise direction. Bucked shins may be the result of high-strain cyclic fatigue caused by excessive compression on a bone tl1at has not remodeled enough to tolerate the stress placed on it. Stressed bone forms a new layer of bone at the point of stress. This new bone is weaker at1d, in the process of rapid bone formation, the periosteum becomes elevated at1d inflamed. Diagnosis is typically by clinical examination at1d history (soreness over the dorsal aspect of the cat1non bone, soreness after high-speed work or the first race, or soreness the day after). Radiography is beneficial to determine the amount of periosteal reaction at1d if actual stress fracture(s) are present in the dorsal c01tex. Treatment typically consists of altering the training schedule to short bw-sts of speed work 2-3 times a week Rest from training is also importatlt until the soreness at1d inflatnrnation resolve. The acute inflat1lllla­ tion may be relieved by at1ti-inflatnrnatory at1algesics ai1d application of cold packs. Screw fixation with or without osteostixis is the method of choice to treat radiographi­ cally demonstrated stress fractures.

EXOSTOSES OF THE SECOND AND FOURTH METAC ARPAL BONES (Splints) Splints ptimarily involve the interosseous ligat11ent between the large (third) at1d small

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LAMENESS IN HORSES

(second) metacarpal (less frequently the metatarsal) bones. The reaction is a periosti­ tis with production of new bone (exostoses) along the involved splint bone. Possible contributory factors include trauma from concussion or injwy, strain from excess training (especially in the inunature horse), faulty confom1ation, imbalanced or ovemutrition, or improper shoeing. Splints most commonly involve the second metacarpal bone. Lameness is seen only when splints are forming and is seen most frequently in young horses. Lameness is more pronounced after the horse has been worked. In tl1e early stages, there is no visible enlargement, but deep palpation may reveal local, painful, subperiosteal swelling. In the later stages, a calcified growth appears. After ossification, lan1eness disappears, except in rare cases in which the growth encroaches on the suspensory ligament or carpometa­ carpal articulation. Radiography is necessary to differentiate splints from fractured splint bones. Complete rest and anti-inflanunatory therapy is indicated. lntralesional cortico­ steroids may reduce inflan1mation and prevent excessive bone growth. Their use should be accompanied by counterpressure bandaging. If the exostoses inlpinge against the suspensory ligan1ent, surgical removal may be necessary.

FRACTURES OF THE SMALL METACARPAL {SPLINT) BONES Fractures of the second and fourth metacarpal (splint) bones are not uncom­ mon. The cause may be from direct trauma, such as interference by the contralateral leg or a kick, but often accompany or follow suspensory desrnitis and the resulting fibrous tissue buildup and encapsulation of the distal, free end of the bone. The usual site of these fractures is through the distal end, -2 in. (5 cm) from tl1e tip. ln1mediately after the fracture occurs, acute inflanunation is present, usually involving the suspensory ligament. Lameness is typically noted (may be severe initially), which may recede after several days rest and recur only after work. Diagnosis is confirmed by radiography. Ultrasound exaniination of the suspensory ligament may also be beneficial to deter­ mine a more accurate prognosis as well as guide a rehabilitation program. Surgical removal of the fractured tip and callus is the treatment of choice. Fractures involving tl1e proximal one-tllird of tl1e bone may require surgical stabilization of tile bone to prevent carpal instability, particularly if the fracture involves the second metacarpal bone. Prognosis is based on severity of the

Lateral condylar fracture of the distal third metacarpal bone (arrow) in a horse. Courtesy

of Dr. Matthew T. Brok ken.

associated suspensory desmitis, which has a greater bearing on future performance than the splint fracture itself.

FRACTURE OF THE THIRD METACARPAL {CANNON) BONE The most common site of.major fracture of the tllird metacarpal bone is in the distal articulation (condylar fractures). Vertical fractures in the sagittal plane of the distal cannon bone (condylar fractures) occur predominately in young racehorses. Most condylar fractures are in the lateral condyle. In Thoroughbreds, condylar fractw·es of the third metacarpus are at least twice as conunon as third metatarsal fractures, but in Standardbreds, the ratio 10 mm or removal of the fracture fragments if they are thin or not an1enable to lag screw fixation.

Accessory Carpal Bone Fractures These are less common than other fractures in the carpus. Lameness is typically acute

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and severe, and there may be synovial effusion in the carpal sheath and, less commonly, the radiocarpaljoint. Radio­ graphs confum the diagnosis. These fractures are typically treated conserva­ tively; however, if the fracture is articular and fragmented, surgical removal of the fragments has been perfom1ed. Fibrous union may enable a horse to return to athletic activity.

SUBCHONDRAL BONE DISEASE OF THE THIRD CARPAL BONE Degeneration and necrosis of the subchon­ dral bone is common in racehorses and may precede slab fractures of the third carpal bone. The condition was initially identified in the proximal articular surface of the third carpal bone and is considered to be a consequence of cyclic trauma. Clinical signs include lameness, reduced perfom1ance, and effusion of the middle carpal joint. Horses typically in1prove with intra-articu­ lar analgesia of the middle carpal joint. A skyline view radiograph is critical for diagnosis and typically shows lysis and sclerosis in the third carpal bone (typically radial facet). Arthroscopic examination is the treatment of choice, with removal of the abnormal cartilage and subchondral bone.

TE ARING OF THE MEDIAL PALM AR INTERCARPAL LIGAMENT This il\iury, first describ"ed in 1990, most commonly involves the medial palrnar intercarpal ligament but may involve the lateral palma.r interca.rpal ligament. A typical presentation is synovias and capsulitis unresponsive to therapy or the presence of carpal chip fragments with an untoward amount of lan1eness. Diagnosis is made aithroscopically, and treatment is artlu·oscopic debridement of the tom fibers. Prognosis depends on the degree of teai·ing, as well as lack or presence of concuITent subchondral bone damage.

OSTEOARTHRITIS OF THE CARPUS Radiocarpal and/or middle carpal osteoa.i0 thritis typically appears with clu·onic thickening of thejoint capsule and usually associated decreased range of motion. Radiographic changes develop slowly, and usually the degree of articular cartilage compromise is severe. Cases that can possibly lead to osteoarthritis should be treated aggressively and correctly. Treatment

Marked new bone proliferation (arrow) in a horse with osteoarthritis of the carpometa­ carpal joint. Courtesy of Dr. Matthew I Brokken. of severe osteoa.rtluitis is largely palliative. Osteoarthritis of the carpometacai-paljoint has been described ma.inly in Arabian and Quarter horses. This condition typically affects the medial aspect of thejoint and is characterized by lan1eness (minimal at first), fu111 swelling over the medial aspect of tl1e distal carpus, and response to intra-articula.i· analgesia of tl1e middle carpaljoint. Radiographs typically show periarticular new bone proliferation (sometimes marked) overtl1e proximal second a.i1d/or third metacarpal bone, lysis and/or sclerosis of tl1e bones surrounding tl1e medial carpometacar­ paljoint, and possible loss oftl1e medialjoint space. Treatment consists of conservative tl1erapy (systemic and/or intra-articular anti-inflanunatories) and possible facilitated artlu·odesis witl1 use of passage of drill bits across thejoint. (See also OSTEOARTIIRms, p 1063.)

DISTAL RADIAL EXOSTOSIS A ND OSTEOCHONDROMA OF THE DISTAL RADIUS Exostosis of the caudal aspect of the distal radial physis can cause tenosynovitis of tl1e carpal sheath and da.tnage to the deep digital flexor tendon. Exostosis is differentiated

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LAMENESS IN HORSES

from an osteochondroma based on its location and histologic appearance. Osteochondromas are present on the caudal aspect of the distal radius metaphysis normally 2-4 cm proximal to the distal radial physis. Osteochondromas also have hyaline cartilage remnants present on histologic examination (exostosis do not have hyaline caitilage). ltTespective of origin, these two conditions can cause lameness (swinging leg) and carpal sheath tenosynovitis. Diagnosis is generally made by radiogra­ phy, but ultrasonic examination may be helpful to define the presence of soft-tissue injury. The condition can be treated successfully via tenoscopy of the carpal sheath with removal of the protruding mass and identification and debridement of any concomitant damage to the deep flexor tendon. The prognosis is good and depends on the degree of soft-tissue danrnge.

CARPAL HYGROMA A carpal hygroma is a subcutaneous swelling over the cranial/dorsal aspect of the carpus. Typically, a history of trauma to the carpus is noted. The swelling is typically aseptic, but risk of infection can develop after drainage or injection. Typically, a hygroma is a cosmetic blemish, and lameness is not usually present. The diagnosis is made by palpation and visualization. Irtjection of contrast material into the hygroma and subsequent radiographic examination outlines the extent of the hygroma. Communication between joint and hygroma is confirmed or excluded through fluid injection into the cai-pal joints. Hygromas can be treated in the early stage with drainage, steroid i.ajections, and bandaging. When infection is present, surgical resection of the infected tissue is recommended.

RUPTURE OF THE COMMON DIGITAL EXTENSOR TENDON This condition occurs in foals and may be present when the foal is born or develop in the first weeks of life. It can be primary or secondary to carpal or fetlock flexural deformities (seep 1150). Affected foals have a characteristic soft/fluid swelling over the dorsolateral aspect of the carpus and distal radius. Ultrasound exan1ination is confirmatory. Management involves stall rest and preventing secondary tendon contracture with tl1e use of bandaging with or without PVC splints to prevent knuck­ ling, if appropriate. Prognosis is excellent in foals without concurrent flexural deformi­ ties or cuboidal bone abnormalities.

1127

Shoulder lameness in horses is less common than many owners expect. Although cases are often described as having a typical gait (reduced protraction/cranial phase, wearing of the toe, a swinging lameness), they are still difficult to diagnose sin1ply from analysis of tl1e animal's walk or trot. However, almost all cases have atrophy of the proximal lin1b muscles (especially supraspinatus, infraspinatus, the cranial shoulder muscles, and muscles of the cranial antebrachium) beyond that which would nonnally be expected for lameness caused by distal lin1b disease. This is associated not with shoulder pat110logy per se, but is a general feature of proximal limb lan1eness. mtra-articular anesthesia, medication, and centesis can be accomplished by passing a 90-mm spinal needle between tl1e cranial and caudal parts of the lateral tuberosity of the humerus, angling caudodistally, from above; an ultrasound-guided teclmi.que is also described. Radiography is limited to the me­ diolateral projection, with the limb extended, and in some cases oblique projections (usually caudolateral-craniomedial or proximocranial-proximodistal). Ultrasonog­ raphy is essential for full assessment of thP shoulder region, particularly the soft tissues.

DEVELOPMENTAL DI SEASES Developmental orthopedic disease manifests in the scapulohurneral (shoulder) joint principally as subchondral cyst-lil107°F [41.7°C]) as pigs become anorexic and lan1e; sometimes H parasuis causes neurologic signs. At necropsy, polyarthri.tis and polyserosi­ tis are seen with both mycoplasma infection and Glasser's disease, and pneumonia may

1159

have developed. The initial, exudative response is usually serous or serofibrinous with a mycoplasmal infection; however, it is fibri.nous or fibrinopurulent with G lasser's disease. Hence, M hyorhinis causes a mild synovitis with villous hypertrophy and hyperplasia; an excess of clear, yellow, or brown synovia; and a serofibrinous pericarditis, pleuri.tis, and peritonitis. Otitis media has also been reported. With H parasuis, a fibri.nopurulent synovitis with periarticular edema, polyserositis with pseudomembranes, and sometimes fibri.nopwlllent meningitis are seen. The articular surfaces are usually unaffected in either condition. Diagnosis is based on clinical signs, necropsy findings, and detection of the organism. PCR tests are available to detect M hyorhinis and H parasuis. This is in.1portant, because bacterial culture of both bacteria can be challenging if any treatment has been instituted or if the pig has been dead more than a few hours. Treatment for either disease must be aggressive and start soon after the onset of clinical signs if it is to be effective. The effectiveness of treating M hyorhinis infections with tylosin, tetracycline, or lincomycin has been variable. Organisms may be susceptible in vitro and resistant in vivo. Treatment of Glasser's disease is discussed in the rele­ vant chapter (seep 720). With chronicity, success in treating either disease is wilikely. Appropriate changes in management to reduce stress, strict all-in/all-out housing, and control of viral infections should all minin.1ize the inlpact of Glasser's disease. Herds that maintain an SPF status may be free of both M hyorhinis and H parasuis, but in herds with documented outbreaks of Glasser's disease, morbidity and mortality were high and productivity was decreased. Some 15 serovars of H parasuis have been identified, with much strain variation. Vaccination with conunercial or autogenous H parasuis bacteri.n may alleviate clinical disease in SPF herds. It is important to vaccinate SPF pigs that ai·e to be shipped to conventional herds with vaccine effective against the serovars present in the recipient herd. There is cross-protection among some serovars. Vaccination of sows againstH parasuis reduces the prevalence of the problem in nursery pigs through passive in.UTiunity. Streptococcosis: The streptococcal disease of main concern to the pig industry is caused by S suis (seep 731). Although this organism can cause arthritis, CNS signs and pneumonia are the most common clinical presentations.

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LAMENESS IN PIGS

Erysipelas: Although acute erysipelas can be seen in nursery pigs, it may be more typical of growing/finishing pigs (seep 1160). If the acute form of the disease affects nursery pigs and is not treated appropri­ ately, the subsequent progression of the disease to the chronic form is seen in the grower/finisher pigs. Adequate vaccination protocols are essential to controlling erysipelas. (See also SWINE ERYSIPELAS, p 626.) Vertebral Deformities: Kyphosis or lorclosis and cuneiform deformities of vertebrae have been seen in weaned pigs. The condition has been reproduced experiment.ally using gestation and nursery diets deficient in calcium, phosphorus, and vitamin D. "Humpy back" pigs are seen sporadically in some herds; the spine is curved in the vertical plane such that the lwnbar vertebrae are higher than the thoracic vertebrae, and there is a "kink" between the two segments. Rickets is usually not seen clinically until the grower phase, but lesions must be initiated earlier, giving time for typical pathologic changes to develop by -10 wk of age. PIGS IN GROWER/FINISHER AREAS Lameness in pigs is of increasing interest in North American swine production. Mycoplasma hyosynoviae in particular has received more attention due, in patt, to more intensive diagnostic efforts. Metabolic bone disease has also been area of focus as problems have arisen after more complex fonnulations for gestation and grow-finish diets.

an

Arthritis: Arthritis caused by Myco­

plasma hyosynoviae and Erysipelothrix rhusiopathiae emerge as important causes of lai.neness in pigs that have been moved to the grower/finisher areas. Again, mixing and moving groups of pigs; overcrowding; cold, drafty environments; or changes in management and feed may precipitate outbreaks of lai.neness. In the case of M hyosynoviae, the upper respiratory tract of sows and older pigs in peer groups is the likely source. As colostral immunity wanes at 4-8 wk of age, pigs become susceptible to infection. Generally, morbidity is low to moderate, but up to 500A, of pigs may be affected; mortality is very low. An acute lai.neness, lasting up to 10 days, develops in groups of grower/finisher pigs or selected replacement stock. Artluitis may be exacerbated by trauma or stress,

and pigs exhibit pain in majorjoints (eg, elbows, stifles, and hocks) that may develop soft, fluctuant swellings. On necropsy, lesions are restricted to thejoints, especially the stifles, and include an excess of clear, yellow synovial fluid that may have fibrin flakes, and yellow synovium with obvious villous hypertrophy. Articular surfaces and periarticular tissues usually ai.·e unaffected. M hyosynoviae has been isolated at slaughter or necropsy in pigs with degenerativejoint disease that is part of the osteochondrosis syndrome, but it is a secondai.y rather than a causal agent. Diagnosis is based on the age of onset of clinical disease and clinical signs, including lai.neness in one or more legs that may be accompanied by fluctuating swelling and puffiness aroundjoints. Typically, pigs are afebrile and there is no evidence of pneumonia, pleuritis, and peritonitis. If a definitive diagnosis is to be made based on detection of the organism, sai.nples of synovium and synovial fluid should be collected from untreated pigs within 3-4 clays of the onset of clinical signs. However, M hyosynoviae can be cultured from healthy joints and is not always recovered from affected joints. Lack of a response to penicillin in acute cases has been used to differentiate th.is disease from erysipelas. Unlike polyarthritis caused by M hyorhinis, response to treatment with tylosin and lincomycin is generally good if administered promptly, and tiatnulin or tetracycline may be effective where allowed. Mycoplasmal arthritis may exacerbate clinical signs associated with degenerativejoint disease and osteoarthrosis and vice versa.

Erysipelas: Erysipelothrix rhusiop­ athiae, the cause of erysipelas, is acquired from healthy carrier pigs or the environment, in which the organism can survive for short periods. Erysipelas can be peracute, acute, or chronic. In the peracute form, pigs die without clinical signs. In the acute form, pigs become febrile and may be lethargic and anorectic and unwilling to rise because of pa.infuljoints and cyanosis of the extremi­ ties; the latter is associated with vasculitis in peripheral vessels. After 2-3 days, the classic "dian1ond" skin lesions (focal urticaria) develop over the body surface. In some outbreaks, lai.neness is seen without the skin lesions. In the chronic form, arthritis progresses such that the stifles and hocks become swollen and feel finn on palpation; skin necrosis can result in extensive sloughing of portions of the integun1ent. In chronic cases, discospondylosis also may

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LAMENESS IN PIGS develop if intervertebraljoints are affected. As the arthritis progresses andjoints fuse, pain in the lumbar vertebrae may reduce boar libido. Cyanosis in the extremities in chronic cases may be related to heart valve failure. A presumptive diagnosis of acute disease is based on the clinical signs, of which the "diamond" skin lesions are most consistently useful. All three fom1s of the disease may be seen in the same herd if the problem has not been investigated and treatment has been delayed. If the chronic fonn of erysipelas is investigated as a lameness problem and pigs are necropsied, early changes in the disease process will have subsided (eg, hemor­ rhages in lymph nodes, kidneys, and muscles). An excess of synovial fluid accumulates during the acute phase, but in chronically affected joints, there is villous hypertrophy and hyperplasia, hyperemia, and pe1iarticular fibrosis. If pannus has formed, ilie aiticular surface becomes disrupted. Raised, focal skin lesions progress to sloughed areas and, in extreme cases, ilie ears and tail may have sloughed. Vegetative, valvular endocarditis is another finding. Isolation of the causal organism is important for a definitive diagnosis and is most successful if acutely affected, untreated pigs are necropsied andjoint fluid is cultured. PCR testing of chronic lesions (eg, endocarditis) can be used to detect the bacteria in chronic cases. A bacterial culture with an antibiotic sensitivity profile is useful during treatment of the herd. Sometimes, a rapid response of the acute condition to penicillin is a diagnostic aid. Provided ilie E rhitsiopathiae is sensitive to penicillin, this may still be an economic choice for treatments. However, tylosin and lincomycin are also labeled for treatment of erysipelas, and tetracycline may be successful if the organism is susceptible. Vaccination with either modified-live or killed orgaJ1isms effectively controls erysipelas in a herd, and outbreaks may be related to noncompliance witl1 vaccination protocols rather than to changes in the virulence of the causal organism or the nature of the disease. Therefore, any investigation of the problem should begin with a detailed vaccination history to ensure that sows are regularly vaccinated. Even with sow vaccination, infection is seen in grower/finisher pigs in some herds. On these farms, growers must be vaccinated in addition to ilie sows. In tl1e face of an outbreak, concurrent use of killed vaccine and antibiotic is likely to be the most effective control measure (seep 626).

1161

Osteomyelitis: Osteomyelitis can be

seen in pigs of any age. If the integument is damaged, sepsis develops and a suppurative lesion extends to ilie periosteun1 and bone. Alternatively, organisms can invade bone from the synoviwn of infectedjoints. Poor processing or iJtjection techniques can initiate abscesses that can extend into adjacent bone. Disruption of the integrity of the hoof wall initiates cellulitis and osteomyelitis of a phalangeal bone. Ear and flank biting wounds are other foci of infection. Tail biting can result in local infections that ascend the spinal canal and lead to epidural abscesses iliat can invade and affect vertebral bodies. Lesions and clinical signs may develop slowly. Depending on ilie site of infection, the pig may become ataxic and, ultimately, paralyzed in tl1e pelvic limbs. If bones or joints of a limb ai·e affected, the condition is usually chronic and the pig becomes three-legged lame. Young pigs cease to grow. At necropsy, creain or green caseous pus is seen at ilie site of the lesion. If T,ue­ perella pyogenes is involved, there ai·e abundant pockets of green, semiliquid pus. Other organisms isolated from these abscesses may include streptococci, staphylococci, and enterobacte1ia. Treatment is not usually feasible, and pigs should be culled for humane reasons. However, when applicable, hygiene can be in1proved, and problems such as tail biting controlled or prevented. Osteochondrosis and Osteoarthrosis:

Lameness associated witl1 these problems may become clinically relevant by ilie tin1e t11e pigs are 4---6 mo old, but the major ranufi­ cations are in gilts, sows, and boars (see p 1158). Because there is a hereditary component, ilie importance of these problems increases if affected replacement breeding stock is brought into a herd tl1at was previously free of eitl1er condition. Rickets: Although now uncommon, rickets

(see p 1051) is occasionally seen, usually associated with a feed formulation or mixing error. Rickets affects rapidly growing, young pigs with a clinical onset at -10 wk of age. Morbidity is high, and affected pigs become crippled, anorectic, and unthlifty. Limbs are stunted and bowed,joints are swollen, and ilie head may seem disproportionately large. Long bones of the limbs can spontaneously fracture so that the pig becomes severely lame and unwilling to move. Ribs may fracture. Some pigs develop poste1ior pai·esis and sit on the ground if vertebral bodies fracture and damage the spinal cord.

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LAMENESS IN PIGS

Absolute deficiencies of calcium, phosphorus, or vitamin D, or an imbalance of the calcium:phosphorus ratio causes cessation of mineralization at the metaphy­ sis and thickening of the growth plate and epiphyseal growth cartilage. On necropsy, bones should be dissected to determine whether there are any fractures or healing fractures, particularly in the ribs, humeruses, and femurs. The costochondral junctions of most ribs are enlarged to forn1 a rachitic rosary, and ribs may bend with moderate manual force. Bone remodeling is inadequate and, radiographically, long bones and ribs are poorly mineralized. Failure of calcification and endochondral ossification results in thickened, irregular growth plates and epiphyseal growth caitilages in which hemorrhages may be seen grossly if slab sections of the ends of long bones are cut on a band saw. In chronic cases, bones can be cut with a knife. A sudden increase in cai·cass condemnations or paitial condem­ nations because of fractured limb bones, ribs, or vertebrae at slaughter should trigger investigation of rations and their ability to meet the nutritional needs of growing pigs, particularly with some of the fast-growing, lean contemporary hybrids. Ration analysis is useful, but ctrrrent batches of feed may have been mixed correctly or with different lots of ingredients, thus making it difficult to relate cause and effect. Keeping frozen samples of each batch of feed for retrospec­ tive analysis is a good practice. Although rations can be corrected and vitainin D given parenterally, thel"e is no effective treatment, and attempts to reai· large numbers of affected pigs have been economically disastrous. Culling affected pigs may thus be the most cost-effecti\'e alternative. Foot Disorders: On occasion, grower/ finisher pigs have overgrown claws or bruises and cracks in the wall or sole of the hoof. The floor type and condition is perhaps the single greatest factor in detern1ining whether lesions develop or resolve. Floors with wide slots enable digits to fall between tile slats, causing damage. Floors kept too wet can soften tile hoof wall, making tllem more prone to trauma. Utile floor is too smooth, the balance between growth and wear of the horn is lost; if it is too rough, tile hoof wall, coronary band, or skin above the hoof is damaged so tllat infectious agents can penetrate tile foot or adjacentjoints, resulting in abscess forn1ation. An absolute or intermittent deficiency of biotin results in weak, flaky keratin that

makes hoof walls susceptible to cracking; flaky skin accompanies hoof lesion and t11ere is generally poor reproductive performance in tile herd. As gilts are prepared for breeding, supplementing biotin may be helpful. Recommended inclusion rates of biotin are 250-400 mcg/kg complete feed. Trace mineral deficiencies or in1balances can also contribute to compromised hoof wall and heel epidermis fo1mation. Seleniwn toxicosis can cause coronary band swelling and necrosis in addition to more generalized signs such as anorexia or even paralysis (seep 3085). Selenium and ergot toxicity can result in hoof sloughing in pigs. Nutritional Myopathy (White Muscle Disease): In contemporary

systems with adequate ration preparation and storage, nutritional myopathy should not be problematic (seep 1174). Altl1ough unexpected deaths are typical of seleniun1 and/or vitamin E deficiency, sometimes pigs are found recwnbent and unable to rise and walk. At necropsy, a variety of pathologic changes may be seen, including pale muscle masses, epicai·dial hemorrhages (mulberry heart disease), and a pale, scan·ed liver with an uneven surface (hepatosis dietetica). Prevention includes supplementation with selenite so that the total ration concentration is 0.3 ppm selenium. lithe condition is diagnosed in a batch of pigs, injectable seleniwn/vitainin E can be given as a stopgap measure until supplemented feed is part of the nutrition prograin.

BREEDING GILTS, SOWS, AND BOARS After reproductive failure, lameness is typically the most important reason for removal of breeding stock from tile herd. Lameness in breeding swine can result in the following: 1) higher rate of breeaing stock replacement with attendant increased risk of disease introduction; 2) an inability to maintain a breeding schedule due to an wu-eliable pool of breeding pigs and, ultimately, an impact on pig flow in the grower/finisher area; 3) increased cost of maintaining additional breeding stock; 4) poorer reproductive perforn1ance due to regular replacement of la.me sows witll gilts; 5) poorer growth and feed efficiency in progeny pigs due to a higher proportion of pigs produced by first-parity sows; 6) reduced pigs born alive because of higher stillborn rates in lan1e sows and reduced subsequent litter size due to poor lactation feed intake; 7) increased preweaning

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LAMENESS IN PIGS mortality due to clumsy, lame sows that tread or lie on baby pigs; 8) reduced weaning weights of pigs due to reduced feed intake of sows in lactation; 9) reduced salvage value of cull sows due to increased lactation weight loss and sow mortality; and 10) reduced fertility in sound boars that are overworked while others are lan1e or being replaced. In sum, the impact of breeding herd lan1eness on the biologic and economic perfom1ance of a f3.1.m can be substantial. Many diseases that affect grower/finisher pigs (seep 1160) can also affect young gilts and boars selected as breeding stock. Arthritis caused by Mycoplasma hyosyno­ viae or acute or chronic erysipelas can cause an incapacitating lameness. Poly­ artlu·itis and polyserositis caused by M hyorhinis 3.1.·e seen occasionally in these older pigs. Susceptible, stressed adult pigs can succw11b to M hyorhinis with a higher fever and a more severe l3.111eness than is seen in nw-sery pigs. Likewise, Haemophilus parasuis can develop as an acute epidemic disease in gilts sow-ced from herds free of the bacteria after entering a herd endemically infected. High morbidity and even mortality that is quite refractory to treatment can result. If 1ickets or skeletal wealrness was a problem in the growing phase, pigs that could have been affected should not be retained as breeding stock. Ambulation should be assessed as a component of breeding stock selection. Pigs with conformational abnormalities of their limbs or restricted or abnormal 3.1.nbulation should be culled. Feet should be evaluated for uniformity 3.1.nong and angulation of the digits and for integrity of the wall, sole, and heel. If any problems are identified, including abnormal traits such as over­ growth of the major or secondary digits in a particular line of pigs, these pigs also should be culled. Rickets, Osteomalacia, and Osteopo­ rosis: These syndromes can affect older

age groups of pigs, with various clinical outcomes. Most pigs, including breeding stock, are slaughtered before their skeleton has fully matw-ed; some growth plates are functional up to 3.5 yr of age and, therefore, are susceptible to rachitic or other changes. Osteomalacia is characterized by an excess of unmineralized or poorly mineralized osteoid that forms as bone remodeling occw-s (or does not occur). Hence, osteomalacia is the component of rickets (seep 1161) that affects the growth plate and is described in younger pigs. In contrast, osteoporosis develops when

1163

established bone loses mineral and mass by a process of osteolysis, a different pathogenesis from that of either rickets or osteomalacia. Gilts that have normal skeletal develop­ ment and are selected as breeding stock must continue to have their nutritional needs met, both for their own growing skeleton and, once pregnant, that of the growing fetuses. This may precipitate as osteomalacia if amounts of calcium, phosphorus, or vitan1in Dare inadequate or, in the case of the minerals, inappropriately balanced. The problem is fw-ther com­ pounded once the sow farrows, due to secretion of calciwn in the milk. A first-parity sow may soon draw on her skeletal reserves and become osteoporotic. Because sows C3.ll become pregnant within 7 days of we3.11ing, there is little time for recovery of skeletal mass between one breeding cycle and the next, so the skeleton becomes progressively weaker. Lin1ited exercise may also exacerbate calciun1 mobilization and bone loss. Consequently, in sows late in gestation, dw-ing lactation, or soon after we3l1ing, bones that have become weak are susceptible to fractures. It is not sw-prising that considerable nwnbers of first- and second-litter sows are culled because of fractures and 13.1.neness. Factors that may lead to bone fractures include entrapment of a limb in or under the bars of a farrowing crate, activity as sows are moved from their farrowing crates, and fighting as new groups of weaned sows reestablish a social order in the breeding or gestation 3.1.·ea in group housing conditions. Sows mounted by other sows that are in estrus are also prone to injury. The most frequent sites of fractures are femurs, hwneruses, lwnbar vertebrae, and occasionally ribs. Whatever the factors that precipitate the fractures, affected sows are in pain and are either severely 13.1.ne and unwilling to move or paraplegic. Diagnosis is based on a histo1y of acute lameness or paraplegia in pregnant, lactating, or recently weaned gilts or sows. Sometimes, crepitus can be detected in affected limbs. A neurologic examination can help locate spinal lesions if a sow is paralyzed in the pelvic lin1bs. Affected sows should be culled or euthanized after an early diagnosis. Prevention through adequate nutrition and exercise for gilts and sows curtails the problem. Osteomyelitis and Spinal Abscesses:

In addition to the causes discussed under grower/finisher pigs, osteomyelitis may also develop secondary to a vertebral fracture or

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LAMENESS IN PIGS

an epiphyseal separation. It is reasonable to assume that occasional "showering" with organisms from superficial wounds, abscesses, or the respiratory or GI tracts can be a source of infection. True'J)erella pyogenes seems to be a frequent cause of the suppuration and abscessation. Osteomyelitis of the ulnar epiphysis in young boars and sows has been reported. Vertebral osteomyelitis and epidural abscesses can cause a variety of signs, including nonspecific lameness, hyperme­ tria, ataxia, or bilateral flaccid paralysis of the pelvic lin1bs. Except for the temporal nature of the infectious process, clinically it is difficult to differentiate a destructive or space-occupying abscess from a fracture. Regardless of underlying cause, recovery is unlikely, and the pigs should be culled. Osteochondrosis and Leg Weakness Syndrome (Degenerative Joint Disease, Dyschondroplasia):

Degenerative joint disease (DJD) and leg weakness syndrome are generic tem1s for a clinical syndrome that is a major cause of lameness and culling for lan1eness in swine breeding stock. Although the conditions are more often investigated in purebred stock, they can cause major losses in commercial pig herds. Given the increased scale of production in many herds and the shift toward pigs that grow faster, are more muscular, and finish heavier, DJD and leg weakness are critical issues. Osteochondrosis is a specific develop­ mental condition that represents the major cause of DJD. Osteochondrosis is a defect in the development of cartilage of the growth plates or articular cartilage in growing pigs. The pathogenesis of osteochondrosis is increasingly but still incompletely understood. In osteochondrosis, growth plates are more prone to fracture because of areas of retained hypertrophic cartilage that focally thicken and weaken the cartilage. Lesions develop when articular cartilage on the interior aspect of the joint surface becomes necrotic, ostensibly due to loss of vascular supplies. The necrotic cartilage interferes with the advancing ossification front, and the resulting irregular ossification underlying the weight-bearing cartilage surfaces is prone to clefting (displaced cartilage "chips," or osteochondrosis dissecans), exposing the endochondral bone and causing pain and lameness. The developmental lesions have a very high prevalence in young pigs but mostly resolve with age and further development. Osteochondrosis is apparently seen in all the major breeds of purebred and comme1°

cial hybrid pigs. Dyschondroplasia results in deformed long bones, particularly the ulna. Pigs that have valgus deformity or pem1anently flexed carpi tend to be unsuitable for sale as breeding stock and may be lame. In addition, epiphyseolysis and epiphyseal separation may be precipitated by weakening of underlying growth plates and cause an incapacitating lameness. Although lesions that precede or develop into DJD or result in limb defonnities begin to develop in younger pigs, clinical problems are not usually seen until pigs are >4-8 mo old. Frequently, the fastest growing, most muscular, and heaviest pigs are affected. Given time, some pigs (if not culled) recover from episodes of lameness, but defonnities remain. Clinical signs vary with the site and extent of lesions and can range from stiffness and a shortened stride or a stride affected by an angular lin1b defonnity to a three-legged lameness or an inability to stand. Most commonly, tl1ese animals have a weight-bearing, shifting lameness because of bilateral lesions that affect multiple joints in the same pig. Pigs that "walk" on flexed carpi usually have severe DJD in the elbows, and pigs that tuck their pelvic limbs under their abdomen in a stance that resembles a "circus elephant balancing on a ball" often have DJD that affects stifles, tibial tarsal bones, or joints on intervertebral processes. If epiphyseal separation of the femoral head has occurred, the pig has difficulty standing and initially will not use the affected limb. A pig t11at has unilateral separation of the ischiatic tuberosity also has difficulty standing and a tendency to slip; if both tuberosities are affected, the pig has a hopping gait for a few steps after being lifted and then collapses. The severity of clinical signs in any of these conditions varies, and joints with less extensive lesions appear to be protected by the gait if they are more painful than other degeneratingjoints. Severe joint lesions also have been seen in pigs that did not appear to be lame. In pigs that have limb defonnities ( eg, dyschondroplasia affecting the distal ulnar growth plate), thickened, irregular growth plates are seen on radiographs or at necropsy. In degenerating joints, there is an excess of yellow synovia, and synovial villi may have proliferated. There are various irregularities of the articular surface, including folds in the cartilage, clefts into the cartilage, flaps of cartilage, and in severe cases, craters and exposed subchondral bone. In chronic cases, osteophytes develop, detached fragments of cartilage

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LAMENESS IN PIGS

become embedded in the synovium and start to ossify, and craters fill with fibrocartilage. If vertebral joints are affected, vertebrae eventually fuse. Growth plates that are most severely affected by dyschondroplasia are those of the distal pa.it of the ulna and the ribs, whereas joints most often affected by DJD include the elbow, stifle, and hock, or the intervertebral synovial joints. Many potential causes of DJD or osteochondrosis have been investigated. There is evidence of a genetic component, because wiLhin breeds, specific boars have been identified to have progeny with a higher incidence of osteochondrosis. Breeds and lines of pigs that are heavy and well muscled, particularly in the hams, are commonly affected; therefore, crossbreed­ ing for hybrid vigor (ie, to create faster growing, muscular hybrids) does not solve the problem. The fastest growing pigs in a group seem to have a greater propensity for lesions to develop in either growth plates or joints, but once slower-growing pigs reach the body weight of their faster-growing peers, lesions ai·e comparable. Growth hon11one may affect chondrocyte metabo­ lism and thereby influence the onset of aiticulai· lesions. Research into manipulating the energy, protein, and mineral concentrations of the ration in an attempt to influence the development of lesions has been inconclu­ sive, even contradictory. None of the imbalances or deficiencies of nutrients that typically are associated with lesions of cartilage or bone (calcium, phosphorus, and vitamins A, C, and D) seemed to exacerbate osteochondrosis. Deficient or excess zinc and manganese may be causal factors in osteochondrosis, but there is a paucity of evidence from research. The stress of mixing pigs appears to have little impact on the frequency of osteochon­ drosis, but trauma from handlil1g or housing conditions have been found to affect clinical osteochondrosis. The culling rate due to lai11eness for sows kept on solid floors is less thai.1 that for those kept on slats, but the benefits of placing pigs with DJD on dirt lots or pasture is equivocal. Although such pigs usually become clinically sound within6 wk, they are potential carriers of the syndromes. Because osteochondrosis and DJD interfere with production efficiency, the prognosis for affected pigs is poor. At best, the following practices are recommended: selecting against replacement pigs that are lame or have poor confom1ation, providing adequate rations for the growth of a strong

1165

skeleton, housing gilts in pens with �12 sq ft (1.1 sq m) per animal, and promoting exercise on nonslip floors. In problem herds, providing a "hardening off' period for gilts is encouraged. This includes purchas­ ing gilts at l,000 U/L) and, unlike in other forms of rhabdomyolysis, subclinical episodes characterized by persistently abnormal CK levels are common. Clinical signs in draft horses may include loss of muscle mass, progressive weakness, and recwnbency. CK and AST may be normal in draft horses with this syndrome. When draft horses develop rhabdomyolysis, CK and AST may be markedly increased, and horses can become myoglobinuric, weak, and reluctant to rise. Type 2 polysaccharide storage myopathy occurs in light breeds such as Arabians, Morgans, Thoroughbreds, a variety of Warmblood breeds and some Quarter horses. A diagnosis is made by identifying an abnormal pattern of glycogen storage in muscle biopsies in a horse with a negative GYSJ genetic test. In Quarter horses < 1 yr old, it may cause difficulty rising from a recwnbent position and increased serwn CK activity. Chronic episodes of muscle stiffness, soreness, and muscle atrophy with normal to modest increases in semm CK are common in horses with type 2 PSSM. The most common presentation of this disorder in Warmbloods is a gait abnorn1ality, exercise intolerance, and loss of muscle mass when out of work that is not necessarily accompanied by a concomitant rise in serum CK. Malignant hyperthermia is caused by an autosomal dominant mutation in the skeletal muscle ryanod.i.ne receptor gene (RYRJ). The mutation is responsible for both anestl1esia-related and non-anesthesia­ related causes of rhabdomyolysis in Quarter

1179

horses. A diagnosis can be made by genetic testing of blood or hair roots. Signs related to inhalation anesthesia include tachycardia, tachypnea, hyperthemtia, muscle rigidity accompanied by a severe lactic acidosis, increased serwn CK, and electrolyte derangements. Exe1tional rhabdomyolysis in Quarter horses witll malignant hypetther­ rnia can result in sudden death. Signs are preceded by excessive sweating, tachycar­ dia, tachypnea, hyperthermia, and muscle rigidity. Some Quarter horses have botll malignant hyperthennia and PSSM, which results in more severe signs of exertional rhabdomyolysis than tllose seen in horses witl1 PSSM alone. Recurrent exertional rhabdomyolysis is seen frequently in Thoroughbreds, Standardbreds, and Arabian horses. It is likely due to abnorn1al regulation of intracellular calcium in skeletal muscles. It appears tllere is intermittent disruption of muscle contraction, particularly when horses susceptible to the condition are fit and have a nervous temperament. In Thoroughbreds, it is likely inherited as an autosomal dominant trait. Diagnostic tests to detetmine tl1e cause of chronic tying-up include a CBC, serum chemistry panel, serwn vitamin E and seleniwn concentrations, urinalysis to determine electrolyte balance, dietary analysis, exercise testing, muscle biopsy, and genetic testing. An exercise challenge test is useful to detect subclinical cases; serun1 CK is measured before and 4 hr after light exercise. In addition, quantifying the extent of exertional rhabdomyolysis during mild exercise is helpful in deciding how rapidly to reinstate training. A diagnosis of type l PSSM is based on identification of the GYSJ mutation and/or tl1e presence of muscle fibers with subsarcolemmal vacuoles, dark periodic acid-Schiff (PAS) staining for glycogen, and most notably, amylase-resistant abnormal complex polysaccharide accwnulation. A diagnosis of type 2 PSSM is based on the absence of the G YSJ mutation and the presence of muscle fibers witll aggregates of amylase-sensitive PAS-positive staining glycogen and occasionally small amounts of amylase-resistant PAS-positive material. A diagnosis of recurrent exertional rhabdomy­ olysis is based on history, clinical signs, increases in serwn CK and AST, and muscle biopsy. Horses with type 1 PSSM have constitu­ tively active glycogen synthase that is further stimulated by increased blood insulin concentrations, resulting in high

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MYOPATHIES IN HORSES

muscle glycogen concentrations. When fed a starch meal, these horses take up a higher proportion of the absorbed glucose in their muscles than healthy horses. Horses with type 2 PSSM also have abnormal glycogen storage, but the cause of this myopathy is unknown. Thus, the ideal diet for PSSM is based on feeding forage at a rate of 1.5%-2% body wt, providing>15% of digestible energy as fat and limiting starch to< lOOA, of daily digestible energy by limiting grain or replacing it with a fat supplement. Caloric needs should be assessed first to prevent horses becoming obese on a high-fat diet. Improvement in signs of exertional rhabdomyolysis for horses with PSSM requires both dietary changes and gradual increases in the amount of daily exercise and turn-out. Horses with malignant hype1themtia. may benefit from premedication with dantrolene (4 mg/kg, PO) 60-90 min before exercise, paiticula.rly under hot conditions. Management of recun-ent exertional rha.bdomyolysis is aimed at decreasing the triggering factors for excitement and pha.m1a.cologic alteration of intra.cellulai· calcium flux with contraction. Management changes that may decrease excitement include minimizing stall confinement by using tum-out or a hot walker, exercising and feeding horses with recun-ent exe1tional rha.bdomyolysis before other horses, providing compatible equine company, and the judicious use of low-dose tranquilizers during training. A high-fat, low-starch diet is beneficial, possibly by decreasing excitement. In contrast to horses with PSSM, those with recwTent exertional rha.bdomyolysis often require ltigher calo1ic intakes (>24 Meal/day). At these high caloric intakes, specialized feeds designed for exe1tional rhabdomyolysis a.re necessaiy, because additional vegetable oil or rice bran cannot supply enough calories for equine athletes in intense training. Hay should be fed at l.5o/o-2% body wt, and high-fat, low-stai·ch concentrates should be selected that provide �20% of daily digestible energy as nonstructural carbohydrate and 20o/o-25% of digestible energy as fat. Dantrolene (4 mg/kg, PO) given l hr before exercise may decrease the release of calcium from the calcium release channel. Phenytoi.n (1.4-2.7 mg/kg, PO, bid) has also been advocated as a treatment for horses with recurrent exertional rha.bdomyolysis. Therapeutic levels vai-y, so oral dosages a.re adjusted by monitoring serum levels to achieve 8-12 mcg/mL. However, longterm treatment with dantrolene or phenytoin is expensive.

INFECTIOUS MYOPATHIES Virus-associated Myositis Necrosis of skeletal ai1d cai·dia.c muscle may occur in association with viral diseases such as equine influenza. and equine infectious ai1emia. In most situations, viral-induced muscle dai11age represents a component of systentic multiple organ system involve­ ment. Equine influenza. 2 has been found to cause severe rhabdomyolysis, a11d equine herpesvirus l has been reported to induce primaiy muscle stiffness and clinical signs resembling exe1tional rha.bdornyolysis. Sarcocystis Myositis Cysts of the sporozoan pai·asite Sarcocystis a.re present in 90% of esophageal muscles from horses>8 y:r of a.ge ai1d in 6% of gluteal muscle biopsies from healthy horses. Occasionally, heavy infestations occur tlu·ough contamination of feed with canine feces, resulting in signs of fever, ai1orexia., stiffness, weight loss, muscle fasciculations, atrophy, and weakness. Diagnosis of sa.rcocystosis requires hist01y, clinical signs, laboratory evaluation, and the demonstra­ tion of an i:nilanm1a.tory reaction to immature cysts in muscle biopsies. Treatment includes NSAIDs a11d drngs such as trin1etl10prim sulfa and py:rimethan1ine or pona.zuril. (See also SARCOCYSTOSIS, p 1058.) Anap/asma-associated Rhabdomyolysis Horses tl1a.t acquire Anaplasma phagocy­ lophilum from tick i:ni"esta.tions can rai·ely develop clinical signs of severe muscle stiffness in addition to fever, malaise, ai1d limb edema. Hematologic findings include ai1entia, tlu·ombocytopenia, neutropenia., morula. visible in grai1ulocytes, and marked increases in serum CK and AST levels. A diagnosis is con.finned by PCR testing of blood for A phagocytophilum. A direct toxic effect of A phagocytoph'ilum on muscle cells is postulated. Treatment should includP IV oxytetra.cycline ai1d supportive cai·e. Streptococcus equi Rhabdomyolysis Severe rha.bdomyolysis can occur in horses with Streptococcus equi equi submandibu­ lai· lymphadenopa.thy and/or guttural pouch empyema. A stilf gait is the i.Jtitial clinical sign, which progresses rapidly to severely pa.i.Jlful, finn, swollen epaxial and gluteal muscles. Many horses become rectm1bent with unrelenting pain that may warrant euthanasia. It is not clear whether myo­ necrosis is a direct toxic effect of S equi

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MYOPATHIES IN HORSES on muscle cells or is due to profound nonspecific T-cell stimulation by strepto­ coccal superantigens and the release of high levels of inflammatory cytokines. A diagnosis is based on hematologic abnormalities typical of S equi infection, marked increases in CK(> 100,000 U/1), and PCR or bacterial culture. Titers to the M protein of S equi are low in affected horses, unless they have recently been vaccinated for strangles. At postmortem, large, pale areas of necrotic muscle are evident in hindlirnb and lumbar muscles. The histopathologic lesions are characterized by severe acute myonecrosis with a degree of macrophage infiltration. Sublun1bar muscles often show the most severe and chronic necrosis, as indicated by greater macrophage infiltration of myofibers. The prognosis becomes guarded if animals become recumbent. Appropriate therapy includes IV penicillin combined with an antimicrobial that inhibits protein synthesis, such as rifampin. Flushing infected guttural pouches and draining abscessed lymph nodes will diminish the bacterial load. NSAlDs and possibly high doses of short-acting corticosteroids may diminish tile inflan1rna­ tory response. Control of unrelenting pain is a major challenge in horses witll severe rhabdomyolysis. Constant-rate infusion of lidocaine, detomidine, or ketamine may provide better anxiety and pain relief than periodic iltjections of tranquilizers. Horses should be placed in a deeply bedded stall and moved from side to side every 4 hr if tlley are unable to rise. Some horses may benefit from a sling if they will bear weight on their hindlirnbs when assisted to stand.

Clostridial Myositis A variety of clostridial bacteria can sporulate at tile site of an injection or deep wound, causing focal muscle swelling and systemic toxemia in horses. Clostridium septicum, C chauvoei, C sporogenes, and mixed infections are associated with a high fatality rate, whereas C perfringens type A has a mortality rate of 20% with early and aggressive treatment. Clostridial spores may lie donnant in skeletal muscle, or spore deposition directly into the tissue may occur in association with penetration. If suitable necrotic conditions exist, tile spores convert to the vegetative form, releasing powerful exotoxins. Within 48 hr, horses show depression, fever, toxemia, tachypnea, and swelling and variable crepitus at the iltjection site. Tremors, ataxia, dyspnea, recumbency, coma, and

1181

death may occur in the next 12-24 hr. Myocardial damage occurs in some horses. Hematology and serum biochemical analyses usually reflect a generalized state of debilitation and toxemia (eg, hemocon­ centration and a stress/toxic leukogram may be present). Serum CK and AST are usually moderately increased; however, they often do not reflect the toxicity of clostridial myonecrosis.. Ultrasonographic evaluation of swollen areas may reveal fluid and characteristic hyperechoic gas accw11ulation. Aspirates of affected tissues examined via direct smears or fluorescent antibody staining should show characteristic rod-shaped bacteria. Anaerobic bacterial culture of freshly acquired samples may also be of value. Cut tissue from tile affected area may reveal abundant serosanguineous fluid with an odor of rancid butter. At postmortem, swelling, crepitus, and autolysis are rapid, and bloodstained fluid is often seen discharging from body orifices. Wound fenestration and aggressive surgical debridement over tile entire affected area is required for successful treatment. Additional treatment includes high doses of IV potassiun1 penicillin every 2-4 hr until the horse is stable (1 to 5 days), combined with or followed by oral metronidazole along with supportive fluid therapy and anti-inflammatory agents. Extensive skin sloughing over the affected area is common in surviving horses.

Muscle Abscesses Staphylococcus aureus, Streptococcus equi, and Corynebacte1ium pseudotuber­ culosis are common causes of skeletal muscle abscessation, which develops after penetrating iltjuries or by hematogenous or local spread of infection. Initially there is an ill-defined cellulitis, which may heal or progress to a well-defined abscess. An abscess may heal, expand, or fistulate, usually to tile skin surface witll potential for a chronic granuloma with intennittent discharge. Prognosis is usually good for superficial abscesses. Deep abscesses are more difficult to manage successfully. The effect of an abscess on tile horse's gait depends on its location and can vary from mild stiffness to severe lameness. Ultra­ sonography and culture of aspirated fluid are tile best means of diagnosis in superfi­ cial sites. Abscesses lying deep within muscles can be difficult to diagnose. There may be an increased fibrinogen and nucleated WBCs. The synergistic hemolysin inhibition test, which detects antibodies to

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MYOPATHIES IN HORSES

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C pseudotuberculosis, can be helpful for

detection of internal abscesses. Treatment consists of poulticing, lancing, flushing, and draining. Occasionally, surgical removal may be required for complete excision. If antimicrobial therapy is used, it should be continued for several weeks. IMMU NE- MEDIATED MYOPATHIES lnfarctive Hemorrhagic Purpura Pw1Jura hemorrhagica is often associated with mild increases in serum CK activity; however, horses vaccinated for, or exposed to, Streptococcus equi within the last month rarely may develop extremely high semm CK activity, variable edema, acute colic, finn swellings within muscle and under the skin, and unilateral lameness. Clinical signs are due to painful infarctions of skeletal muscle, subcutaneous tissue, focal areas of the GI tract, and lungs resulting from a severe immune-mediated vasculopathy. Hematologic abno1111alities include leukocytosis, hyperfibrinogenemia, hypoalbwninemia, and marked increases in serwn CK and AST. A diagnosis is often established based on clinical signs, a leukocytoclastic vaseulitis in skin and affected tissues, and a very high S equi M protein titer. Successful treatment requires early detection, penicillin for 14 days, and prolonged high doses of dexamethasone (0.12-0.2 mg/kg) for at least 10 clays, followed by tapering doses of prednisolone at an initial dosage of 2 mg/kg. Without aggressive steroid treatment, the condition progresses to intestinal infarction �d death. Immune-mediated Polymyositis Immune-mediated polymyositis is characterized by rapidly developing atrophy of the epaxial and gluteal muscles. It is seen in Quarter horses, although other breeds may be affected. The condition shows a binlodal age di tribution, affecting horses 16 yr of age. In approxin1ately one-third of affected horses, a niggering fac­ tor appears to have been exposure to S equi or a respiratory disease. Rapid onset of atrophy of the back and croup muscles is accompanied by stiffness and malaise. Atrophy may progress to involve 500A, of the horses' muscle mass within a week and may lead to generalized weakness. Focal symmetric atrophy of cervical muscles has been reported in a pony with immune­ mediated polymyositis. Hematologic

abnormalities are usually restricted to mild to moderate increases in serun·1 CK and AST. However, in some chronic cases serum muscle enzyme activities are normal. Muscle biopsy of epaxial and gluteal muscles shows lymphocytic vasculitis, anguloid atrophy, myofiber infiltration with lymphocytes, fiber necrosis with mac­ rophage infiltration, and regeneration in acute stages. Biopsies of semitendinosus or semimembranosus muscles may show some evidence of atrophy and vasculitis, but significant inflammatory infiltJ·ates may be absent. The extent of the inflan1rnatory infiltrates in epaxial muscles is such that a diagnosis can often be established from several fo1malin fixed-core needle biopsy samples. The reason why specific muscle groups are affected is unclear. TreatJnent involves antibiotic therapy for horses with concurrent signs of infection and administration of dexamethasone (0.05 mg/kg for 3 clays), followed by prednisolone (1 mg/kg for 7 1- 0 days) tapered by 100 mg/wk throughout 1 mo. Sen.mi CK often normalizes after 7-10 days of treatment. Generally, muscle mass gradually recovers throughout 2-3 mo even without corticosteroid tJ·eatment. Recur­ rence of atJ·ophy in susceptible horses is common and may require reintroduction of corticosteroid therapy. MUSCLE CRAMPING Muscle cramping is a painful condition that arises from hyperactivity of motor tmits caused by repetitive firing of the peripheral and/or central ne,vous system. The origin of tl1e cramp in most cases is believed to be the intramuscular portion of the motor nerve temiinals. Most muscle cramps are also accompanied by fasciculations in the san1e muscle and normal serum CK activity. Muscle cramps can be induced by forceful contJ·action of a shortened muscle, by changes in the electrolyte composition of extracellular fluid, and by ear tick infestations. In contrast, muscle contrac­ tures, like those seen in exe1tional rhabdomyolysis, are painful muscle spasms that represent a state of rn uscle contracture unaccompanied by depolarization of the muscle membrane. Muscle contractures are invaiiably accompanied by markedly increased serwn CK activity. Electrolyte Disturbances Muscle cran1ping in endurance horses is most frequent in hot, hwnid weather. Horses may lose fluids at a rate of up to

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MYOPATHIES IN HORSES 15 Ulu in the fom1 of sweat and develop remarkable deficits in sodium, potassium, chloride magnesium, and calcium. Clinical signs of electrolyte derangements include muscle stiffness and periodic spasms of muscle groups. In addition, exhausted horses are often dull, depressed, and clinically dehydrated with increased heart and respiratory rates and persistently increased body temperature. Synchronous diaphragmatic flutter may be seen in association with cramping. Affected horses do not generally develop myoglobinuria or have marked increases in serum CK and AST levels. Mild muscle cran1ping is self-limiting, and the signs abate with rest or light exercise. However, exhausted horses with metabolic derangements require inunediate treatment, including plasma volume expansion with oral or IV isotonic polyionic fluids and cooling ( using water and fans). Because most horses with this condition are alkalotic, administration of solutions containing sodium bicarbonate is contra­ indicated. Daily direct addition of2 oz of sodium chloride and 1 oz of potassium chloride to the feed is recommended for horses with recurrent cramping, in addition to electrolyte supplementation before and after endurance rides.

Hypocalcemia Hypocalcemia is a relatively rare disorder in horses that has also been referred to as lactation tetany, transport tetany, idiopathic hypocalcemia, and eclampsia. Clinical signs, diagnosis, and treatment are discussed elsewhere (seep 987). In addition to hypocalcemia, a metabolic alkalosis, hypomagnesemia/hypennagnesemia, and hyperphosphatemia/hypophosphatemia may be present and need correction before a return to normal function is seen. Relapses do occur.

Synchronous Diaphragmatic Flutter ("Thumps") Synchronous diapluagmatic flutter is due to firing of the phrenic nerve in synchrony with atrial depolaiization, causing the diaphragm to contract with each heartbeat. Th.is occasionally produces an audible thumping sound. Inciting causes include endurance exercise, hypocalcemia, hypoparathyroidism, digestive distur­ bances, and repeated administration of calciun1-containi.ng fluids to performance horses. Synchrnnous diaphragmatic flutter may be a singular occurrence or a chronic

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recurring problem. The most consistently reported metabolic derangement is low serwn ionized calciwn concentrations usually associated with hypochloremic metabolic alkalosis. Metabolic alkalosis may alter the ratio of free to bound calcium (increasing calciun1 binding to protein and decreasing ionized calciun1), which possibly induces diaphragmatic flutter. Most horses undergo rapid remission of signs when given calciwn solutions IV. Altl1ough hypomagnesernia is often present witl1 syncluonous diapluagmatic flutter, horses do not respond to magnesiun1 supplementation wtless calcium is administered concurrently. Response to tl1erapy is also reflected by improved mental status, return of appetite, and gut motility. For horses with chronic diaphragmatic flutter, providing chloride, potassiwn, sodiw11, calciwn, and magnesiun1 dwing prolonged exercise may help reduce fluid losses and the metabolic alkalosis. Alternative approaches involve reducing dietary calciwn for a few days before competition in horses prone to diapluag­ matic flutter. Th.is reduction in dietary calcium may stin1ulate the endocrine homeostatic mechanisms and increase osteoclastic activity. Lintiting alfalfa hay, which has a relatively high calciun1 concentration, may be indicated in chronically affected horses.

Ear Tick-associated Muscle Cramping Otobius megnini infestations in tl1e ear canal can produce remarkably painful intemtittent muscle cramps not associated with exercise tl1at last from minutes to a few hours and often resemble colic. Horses may fall over when stin1ulated. Between muscle cramps, horses appear to be nonnal. Percussion of triceps, pectoral, or semitendinosus muscles results in a typical myotonic cramp. Horses have increased serum CK, ranging from 4,000 to 170,000 IU/L. Nun1erous ear ticks can be identified in tl1e external ear ca11al of affected horses. O megnini is found in tl1e soutl1westem USA. Without treatment, the spasms continue; however, local treatment of the ear ticks using pyrethrins and piperonyl butoxide results in recovery within 12-36 hr. Acepromazine may be helpful to relieve painful cran1ping.

Shivers "Shivers" is a spastic condition of the ltind­ and occasionally forelimbs of horses tl1at is

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MYOPATHIES IN HORSES

usually only evident when horses are backing or having their feet picked up. It is most common in adult draft horse breeds, Waimbloods, Warmblood crosses, and Thoroughbreds > 16.3 hands tall. The condition is characterized by periodic, involuntary spasms of the muscles in the pelvic region, pelvic limbs, and tail that are exacerbated by backing or picking up the hindlimbs. The affected limb is elevated, abducted, and may actually shake and shiver; the tail head is usually elevated concurrently and trembles. When more severely affected animals are backed up, the hindlimb is suddenly raised, semiflexed, and abducted with the hoof held in the air for several seconds or minutes. The tail is elevated simultaneously and trembles. After a variable pe1iod of time the spasms subside, tl1e limb is extended, and the foot is brought slowly to tl1e ground. Some horses will refuse to pick up their hindlimbs and are very difficult to shoe. Suggested causes include genetic, traumatic, infectious, and neurologic diseases, although the exact etiology is unknown. The condition in draft horses is usually progressive and eventually debilitating; in Warmbloods and Thorough­ breds, it usually has less impact on perfor­ mai1ce and progresses more slowly. There are no known treatments, but avoiding stall rest and keeping horses fit appears helpful.

MYOTONIC DISORDERS Myotonic muscle disorders share the feature of delayed relaxation of muscle after mechanical stimulation or voltmtary contraction due to abnonnal muscle membrane conduction. Horses have tllree known forms of myotonia: myotonia congenita, myotonia dystrophica, and hyperkalemic periodic paralysis (HyPP).

Myotonia Congenita and Dystrophica The initial signs of myotonia in foals are well-developed musculature and mild pelvic limb stiffness. Bilateral bulging (dimpling) of the thigh and rump muscles is often obvious and gives tl1e impression that tile aninlal is very well developed. Percussion of affected muscles exacerbates the muscle dimpling below a large ai·ea of tight contraction tllat can persist for a minute or more with subsequent slow relaxation. Myotonia congenita usually does not show progression of clinical signs beyond 6-12 mo of age, and muscle stiffness may improve with exercise. The cause has not been identified.

Foals witll myotonia dystrophica show a progression of signs in tile fu'st 1-2 yr of life to include areas of muscle atrophy fibrosis and stiffness tl1at worsens witll exercise. Retinal dysplasia, lenticular opacities, and gonadal hypoplasia have been seen in Quarter horse, Appaloosa, and Italian-bred foals with myotonic dystrophy. A tentative diagnosis of myotonia can be made on the basis of age and clinical signs of stiff gait, muscle bulging, and prolonged contractions after muscle stimulation. Definitive diagnosis of myotonia requires electromyographic examination. Affected muscle mailifests pathognomonic, cre­ scendo-decrescendo, high-frequency repetitive bursts with a chai·acteristic "dive bomber" sound. Myotonia dystrophica shows dystrophic changes in muscle biopsies not present in myotonia congenita. Dystrophic changes include ringed fibers, numerous centrally displaced myonuclei, sarcoplasmic masses, and an increase in endomysial and perimysial connective tissue. Fiber type grouping and atrophy of botl1 type I and type II muscle fibers may be present. Horses witll myotonia congenita or dystrophica are rai·ely serviceable, and eutllanasia is usually warranted in dystrophic foals because of the severity of stiffness and atrophy tllat develop over time. Conclusive evidence regarding tile genetic basis of tl1is disorder in horses is still not available.

Hyperkalemic Periodic Paralysis HyPP is an autosomal dominant trait affecting Quarter horses, American Paint horses, Appaloosas, and Qua1ter horse crossbreeds worldwide. The point mutation in tile voltage-dependent skeletal muscle sodium chaimel alpha subunit occurs in -4% of Quarter horses, but this percentage is much higher in halter and pleasure horse performance types. Clinical signs range from asymptomatic to intennittent muscle fasciculations and weakness and are first identified in foals to horses 3 yr of age. Homozygous horses are often more severely affected and may be identified at a younger age tllan heterozy­ gotes. A brief period of myotonia is often seen initially, witll some horses showing facial myotonia and prolapse of the tllird eyelid. Muscle fasciculations beginning on the flanks, neck, and shoulders may become more generalized. Altllough most horses remain standing during mild attacks, weakness witll swaying, staggering, dog­ sitting, or recmnbency may be seen, witll severe attacks lasting 15-60 min or longer.

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Heart and respirato1y rates may be increased, but horses remain relatively bright and alert. Respiratory distress occurs in some horses as a result of upper respiratory muscle paralysis. Once episodes subside, horses regain their feet and appear nonnal with absent or minimal gait abnmmalities. Young horses that are homozygous for the HyPP trait may have respiratory stlidor and pe1iodic obstruction of the upper respiratmy tract that can be fatal. Common factors that ttigger episodes include sudden dietary changes or ingestion of diets high in potassiw11 (>1.1%), such as those containing alfalfa hay, molasses, electt·olyte supplements, and kelp-based supplements. Fasting, anesthesia or heavy sedation, trailer rides, and stress may also precipitate clinical signs. TI1e onset of signs, however, is often unpredictable. Exercise per se does not appear to stimulate clinical signs; serun1 CK shows no or minimal increases dwing episodic fasciculations and weakness. Descent from the stallion Impressive in a horse with episodic muscle tremors is strongly suggestive ofHyPP.Hyperkalemia (6-9 mEq/1), hemoconcentration, and hyponatremia are seen dwing clinical episodes, but a definitive diagnosis requires DNA testing of mane or tail hair. Electro­ myographic examination of affected horses between attacks reveals abnom1al fibrillation potentials and complex repetitive discharges, with occasional myotonic potentials and trains of doublets between episodes. Differential diagnoses for hyp erkalemia include delay before sernm centrifugation, hemolysis, chronic renal failure, and severe rhabdomyolysis. Many horses recover spontaneously from HyPP episodes. Owners may abort early mild episodes using low-grade exercise or feeding grain or com syrnp to stimulate insulin-mediated movement of potassium across cell membranes. In severe cases, administration of calcim11 gluconate (0.2-0.4 ml/kg of a 23% solution diluted in 1 L of 5% dextrose) or IV dextrose (6 ml/kg of a 5% solution), alone or combined with sodimn bicarbonate (1-2 mEq/kg), often provides immediate in1provement. With severe respiratory obstrnction, a tracheostomy may be necessary. Acute death is common, especially in homozygous anin1als. Prevention requires decreasing dietaty potassium to 0.6%- l.1% total potassium concentt·ation and increasing renal losses of potassiun1.High-potassium feeds such as alfalfa hay, first cutting hay, brome hay, sugar molasses, and beet molasses should be avoided. Optin1ally, later cuts of timothy or Bem1Uda grass hay; grains such as oats, com,

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wheat, and barley; and beet pulp should be fed in small meals several tin1es a day. Regular exercise and/or frequent access to a large paddock or yard are also beneficial. Pasture is ideal for horses withHyPP, because the high water content of pasture grass makes it unlikely that ho1ses will consume large amounts of potassium in a short period of ti.me. Complete feeds for horses withHyPP are conrn1ercially available. For horses witl1 recurrent episodes even with dietary alterations, acetazolamide (2---4 mg/kg, PO, bid-tid) or hydrochlorothiazide (0.5-1 mg/kg, PO, bid) may be helpful. Breed registries and other associations have restlictions on tl1e use of these drugs dwing competitions. Some hmses have bothHyPP and polysaccharide storage myopathy (PSSM) (seep 1178), which may result in an episode of rhabdornyolysis dming a hyperkalemic paralytic event with subsequent increased serum CK activity and prolonged recun1bency.

NUTRITIONAL MYOPATHIES Nutritional Myodegeneration Yow1g, rapidly growing foals born to dams that consun1ed selenium-deficient diets dwing gestation can develop nutlitional myodegeneration (NMD; see p 1172). Seleniun1 deficiency has also been in1plicated in rnasseter muscle myopathy and occasion­ ally nonexertional rhabdomyolysis in adult hmses. Seleniw11 and vita.min E appear to be synergistic in preventing NMD. Clinical signs in foals include dyspnea; a rapid, ilTegular heaitbeat; and sudden death in those witl1 myocai·dial involvement. Dysphagia, muscle stiffness, trembling, finn muscles, difficulty rising, and myoglobinuria may also be seen. Aspiration pnewnonia is a frequent complica­ tion. Diagnosis is based on finding moderate to markedly increased serun1 CK and AST, combined with low whole blood seleniw11 concentt·ations ( 24 hr after initial recLUTibency, they may develop a secondary recwnbency from pressure dan1age to muscles and nerves, often tem1ed "downer cow syndrome." An alert downer cow does not show signs of systemic illness or depression, is able to eat and drink, and remains in sternal recLUTI­ bency for no apparent reason. A nonalert downer cow appears systemically sick and depressed. Downer cow syndrome also describes the pathology of pressure-induced muscle and nerve ir\jwies after prolonged recLUTibency. The most inlportant patho­ physiologic event that develops dwing prolonged recLU11bency is a pressure-induced ischemic necrosis of the thigh muscles that frequently affects both hindlegs. onambulatory disabled livestock are those that cannot rise from a recLUTibent position or that cannot walk. This includes, but is not limited to, those with broken appendages, severed tendons or ligaments, nerve paralysis, a fractured vertebral column, or metabolic conditions. Downer cows have been categorized according to potential diseases of the C S into nonarnbu­ latory cows wiili progressive or nonprogres­ sive neurologic findings. Etiology and Pathogenesis: ln most cases, downer cow syndrome is a complica-

tion of petiparturient hypocalcemia (milk fever, see p 988) in cows that do not fully respond to calciw11 therapy. Calving paralysis after clystocia may also result in recrnnbency clue to traLUTiatic ir\jury to tissues and nerves inside the pelvic cavity. Regardless of tl1e initial cause of recLU11bency, all cattle develop pressure-induced damage to muscles and nerves of ilie pelvic limbs, especially when lying on a hard surface. The hindlimb muscles of the leg the animal is lying on a.re compressed between tl1e bones and ilie skin by ilie physical pressure from ilie weight of the recLUTibent cow. Wiili prolonged recumbency (eg, if treatment of hypocalcemia is delayed), the lyn1phatic and venous drainage to muscle is decreased because of sustaine\:I pressure with no decrease in arterial blood flow. The net result of pressure-induced changes in blood flow is an increase in interstitial fluid voltm1e and presstu-e within the muscle, because the fascia around each muscle cannot expand sufficiently to accommodate ilie increase in interstitial volLUTie. ln severe and prolonged cases of recw11bency, the increase in intran1uscular pressure is visible as a finn swelling of the muscle. The resulting compre�sion of muscles, nerves, and blood vessels witlli.n an enclosed compartment induces ischemic pressw-e dan1age of muscle and nerves, also named compaitment syndrome. The sevetity of pressure dainage to tl1e muscles depends on regional anatomic factors (bones), duration

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BOVINE SECONDARY RECUMBENCY

of compression, and the surface on which the animal is kept. Pressure myopathy in downer cows is often complicated by damage to and functional loss of the sciatic neive and its peroneal branch. The sciatic neive may be damaged by direct compression against the caudal femur, secondary swelling of the sun-ounding muscles, or both. The degree of dan1age to the sciatic neive is thought to be a critical factor for recovery of downer cows. Damage to the peroneal branch of the sciatic neive results from direct pressure on the neive as it crosses over the lateral condyle of the femur. Experin1ental sternal recumbency in halothane-anesthetized cattle for 6--12 hr, with the right hindlin1b positioned under the body, resulted in a swollen and rigid limb and pe1manent (tem1inal) recumbency in 500Ai of the cases. Cattle able to stand after anesthe­ sia showed hyperflexion of the fetlock, indicating peroneal neive paralysis, and myoglobinuria with dark brown urine. Necropsy of terminal downer cases revealed extensive necrosis of the caudal tl1igh muscles and inflanrn1ation of the sciatic neive caudal to tl1e proximal end of the femur. Additional complications of prolonged recumbency include acute mastitis, decubital ulcers, and traumatic irtjuries to the limbs (eg, laceration and rupture of muscle fibers in the thigh) from struggling and efforts to rise.

Clinical Findings: Periparturient cows may be found in lateral recumbency, which may indicate an unresolved metabolic problem such as hypocalcen1ia or hypomagnesen1ia Inquilies into the severity and duration of parturition may suggest tl1at the recun1bency is at least partially due to exhaustion. In involuntary sternal recum­ bency, some cows may have a dull, listless appearance. This may indicate hypocalce­ n1ia in peripaiturient mature cows. The second most likely cause of depression is toxemia, the cause of wl1ich is most commonly found in the genital tract or mam­ mary gland. Other cows found in involun­ tary sternal recun1bency may be bright and alert in appearance-the most typical demeanor of the true problem downer cow. If the animal is young or not pregnant, the cause is likely to be either physical damage or a rare condition, either of which requires careful, detailed examination. The environment of the animal can have a bearing on the cause. If the footing is slippery, physical damage to tl1e musculo­ skeletal system should be suspected. This is much less likely among cows in open space witl1 a dirt or well-bedded surface.

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The positioning of the hindlimbs may indicate the cause of the recumbency. Limbs splayed out behind tl1e anin1al may indicate obturator neive paresis or paralysis, hip dislocation, or fracture of the femur or tibia. Fracture should be suspected whenever the upper lin1b is extended sideways in such a maimer that a crease is formed in the skin. Physical Examination: A thorough physical exan1ination should be pe1fonned when the cow is first presented. The rectal temperature should be wiU1in the normal range. If it is lower than normal, some level of shock might be present. Recession of ilie eyes into tl1e orbit or persistence of a skin fold for >2 sec indicates dehydration. Pallor of the mucous membranes suggests toxen1ia, in which case a weak pulse and tachycardia may be present. The respiration of a recumbent cow may be labored by virtue of tl1e pressure of tl1e abdominal contents on the diaptu·agm. Vaginal exploration is mandatory in every peripartwn, recumbent cow and may lead to discovery of a decomposing fetus. Damage to and infection of tl1e wall of the vagina is conunon. Metritis and an associated toxemia can contribute to postpaitun1 recun1bency. Rectal exploration is essential for differential diagnosis. The degree of uterine involution should be appropriate for the number of days postpartwn. Ballottement of fluid in tl1e organ or lack of tonicity should be noted. Unexpected anomalies may be palpated. Adhesions, lwnps of necrotic fat,. and enlargement or turgidity of tl1e ceIVix or vaginal wall are all sequelae of a difficult birtl1. Hip dislocations and fractures of tl1e pelvis may be palpated per rectum, particularly if an assistant vigorously manipulates the upper limb of a cow in lateral recun1bency. Movement of the head of tl1e femur in the obturator foran1en may also be detected in cattle witl1 caudoventral hip dislocation. Craniodorsal dislocation of the hip, tl1e most common direction for hip dislocation, or fracture of the femoral neck or proximal femur should be suspected if the affected limb appears shorter than the contralateral limb. Pelvic fractures can be associated with sciatic neive paralysis, whereas hip dislocation may be associated with some degree of obturator nerve paralysis. If eitl1er condition is suspected, the sensory state of tl1e lin1bs should be evaluated by judicious and hw11ane application of an electric prod to the distal limb. lnvoluntaiy sternal recun1bency may be associated with lyrnphosarcoma of the spinal canal, ve1tebral abscesses, or bizan·e traun1atic irtjuries.

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Manunary gland examination should always be performed on recumbent cows. A toxic infection of the udder with an organism such as Escherichia coli can be a primary cause of recumbency. However, such an infection may be precipitated by the recw11bency, especially if the udder is engorged and remains wunilked. Blood samples are not usually taken when treating routine cases of hypocalcemia However, hypocalcemia, hypophosphatemia, and hypokalemia should be assumed to be present in all recwnbent cattle, and dete1° mination of the biochemical status of cattle unresponsive to calcium therapy frequently helps guide treatment and prognosis. Hypokalemia and hypophosphatemia are conunonly quoted causes of creeper cows (cows able to crawl but Wlable to stand). Ale1t downer cows may have normal serW11 concentrations of calciw11, potassium, magnesiwn, and phosphorus. Downer cows have increased serwn CK, AST, and LDH; cows that do not recover have higher serum AST and CK activities than cows that do recover. Increased serum CK activity is a specific indicator of muscle damage; however, CK activity peaks shortly after the stait of muscle damage and declines noticeably within 4 hr. For this reason, increased serW11 AST activity is the best prognostic indicator in recwnbent cattle, with higher AST activities indicating a poorer prognosis. In cattle with severe muscle dan1age, the urine may contain myoglobin as well as higher than nonnal concentrations of protein. The age and mean serum concentrations of phosphorus, magnesium, sodium, bilirubin, glucose, and urea are not significantly different between recovering and nonrecovering c;;ows. Lesions: Ischemic necrosis and ruptw·e of muscles of the thigh region are conunon necropsy findings in downer cows. Hemor­ rhage and rupture of adductor muscles may be seen if the aninlal "spread-eagled" itself while stiuggling to rise on a slippery surface such as wet or icy concrete. Trawnatic and inflanunatory irtjuries to sciatic and peroneal ne1ves are also foWld in downer cows. Damage to intra.pelvic nerves, such as the sciatic and obturator nerves, accollilt for most cases. Decubital ir\juries to the lateral aspect of the stifle can be associated with damage to the peroneal ne1ve. Treatment: Downer cows are often

hypocalcemic. If an apparently hypocalce­ mic cow does not respond to calcium therapy, potassiw11, phosphorus, and magnesiw11 should be given as additional

treatments pending results of laboratory tests. Monitoring blood mineral status is an important part of downer cow management. ln most cases, recovery depends on the quality of recumbency management and nursing care. Lateral recW11bency must be corrected inu11ediately to avoid regurgita­ tion and inspiration of stomach contents. The anin1al should be rolled into sternal recumbency. However, if this posture is to be maintained, the lin1b on which the animal has been lying should be drawn from Wlder tile body. In oilier words, if the animal was presented in lateral recW11bency on its left side, it should be rolled into sternal recumbency on its right side. Suppo1t (eg, straw bale) placed Wlder the shoulder may be required for some animals to maintain sternal recW11bency. Attempting to stabilize a recW11bent cow on a concrete surface is highly undesirable but sometimes unavoidable. Bedding the area around and Wlder the cow with wet, sticky manure to a depth of >6 in. is a common practice. At least 10 in. of dry straw should be distributed over the wet mass. If the cow struggles and scrapes the wet manure, exposing concrete, more manure must be added. The manure pack provides good footing but also may soil tl1e skin with wine and manure. Dermatitis can result, and cow comfort is reduced. More seriously, the risk of mastitis resulting from tile containinated environment is ve1y high. A bed of sand > 10 in. deep provides a more effective method to house a recW11bent cow. A sand bed usually drains well, and good hygiene can be maintained if voided manure is removed several times a day. Some recumbent cattle appear to lose interest in trying to stand; tllese cattle may benefit from use of a specially designed flotation tank that has a volume of -2,500-3,000 L. Cattle are loaded into tile flotation tank by being dragged on a mat into the empty tank Doors are then put in place, and the tai1k is filled witll lukewan11 water. Cold or hot water should be avoided, because it can induce hypotl1er.n1ia or hyperthernua. Cattle should be encouraged to stand once the water reaches tile level of the scapulohurneraljoint. When tile cow stands, the musculoskeletal and nervous systems should be thoroughly examined to identify Wlderlying disease processes. Cattle that can'support tlleir own weight should be pern1itted to stand for 6-8 hr; however, tile water in tile tank should be removed as soon as cattle exhibit trembling. Cattle that remain standing should be encouraged to walk slowly from the tank on a nonslip surface. Cattle able to walk out of

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BOVINE SECONDARY RECUMBENCY

the tank after the first flotation treatment are 4.8 times more likely to smvive than those that do not walk out of the tank. Cattle that stand on all fom limbs during the first flotation treatment are 2.9 times more likely to smvive than those that had an asymmet­ ric stance or were unable to stand. Reported success rates in retmning recumbent cattle to nonnal ambulation range from 37%-46%. Hobbling may be considered in cows suspected to have obturator or sciatic nerve damage to prevent overabduction that can lead to muscular damage. Ropes should never be used for this purpose. A soft nylon strap may be wrapped twice around the middle of each metatarsus, alJowing a distance of at least 3 ft between the legs. Assisting Cows to Rise: On every day of the recw11bency, an attempt should be made to bring the cow to its feet. Several simple but effective techniques can be tried. In one method, the clinician stands with feet pressed under the cow at a point below the scapulo­ hwneraljoint. A sharp blow is delivered by chiving the knees into the muscle mass below and caudal to the scapula. This metl10d must not be used on the thoracic walJ unprotected by the muscle mass to avoid fractming the ribs. If the anin1al struggles to rise, an assistant should grasp the root of the tail with both hands and lift. Lifting on any other part of tl1e tail may cause damage. Recently calved cows can be motivated to rise if they hear their own calf bawling with htmger. The calf is best restrained close to the cow but out of her sight. Some workers use electric goads and various anecdotal or traditional methods of inflicting pain to stimulate a cow to rise; tl1ese measmes have a low success rate in inexperienced hands and are not recom­ mended. The value of hip clamps is controversial. Their proper use requires experience, skill, and a delicate touch. Continual use causes trauma and pain that is counterproductive. The forelin1bs support 600Ai of a cow's weight and, therefore, the use of a canvas sling under the stemun1 is almost mandatory for consistent success. A chest band is required to prevent the sling from slipping backward. If the sling is suspended from the tine at one end of a fork lift, and the hip clamps from a tine at the other end, minimal trauma results. If a fork lift is not available, a T-bar suspended by a pulley from an overhead beam (or a tripod for anin1als at pastme) will serve. Thejaws of the clan1ps must be well protected with synthetic foam or rubber secured in place with a wrap of duct tape. Hip clamps should not be applied too tightly and should lift the cow slowly to allow time for the circulation of the lin1bs to

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become reestablished. The device is lifted until the hindfeetjust touch the ground. Often, the cow will hang with the limbs slightly flexed. This should not be confused with unilateral flexion, which indicates peroneal paralysis. Next, one assistant on each side of the cow presses a shoulder into the paralun1bar fossa while facing the hindlimb. The device is slowly lowered as the assistants attempt to force each hindlimb into a weightbearing postme and to reduce the flexion by manipulating the stifle and hock. As soon as any weight is supported by the two limbs, the device should be lowered 1-2 in. This process may have to be repeated several times. Even if the cow does not stand, the lifted position provides an opportw1ity to manipulate the limbs, auscultate for crepitation, and perfom1 vaginal and rectal examinations. Moving Recumbent Cows: The chances of resolution are considerably enhanced by moving the cow to a location with an earthen floor. In warm, relatively dry weather, the best location for a recumbent cow is grassy pastme, altl10ugh tl1is means that a metl10d to lift the cow must be readily available. Otherwise, the location selected should have a roof and some protection from the elements. These conditions often exist in a hay barn or implement shed, which may have the added benefit of allowing installation of a pulley system to lift the cow. Moving the cow requires rolling her into lateral recun1bency. The cow can then be slid over clI-y straw for a short distance by pulling on a rope attached to a lower forelimb and a halter rope. Transportation over longer distances can be accomplished using a suitably prepared frum gate hauled by tractor. The longest dimension of the farm gate is closely applied to the back of the cow still in lateral recw11bency. A tarpaulin is placed on the gate to protect the cow from contact with the ground. 01-y straw is spread on the tarpaulin, and the cow is rolled over onto the makeshift stretcher. The halter should be tied to the gate to minimize struggling, and a sack placed over tl1e eyes to minin1ize alam1 while the cow is being moved. The tail is best tied to the hock of the upper lin1b. Once moved, the cow should be restored to sternal recun1bency. A few cows, particu­ larly if< 12 hr postpartum, will rise i.nm1ediately after being moved to a location with good footing. Recun1bent cattle should be examined daily to detemtine any change in ability to rise or bear weight. The chance of in1prove-

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BOVINE SECONDARY RECUMBENCY

ment is very low if the cow does not show any improvement within 5 days of moving to a location with good footing and correction of any serum electrolyte abnonnalities. Supportive Care of Recumbent Cows: It is vital that recumbent cows be provided with clean water at all times. A shallow rubber feed bowl prevents spillage. If the cow does not drink, she must be given fluid therapy either by drench or parenterally. Every effort must be made to roll the cow from one side onto the other at least three times a day, with more frequent movement being desired. If this is not done, the weight of the cow results in continued ischemia of the muscles of the hindlin1b and exacerba­ tion of compartment syndrome. Protection from the elements is essential. Rain and wind can reduce body tempera­ ture considerably and worsen shock if present. A windbreak of straw bales is vital. Straw bedding should be provided to help insulate the cow from the ground. A recumbent cow does not require a wann environment; however, in a cold environ­ ment, an inactive animal can gradually succumb to hypothermia. The downer cows most difficult to treat are those that do not try to eat. A cow that salivates on its feed will not eat it later. Rather than being offered large an10unts of feed, the cow should be tempted with sweet hay. This should be cleared away eve1y 30 min if not accepted. Placing bitter-tasting weeds such as ivy or dandelion in the mouth may provoke salivation and an interest in eating. Lettuce a.nd'cabbage leaves are accepted by some cows. In extreme cases, the cow can be drenched with rumen contents. Prevention: Effective strategies to prevent milk fever are important to decrease downer cow syndrome. All dairy cows should be

monitored closely around calving for early signs of partwient paresis (seep 988). Prophylactic administration of calciwn to all cows, beginning with cows entering their second or later lactation, is beneficial in herds with a high incidence of milk fever, especially in smaller farms that cannot implement feeding acidogenic salt diets. The critical issue seems to be the length of time (several hours) from when clinical signs of milk fever begin until treatment. Every cow that has been successfully treated for hypocalcernia should, if .necessary, be moved to a location with a good footing and remain there for 48 hr. Straw over sand provides good insulation and good footing. Animal Welfare Considerations:

Although a cow may rise after being recun1bent for >14 days, this does not in1ply that a cow should be unmonitored for this period. So long as the cow looks bright, occasionally struggles to rise, and continues to eat and drink, recovery is a possibility. However, if the cow becomes listless shows no interest in feed, or has decubital l�sions or starts to lose condition, euthanasia on hwnane grounds must be considered irrespective of how long she has been recumbent. A cow that has decubital lesions, a poor appetite, or shows signs of wasting is unsuitable for salvage slaughter. Attempting to send anin1als in this condition to the slaughterhouse is considered an act of cruelty in many countries. "Dragging" recumbent cows is illegal in some countries. Both veterinarians and producers must be aware oftlle legal interpretation of the word "dragging." Access to some locations may be so restricted that rolling the anin1al onto an in1provised sled may be impossible. At all tin1es, even when usmg a sled, great care must be taken to avoid injwy to dependent parts of tlle anin1al such as tl1e udder, ears, and tail.

LAMENESS IN SMALL ANIMALS Signs of musculoskeletal disorders include weakness, lameness, limb swelling, and joint dysfunction. Motor or sensory neurologic impairment may develop secondary to neuromuscular lesions. Abnormalities of the musculoskeletal system may also affect other organs of tlle

endocrine, urinary, 'digestive, hemolyrn­ phatic, and cardiopulmonary systems. Evaluation of musculoskeletal disease is aimed at localizing and defming the lesion(s). Diagnosis requires accurate revie.w of the signalment, history, and physical status of the animal. A lan1eness

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LAMENESS IN SMALL ANIMALS

1193

examination is critical to determine a diagnosis. Useful ancillary tests include radiography, ultrasonography, arthrocente­ sis, arthroscopy, arthrography, electromyo­ graphy, and tissue biopsy and histopathology. For subtle lesions, advanced in1aging techniques, including bone scans, CT, and MRI, a.re being used with greater frequency in specialty clinics and university hospitals.

refeITal centers. Nuclea.r scintigraphy involves IV irtjection of a radioactive compoW1d that localizes and highlights pe1iosseous soft tissue and bone lesions. CT imaging pennits high contrast and resolution of osseous structures, whereas MRI is helpful to delineate soft tissue ai1djoint irtjwies. Both can also be used to assess the spinal colunm, although MRI is a better standard to evaluate nervous tissues.

THE LAMENESS EXAMINATION

Arthroscopy: Althroscopy is a minin1ally invasive tool used for diagnosis and therapy of !rune ailimals. Advantages of the technique include improved visualization and diagnosis ofjoint pathology, ability to treat irtjuries by removal of damaged cartilage or ligament, and reduced surgical dissection. Disadvantages ai·e costs of equipment and development of expertise in its use. Common conditions that can be diagnosed or treated by arthroscopy include osteochondrosis, bicipital tenosynovitis, joint fractures, ai1d cranial cruciate ligai11ent and medial meniscal injuries.

The lameness exarnination is a key featw·e to identify musculoskeletal lesions. Evaluation is performed with the animal at rest, rising, and during locomotion on flat or inclined surfaces. Single- or multiple-lin1b lameness is noted, with tl1e severity related to the type of activity. With a forelimb lan1eness, the head is elevated during weight bearing on the W1Sound limb. The stride is also shortened on the affected side. For hindlimb lan1eness, the head is dropped during weight bearing on the affected limb. Limbs should be assessed from a distal to proximal manner, and bones,joints, and soft tissue should be palpated. Abnormali­ ties to note include swelling, pain, instability, crepitation, reduced range of motion, and muscle atrophy. In evaluation of a subtle or obscure lameness, serial examinations before and after exercise may be necessaiy. For fractious animals, sedation may be required; palpation, radiography, and arthrocentesis can often be perfom1ed while an anin1al is sedated with IV butorphanol and acepromazine; propofol; medetomidine (alone or combined with butorphanol or hydromor­ phone); or a combination of ketamine, diazepan1, and acepromazine. Imaging Techniques: Helpful imaging procedures to diagnose laineness include survey and contrast radiography, ultrasonog­ raphy, nucleai· scintigraphy, CT, and MRI. Animals undergoing these evaluations should be heavily sedated or anesthetized. Swvey radiography of affected lin1bs or the spine requires multiple, orthogonal views. Subtle lesions a.re often identified after compaiison with the contralateral nonnal limb. The most frequent contrast studies used to evaluate lan1e animals ai·e arthro­ gran1s forjoint diseases and myelography for spinal canal disorders. Ultrasonography is useful to evaluate musculotendinous irtjuries such as bicipital tenosynovitis, Achilles tendon rupture, and muscle contracture. Nuclear scintigraphy, CT, and MRI studies a.re usually available at private or academic

PAIN MANAGEMENT Control of pain in Jaine or operative aili.mals involves broad classes of compoW1ds such as NSAIDs and opioids (see also PAIN ASSESSMENT AND MANAGEMENT, p 2104). Analgesic agents can be administered via oral, parenteral (including constant-rate infusions), epidural, local, or transdermal routes. Nonpham1acologic pain management strategies include acupuncture therapy, massage, physical therapy, and diet. Commonly used NSAIDs include deracoxib (4 mg/kg/day, PO), firocoxib (5 mg/kg/day, PO), meloxicam (dogs: 0.1 mg/kg/day, IV, SC, PO; cats: 0.1 mg/kg/day, IV, SC, PO, for 1-3 days), carprofen (2.2 mg/kg, PO, bid), ketoprofen (1 mg/kg/day, PO, IV, SC, IM), etodolac (12.5 mg/kg/day, PO), tepoxalin (10 mg/kg/day, PO), and aspirin (dogs: 22 mg/kg, PO, bid; cats: 10 mg/kg, PO, every 48 hr). The use of NSAIDs is contraindicated in animals with hepatic or renal insuffi­ ciency, gastroenteritis, or coagulopathy, and in anin1als receiving conctment corticoste­ roid therapy. Opioid analgesics bind toµ, K, and 8 receptors in the CNS to provide pain relief. Commonly used opioids include morphine (0.1 mg/kg, IV, IM, SC, every 3--4 hr), oxyn10rphone (0.05 mg/kg, IV, IM, SC, every 3--4 hr), hydromorphone (0.1 mg/kg, IV, IM, SC, every 2-4 hr), butorphanol (0.1 mg/kg, IV, IM, SC, eve1y 2-4 hr in dogs and cats), and buprenorplli..ne (0.01 mg/kg, IV, IM, SC,

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LAMENESS IN SMALL ANIMALS

tid in dogs and cats, also transmucosal in cats). Opioid narcotics can be given with sedatives such as acepromazine (0.5 mg/kg, IV, IM, SC, every 4-6 hr) for enhanced efficacy of analgesia and sedation. Oxymorphone, hydromorphone, and butorphanol are more potent than morphine. Buprenorphine has the longest duration of action. Another opioid, fentanyl, is most frequently administered via transdem1al patches applied for 3 days on shaved areas. Oral opioids used for pain relief include tran1adol (5 mg/kg, tid), butorphanol (1 mg/kg, tid), hydromorphone (0.5 mg/kg, tid), codeine (1 mg/kg, tid), and oxycodone (0.3 mg/kg, tid). Local administration of analgesics involves joint ir\jections with morphine (1 mg diluted in 5 mL of saline), bupivicaine (1 mU20 kg body wt), or lidocaine (1 mU20 kg body wt) before joint surgery as a preemptive block of intracapsular pain receptors. Epidural morphine (0.1 mg/kg) in the lumbosacral space is also a useful adjtmct for postoperative pain relief in the hindlimbs and for reduced anesthetic requirements. Corticosteroids are considered weak analgesic adjuncts, because they indirectly reduce pain by their

primary action as local anti-inflammatory agents at the site of injury. Drugs used include preclnisone or preclnisolone (1 2- mg/kg/day, PO) or dexamethasone (1-2 mg/kg/day, IV). Their use is contraindi­ cated during concurrent NSAID treatment. Gabapentin (10 mg/kg, PO, bid) is a calcimn charmel blocker used to inhibit neurons stimulated by pain; it is useful for treatment of anin1als with chronic or neuropathic pain. Dexmedetomicline (5 mcg/kg/day, IM) and medetomicline (10 mcglkg/day, IM) are newer analgesic­ sedative, a2-receptor blocking agents useful to facilitate examinations or diagnostic evaluations. Joint fluid modifiers (glucosa.rnine, chondroiton sulfate, hyaluronan, pentosan polysulfate, omega-3 fatty acids) have received extensive attention in treating degenerative joint disease and alleviating discomfort. While contraindications and adverse effects are few, scientifically proven efficacy of these compotmds is linuted and most reports are regarded as anecdotal evidence. Stem cell therapy to alleviate pain and discomfort of diseased joints is also a newer modality for which scientific validity is pending.

ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS Many arthropathies are developmental, including aseptic necrosis of the femoral head, patellar luxation, osteochondrosis, elbow dysplasia, and hip dysplasia. Other arthropathies are degenerative, infectious or septic, inunune-mediated, neoplastic, or traumatic.

ASEP TIC NECROSIS OF THE FEMORAL HEAD (Legg-Calve-Perthes disease)

This deterioration of the femoral head seen in y0tmg miniature and small breeds of dogs is associated with ischemia and avascular necrosis of the bone. The exact cause is unknown, although there may be a hereditary component in Manchester Terriers. Infarction of the bone leads to collapse of tl1e femoral head and neck,

followed by revascularization, resorption, and remodeling. The lesion is often bilateral. Clinical signs include hindlimb lameness, atrophy of the thigh muscles, ·and pain during manipulation of the hip joint. Radiography reveals irregular bone density of the femoral head and neck, collapse, and fragmentation of the bone. Chronic cases have evidence of degenerative joint disease. Treatment involves surgical excision of the affected femoral head and neck and early postoperative physical therapy to stimulate limb usage. Prognosis for recovery is excel.lent.

PATELLAR LUXATION This hereditary disorder in dogs and cats is characterized by ectopic development of

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ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS

the patella medial or lateral to the trochlear groove of the femur. Patellar luxation can be associated with multiple deformities of the hincllimh, involving the hipjoint, femur, and libia. Medial patellar luxations can be involved with a reduced coxofemoral angle (coxa vara), lateral bowing of the femur, internal rotation of the tibia, shallow trochlear groove, and hypoplasia of the medial femoral condyle; lateral luxations cause the reverse changes. Clinical signs are variable and based on the severity of luxation. Animals of any age may be affected. In general, cats and small and miniature breeds of dogs have a medial luxation, and large dogs have a lateral luxation. Affected animals are lan1e or ambulate with a skipping gait. Palpation of the stiflejoint reveals displacement of the patella. In Grade I, clinical signs are mild and infrequent, and the patella can be manually luxatecl but easily returns to the trochlear groove. In Grade II, the patella luxates during flexion of thejoint and is repositioned during extension, causing animals to have a resolvable skipping lameness. In Grade III, the dislocated patella is more frequently out of, instead of in, the trochlear groove, and lameness is consistent. Bone deformities are evident in these animals. In Grade IV, lameness and limb deforma­ tions are most severe. Radiography of affected animals reveals various degrees of limb changes based on the grade of the luxation. The type of surgery is based on the severity of the luxation and can include both orthopedic and soft-tissue procedures. Useful procedures involve fascia! releasing incisions (on the side of the luxation),joint capsule and retinaculum imbrications (on the side opposite the luxation), deepening of the trochlear groove, tibial crest transposition, and fabella to tibial tuberosity derotation sutures. Severe deforn1ations may require femoral or tibial osteotomies, stiflejoint arthrodesis, or limb an1putation. Prognosis for recovery is good in mild or moderately affected animals. Concur­ rent cranial cruciate ligament and medial meniscal injuries should be identified and treated. Cats are less severely affected than dogs and have an excellent prognosis.

OSTEOCHONDROSIS Osteochondrosis is a developmental disorder of medium and large rapidly growing clogs that is characterized by

1195

abnormal endochondral ossification of epiphyseal cartilage in the shoulder, elbow, stifle, and hockjoints. Although the exact cause is unknown, excessive nutrition, rapid growth, trauma, and a hereditary component are suspected to be contribut­ ing factors. As a result of abnormal maturation and vascularity, basal cartilage cells thicken and weaken, thus leading to cartilage cracks, fissures, and flap formation (osteochonclritis dissecans) after minor trauma or normal pressure to thejoint. Abnormal cartilage congruency andjoint debris lead to a synovitis and subsequent arthritis and continued cartilage breakdown. Cartilage flaps can break loose and attach to thejoint capsule or migrate and deleteriously affectjoint motion. Clinical signs are lan1eness, joint effusion, and reduced range of motion in affectecljoints or limbs. Locations of the lesions include tl1e head of the humerus (shoulderjoint), the medial aspect of the humeral condyle (elbowjoint), the femoral condyles (stiflejoint), and the trochlear ridges of the talus 010ckjoint). Addition­ ally, fragmented medial coronoid process and ununited anconeal process in the elbowjoint may be related conditions. Radiography is useful in identifyingjoint lesions; changes may include flattening of joint surfaces, subchondral bone lucency or sclerosis, osteophytosis, joint effusion, and "joint mice." Arthrography can be used to delineate cartilage flaps, and arthros­ copy can also be perfonned to identify and treat crutilage orjoint lesions. CT in1aging also helps identify subchondral bone changes. Treatment involves surgical excision of cartilage flaps or free-floating fragments and curettage of subchondral bone to stimulate fibrocartilage forn1ation. Animals with degenerativejoint disease may benefit from NSA!Ds, eg, aspirin (10 mg/kg, PO, bid), Catl)rofen (2.2 mg/kg, PO, bid), deracoxib (4 mg/kg/day, PO), firocoxib (5 mg/kg/day, PO), meloxican1 (0.1 mg/kg/day, PO), tepoxalin (10 mg/kg/day, PO), or etodolac (12.5 mg/kg/day, PO). Joint fluid modifiers such as polysulfated glycosan1inoglycan (4.4 mg/kg, IM, twice a week for 4 wk) may also help prevent cartilage degenera­ tion. Prognosis for recovery is excellent for the shoulders, good for the stiflejoint, and fair for the elbow and tarsaljoints. Concomitant signs of degenerativejoint disease, other joint conditions, or insta­ bility (hockjoint) deleteriously affect recovery.

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ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS

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ELBOW DYSPLASIA

canine elbow. Bone fragments can be seen by raruography, arthroscopy, or CT.

(Ununited anconeal process, Fragmented medial coronoid process, Osteochondrosis of the humeral condyle)

Osteochondrosis of the Medial Humeral Condyle: This results from a

Elbow dysplasia is a generalized incongru­ ency of the elbowjoint in young, large, rapidly growing dogs that is related to abnonnal bone growth,joint stresses, or cartilage development. One or more of the following lesions may be present in the joint: an ununited anconeal process of the ulna, fragmentation of the merual coronoid process of the ulna, and osteochondrosis of the merual aspect of the humeral condyle. Railiographic grarung of dysplastic elbow joints is performed by the Orthoperuc Foundation for Animals in the USA and in Scanrunavian and European kennel clubs.

Treatment: Early surgical treatment is

Ununited Anconeal Process: This

result.s when there is separation of the ossification center of the anconeal process from the proximal ulnar metaphysis. Fusion should be completed by 5--6 mo of age. The fracture is postulated to result from a biomechanical imbalance of force and movement in the rapidly growing elbow. Initially, the anconeal process is connected to the ulna by a bridge of fibrous tissue, which fragments to fom1 a pseudoarthrosis, and the elbow becomes unstable. Thisjoint laxity continues to daniage the articular cartilage, and secondary osteoarthritis results. A hererutary basis has been implicated but not proved. Lameness develops insiruously between 4 and 8 mo of age; however, some bilateral cases may not be ruagnosed until dogs are > 1 yr old. Affected elbows may deviate laterally, and the range of motion is restricted. Advanced cases hav� osteoar­ thritis,joint effusion, and crepitus. Clinical signs are suggestive, and the ruagnosis is confim1ed by radiography. A lateral radiograph of the elbow in the flexed position allows visualization of the ununited process. Both elbows should be exanlined because the condition can be bilateral. Fragmentation of the Medial Coronoid Process: In this condition

of the medial compartment of the canine elbow, the coronoid process fails to unite, either partially or totally, with the ulnar diaphysis and, thus, does not become a pait of the articular surface of the trochlear notch. Joint laxity, irritation, and finally osteoarthritis result. This conrution and osteochondrosis of the merual humeral condyle are considered to be the most common causes of osteoarthritis of the

rusturbed endochoncl:ral fusion of the epiphysis of the medial epicondyle with the distal end of the hun1erus. The exact cause is tmknown, but because the carpal and rugi­ tal flexors originate from the ventral aspect of this structure, it may represent an epiphyseal avulsion. It results in pain on flexion of the elbow or deep digital palpa­ tion and is accompanied by soft-tissue swelling. Raruographically, raruodense structures have been seen caudal and rustal to the ai·ea of the merual epicondyle.

recommended before degenerativejoint disease develops. For fragmentation of the merual coronoid process, a medial arthrotomy or arthroscopy is performed and the fragmented process removed. For ununited anconeal process, either a lateral arthrotomy is perfom1ed and the unwlited process removed, or a nlidshaft ulnar osteotomy is perfom1ed to relieve asynctu·onous growth and result in union of the process. Reattactunent of the process by screw fixation is also an option. For osteochondrosis, the subchondral bone lesion is curetted to stimulate fibrocartilage fom1ation. Prognosis after surgery is good if degenerativejoint disease has not developed in thejoint. Aspirin or NSAJDs (eg, carprofen, deracoxib, flrocoxib, etodolac, meloxicarn, tepoxalin) can be used to reduce pain and inflammation. Joint-fluid modifiers (glycosanlinoglycans, hyaluronic aid) may be useful.

HIP DYSPLASIA Hip dysplasia is a multifactorial abnom1al development of the coxofemoraljoint in dogs that is characterized byjoint laxity and subsequent degenerative joint rusease. It is most common in large breeds. Excessive growth, exercise, nutrition, and hereclitary factors affect the occurrence ofh.ip dysplasia. The pathophysiologic basis for hip dysplasia is a dispaiity between hip joint muscle mass a11d rapid bone development. As a result, coxofemoraljoint laxity or instability develops and subsequently leads to degenerativejoint changes, eg, acetabu­ lar bone sclerosis, osteophytosis, thickened femoral neck,joint capsule fibrosis, and subluxation or luxation of the femoral head. Clinical signs are variable and do not always correlate with raruographic

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ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS

abno1malities. Lameness may be mild, moderate, or severe and is pronounced after exercise. A "bunny-hopping" gait is sometimes evident. Joint laxity (Ortolani sign), reduced range of motion, and crepitation and pain during full extension and flexion may be present. Radiography is useful in delineating the degree of aithritis and plaiming of medical and sw-gical treatments. Standard ventrodorsal views of sedated or anesthetized animals cai1 be graded by the Orthopedic Foundation for Animals, or stress radiographs performed andjoint laxity measw-ed (Penn Hip). A dorsal acetabulai· 1irn view is used by some sw-geons to evaluate the acetabulum before reconstructive surge1y. Modified ventrodor­ sal ai1cl dorsoventral projections have also been proposed in an effort to minlic the normal standing postw-e of clogs. Recent reviews of American and international radio­ graphic screening programs have failed to identify a "gold standard." An evaluation shift toward genome screening may yield more promising results in the future. Treatments ai·e both medical and sw-gical. Mild cases or nonsw-gical candidates (because of health or owner constraints) may benefit from weight reduction, restiiction of exercise on hard surfaces, conti·olled physical therapy to strengthen and maintain muscle tone, anti-inflanunatory drugs (eg, aspirin, cmticosteroids, NSAlDs), and possiblyjoint fluid modifiers. Sw-gical treatments include pectineal myotenectomy to reduce pain, tliple pelvic osteotomy to prevent subluxation, pubic fusion to prevent subluxation,joint capsule denervation to reduce pain, dorsal acetabulum reinforce­ ment to reduce subluxation, femoral head and neck resection to reduce aithritis, and total !lip replacement for optimal restoration ofjoint and limb functions. Additionally, femoral corrective osteotonlies can be performed to reduce femoral head sub­ luxation, although degenerative artluitis may persist. Prognosis is highly variable and depends on the overall health and environment of the animal. In general, if sw·ge1y is indicated and pe1formed correctly, it is beneficial. Animals on wllich sw-gery is not performed may require a change in lifestyle to live comfortably.

DEGENERATIVE ARTHRITIS (Degenerative joint disease, Osteoarthritis) Progressive deterioration of aiticular cartilage in diarthrodialjoints is character­ ized by hyaline crutilage thinning, joint effusion, and periaiticular osteophyte

1197

formation. Joint degeneration can be caused by tratm1a, infection, immune­ mcdiatccl diseases, or developmental mal­ f01111alions. The inciting cause initiates chonclrocyte necrosis, release of degrada­ tive enzymes, synovitis, and continued cartilage destruction and inflanunation. Abnormal caitilage congruency and joint capsule anatomy can fwther lead to alteration in normal joint biomechrulical function. Pain and lameness develop secondary tojoint dysfunction or muscle atrophy and to limb disuse. Although more common in clogs, joint degeneration may also be seen in cats. Clinical signs of degenerativejoint disease include laineness,joint swelling, muscle ati·ophy, pericapsular fibrosis, and crepita­ tion. Radiographic changes in thejoint includejoint effusion, pe1iaiticular soft­ tissue swelling, osteophytosis, subchondral bone sclerosis, and possibly nanowedjoint space. Althrocentesis may be unremai·kable or yield minor changes in color, tw-bidity, or cell cow1ts of synovial fluid. Treatments can be medical or surgical. Nonsurgical therapies include weight reduction, controlled exercise on soft surfaces, and therapeutic application of warm compresses to affectedjoints. NSAlDs (eg, aspirin, etoclolac, cai-profen, deracoxib, meloxicrun, firocoxib, tepoxalin) reduce pain ai1d inflan1mation. Caution is advised with longtenn NSAlD usage in dogs. The most frequently cited adverse effects include GI problems such as inappetence, vonliting, and hemorrhagic gastroenteritis. A cai-profen-associated hepatopathy in Labrador Retrievers has also been repmted. C01ticosteroicls also suppress prostaglandin synthesis and subsequent inflainmation, but sh01t-tem1 use is advised to prevent iatrogenic hyperadrenocorticism, caitilage degeneration, and intestinal perforation. Joint-fluid modifiers such as glycosanli.no­ glycans or sodium hyalw-onate may prevent cartilage degradation. Sw-gical options includejoint fusion (artlu·odesis), most frequently pe1fom1ed on the cai-pus ai1d tarsus; joint replacement, such as total hip replacement; joint excision, such as femoral head and neck osteotomy; and amputation. Prognosis is variable and depends on the location and severity of the ruthropathy.

SEPTIC ARTHRITIS Infectious arthritis is most frequently associated with bacte1ial agents such as staphylococci, streptococci, and colifonns. Causes include hematogenous spread or penetrating trauma, including surgery.

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ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS

Other agents producing a septic arthritis include 1ickettsia (Rocky Mountain spotted fever, ehrlichiosis) and spirochetes (borreliosis). Clinical signs of septic arthritis include lan1eness, swelling, pain of affectedjoint(s), and systemic signs of fever, malaise, anorexia, and stiffness. Racliography may revealjoint effusion in early cases and degenerativejointclisease in chronic conditions. Arthrocentesis reveals increased levels ofWBCs, especially neutrophils. The synovial fluid may be grossly purulent. Bacterial culture and antimicrobial sensitivity testing may confim1 the diagnosis. Serologic testing is used for nonbacte1ial agents. Treatment is with appropriate IV and oral antibiotics,joint lavage, and surgical debridement in severe cases.

IMMUNE-MEDIATED ARTHRITIS Inflammatory polyarthritis secondary to deposition of inunune complexes can produce erosive ( destruction of articular cartilage and subchondral bone) or nonerosive (periarticular inflanm1ation) fonns ofjoint diseases. Rhem11atoid aithritis, Greyhound polyarthritis, and feline progressive polyarthritis are exat11ples of erosive arthritides. Systemic lupus erythematosus (SLE) is the most conunon form of nonerosive arthritis. Clinical signs are lat11eness, multiple joint pain,joint swelling, fever, malaise, and anorexia. Clinical signs conunonly wax and wane. Diagnosis is aided by radiography, biopsy, arthrocentesis, and serologic testing. Radiography reveals periaiticular swelling, effusion, andjoint collapse plus subchon­ clral bone destruction in erosive conditions. Althrocentesis reveals synovial fluid with reduced viscosity and increased inflanuna­ tory cell counts. Biopsy of synovial tissue reveals mild to severe inflanunation and cellulai· infiltrates. Serologic testing is performed for rheumatoid factor and antinuclear antibodies. Treatment involves anti-inflanm1atory medications (eg, corticosteroids) and chemotherapeutic agents (eg, cyclophos­ phai1lide, azathioprine, or methotrexate). Prognosis is guai·ded because of relapses and inability to detemline the inciting cause of the autoinlmune reactions.

NEOPLASTIC ARTHRITIS Synovial cell sarcoma is the most common malignant tumor involving thejoints. The

tumor arises from primitive mesenchymal cells outside the synovial membrane. Clinical signs include lat11eness and joint sweJling. Radiography reveals soft-tissue swelling and a periosteal reaction. Pulmonaiy metastasis is detected in -25% of animals at initial exat11ination. Biopsy reveals evidence of a soft-tissue tm11or. Limb at11putation is the treatment of choice, although palliative radiation may be considered for cases with a low tLU11or burden not involving bone.

POLYARTHRITIS Polyarthritis involves inflanm1ation of multiplejoints and is classified as infectious (septic artluitis, seep 1197) or noninfec­ tious (erosive or nonerosive [ immtme-medi­ ated]). Nonerosive can be idiopathic or breed (Akita) associated, while erosive is characteristic of feline progressive artluitis and rheLU11atoid arthritis. Clinical signs of a polyarthritis include fever, lat11eness, swollenjoints, lethargy, and inappetence. Diagnosis is by radiography Qoint effusion, possible erosive bone destruction) and abnom1al (increased cell counts)joint fluid analyses. Treatments involve longtem1 glucocorticoid therapy or other inununo­ suppressive medications such as azathio­ p1ine or cyclophosphatllide. Prognosis in most cases is guarded or poor, with relapses conunon.

JOINT TRAUMA Cranial Cruciate Ligament Rupture Rupture of the crani.al cruciate ligan1ent is most frequently due to excessive tramna ai1d a possibly weakened ligan1ent secondaiy to degeneration, inlmune-medi­ ated diseases, or conformational defects (straight-legged dogs). Plasmacytic-lympho­ cytic synovitis is sometimes diagnosed concurrently with ligat11ent ir\jUI)', but it remains unclear whether it is a cause or effect of thejoint instability. Stable (nonsurgical)joints with an early or mild condition can be treated with steroids or an NSAID. Most irtjuries involve a midsub­ stance tear (mature dog), although bone avulsion (immature dog) at the origin of the ligat11ent is possible. Instability of the stifle joint after rupture of the cranial cruciate ligat11ent can lead to medial meniscal ir\jlU)', joint effusion, osteophytosis, andjoint capsule fibrosis. Cllilical signs involve lat11eness, pain, medialjoint swelling, effusion, crepitation, excessive cranial laxity of the proximal tibia relative to the distal femur (drawer sign, or

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ARTHROPATHIES AND RELATED DISORDERS IN SMALL ANIMALS

positive compression test), and increased int ernal tibial rotation. Partial cranial crlJCial ligament tears are characterized b y a reduced cranial laxity, usually more pro nounced in flexion. Medial meniscal ir\jury may be identified by a clicking sound during locomotion or flexion and extension. A tibial compression test (flexion of the hock and cranial displacement of the tibial tub erosity) can also be used to demonstrate 1a.J(ity of the cranial cruciate ligament. Radiography reveals joint effusion and signs of degenerative joint disease in chronic injuries. Arthrocentesis may reveal mild cellular increases and hemarthrosis. Afthroscopy can confirm the diagnosis but requires specialized equipment. 'Treatments include medical and surgical therapies. Weight reduction, controlled physical therapy, and NSAIDs alleviate pain and discomfort from inflammation and degenerative joint disease. Surgical stabilization of the stifle joint is recom­ mended for active dogs. Extracapsular techniques include fascial suturing, fabella to tibial tuberosity imbrication sutures, cranial transposition of the fibular head, leveling of the tibial plateau, tibial tuberosity advancement, and synthetic grafts· lntracapsular techniques include fascia lata or patellar tendon grafts sutured over the top of the lateral femoral condyle. Medial meniscal iJ\iury requires removal of dar11aged avascular tissue. Postoperative physical therapy is critical for clinical recovery. Prognosis after surgery is good. Joint Fractures Trn.umatic fractures frequently involve the shoulder, elbow, carpal, hip, stifle, and tarsal joints. In immature animals, the weakness of we physis compared with adjacent bones, ligarnents, and joint capsule predisposes this area to ir\jury. A Salter-Harris classifica­ tion scheme (l-V) is often used to describe the location of the fracture relative to the

Capital physeal fracture. Courtesy of Dr. Ronald Greefl·

1199

physis and joint. Specific conunon sites of injury include the greater tubercle and condyle of the hun1erus, distal ulnar physis, and the head and condyles of the femur. The hwneral. condyle is also frequently injured in mature Spaniel breeds and characterized by Y or T fracture configurations. This may be related to incomplete ossification and vascularity of the bone. Clinical signs of joint fractures include lameness, pain, and joint swelling. Chronic iitjuries may be characterized by angular limb deformities if the injury affected an open growth plate. Radiography and CT are useful in delineating the fracture. The goal of joint fracture treatment is stable anatomic reconstruction to maintain joint congruency and joint and limb functions. Internal fixation wifu pins, wires, or screws is performed to achieve stable fixation. Prognosis for recovery is good if proper surgical technique has been used and joint trawna has not been excessive. Palmar Carpal Breakdown This hyperextension injury secondary to falls or jumps produces excessive force on fue carpus, which leads to collapse of tl1e proximal, middle, and/or distal joints secondary to tearing of fue palrnar carpal ligaments and fibrocartilage. Clinical signs include lameness, carpal swelling, and a characteristic plantigrade stance. External splints or casts may be attempted in mild cases, alfuough surgical treatment is usually required to restore limb function. Surgery involves fusion (arthrodesis) of fue affected joints using a bone plate and screws, pins and wires, or external skeletal fixation. A cancellous bone graft is used to enhance bone wuon, and postoperative support is necessary. Prognosis for recovery is good. Hip Luxation Traumatic dislocation of the hip is most frequently a craniodorsal displacement of the femoral head relative to fue acetabulwn. Clinical signs include lameness, pain during manipulation of the hip joint, and a shortened limb due to dorsal displacement of the femur. Radiography is useful in confinning fue luxation and delineating the presence of oilier fractures in the femoral head or acetabulum. Treatment involves eifuer closed manipulation and postopera­ tive slings to maintain the reduction or open surgical stabilization using sutures or toggle pins. Femoral head and neck resection or total hip replacement can be performed after failed reductions. Prognosis for recovery is usually excellent.

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MYOPATHIES IN SMALL ANIMALS

MYOPATHIES IN SMALL ANIMALS Myopathies can be congenital, hereditary, idiopathic, inflammatory, metabolic, neoplastic, traumatic, or due to nutritional imbalances.

YELLOW FAT DISEASE (Nutritional steatitis, Nutritional panniculitis) YelJow fat disease is characterized by a marked in.tlanm1ation of adipose tissue and deposition of"ceroid" pigment in fat cells. It may be seen alone in cats or with accompa­ nying myopathy in rats, mink, foals, and pigs. It is believed that an overabundance of unsaturated fatty acids in the raLlon, together with a deficiency of vitanlin E or other antioxidants, results in lipid peroxidation and deposition of"ceroid" pigment in the adipose tissue. Most natmally occuning and experimentally induced cases have been in animals that have had fish or fish by-products as alJ or prut of the diet. The specific cause is believed to be related jointly to the high unsaturation of tl1e fish oil fatty acids and tl1eil" Jack of protection with vitru11in E or otl1er antioxidants. Affected cats ru·e frequently obese, usualJy young, and of either sex. They lose agility, are unwilling to move, and resent palpation of tile back or abdomen. In advanced disease, even a light touch causes pain. Fever is a constant finding, and anorexia may be present. • In nlink, kits may be affected witll steatitis shortly after weaning and, if untreated, losses may continue until pelting tin1e. Signs appear suddenly; the kits may refuse a night feeding and be dead by monling. Affected mink may refuse their feed and show a peculiar, unsteady hop, folJowed by complete impainnent of locomotion aml coma. At pelting, swvivors show yelJow fat deposits and hemoglobinuria. The typical laboratory finding is an increased WBC count, with neutrophilia and sometimes eosi.nophilia. Biopsy of tl1e subcutaneous fat shows it to be yellowish brown and finn. Histologic examination reveals severe inflammato1y changes and associated ceroid pigment. The offending excessive f at source must be removed from the diet. Administration of vitan1in E, in tile fmm of a-tocopherol, at

least 30 mg daily for cats, or 15 mg daily for mink, is necessruy. Antibiotics are of doubtful value, despite tile fever and leukocytosis. Parenteral use of fluids is not advisable wtless dehydration exists. Because of associated pain, affected ruli.mals should be handled as little as possible.

LABRADOR RETRIEVER MYOPATHY (Centronuclear myopathy) This inhe1ited (autosomal recessive) condition is characterized by a type 2 muscle fiber deficiency and is now called centronuclear myopathy. Clinical signs ru·e seen at 24 mo of age. A high proportion of peripheral lymphocytes may show cytoplasmic vacuolation. A DNA-based blood test is available for diagnosis. Prognosis is poor, and there is no effective treatment. oc-Mannosidosis has been seen mainly in cats and may cause retinal and skeletal abnormalities as well as neurologic deficits. Cerebellar signs are the most consistent feature of the otherwise somewhat variable neurologic deficits. Mucopolysaccharidoses (Types I, II, Ill, VI, VII): Mucopolysaccharidosis is primarily a disorder of cats, although some subtypes affect dogs. This disorder is associated with a flattening of tile face,

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CONGENITAL AND INHERITED ANOMALIES OF THE NERVOUS SYSTEM

corneal clouding, and multiple bone dys­ plasias. Plott hounds can also be affected. Several types of this disease are reported; type V I is often associated with progressive paraparesis secondary to focal bony protrusions into the vertebral canal. The skeletal changes are nonprogressive after 9 mo of age, and decompressive surgery may in1prove the neurologic deficits. Glycogen Storage Disorders: Glycogenosis (types II, III, IV, VII) and mucolipidosis II arc not as well described. English Springer Spaniels, Lapland dogs, German Shepherds, Akitas, and Norweigan Forest cats are among those described. Clinical signs generally include neuromus­ cular weakness, exercise intolerance, muscle tremors, or dysphagia. Mucolipidosis II affects domestic sho1thaired cats and generally causes skeletal malforn1ations. Other Storage Disorders: Ceroid lipofuscinosis is characterized by reduced vision, personality change, ataxia, and seizures. Clinical signs typically appear when animals are 12-24 mo old, although some can be older. The condition is an autosomal recessive trait in English Setters, Tibetan Terriers, and Border Collies. It has been reported in many additional breeds of dogs, as well as in Siamese cats. The genetic mutation has been identified in some breeds of dogs. The phenotype and age of onset are variable, and signs tend to slowly evolve throughout several years. La Fora disease occurs most commonly in miniature Wirehaired Dachshunds but also can affect other breeds, such as Bassett

Hounds, Beagles, Poodles, and mixe d b - reed dogs. It is most well known and genetically understood in the miniature Wirehaired Dachshund, and a genetic test is available for diagnosis in this breed. Clinical signs can include late-in-life onset myoclonic seizures that can in some cases be triggered by visual or auditory stimuli. Other clinical examina­ tion findings are not commonly reported.

MISCELLANEOUS CONGENITAL DISORDERS Large Animals Pendular nystagmus is seen in various breeds of dairy cattle but appears to have little clinical significance. Congenital deafness has been repo1ted in horses.

Small Animals Pendular nystagmus is seen in various breed of Asian cats but appears to have little clinical significance. Compared with pathologic fonns of nystagmus, in pendular nystagmus there is no fast or slow phase, and the nystagmus arcs are similar to the pendullllll movement of a clock. Congenital deafness is primarily associated with Dalmatians but has also been recorded in a nun1ber of breeds, including Australian Blue Heelers and Shepherds, English Setters, Boston Terriers, and Old Eng­ lish Sheepdogs. It is linked to blue eye color in white cats. The brain stem auditory evoked response (BAER) is a useful diagnostic test primarily used to identify carriers in a litter of affected animals. (See also DEAFNESS, p 518.)

DEMYELINATING DISORDERS Hypomyelination and dysmyelination are disorders of myelin development characterized by axons with thin myelin sheaths, or by axons that are nonmyelin­ ated or have abnormal myelin. There are two possible pathologic classifications: 1) thinly myelinated axons with predomi­ nantly normal myelin and occasional nonmyelinated axons, or 2) thinly myelinated axons with predominantly abnom1al myelin and mainly nonrnyelin­ ated axons. These categories have been called hypomyelinating and dysmyelinat-

ing disease, respectively, and are charac­ teristic of tl1e congenital rnyelin disorders seen in young animals. These pathologic changes should not be confused with dernyelination, in which there is a breakdown and Joss of previously normal myelin. In general, these types of demyelin­ ating diseases do not present clinically as congenital problems.

Etiology and Epidemiology: Demye­ linating disorders have been reported worldwide in people, mice, pigs (British

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DEMYELINATING DISORDERS

saddleback, Landrace), cattle (Hereford, Holstein-Friesian, Jersey, Murray grey, Shorthorn), hamsters, rats, sheep, Siamese kittens, and a number of dog breeds, including Chow Chow, Springer Spaniel, Dalmatian, Samoyed, Golden Retriever, Lurcher, Bernese Mountain Dog, Weima­ raner, Australian Silky Ten-ier, and mixed breeds. This problem has also been documented in a litter ofVizslas and Catal10ula Cur dogs. In utero infect.ion and heredity are the general causes of hypomyelination. The viruses of classical swine fever, border disease, and bovine viral diarrhea have been incriminated, but mechanisms responsible for the hypomyelination have not been defined; these tlu·ee pestiviruses are closely related members of the family Togaviridae and are transmitted both vertically and horizontally. The inflanunatory neuraxial disorders in domestic anin1als in which demyelination is found are canine distemper, visna, and caprine arthritis encephalitis syndrome. In none, though, does CNS demyelination occm as the predominant central featme of U1e disorder as it does in human multiple sclerosis. Most toxins that affect myelin cause demyelina­ tion. One in particular, trichlorfon, is an organophosphate (seep 3064) with a unique toxicity that causes Type A-V porcine congenital tremor syndrome. Pregnant sows treated with trichlorfon dw-ing mid and late gestation (days 4&--77) produce litters in which up to 900/o of the piglets develop a marked tremor syndrome secondary to cerebellar hypoplasia and hypomyelinogenesis. The mortality rate is high. Other disorders resulting in hypomyelina­ tion are hereditary. Almost all of these disorders result in CNS hypomyelination, except in Golden Retrievers, in which hypomyelination of the peripheral ne1vous system (PNS) has been reported. In CNS hypomyelination, the basic defect involves interference with the functional maturation of oligodendrocytes. The exacl mechanisms for the defect are not known, but a point mutation on a critical gene has been found in Springer Spaniels. In PNS hypomyelina­ tion, the defect involves Schwarm cells. The genetic basis for the inherited hypomyelination syndromes is not fully defined, but in most instances, males are affected more often and more severely than females. This supports a sex- linked recessive trait or mode of inheritance. Clinical Findings: Clinical signs from hypomyelination of the CNS can be seen as

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ear·ly as 10-12 days of age and certainly by U1e time of weaning. Signs include, most notably, a gross whole body tremor that involves the limbs, trunk, head, and eyes. The tremor lessens or disappears when the animal is resting or sleeping but reappears on ar·ousal and increases with excitement. The tremors are very noticeable when the animal is eating and are a severe form of intention tremor. In addition, some animals may have difficulty standing ar1d arnbulating and may have weakness in the limbs. Secondary to this, postural test reactions may be deficient. Affected animals appear to have vision and other cranial nerve function, but occasionally a pendular· nystagmus or a jerk nystagmus is seen when the globes are voluntarily moved. These nemologic deficits may be so severe in some animals that euU1anasia is warranted. In some breeds of dogs, such as Chow Chows and Catal1oulas, the signs usually dissipate over the first year of life, and the dogs are nonnal by 12-18 mo of age. In some dogs, the signs may disappear· as ear·ly as 12-16 wk of age. In Golden Retrievers with PNS hypomy­ elination, the clinical signs include ataxia, paresis, muscle atrophy, ar1d hyporeflexia to areflexia. There is no evidence of CNS hypomyelination in Uus breed, and tremors ar·e not present. Lesions: In CNS hypomyelination, gross pathology reveals pallor of the white matter of the brain and spinal cord and possibly a gelatinous appearance. In PNS hypomyel.i­ nation, the gross char1ges are minimal a11d there is no evidence of CNS involvement. In CNS hypomyelination, the microscopic changes include lack of myelin (which is usually severe but not absolute), fewer oligodendrocytes, astrocytes outnw11bering oligodendrocytes, oligodendrocytes that differ in appearance from those in healthy animals, a11d abnonnal types of glial cells. In PNS hypomyelination, the microscopic cha11ges consist of paucity of myelinated fibers, fibers with inappropriately thin myelin sheaths relative to the caliber of U1eir enclosed axons, occasional fibers with poorly compacted myelin, Schwarm cells with larger than nonnal cytoplasmic volw11e, and increased numbers of Schwarm cell nuclei. Diagnosis: The diagnosis of CNS hypomyelination is made primarily from the spectrum of nemologic deficits and signs and the ear·ly age of onset. Unfortunately, histopathology is the only definitive method to confim1 a diagnosis. In cases with a

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DEMYELINATING DISORDERS

heritable basis, pedigree evaluation may be helpful. In cases with a viral cause, confirmation may involve immunofluores­ cent antibody-staining techniques or virus isolation from nervous tissue (or both). In cases of PNS hypomyelination, biopsy of peripheral nerves is beneficial. Differential diagnoses include disorders that could cause tremors in young animals. The possibilities are numerous, but some of the more common include glycogen storage disease, lysosomal storage disease, cerebellar hypoplasia, encephalitis, hypocalcemia, hypoglycemia, hyperam­ monemia, toxins (eg, metaldehyde,

organophosphates, chlorinated hydrocar­ bons, fluoroacetate, strychnine, hexachloro­ phene, bromethalin), and mycotoxins (eg, penitrem-A). Treatment, Control, and Prevention:

There is no specific treatment for hypomy­ elination. The only means of control and prevention is selective breeding (for heritable syndromes) and inununization (for viral-induced syndromes). If given time to develop normal or fwther myelin, some animals with congenital hypomyelination syndromes become normal by the age of 12 wk to 18 mo.

DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION Diseases of the peripheral nerve and neuromuscularjunction include degenera­ tive diseases, ini1anunato1y diseases, metabolic disorders, neoplasia, nutritional disorders, toxic disorders, trauma, and vascular diseases. For a discussion of congenital disorders, seep 1222.

DEGENERATIVE DISORDERS Acquired Laryngeal Paralysis: Laryn­ geal paralysis (seep 1420) is conunon in middle-aged and older dogs. Large breeds, such as Labrador Retrievers, Golden Retrievers, and Saint Bernards, are predisposed, but small-breed dogs and cats can be affected. In most cases, no underly­ ing cause is identified and the laryngeal paralysis is a component of a generalized polyneuropathy, canine chronic axonal degeneration. A few cases are due to trauma or neoplasia affecting the neck or mediasti­ nurn. Hypothyroidism (seep 553) is also a potential cause. Clinical signs consist of voice change, laryngeal stridor, and a dry cough. In severe cases, exercise intolerance and episodes of respirat01y---especially inspiratory---distress and cyanosis occur. Some affected anin1als have signs of a more generalized polyneuropathy, such as weakness and proprioceptive deficits. Diagnosis is based on laiyngoscopy with the anin1al lightly anesthetized. There is a unilateral or bilateral lack of abduction of the arytenoid caitilages and vocal folds during inspiration. Management consists of identifying and treating any underlying

disorder. Treatment of idiopathic laiyn­ geal paralysis consists of surgery, such as laryngeal tie back. Surgery does not restore nonnal laryngeal function but is usually successful in diminishing severe inspiratory dyspnea. A potential complication of surge1y is aspiration of food or liquid. Canine Chronic Axonal Degeneration:

Canine chronic axonal degeneration, sometin1es called geriatric-onset laiyngeal paralysis polyneuropathy, affects middle­ aged and older dogs and is characterized by axonal degeneration of peripheral nerves. The cause is unknown. Affected dogs have a wide-based, shuffling gait with ataxia, tetraparesis, and generalized muscle atrophy with decreased spinal reflexes. Laryngeal paralysis is often an early feature. Facial paralysis and dysphagia are also possible. Diagnosis is based on clinical features, electrodiagnostic evaluation showing denervation and slowed motor conduction velocity, and nerve and muscle biopsy showing loss of large-caliber nerve fibers with axonal degeneration and neurogenic muscle atrophy, respectively. It is important to exclude treatable metabolic causes such as hypothyroidism. The neurologic deficits progress slowly over months. There is no specific treatment.

Equine Laryngeal Paralysis: Seep 1458. Dancing Doberman Disease: Dancing Doberman disease is a neuromuscular disease that affects Doberman Pinschers

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DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION

of either sex, 6 mo to 7 yr old, and is likely inherited in an autosomal recessive pattern. Initially, affected dogs intennittently flex the hip and stifle of one pelvic limb while standing. Within several months, most dogs alternately flex and extend both pelvic limbs in a dance-like fashion. They often prefer to sit rather than stand. The condition slowly progresses to mild paraparesis, decreased proprioception, and atrophy of the gastrocnemius muscles. The thoracic limbs are not affected. Pathologic changes have been reported in pelvic limb muscles as well as peripheral ne,ves, and whether this is a primary muscle or nerve disease remains to be clarified. There is no treatment, and signs do not resolve. However, the disease usually does not result in severe disability and does not appear to be painful.

Distal Denervating Disease: Distal

denervating disease is a common polyneu­ ropathy of dogs in the UK; it has not been reported elsewhere. The cause is unknown. Any age and breed of dog may be affected. The onset of signs varies from a few days to several weeks. There is progressive tetraparesis, hyporeflexia, ar1d atrophy of proxin1al skeletal muscles. Sensory deficits are not apparent. Electrodiagnostic evaluation typically shows dene1vatiun of lirnb muscles, relatively nonnal nerve conduction velocity, ar1d markedly reduced amplitude ofM waves. Peripheral nerve biopsies are usually normal, but exan1ination of intramuscular nerves may be diagnostic; distal intran1uscular axons degenerate with collateral axonal sprouting. Treatment is supportive, and the prognosis is excellent, with recovery in 4--0 wk.Relapse has not been reported.

Distal Polyneuropathy of Rottweilers:

Distal polyneuropathy ofRottweilers is characterized by paraparesis that slowly progresses to tetraparesis, hyporeflexia, and muscle atrophy. The clinical course can be progressive or can wax and wane.Male and femaleRottweilers 1-4 yr old have been affected. The cause is unknown. Electrodi­ agnostic testing shows denervation in distal muscles of the limbs and decreased motor nerve conduction velocity. Nerve biopsy changes consist of axonal necrosis and demyelination, often with infiltrates of macrophages, most severe in distal ne1ve fibers. Prognosis is poor, although some dogs may temporarily improve with corticosteroid treatment.

Idiopathic Facial Paralysis: Idiopathic facial paralysis is a common disorder that

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results in unilateral or bilateral paresis or par·alysis of the facial muscles in dogs and cats. Cocker Spaniels, Pembroke Welsh Corgis, Boxers, English Setters, and domestic longhaired cats are at increased risk. There is acute onset of unilateral or bilateral inability to blink, drooping ear, drooping upper lip, and drooling from the comer of the mouth. Facial sensation (mediated via the trigeminal nerve) remains intact. Diagnosis is based on clinical features and exclusion of other causes of facial paralysis, including ear disease, trauma, and brain-stem lesions. Patho­ logic findings consist of degeneration of myelinated axons in the facial nerve. There is no inflammation. The cause is unknown, and there is no specific treatment. Artificial tears often help prevent corneal dan1age. Partial improvement may occur in a few weeks, but persistent dysfunction is common.

Stringhalt: (See also p 1137.) Stringhalt in

horses is characterized by brisk, involtmtary flexion of one or both pelvic limbs during the protraction phase of the gait. Severity ranges from a mild jerk in the limb to flexion so severe that the affected horse can hardly walk. There may be atrophy of the muscles in the distal aspect of the affected limb(s). Stringhalt is seen in two forms. Ordinary or classic stringhalt is seen sporadically throughout the world, usually as a tmilateral problem in individual horses. The cause is unknown. Some cases resolve spontane­ ously, whereas long digital extensor tenectomy is effective in others. Australian stringhalt is seen in outbreaks that affect multiple horses in a region ar1d often affects both pelvic limbs. Horses in Australia, New Zealand, and the USA have been affected, usually in late sununer or autunm. Australian stringhalt is associated with ingestion of Australian dandelion, European dandelion, and mallow, perhaps due to mycotoxins affecting these plants. Pathologically, the distal aspect of axons in the peroneal and tibial nerves degenerates. Horses with Australian stringhalt usually recover spontaneously when removed from offending pastures.

INFLAMMATORY DISORDERS Acquired Myasthenia Gravis: Acquired

myasthenia gravis is characterized by failure of neuromuscular conduction due to reduction in the nun1ber of acetylcholine receptors at the neuromuscular junction. It is caused by the development of circulating

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DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION

antibodies directed against the acetylcho­ line receptors at the neuromuscular junction. It is fairly common in mature clogs, especially German Shepherds, Golden Retrievers, and Labrador Retrievers, but is w1conunon in cats. Three clinical forms exist in anin1als. The generalized form, which affects 57% of clogs with acquired myasthenia, is characterized by exercise­ inclucecl stiffness, tremors, and weakness that resolve with rest. However, weakness is not always associated with exercise. Megaesophagus is conunon in the generalized fom1. Focal myasthenia (43% of affected dogs) presents as facial, pharyn­ geal, or esophageal weakness without generalized weakness. Least common is folminant myasthenia, which presents as acute, flaccid paralysis and megaesophagus, which rapidly progresses to respiratory paralysis and is usually fatal. Generalized weakness often resolves quickly after IV aclministration of edropho­ niw11 chloride (0.1-0.2 mg/kg), which is often used as a diagnostic test. Definitive diagnosis is based on the detection of antibodies in serw11. Treatment consists of anticholinesterase drugs, eg, pyridostignune (1-3 mg/kg, PO, bid-tic!) or neostigrnine (0.04 mg/kg, SC, qid). lnunw10suppressive dosages of prednisone and other in1mu­ nomodulating drugs a.re reconunenclecl in animals that do not respond to anticholinest­ erase therapy. Megaesophagus is managed with upright feeding and in some cases gastrotomy tube placement for feeding and hydration. Aspiration pneumonia. is a frequent complication of mega.esophagus and leads to death or euthanasia. in -500Ai of affected dogs. The prognosis is generally good for animals withoutJ)newnonia., and -85% of dogs will undergo spontaneous remission, evident by a decrease in antibody titer, usually within 6 mo. Acute Idiopathic Polyradiculoneuritis:

Acute idiopathic polyra.diculoneuritis primarily affects the ventral nerve roots and peripheral nerves. It is common in clogs and rare in ca.ts. Clinical signs often develop 7-14 days after a raccoon bite or scratch (Coonhouncl paralysis); however, other affected animals have not been exposed to raccoons. A similar syndrome can develop in dogs and ca.ts witlun 1-2 wk of vaccina­ tion. An inrn1une-mediated reaction to raccoon saliva or other antigen is suspected. Initially, there is a short-stricled gait in the pelvic limbs that progresses within 1-2 days to flaccid tetra.paresis or tetraplegia. and, in some cases, to facial and laryngeal weakness. Occasionally, tl1e thoracic limbs

a.re initially affected. Death from respiratory paralysis can occur in severe cases. Spinal cord reflexes a.re weak to absent, and severe muscle a.trophy is evident witlun 10-14 days. Pain perception is intact, and some dogs may appear hyperesthetic, showing signs of discomfort on palpation of the trunk or limbs. Menta.tion and appetite a.re not affected. Urination, defecation, and tail movement usually remain normal. Analysis of CSF collected from the lumbar suba.ra.chnoid space shows increased protein with a normal cell count. Electromyography shows denerva.tion, and nerve conduction studies show marked dispersion and prolonged latency of F-wa.ves, indicative of slowed conduction in the ventral roots. There is no effective treatment other tlmn nursing ca.re, and c01u­ costeroids are not helpful. Most a1Tected animals begin to in1prove spontaneously wiU1in 3 wk, with complete recovery by 2-6 mo. Animals with severe signs and marked muscle atrophy may recover incompletely. Relapses can occur, especially in hunting clogs tl1a.t frequently encounter raccoons. Histopathologically, there is irtflan1mation, demyelina.tion, and varying degrees of a.xonal degeneration in the ventral nerve roots and peripheral nerves. Chronic Relapsing Idiopathic Poly­ radiculoneuritis: Chronic relapsing

idiopathic polyra.diculonewitis is a rare disease associated with irtflamma.tion of the nerves and ne1ve roots. lt affects mature clogs and cats. Exercise intolerance, ataxia, and weakness develop slowly throughout several montl1s. Some animals have spontaneous temporary remissions. Spinal cord reflexes a.re decreased, and cranial nerves may be affected. In severe cases, decreased sensation is evident. Diagnosis is based on nerve biopsy. There is nonsuppura.­ tive irtfla.mma.tion; a.xonal degeneration; and demyelination of ne1ves, ne1ve roots, and, in some cases, dorsal root ganglia. The ca.use is unknown, altl10ugh irnrnune-mecliatecl mechanisms are suspected. Corticosteroids help in some cases, but the disease tends to slowly wax and wane, gradually becoming more severe throughout months to yea.rs. Chronic Inflammatory Demyelinating Polyneuropathy: Chronic irtflanuna.tory

clemyelina.ting poly.neuropa.hy is a fairly common disorder in adult clogs and cats. The ca.use is unknown. Onset of tetra.paresis with hyporeflexia. is insidious and sometimes accompanied by cranial ne1ve dysf1mction. Electromyography is usually nom1al, but nerve conduction velocities a.re slowed with

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DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION temporal dispersion. Neive biopsy shows multifocal paranodal demyelination. Clinical signs usually improve with ad.ministration of corticosteroids (eg, prednisone 1-2 mg/kg/ day), although signs may relapse when therapy is stopped.

Polyneuritis Equi: Neuritis of the cauda equina (polyneuritis equi) is characterized by inflammation of the sacrocaudal neives and occasionally other neives. It is seen in adult horses of all breeds in Europe and North America. The cause is unknown, although an inlillunologic reaction incited by a viral infection is possible. Affected horses have circulating antibodies against P2 myelin protein. The most consistent clinical signs reflect involvement of the sacrocaudal neives and include urinary and fecal incontinence, tail paralysis, perineal paresthesia or analgesia, atrophy of the gluteal muscles, mild pelvic limb ataxia, and in male horses, penile paralysis. Affected horses may rub the tail. The thoracic limbs and cranial neives may also be affected. Diagnosis can usually be based on clinical findings. CSF may be xanthochromic with increased protein content and mononuclear pleocytosis. Sacral fracture should be excluded by rectal examination and radiography. There is no treatment, and the prognosis for recovery is poor. Histopatho­ logically, there is granulomatous inflanuna­ tion primarily affecting the extradural portions of the sacrocaudal neives. Protozoa! Polyradiculoneuritis: Proto­

zoa] polyradiculoneuritis occurs in dogs, especially puppies, and is caused by infection with Toxoplasma gondii (seep 685) or Neospora caninum (seep 663). Transplacental infection is most conunon, and multiple puppies in a litter can be affected. Affected puppies are normal at birth but by 3---8 wk develop paraparesis and a "bunny-hopping" gait with weak or absent spinal refexes. Over a pe1iod of several weeks, the pelvic limbs develop severe extensor rigidity and muscle atrophy. Without treatment, the disease can progress to the thoracic limbs, eventually leading to dysphagia and fatal respiratory paralysis. Serum CK concentration is often increased. Analysis of CSF usually shows increased pro­ tein and leukocytes (neutrophils, mononu­ clear cells, and eosinophils). Serum or CSF antibodies or identification of the organism on muscle biopsy are helpful in diagnosis. Early treatment with clindamycin (15-20 mg/kg, IM, PO, bid) or trimethoprim/ sulfadiazine ( 15 mg/kg, bid) and pyrirneth­ an1.ine ( 1 mg/kg/day) for 4-6 wk may be

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effective. The prognosis is poor in dogs with pelvic limb rigidity.

Sensory Ganglioneuritis: Sensory

ganglioneuritis affects dogs of any breed, although Siberian Huskies are at increased 1isk. At 1-6 yr of age, there is ataxia of all limbs with no paresis, dysphagia, regur­ gitation, and difficulty prehending food. Hyperesthesia and self-mutilation occur in some cases. There is decreased propriocep­ tive positioning, weak to absent patellar reflexes, and decreased to absent pain perception in the limbs and face. Diagnosis is based on clinical signs, electrodiagnostic testing that demonstrates slowed sensory neive conduction, and biopsy of a mixed or sensory neive that shows loss of myelinated axons and endoneural fibrosis. The cause is unknown, but loss of neurons in dorsal root ganglia with infiltration of lymphocytes and macrophages is seen at necropsy. There is no effective treatment; the disease typically progresses and leads to euthanasia.

Trigeminal Neuritis: Idiopathic

trigeminal neuropathy is conm1on in dogs and unconlillon in cats. It is characterized by acute onset of flaccid jaw paralysis. Affected animals cannot close the mouth and have difficulty eating and drinking. Homer syndrome, facial paresis, and decreased facial sensation are also possible. The cause is unknown. Histopathologically, there is bilateral nonsuppurative inflammation and demyelination in the motor branches of the trigeminal neive. Affected animals u:,ually recover spontaneously within 3---4 wk. Fluid and nutritional support may be necessary.

METABOLIC DISORDERS Diabetic Neuropathy: This unconm1on complication of diabetes mellitus (see p 579) is seen in cats and rarely dogs. Signs include weakness, ataxia, and muscle atrophy. Affected cats often have unilateral or bilateral tibial neive dysfunction, evident as a plantigrade stance. There are several proposed pathophysiologic mechanisms, but prolonged hyperglycemia seems to be the important underlying factor. Pathologic findings in neives consist of demyelination with remyelination, axonal degeneration, or both. Diagnosis is based on clinical findings, laboratory evidence of diabetes mellitus, and neive biopsy. The prognosis is guarded, but partial or complete recovery can occur with insulin therapy. Hypothyroid Neuropathy: This neuropathy is a potential complication of

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hypothyroidism in dogs (seep 553). Mature dogs, especially large-breed dogs, are predisposed. Several syndromes have been reported, including tetraparesis with proprioceptive deficits and hyporeflexia, vestibular dysfunction, megaesophagus, and laryngeal paralysis. In some cases, classic signs of hypothyroid.ism (eg, obe­ sity and dem1atopathy) are absent, and neurologic dysfunction is the only sign of illness. Pathologic findings in peripheral nerves consist of demyelination or remyelination and axonal degeneration. The pathophysiology is poorly understood and, in some affected dogs with motor deficits, a myopathy may also be present. Diagnosis is based on clinical features, laboratory assessment of thyroid function, and response to thyroid supplementation. In some, but not all, cases, signs resolve within several months of starting thyroid replacement therapy.

NEOPLASIA Nerve Sheath Tumors: Nerve sheath tumors include schwarmomas, neurilemmo­ mas, and neurofibromas. They are seen in most domestic aninlals but are most common in dogs and cattle. In dogs, tumors often arise in the nerves of the brachial plexus, initially causing unilateral thoracic limb lameness and pain that may be confused with musculoskel­ etal disease. Pain may be elicited on palpation of the axilla or abduction of the limb; large tumors can be palpated. Muscle atrophy and monoparesis eventually develop. The spinal cord may become compressed by the invasive tumor, causing neurologic deficits in other limbs. The trigeminal nerve is the most frequently affected cranial ne.rve. This results in unilateral atrophy of tile temporalis and masseter muscles and facial dysestl1esia or anesthesia. Eventually, brain-stem compres­ sion can develop. Early surgical excision may be curative, although recurrence at the proxin1al stump of the resected nerve(s) is common. In cattle, nerve sheath tumors are often recognized incidentally in old aninlals at slaughter. Often, multiple nerves, especially autonomic nerves and cranial ne,ve VIIl, are affected. Pelipheral nerves may also be affected by other tumors, including lymphoma and leukemia (See al.so NEOPLASIA OF THE NERVOUS SYSl'EM, p 1267, and PERIPl·IERAL NEllVE SHEATH TUMORS, p 126.) Paraneoplastic Neuropathy: (See

al.sop 1280.) Paraneoplastic neuropathy is associated with neoplasia unrelated to tumor infiltration of nerves. It is most common in dogs with insulinoma but has

been associated with a valiety of tumors, including bronchogenic carcinoma, multiple myeloma, sarcoma, and adeno­ carcinoma. The pathogenesis is not well understood but may be related to an inlmune response directed against the tun1or that cross-reacts with nerve components. Clinically, there is paraparesis or tetraparesis that progresses over several weeks with decreased spinal reflexes and muscle atrophy. Diagnosis is based on identifying the underlying twnor, clinical and electrodiagnostic findings of neuropa­ thy, and in some cases, nerve biopsy. Signs may improve with successful treatment of the underlying tumor.

NUTRITIONAL DISORDERS Pantothenic Acid Deficiency: Panto­ thenic acid deficiency may develop in animals (particularly pigs) on rations of com. Clinical signs include pelvic limb ataxia and a "goose-stepping" gait in which the stifles remain extended and the hips flex to lift the limbs off the ground. Patl1ologic findings consist of degeneration of myelinated fibers in peripheral nerves and chromatolysis and loss of sensory neurons in spinal ganglia Riboflavin Deficiency in Chickens:

Riboflavin deficiency ( curled toe paralysis, seep 2941) can develop if feed is not for­ mulated properly. Affected chicks show poor growth, diarrhea, and weakness. There is inability to extend the hocks and progressive inward curling of the toes, so that chicks rest and walk on their hocks. Mortality is high by the third week. At necropsy the peripheral nerves, especially the sciatic nerves, are swollen. Histopatllo­ logically, tllere is hypertrophy of Schwarm cells, demyelination, and minimal axonal degeneration. Chickens often recover with riboflavin supplementation unless tile curled-toe deformity is longstanding.

TOXIC DISORDERS Botulism: Botulism is intoxication with a neurotoxin produced by Clost1idium botulinum. It is seen in horses, cattle, sheep, and birds worldwide. It is uncommon in dogs and pigs. (For a complete discus­ sion, seep 605 and p 2889.) lonophore Toxicity: (See al.so 10Nor1-10RES, p 1175.) Ionophore toxicity has been seen in cattle, sheep, pigs, dogs, cats, and poultry; horses are particularly susceptible. Lasalocid-contaminated food has caused flaccid tetraparesis witl1 hyporeflexia in

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DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION

dogs. In 1995, cat food contaminated with sialinomycin caused an outbreak of polyneuropathy in -850 cats in the Netherlands and Switzerland. Affected cats had acute onset of tetraparesis, hypore­ flexia, dysphagia, respiratory weakness, and eventual muscle atrophy. Histopathologic findings consisted of degeneration of distal sensory and motor axons. Affected animals usually recover with supportive care and removal of the offending food. Organophosphate Poisoning: Poisoning involving organophosphates (seep 3064) can cause three syndromes. The acute form is due to i.1Teversible inhibition of acetylcho­ linesterase, resulting in increased acetyl­ choline activation of the nicotinic and muscarinic receptors in the parasympa­ thetic nervous system, nicotinic receptors at the neuromuscular junction, nicotinic receptors of the syn1pathetic nervous system, and cholinergic pathways within the CNS. Clinical signs of acute toxicity include muscarinic signs (eg, vomiting, diarrhea, salivation, bronchoconstriction, increased bronchial secretions), nicotinic signs (eg, muscle tremor and twitching), and CNS signs (eg, behavioral change, seizures). The intermediate form is prinlarily manifest as generalized muscle weakness due to accumulation of acetylcholine at the nicotinic neuromuscular junction, causing a depolarizing block. Cats are especially prone to this form of toxicity, most conunonly due to chlorpyrifos. Affected cats often do not have obvious signs of acute toxicity, instead developing tetraparesis and ventroflexion of the neck several days after exposure. Mydriasis is conunon. Diagnosis is based on a history of exposure and the presence of typical clinical signs. Decreased cholinester ­ ase activity in whole blood is supportive. Treatment of acute or subacute toxicity should include administration of atropine (0.2 mg/kg, IM) if dyspnea due to bronchial secretions and bronchoconstJ.iction is present. Atropine will not relieve the nicotinic signs of tremors and weakness, which should be treated with pralidoxime chloride (20 mg/kg, IM or SC, bid). Diphen­ hydramine (4 mg/kg, IM or PO, bid) may help alleviate muscle weakness. Treatment for several weeks may be necessary. The delayed form of toxicity is associ­ ated with degeneration of distal axons in the peripheral and central nervous systems. It is unrelated to inllibition of acetylcholinester­ ase and is seen only with certain organo­ phosphates. Signs develop several weeks after exposure and are characterized by weakness and ataxia of the pelvic limbs. In

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horses, laryngeal paralysis has also been reported. There is no specific treatment. Tick Paralysis: Rapidly progressive

paralysis may be caused by several species of ticks (seep 1314). Some female ticks produce a salivary toxin that interferes with acetylcho­ line release at the neuromuscular junction. In North America, De1macentor variabilis and D andersoni may affect dogs, sheep, and cattle. In Australia, Ixodes lwloc-yclus causes an especially severe fom1 of tick paralysis in dogs, cats, cattle, sheep, pigs, llamas, horses, and occasionally people. In Africa, the major tick associated with paralysis is I rubicun­ dus, with cattle, sheep, goats, and rarely dogs affected. A wide va.tiety of ticks affect aninlals in Europe and Asia. Clinical signs consist of paraparesis that progresses within 24-72 hr to flaccid tetraplegia, with weak to absent spinal cord reflexes. Sensory perception and conscious­ ness remain normal. Dysphagia, facial paralysis, masticatory muscle weakness, and respiratory paralysis may develop in severe cases. Treatment consists of removal of the tick and application of a topical aca.ticide to kill any hidden ticks. For all except I holocyclus paralysis, prognosis is good, and recovery occurs within 1-2 days. Tick antiserum is available for treatment of I holocyclus paralysis, but prognosis is guarded because death from respiratory pa.i·alysis may occur despite treatment.

TRAUMA The immediate effect of injury of a peripheral nerve is a variable degree of dysfunction, depending on the severity of the injury. The mildest form of injury is neuropraxia, which temporarily disrupts function with minimal morphologic alterations in the nerve. Axonotmesis is disruption of axons without disruption of the surrounding connective tissue of the nerve. The most severe fom1 of injury is neurotme­ sis, which is complete severance of the nerve. With both axonotmesis and neurotme­ sis, there is subsequent degeneration of the axons distal to the injury site and in a portion of the nerve proximal to the i_l\jury site. Diagnosis of peripheral nerve injuries is based on the history and clinical assessment of the motor and sensory function of the affected nerve(s). Electromyography often helps identify denervated muscles 5-10 days after injury. Nerve conduction studies may also be useful in diagnosis. Prognosis is guarded. With neuropraxia, complete recovery usually occurs within 3 wk. For function to return after axons are

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DISEASES OF THE PERIPHERAL NERVES AND NEUROMUSCULAR JUNCTION

disrupted (axonotmesis, neurotmesis), the nerve must regenerate from the point of injury all the way to the innervated muscle. The growth rate of regenerating axons in the distal stump is 1-3 nun/day. Recovery is unlikely if the severed axons are substantially separated or if scar tissue interferes with axonal growth. Although vaiious anti-inflainmatory drugs have been recorrunended for traumatic ne1ve ir\jw·ies, there is little evidence of benefit. Surgery to appose the nerve stumps should be performed promptly in cases in which the nerve has been sharply transected. In instances of blunt trawna, surgical exploration and excision of scar tissue may help. Surgery is often successful in horses with fibrous compression of the supra­ scapular nerve. Longterm management consists of physical therapy to minimize muscle atrophy and decreased mobility of joints. Bandages or splints may be necessary to help protect the affected limb. Brachia! Plexus Avulsion: Traumatic ir\jury to the C6 to T2 nerve roots that innervate the thoracic limb can lead to brachia! plexus avulsion in dogs, cats, ai1d birds. With severe extension or abduction of the limb, the nerve roots stretch or tear from their attachment to the spinal cord. Clinical signs vary with tl1e extent of root involve­ ment. Complete avulsion results in flaccid pai·alysis of the limb, anesthesia distal to the elbow, ipsilateral Homer syndrome, and ipsilateral loss of the cutai1eous trunci (panniculus) reflex. The injured ailinlal bears little or no weight on the limb and drags the dorsal surface of the paw on the ground. Sensation to the ventral surface of the paw is spared if only the cranial nerve roots are affected. Avulsion of the caudal nerve roots causes loss of sensation on the caudal surface of the limb with variable loss on the cranial surface. There is no treatment, and with complete avulsion, the prognosis is poor. Amputation of the limb may be necessary because of danrnge from dragging or self-mutilation. Recovery is possible in mild cases in which the roots are contused rather than avulsed. Peripheral Nerve Injuries: These ir\juries are some of the most common neuropathies in aninlals. The sciatic nerve or its branches may be injured by pelvic fractures, during or after retrograde placement of intrainedullaiy pins in the femur, or by ir\jections of irritating substances in or near the nerve. Dainage to the proxin1al aspect of the sciatic nerve causes monopai·esis with inability to flex tl1e stifle. The hock and digits cannot flex or extend, ai1d weight is supported on the

dorsal swface of the foot with the hock excessively flexed. There may be loss of sensation below the stifle except for the medial aspect, which is innervated by a branch of the femoral nerve. lr\jury to the tibial nerve results in inabil­ ity to extend the hock or flex the digits as well as reduced sensation over the plantar surface of the foot. lr\jury to the peroneal nerve results in inability to flex the hock or extend the digits as well as decreased sensation over the crai1iodorsal surface of the foot, hock, and stifle. The femoral nerve may be injured in calves ai1d foals during dystocia if excessive traction stretches or otherwise dainages it. This results in an inability to bear weight on the limb because of an inability to extend the stifle. The patellai· reflex is weak or absent. Sensation is lost along the medial swface of the limb (saphenous nerve). The suprascapular nerve is most commonly injured in large aninlals secondaiy to trauma of tl1e shoulder region. This results in atrophy of the supraspinatus and infraspinatus muscles and instability of the shoulder joint (sweeney, seep 1129). In horses, the nerve may be entrapped by connective tissue that develops in the region of the supraspinous fossa. Calving Paralysis: Calving paralysis is

seen in heifers witl1 oversized fetuses. It has previously been attributed to bilateral compression of the obturator nerve, but damage to the sixth lwnbar ne1ve root, which contributes to the obturator and sciatic nerve, probably accounts for most of the paralysis. Ischernic necrosis of muscles secondaiy to compression, and ruptures of muscles during attempts to 1ise, also contribute to the parapai·esis. Additionally, metabolic derai1gements, such as hypocalce­ mia, may complicate the syndrome. (See also BOVINE SECONDARY RECUMBENCY, p 1188.)

Facial Nerve Trauma: Facial nerve trauma is most common in large ailirnals that become recurnbent with subsequent compression of the side of the face. It can be caused by pressure from a halter in horses during general anesthesia. There is ipsila­ teral lip paralysis, deviation of tl1e muzzle to the contra!ateral side, ai1d weak to absent palpebral reflex. A drooping ear ca.ii result from injuries to the proxin1al aspect of the nerve.

VASCULAR DISEASES lschemic Neuromyopathy: Ischenlic neuromyopathy is most common in cats

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DISEASES OF THE SPINAL COLUMN AND CORD

with arterial thromboembolism secondary to myocardial disease. It also is seen in dogs with a variety of underlying disorders, including hyperadrenocorticism,hypothy­ roidism,renal disease, cancer,and heart disease. Occlusion occurs most commonly at the distal aortic trifurcation,resulting in ischemia of muscles and nerves in the pelvic limbs. There is acute,painful para.paresis and an inability to flex or extend the hock. The flexor reflex and,in some cases,the patellar reflex are lost. Sensation distal to the hock is decreased. The gastrocnemius and cranial tibial muscles are often firm and painful. The nails may be cyanotic, and the femoral pulses are weak or absent. Diagnosis can usually be made based on clinical featmes. Serun1 CK is often increased. Doppler ultrasonography helps evaluate blood flow in the distal aorta and femoral arteries. Pathologic changes are present distal to the level of the middle to

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lower thigh and are characterized as focal muscle necrosis and degeneration of the central portions of the sciatic nerve and its branches. Management consists of analgesics,nursing care,and treatment of any underlying disease (eg, cardiomyopa­ thy). Thrombolytic therapy with streptoki­ nase or tissue plasminogen activator does not improve survival. Anticoagulants, such as unfractionated heparin or low­ molecula .r -weight heparin,are used to reduce continued thrombus formation. Neurologic deficits may improve within 2-3 wk, but 6 mo may be requi.red for complete recovery. Permanent deficits are possible. Approximately 60% of affected cats die or a.re euthanized during the initial episode. In the cats that survive,the longterm prognosis is guarded (median 12 mo) because of the underlying heart disease and high risk of recurrence of thromboembolism.

DISEASES OF THE SPINAL COLUMN AND CORD Diseases of the spinal column and cord include congenital disorders,degenerative diseases,inflanunatory and infectious diseases,neoplasia,nutritional diseases, trauma, toxic disorders,and vascular diseases. Many of these diseases are discussed in full in other chapters and are only b1iefly described here. For a discussion of congenital disorders related to the spinal column and cord,seep 1222.

DEGENERATIVE DISEASES Cervical Spondylomyelopathy: Cervi­ cal spondylomyelopathy,also called cervical vertebral malfom1ation-malarticulation and wobbler syndrome,is compression of the spinal cord caused by abnmmal development of the cervical ve1tebrae. Genetic factors and possibly nutrition may be involved. In dogs, there are two fom1s of the disease,disc-associated wobbler syndrome (DAWS) and bony-associated cervical spondylomyelopathy. DAWS affects middle-aged (mean 7 yr),large-breed dogs, especially Dobennan Pinschers. There is ventral compression of the spinal cord due to protrusion of one or more caudal cervical discs,in some cases complicated by

congenital stenosis of the vertebral canal or hypertrophy of the liga.mentum flavum. Bony-associated compression affects young (several months to 4 yr),giant-breed dogs, including Great Danes,Mastiffs,and Rottweilers. Spinal cord compression is due to bony proliferation of the articular processes and pedicles,usually of the C4 to C7 vertebrae. Clinical signs can be acute or slowly progressive. Mild cases are characterized by subtle ataxia of all limbs,often evident as a long,protracted stride in the pelvic limbs, with short-strided gait in the thoracic limbs. In severe cases, there is paresis or paralysis of all limbs. Neck pain is variable. Differen­ tial iliagnoses include congenital anomalies, trauma,meningomyelitis,discospondylitis, and neoplasia. Survey radiographs cannot confinn a diagnosis of cervical spondylomy­ elopathy but are useful in excluding discospondylitis and bony neoplasia. Definitive diagnosis requires myelography, CT,orMRI. Nonsurgical treatment is indicated for dogs with mild signs and consists of exercise restriction and prednisone (0.5 mg/kg/day). Signs improve in -500/oof dogs and remained unchanged in -25% of

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DISEASES OF THE SPINAL COLUMN AND CORD

dogs with nonsurgical treatment. Surgery is indicated in animals with substantial neurologic deficits and in those that do not respond adequately to nonsurgical treatment. The specific technique is based on the changes evident on imaging and include ventral slot with pa.itial discectomy, dorsal larninectomy, or distraction and fusion of affected vertebrae. Overall, --800A, of dogs do well with surgery. In horses, cervical spondylomyelopathy is the most common noninfectious disease of the spinal cord and occurs in ma.i1y breeds. Most horses present at 8 yr old and develop an insidious onset of nonpainful ataxia and weakness of the pelvic limbs. Spinal reflexes are usually normal or exaggerated, but in adva.i1ced cases there is flaccid tetraparesis a.t1d hyporeflexia reflecting lower motor neuron involve­ ment. Early cases may be confused with orthopedic disorders; however, proprio­ ceptive deficits are an early feature of degenerative myelopathy a.t1d are not seen in orthopedic disease. Myelography or MRI and CSF analysis are essential to exclude compressive and infla.tnrnato1-y diseases. A DNA test based on the SOD l gene is available on the Orthope­ dic Foundation for Animals Web site. Dogs that are homozygous for the mutation are at risk of the disease and will pass one copy of the mutant allele to their offspring. Heterozy­ gotes are at low risk of the disease but have a 500A, chance of passing one copy of the mutant allele to each offspring. Homozygous normals are at low risk of the disease and will not pass the mutation to offspring. There is no specific treatment and no evidence that glucocorticoids, other drugs, or supplements alter the course of the disease. Most dogs are euthanized because of disability within 1-3 yr of diagnosis. Equine Degenerative Myeloencepha­ lopathy: Equine degenerative myeloen­ cephalopathy is a progressive neurologic

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DISEASES OF THE SPINAL COLUMN AND CORD

disorder of horses and zebras characterized by diffuse degeneration of axons, myelin, and neurons in the spinal cord and, to a lesser degree, the brain stem. It has been reported in many equine breeds in North Ametica, Australia, and England. The cause is incompletely understood, but a vitan1in E deficiency and genetic factors are sus­ pected. Clinical signs usually become apparent during the first year of life and consist of ataxia and weakness in all four limbs, although the hindlimbs may be more severely affected. Clinical signs may stabilize or slowly progress. There is no definitive diagnostic test. Clinical diagnosis is based on clinical features and excluding other causes. Myelography and CSF analysis are nonnal. Supplementation of pregnant mares and newborn foals with vitamin E is preventive in predisposed families, and affected horses may in1prove with vitan1in E supplementation. lntervertebral Disc Disease: Degen­ eration and subsequent herniation of the intervettebral disc results in compression of the spinal cord, spinal nerve, and/or nerve root. It is a common cause of spinal cord disease in dogs, with a lifetime prevalence of --3.5%. Clinical signs due to disc disease are rare in cats and horses. Chondrodys­ trophoid breeds of dogs (eg, Dachshw1d, Beagle, Shih Tzu, Lhasa Apso, and Pekingese) are most commonly affected, with Miniature Dachshunds having a lifetin1e prevalence of --200/o. In these breeds, there is chondroid degeneration of the discs within the first few months of life. Disc extrusion can occur as early as1-2 yr of age, and clinical signs are often acute and severe. In contrast, fibroid disk degenera­ tion typically occurs in large breeds of dogs >5 yr old and causes slowly progressive clinical signs. The most common sites of disc herniation are the cervical and tl1oracolwnbar regions. The predominant sign of cervical disc herniation is neck pain, manifested as cervical rigidity and muscle spasms. There may be thoracic lin1b lan1eness or neuro-

1247

logic deficits, ranging from mild tetrapar­ esis to tetraplegia. In thoracolwnbar disc herniation, there may be back pain, evident as kyphosis and reluctance to move. Neurologic deficits are usually more severe than those seen in cervical disc disease and range from pelvic limb ataxia to paraplegia and incontinence. In paraplegic animals, the most important prognostic finding is whether there is deep pain perception caudal to the lesion. This is assessed by pinching the toe or tail and observing whether there is a behavioral response, such as a bark or turn of the head. It is in1portant to pinch the bone to stimulate deep pain receptors, not just the skin, which tests only superficial pain. Reflex flexion of the limb must not be mistaken for a behav­ ioral response. Definitive diagnosis of disc extrusion is based on in1aging studies. Spinal radio­ graphs may show narrowing of the affected disc space, inte1ve1tebral foran1en or articular facets, or radiodense calcified disc material within the ve1tebral canal. However, radiographs are not sensitive or specific enough for definitive diagnosis, which requires myelography, MRI, or CT. Dogs witl1 pain and mininlal to moderate neurologic deficits often recover with 2-3 wk of cage rest. A short course of pred­ nisone (0.5 mg/kg/clay for 3 days) is often helpful in relieving pain. The use of anti-inflanimatory or analgesic medication without concurrent cage rest is contraindi­ cated, because an increase in the dog's activity may lead to further disc extrusion and worsening of spinal cord compression. Clinical signs recur after conservative therapy in 300/o-40% of cases. In animals with severe neurologic deficits, prompt surgery offers the best chance of recovery (see TABLE1). Other indications for surgery are failure of conservative therapy and recurrent episodes. Hemilanlinectomy with removal of the extruded disc material is the most common procedure. Prophylactic fenestration of commonly affected disc spaces (eg, T l l tllrough IA) decreases recurrence in small-breed dogs. Progressive myelomalacia develops in 5%--100/o of dogs with paraplegia and loss of deep pain perception. In this syndrome, affected dogs develop flaccid tetraplegia, the level of anesthesia ascends cranially, and respira­ tory paralysis develops. Diffuse Idiopathic Skeletal Hyper­ ostosis: Also known as Forestier

lntervertebral disc extrusion, L3-L4, in a dog. Courtesy of Dr. William Thomas.

disease in hun1an patients, diffuse idiopathic skeletal hyperostosis (DISH) is

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DISEASES OF THE SPINAL COLUMN AND CORD

RECOVERY RATES AFTER SURGERY FOR INTERVERTEBRAL DISC DISEASE IN DOGS

Patient Type

Recovery Rate

Nonambulatory small-breed dog with thoracolwnbar extrusion and intact deep pain

85%--95%

Small-breed dog with thoracolW11bar extrusion and loss of deep pain24hr

1 yr old are affected, and the prevelance increases with age. As with spondylosis deforrnans, Boxers are at increased risk, with a prevelance of --400/o. The thoracic and lW11bar regions are most commonly affected. It is unclear how often DISH causes clinical signs, and in many cases the radiographic findings a.re incidental. However, spinal pain and stiffness is possible and, in those cases, treatment is analgesics as needed. Equine Motor Neuron Oise se:

Equine motor neuron disease is a progres­ sive, noninflammatory degeneration of motor neurons in the spinal cord and brain stern of horses. It is most conunon in the northeastern USA but has been reported in several areas of North and South America, Europe, and Japan. The cause is uncertain, but vitaminE deficiency is a strong risk

Diffuse idiopathic skeletal hyperostosis (DISH) in a dog. Courtesy of Dr. William Thomas.

factor. Adult horses of any age and breed can be affected, although Quarter horses are affected most conunonly. Affected horses typically do not have access to pasture grass and are fed poor-quality grass hay. Clinical signs consist of generalized synunetric weakness, trembling, and muscle atrophy. Affected horses often stand with their head held low and their feet camped under their body, frequently shifting their weight from one limb to another. Ataxia is not a feature of this disease, in contrast to most spinal cord diseases. Many affected horses have retinal abnormalities, including a distinct reticulated pigment pattern and areas of hyperreflectivity.Electromyogra­ phy and biopsy of the spinal accessory nerve or the sacrodorsalis caudalis muscle a.re useful in diagnosis. There is no specific treatment, but some horses improve partially after 2--3 mo of illness. Horses that lack access to green forage high in vitaminE for prolonged periods should be supplemented with vitaminE. Degeneration of Motor Neurons:

Degeneration of motor neurons is an inherited or sporadic disease seen in Brittany Spaniels, Pointers, German Shepherds, Dobern1an Pinschers, and Rottweilers; ca.ts; Hereford, Brown Swiss, and red Danish cattle; Yorkshire pigs; and goats. Also called spinal muscular atrophy, this disease is characterized by progressive paresis, tremor, muscle a.trophy, and weak spinal reflexes. The age of onset is typically within the first 1-2 yr of life.Electromyogra­ phy and muscle biopsy help docW11ent muscle denervation, but definitive diagnosis is based on loss of motor neurons in the

DISEASES OF THE SPINAL COLUMN AND CORD

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Some of the more common infectious and inflarrunatory diseases in which involve­ ment of the spinal colmnn or cord is a prominent feature are discussed below.

Bacterial Diseases Spondylosis deform ans in a dog. William Thomas.

Courtesy of Dr.

ventral horn of the spinal cord and brain-stem nuclei on necropsy.

Metabolic Storage Disorders: Rare, usually inherited, metabolic disorders can affect the CNS, including the spinal cord.

(See also CONGENITAL AND INHERITED ANOMALIES OF'THE NERVOUS SYSTEM, p 1222.)

Spondylosis Deformans: Spondylosis

defonnans is a noninflammatory condition characterized by formation of bony projections (enthesophytes) at the location where the annulus fibrosus is attached to the cortical surface of adjacent vertebrae. These bony growths vary from small spurs located several millimeters from the junction between the disc and vertebra to bony bridges that span the disc space leaving at least part of the ventral surfa�e of the vertebra unaffected. The enthesophytes typically expand laterally and ventrally but not dorsally and therefore rarely affect the spinal cord. The cause is breakdown of the outer fibers of the annulus fibrosis and stretching of the longitudinal ligament. The increased stress at the vertebral attachment of the longitudinal ligament incites bony production. Spondylosis deformans is seen in dogs, cats, and bulls, and the incidence increases with age. It is uncommon in dogs 180 mm from their respective muscles may be unable to make anatomic contact. If anatomic contact is made, the nerve sheath contracture, which develops over time, may not leave enough room to develop sufficient myelin to conduct an effective electrical in1pulse. Axonoste­ nosis, or nan·owed nerve sheaths with reduced nerve function, may be a sequela of nerve injmies. Neurotmesis is total nerve rnpture, and surgical reattachment is required for regeneration. If no nerve function is found on the initial neurologic examination, neurapraxia, axonotmesis, and neurotmesis can be difficult to differentiate.

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Electrical stimulation of a nerve with neurapraxia is usually nom1al, and the prognosis is good, regardless of the findings of the initial neurologic exanunation. lithe affected nerve does not respond to electrical stimulation distal to the site of the lesion 10 WBC/µL). Any neutrophils obse1ved on cytology in CSF from a foal warrant treatment with antimicrobials that can obtain high therapeutic levels in the CNS. Viral infections and listeriosis typically produce a mild to moderate mononuclear pleocytosis in CSF, with an associated increase in protein levels. However, tl1e CSF is normal in rabies virus infections. Herpes­ virus infections cause markedly increased proteins and xanthochromia(yellow to reddish discoloration) without dramatic increase in cell count. Feline infectious peritonitis (FJP) in cats and Eastern equine encephalitis in horses are exceptions and can cause markedly high neutrophil counts. In FIP, a markedly high protein concentra­ tion(>200 mg/dL) can also be seen. Parasitic and fungal meningoencepha­ litides cause eosinophilic or occasionally a highly degenerate neutrophilic pleocytosis. Granulomatous inflanunations usually induce moderate to high cell numbers and increased protein in the CSF. The cell population is predominantly mononuclear or a mixed population of neutrophils and mononuclear cells. Distinguishing a granulomatous infection due to a fungal or protozoa! organism from granulomatous meningoencephalitis is often difficult. The necrotizing encephalitides typically cause a

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MENINGITIS, ENCEPHALITIS, AND ENCEPHALOMYELITIS

mild increase in CSF mononuclear cells and protein concentration. Occasionally, bacteria are seen on cytologic examination of the CSF and identi­ fied with Gram stain. Successful culture of bacteria from CSF is more likely in large animals than in dogs. In some cases, serial blood cultures are more successful, especially in foals. Fungi and occasionally protozoa have been identified in CSF, but serology is usually necessary to confirm mycotic and protozoa! infections in vivo. Many of these diseases are fatal, and final identification is made at postmortem with in situ identification of the organism. For premortem etiologic identification, agent-specific testing is recommended; however, most agents, once in the CNS, are not detectable by direct testing through culture or nucleic acid-based testing of body fluids. Serologic testing is available for most viral encephalitides and, in particular, for arboviruses the most reliable test exan1ines IgM in a single sample. Paired serum is required for IgG-based tests, especially those confounded by vaccina­ tion. Although CSF analysis is rewarding in tenns of clinical pathology, detection of a pathogen within the CSF can also be unreliable depending on the location and pathogen load within the CNS. Culture of the CSF will often yield growth of the organism in bacterial meningitis; however, the detection rate is often 7 yr old and in cats >9 yr old, although they have been seen in young cats (24 mo old. No cases of vCJD have been seen in laboratory workers, but appropriate safety precautions for handling the BSE agent and conducting necropsies of cattle suspected of being infected are recommended. Safety precautions should primarily be aimed at avoiding accidental exposures.

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CHRONIC WASTING DISEASE

CHRONIC WASTING DISEASE Chronic wasting disease (CWD) is a contagious disease of captive and free­ ranging deer, elk, and moose that causes progressive, fatal neurodegenerative disease in adult animals. It is a member of the transmissible spongiform encephalopa­ thy (TSE) family of diseases, or prion diseases, that includes bovine spongiform encephalopathy; scrapie of sheep and goats; transmissible mink encephalopathy; and kuru, Creutzfeldt-Jakob disease (CJD), and variant CJD of people. CWD was first identified as a clinical syndrome in the late 1960s among captive mule deer in Colorado; a decade later, it was recognized to be a spongifonn encephalopathy with character­ istics similar to those of scrapie (seep 1288). It is found in free-ranging populations of mule deer, white-tailed deer, and elk (wapiti) in 18 states (USA) and 2 Canadian provinces. Recently, the first cases of CWD in free-ranging moose were diagnosed in Colorado and in Alberta, Canada. CWD has also been found in fanned elk and white-tailed deer in a munber of western states and Canadian provinces and a few midwestem states. CWD has been identified outside of North America only once; a few elk imported into Korea from Canada had CWD. Many states and provinces have developed regulations for control and management of CWD in fam1ed popula­ tions, and federal regulations are in place in Canada and the USA. It is a reportable disease in most jurisdictions.•

Etiology: CWD is caused by prions. These

unconventional pathogens consist solely of protein, namely the misfolded isoform Prf>& of the n01mal host-encoded cellular prion protein (Prpc), which is a cell surface glycoprotein with highest expression levels in the CNS. On direct binding of Prpc to Prpsc, Prpc adopts the disease-associated confom1ation. In contrast to Prpc, PrPSc is partially resistant to protease digestion and accumulates within neurons, which eventually leads to neuronal death. CWD is known to naturally affect mule deer, white-tailed deer, elk, and moose. Transmission after oral inoculation of other cervid species, eg, reindeer, has been reported. Experimentally, CWD can be transmitted by intracerebral inoculation to cattle, sheep, goats, domestic feITets, mink, mice, han1sters, and squiITel monkeys.

Transmission efficiency to cattle varies depending on the ce1vid species from which the CWD-infected brain homogenate used for infection is derived. A large study to investigate susceptibility of cattle by the more natural route of oral or contact exposure began in 1997, and there has been evidence of CWD in the experimentally exposed cattle. Differences in species susceptibility to CWD probably relate to sequence differences among normal host PrP proteins.

Transmission, Epidemiology, and Pathogenesis: CWD is transmitted

horizontally. Because prions are highly resistant to environmental and chemical inactivation, they may accumulate in the environment and thus be available to infect susceptible cervids. Consequently, close confinement of fann-raised ce1vids will likely potentiate the spread of CWD. Likewise, winter feeding of deer and elk will concentrate cervid populations and likely potentiate ho1izontal transmission. Foraging on feeding grounds contanlinated by urine or feces of infected animals or contact with either infected anin1als or decomposing carcasses of animals with CWD results in transmission of disease to other susceptible cervids. Vertical transmission has also been reported. The agent probably enters a susceptible host via ingestion and is taken up by lyn1phoid tissues associated with the GI tract. The agent can be detected in lymphoid, nervous tissues, muscle tissue, antler velvet, blood, saliva, urine, and feces. Prions can be detected in the blood and �aliva of infected animals as soon as 3 mo after infection. In urine and feces, detection of prions is also possible already at a preclinical stage of the disease. The agent most likely anives in the brain by retrograde movement up the vagus nerve to tl1e dorsal motor nucleus of the vagus at the obex region of the medulla oblongata. Spongifom1 lesions in the brain develop first in the vagal nucleus at about the time of onset of clinical disease. This occurs naturally witl1 an incubation period of -1.5--3 yr; however, incubation periods in all species known to be affected by CWD are influenced by certain PrP polymor­ phisms. Prevalence in captive herds of deer and elk may reach nearly lO()OA, in heavily contanlinated facilities; prevalence in

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CHRONIC WASTING DISEASE free-ranging cervids is extremely variable, from 16 mo old and show a spectrum of signs. The earliest and most difficult to appreciate are subtle changes in behavior and weight loss. These changes are often detectable only by animal caretakers familiar with the individual animal. As the disease progresses, behavioral changes may include alterations in how the animal interacts with herdmates and caretakers, Joss of wariness, somnolence, persistent walking, polydipsia and polyuria., and hyperexcitability when handled. Affected animals may show variable locomotor signs, including ataxia (especially posterior ataxia) and head tremors. Late in the disease, animals may have a low head carriage, drooped ea.rs, and fixed staring gaze; they may hypersalivate and grind their teeth. Dea.th after routine chemical immobilization has been noted. Aspiration pneumonia may be the only presenting clinical sign and is often the ca.use of death. CWD should be suspected in any adult cervid with aspiration pnewnonia.. Weight loss is progressive throughout t11e course of disease, even when adequate feed is present, but it is important to recognize that CWD may be present in cervids that are not emaciated. Dea.th of CWD-a.ffected animals may be precipitated by cold weather or other acute stressors. Affected cervids are more susceptible to hunting, predation, vehicle collisions, and other f01ms of death by misadventure. Carcasses and offal should be disposed of in a manner that limits the exposure of farm-raised and free-ranging cervids to any potentially infectious material. Lesions: Lesions a.re seen in tJ1e gray matter of the CNS. Lesions a.re bilaterally symn1etrical and anatomically constant among anin1als. Spongiform appearance is

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obvious; vacuolization occurs in neuronal perika.rya. and neuronal processes. Along with neuronal degeneration, astrocytic hyperplasia and hypertrophy may appear. H&E staining of brains of affected animals reveals amyloid plaques that appear as pale, fibrilla.r, eosinophilic areas of neuropil and a.re sometimes surrounded by vacuoles (fl01id plaques). Detection of PrPSc in brain sections by immunohistochemistry (II-IC) provides a very good way to visualize CWD pathology while maintaining the structural context. A drawback of II-IC is that it is not useful in diagnosis of subclinical CWD because spongiform encephalopathy develops about the same time clinical features do. PrPSc is detected by II-IC or inununoblot in a variety of tissues in cervids showing clinical symptoms. Although PrPSc can be found in regions of the brain not exhibiting spongifom1 change, typically there is correlation between PrPSc deposition and spongifonn appearance.

Diagnosis: Diagnosis based on clinical signs is not reliable, because they a.re unspecific and mild at the beginning of disease. Therefore, it depends on detecting disease-associated PrPSc in CNS or lymphoid tissues. In mule deer and white-tailed deer, the CWD PrP accumulates in the retro­ pha.ryngeal lymph node before arriving in the brain; thus, it is considered to be the most important tissue to collect for testing. Both brain and lymph node samples should be collected from elk. The correct portion of the brain (ie, the obex, at the caudal enq of the fourth ventricle below the cerebellum) must be collected for a meaningful test. The laboratory should be consulted to detennine whether the samples must be fixed in l()OA, buffered formalin, chilled or frozen, or if portions of the samples should be sent both fixed and frozen. San1ples should be, and in many jurisdictions a.re required to be, submitted to certified laboratories to be tested for evidence of CWD. It is good practice either to send the carcass to the diagnostic laboratory or to collect a wide variety of samples, so that if diseases other than CWD a.re present they will be identified. At a n1inin1um, samples for CWD testing should include brain and retropha.iyngeal lymph nodes. Many laboratories accept whole heads from cervids for testing. Surveillance progran1s for free-ranging cervids va.iy depending on thejwisdiction and are usually conducted by the local wildlife management agency, which should be consulted if CWD is suspected in a free-ranging deer or elk. Surveillance depends mainly on submission of heads

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CHRONIC WASTING DISEASE

from hunter-harvested animals. In some areas, active stuveillance is done by taking biopsies from tonsils, retropharyngeal lymph nodes, and recto-anal mucosa-associ­ ated lymphoid tissue (RAMALT). Diagnostic tests include detection of PrJ>Sc by IHC, ELISA, or Western blot in brain and/or lymphoid tissues. In the USA, these tests are run only at USDA-certified laboratories. ELISA is used as a screening test, and IHC, which is considered the prefe1Ted test, is used to confirm positive ELISA. Nevertheless, more sensitive in vivo diagnostic tests are desirable. Using in vitro conversion such as protein misfoldi.ng cyclic amplification (PMCA) or real-time quaking-induced conversion assay (RT-QUiC), CWD prions are detectable already at a preclinical stage in specimen that can be obtained antemortem by noninvasive methods, such as blood, urine, feces, or saliva. However, these newly devel­ oped assays are not yet certified. Differential diagnoses for animals suspected of CWD include brain abscesses, traumatic il\iuries, meningitis, encephalitis, peritonitis, pneumonia, arthritis, statvation and nutritional deficiencies, dental attrition, and anesthetic deaths.

Treatment and Control: There are no

treatments available for any TSE. Control in farmed cervids is by depopulation with indemnity and development of a National CWD Herd Certification Program in the USA. This is designed to be a voluntary federal-state-industry cooperative program administered by the USDA Animal and Plant Health Inspection Service. This plan typically requires 5 yr of monitoring to achieve the highest status. The bases for CWD control programs in"the farmed cervid industry are individual animal identification, CWD testing in all animals in the herd that die over a certain age, and limiting new herd additions to animals from herds of compara­ ble or higher CWD status.

Control of CWD in free-ranging popula­ tions is extremely difficult and varies depending on the location. All jurisdictions have banned movement oFlive cervicls from endemic areas for translocations, and many have regulations on movement of parts of hunted deer and elk. In areas where CWD occurs, attempts at control have included population reduction, test and removal, and intensified surveillance. Only a few clisinfectants and methods of disposal inactivate prions. Fresh household bleach at 50% concentration for 30-60 min or sodium hyclroxide (1 M) for 60 min will inactivate the agent and is inexpensive and reacilly available but may be corrosive to some surfaces and instrtunents. Additional disinfectants are being considered for general use but are not yet approved. Incineration in a medical incinerator, alkaline digestion in specially designed equipment, and disposal in certified municipal landfills are used for disposal of tissues and carcasses of animals with CWD.

Zoonotic Risk: Although CWD has been present in htu1ted populations of deer and elk for >30 yr, no case of hun1an CWD has been identified. The risk to people appears to be minimal. The CWD agent has been detected in the muscle tissue of infected cervids. Public health authorities and wildlife management agencies suggest the following precautions for hunters and people handling cervids in areas where CWD is found to further reduce risk of human exposure: do not harvest deer or elk that appear to be sick or abnormal; wear rnbber, plastic, or latex gloves when clressing the carcass; avoid contact with brain, spinal cord, and lymphoid tissues; debone the meat when processing; clisinfect knives, saws, and tables with 500Ai bleach; and have the anin1al tested for CWD. All public health authorities recommend that animals positive for ariy TSE not be consumed by people or other anin1als.

SCRAPIE Classic scrapie, a natural clisease of sheep and goats, is seen worldwide except in Australia and New Zealand. It is one of the transmissible spongifonn encephalopathies (TSE), related to bovine spongiform encephalopathy and chronic wasting

disease of deer and elk, all of which are thought to result [rom the accumulation of an abnonnal fom1 of a cellular protein in the brain. Natural transmission of scrapie to other species has not been shown. In the USA, scrapie primarily affects black-faced

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SCRAPIE

sheep breeds (eg, Suffolk, Hampshire, and their crosses), accounting for -96%of cases. In other countries, the disease is commonly seen in other breeds, including those with white faces. Etiology, Transmission, and Patho­ genesis: An abnormal protein designated

as PrPSc, found in all TSE, appears to convert a normal cellular protein called p1ion protein (PrpC) to its abnormal form (Prpsc) in susceptible animals. In sheep, the susceptibility is controlled genetically; however, genetic susceptibility has not been established in goats. As it accumulates within a cell, PrPSc is deposited as an amyloid plaque in lymphoreticular and nervous tissue, where its accun1ulation is hypothesized to cause the nervous signs associated with the disease. Although some researchers still do not believe that PrPSc itself is the disease agent, its presence is a reliable diagnostic test for prion disease. When PrPC is induced to change to Prpsc, the conformation of the protein's structure is reconfigured. Although the chemical composition of the molecule is the san1e, its chemical properties change. The normal protein is soluble in denaturing detergents and is digested by cellular proteases such as proteinase K. However, PrJ>Sc (as well as the infectivity) is not destroyed by detergents and is resistant to breakdown by rendering processes presently used, heat sterilization temperatures, ultraviolet light, ionizing radiation, and most disinfecting agents. It is only partially inactivated by protease K. The genetics of scrapie in sheep is located on chromosome 13, and three codons (136, 154, and 171) seem to control most of the susceptibility to scrapie. Codon 136 codes for either valine (V), alanine (A), or threonine (T); 154 codes for arginine (R) or histidine (H); and codon 171 codes for glutamine (Q), lysine (K), H, or R. Resis­ tance to scrapie is correlated with 136A, 154H, and l 71R. These small changes in the amino acid components of PrpC apparently enable it to resist reconfiguration. Scrapie is usually related to polymorphisms at codon 171. Among sheep in the USA, 91%of brain samples testing positive for scrapie originated from sheep with the 136/154/17 l AARRQQ genotype. However, sheep with codon 136V are at the highest risk of developing scrapie, even when they also carry one R at codon 171. Recently, it was shown that these cases are actually affected by another strain of tl1e agent that at one tin1e was referred to as the V-dependent strain. It was first described in Cheviots by Irish researchers and has been reported in

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Europe and the USA. The 171RR genotype is considered to be resistant to classic scrapie. Scrapie is also rare in sheep with the 136/171 AAQR genotype. However, at least 83 atypical cases of scrapie from more than 110,000 tested samples have been recorded by The Veterinary Laboratories Agency of Great 81itain. These discordant cases, most classified as Nor 98 (first found in Norway in 1998) usually involve only a single sheep in a flock with no obvious contacts between affected flocks. Nor 98 has been seen in sheep with genotypes considered to be resistant, and many of them have one or two of the amino acid leucine (L) at codon 131. This has led to the belief that such cases represent a spontaneous prion disease, analogous to sporadic Creutzfeldt.Jakob disease in people, and that the prion is not transmitted by direct contact. It has been reported in almost every European country, the Falklands, Canada, and New Zealand, even though classic scrapie has not been reported from New Zealand. Eight such cases have been reported in the USA since 2003; the World Health Organization has classified th.is as a separate disease and declared that it should not affect trade. The classic disease is naturally transmit­ ted during lambing from infected dan1s via ingestion of infected placenta or allantoic fluids by flock mates and newborn lambs. Wected males are not believed to transmit the disease, although there is one report of PrPSc detected in semen of several 131/171 VVQQ and AVQQ V-dependent scrapie affected-ran1s. This occurred after apparent transmission of scrapie to some of their offspring from 131/171 VVQQ scrapie eyelid and rectal mucosa-negative ewes. However, because of the rarity of 136/171 VVQQ genotype in the USA at this time, it is unlikely that this should be of concern. The embryo or fetus is not exposed to scrapie while in utero in a scrapie-infected dam, because there is physical separation from PrPSc -containing allantoic fluid and chorioallantois by the anlnion, which remains free of PrP8c even when the other placental tissues are infected. Lambs delivered via cesarean section from infected dams, kept separate from the allantoic fluid, and isolated from infected sheep remain disease free. Despite the wide distribution of normal prion protein in reproductive, placental, and fetal fluids, PrPSc has been detected only in the caruncula.r portion of the endometritun and cotyledonary chorioallantois (the fetal-maternal interface) of pregnant scrapie-infected ewes-but only if both the dan1 and fetus are of a susceptible genotype. Although

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SCRAPIE

tissues of the maternal side of the placenta carry a susceptible prion protein, it requires susceptible prion-containing cells from the fetal side of the placenta for conversion to PrPSc. However, there can be partial or incomplete anastomosis between fetal blood supply to the cotyledons an1ong fetuses of different genotypes on the san1e side of the uterine horn, which in rare cases can result in PrPSc accumulation in cotyledons with resistant genotypes. Previous contamination of premises is believed to be another source of scrapie infection. Anecdotal accotmts abound of flock depopulation and premises decon­ tan1ination that are followed by reclllTence of disease in repopulated infection-free but susceptible sheep. Clinical Findings: Classic scrapie, which results from ingestion of PrPSc by a genotypically susceptible sheep, is a longterm, progressive, and debilitating nemologic illness believed to always be fatal. Clinical signs may be noticed 18 mo to 5 yr after exposme and include progressive weight loss with no concmrent loss in appetite, progressive ataxia, fine head tremors (most apparent in the ears), and cutaneous hypersensitivity. Pruritus develops in -7QOA, of cases. Sheep may assume a vacant, fixed stare or, less often, become suddenly aggressive. Signs of hypersensitivity a.re often elicited by nibbing or scratching the sheep's back, which induces the sheep to throw its head back, make chew.mg motions and lick at the air, or compulsively nibble at the lin1bs below the carpus. Ataxia is first detected when sheep are running. The hindlin1bs appear to be uncoordinated with the.forelimbs, and affected a.nin1als adopt a bunny-hopping gait. Sheep often have a high-stepping gait in the forelimbs, resembling a prancing horse. As signs worsen, the hindquarters sway while standing. Clinical signs last from 1 to >3 mo; sheep generally become recumbent because of weakness and incoordination. If helped up, an affected sheep may be able to remain standing for hours but cannot rise unassisted if it falls or lies down. Death follows 1-2 wk after a sheep can no longer right itself. Blindness, resembling that seen with polioencephalomalacia, occasionally develops. The clinical signs of scrapie can vary, depending on the sheep's genotype and the strain of scrapie. The V-dependent strain has a substantially more rapid clinical course of3-30 days and death in 2-3 days after recurnbency. In these cases, weight

loss and signs of prmitus are often not seen. This strain, found in the University of Idal10 research flock, made up of local flocks found to have scrapie, mainly infects 131/171 VVQQ and 131/171 AVQR sheep. It is probably present whenever scrapie and the 136AV and V V genetics a.re found together. Most veterinarians or producers would not recognize sheep with the V-dependent gene as having scrapie. Diagnosis: A complete necropsy should be perfonned on any sheep dying mysteri­ ously, including submission of the brain for immunohistochemical (IHC) testing for scrapie. Differential diagnoses include caseous lymphadenitis, abomasal emptying disease, Johne disease, ovine progressive pneumonia (visna), dentition problems, and meningitis. Cmrently, a.II diagnostic tests for TSE require infected tissue and the use of antibody reactions. Because animals generally do not produce antibodies against self, antibodies a.re mostly monoclonal in origin or a.re made in rodents bred to have no prion protein. IHC and ELISA a.re used for routine testing. In the EU, ELISA tests a.re used for slaughter surveillance, but they are not licensed for scrapie testing in the USA. However, several test kits are used for diagnosis of chronic wasting in wild elk and deer. The IHC test is used as a coniinnatory test and is considered to be the gold standard worldwide. Detection of PrPSc in reticuloendothelial organs (spleen, lymph nodes) before appearance of clinical signs or PrPSc in the brain is possible. Detection of PrP5c has been reported in76% of tonsils examined and 57% of lymphoid tissue specin1ens collected from the third eyelid of infected sheep. A small percentage of sheep in which the brain contains PrPSc do not have detectable PrpSc in the lymph nodes, which may be influenced by genotype or scrapie strain. The atypical strains a.re not often found in lymphoid tissues. The palatine tonsil has been used for biopsy and diagnosis; biopsy of the lymph follicles of the third eyelid is sin1pler and is validated in the USA as a diagnostic test. It yields a high percentage of unreadable samples due to lack of follicles in the sample in as many as 400/o-600A, of adult sheep. Biopsy of the lymphoid ring in the rectal mucosa has also been validated and yields positive diagnoses in -55%--65% of positive sheep. Use of the mandibular lymph nodes has not been validated; however, biopsy of that site may be useful diagnostically, because exan1ination of

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS several tissues improves the chances of a positive diagnosis. It has not been estab­ lished in the course of the disease when the agent will consistently appear in these tissues, but it may be as early as 14 mo after exposure. The interval likely depends on the age of the sheep at exposure and genotype or strain of scrapie. The pathologic changes associated with scrapie are confined to the CNS and include vacuolation, neuronal loss, astrocytosis, and accumulation of amyloid plaques. However, because histologic changes are often lacking, diagnosis is made on the basis of IHC staining of the obex, other parts of the brain, and/or lymphoid tissue for PrPSc. Control: For disinfection, instruments should be soaked in 2.5N Na.OH or a disinfectant shown to be effective against a.bnom1al prions. Incineration or digestion by sodium hydroxide are considered appropriate to adequately inactivate infected carcasses. Individual and premises identification are required for all breeding sheep leaving their original premises as part of the USA mandatory Sera.pie Eradication Program. A scrapie slaughter surveillance program initiated by the USDA/APHIS has been underway since 2003 in which brains and

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lymphoid tissue of aged black-face and black-face crosses and sheep sold for slaughter with signs of scrapie ( ataxia, poor body condition scores, a.lopecia. from rubbing) are tested for scrapie by IHC. Sheep found to be positive are traced back to the herd of origin, which is quarantined, and all animals are tested. All positive sheep and those with the l 71QQ genotype are eutha.nized. Animals sold from the flock are also traced and tested. Since the program was initiated, the prevalence of scrapie has decreased 900/o, from -0.5% to -0.015% as of the end of 2013. The goal is to have the USA declared free of scrapie by 2017. Voluntary efforts to control and eliminate the disease have been undertaken by producers in the USA by selecting sheep with at lea.st one l 71R codon and culling sheep with susceptible genotypes; the expectation is that the remaining sheep will be resistant t.o scrapie infection. However, some concern has been expressed that reliance on genetics for elimination of the disease may inadvertently select for the atypical strain of scrapie that infects the 171RR genotype. So far there are no data to support that concern. Rules prohibiting rwninant-to-rurninant protein feeding have been in place in many countries for >10 yr.

EQUINE ARBOVIRAL ENCEPHALOMYEL:.ITIS (Equine viral encephalitis) Equine encephalitides can be clinically similar, usually ca.use diffuse encephalomy­ elitis (seep 1262) and meningoencepha.lo­ myelitis, and are characterized by signs of CNS dysfunction and moderate to high mortality. Arboviruses are the most common ca.use of equine encephalitis, but rabies virus, Sarcocystis neurona (see p 1309), Neospora hughesii (seep 663), equine herpesviruses, and several bacteria. and nematodes may also ca.use encephalitis. Arboviruses a.re transmitted by mosquitoes or other hema.topha.gous insects, infect a variety of vertebrate hosts (including people), and may ca.use serious disease. Most pathogenic arboviruses use a mosquito to bird or rodent cycle. Tickbome encephalitides a.re also a differential ca.use in the eastern hemisphere. A.rboviral diseases are ever emerging, and there are

arboviruses pathogenic to horses on virtually every continent. Etiology and Epidemiology of Arboviral Encephalitides: Alphaviruses: North America is home to some of the most pathogenic encephalitic viruses because of the enduring endemic status of alpha.viruses of the fan1ily Toga.virida.e. Endemic species in North, Central, or South America include Ea.stem equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Highlands J virus, Venezuelan equine encephalitis virus (VEEV), Everglades virus, and Una virus (see TABLE 3). Other alpha.vi­ ruses associated with equine encephalitis are Semliki Forest virus in Africa and Ross River virus in Australia. and the South

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ARBOVIRUSES THAT CAN CAUSE OR ARE LINKED TO EQUINE ENCEPHALOMYELITIS

Virus Species or Variant

Geographic Location

Most Important Reservoir

ALPHAVIRUSES

North American Eastern equine encephalitis virus

Eastern North America, primarily east of Mississippi river

Birds

Madariaga virus

South America, Caribbean

Rodents

Western equine encephalitis virus

Western South America

Birds, rabbits,and snakes Birds

Highlands J virus Venezuelan equine encephalitis virus

Central and South America, Caribbean

Cotton rat and other rodents

Everglades virus

South Florida (USA)

Rodents

Ross River virus

Australia,Papua New Guinea

Marsupial and placental mammals

Sernliki Forest virus

East and West Africa

Unknown

Una virus

South America

Birds

FLAVlVlRUSES

Japanese encephalitis

Asia, India, Russia,Western Pacific

Birds,swine

Murray Valley

Australia,Papua New Guinea

Birds, marsupials,and foxes

Klli\iin virus

Australia

Birds (herons and ibis)

St. Louis encephalitis

North, Central, and South America

Birds

Usutu

Europe,Africa

Birds

West Nile

Africa, Middle East,Europe, North, Central, and South America, Australia

Passerine birds

Louping ill

Iberian Peninsula, UK

Sheep,grouse

Powassan

North America,Russia

Lagomorphs, rodents, mice, skunks

Tickborne encephalitis

Asia,Europe,Finland, Russia

Small rodents

Pacific. EEEV has two distinct antigenic vruiants that ru·e sepru·ated longitudinally. The North Ame1ican variant is the most pathogenic and is found in eastern Canada; all states within the USA east of the Mississippi River and in Arkansas, Minnesota, South Dakota,and Texas; and in the Caribbean Islands. The South American variru1t is less pathogenic and confmed to central and South America and is now called Madariaga virus (MADY).

EEE and WEE viluses are separated in North America primarily latitudinally; however, WEEV is relatively heterogeneous, with several subtypes consisting of WEE, Highlands J virus,Sindbis, Aura, Ft. Morgan, ll.lld Y 62-33. Several varill.llts have been found in horses (see TABLE 3). WEE is found in western Canada, states in the USA west of the Mississippi, and in Mexico and South America. WEE previously isolated in the south and eastern USA has been shown to

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS belong to the Highlands J virus serogroup. VEE has six antigenically related subtypes: subtype I, Everglades, Mucambo, Pixuna, Cabassou, and AGS0-663. Subtype I serovars AB and C primaiily cause epi­ zootics; subtype I and serovar IE caused a large outbreak in Mexico in 1993. Epizootic strains are not generally found in the USA, although there was an epizootic of VEE in 1971. Sylvatic subtype Il (Everglades) has been isolated from people and mosquitoes in Florida; subtype Ill has been isolated in the Rocky Mountains and northern plains states. The general life cycle of alphavimses involves transmission between birds and/or rodents and mosquitoes. In North America, theoretically, EEEY is perpetuated in a sylvatic cycle between avian hosts (passerine birds) and mosquitoes, with primary transmission in this cycle via Culiseta melanura. Birds do not develop disease but develop sufficient virem.ia for transmission to mosquitoes unless the bird belongs to an introduced species that in North America includes European starlings, house sparrows, pheasants, ai1d emus. Field work in Alabama indicates that the northern cardinal is the primary target for C melanura feeding; however, other mosquitoes (C erraticus) are capable of feeding on a wider variety of birds, including robins, chickadees, owls, and mockingbirds. M=aliai1 reservoirs may also be important during years of high EEEY transmission. Experimental infection of cotton rats, a marshland rat found throughout the Americas, resulted in viremiajust being capable of transmitting EEEY, withjuvenile rats developing higher titers and l 00% mortality to infection. Horses and people are clinically affected but do not develop viremia sufficiently high enough to transmit vims to mosquitoes and so are considered "dead-end" hosts. However, young animals are more susceptible to EEEY, and it is not known how important non-neural tissues are for harboring high viral infection. Presumed extraneural sites of infection include cardiac tissue and bone marrow. During epizootics, alpacas, llamas, cattle, swine, cats, and dogs can develop disease. Snakes have been identified as a possible reservoir. Freshwater hardwood swamps are the most associated enzootic niche for EEEV. In the southern USA, which has the highest n un1ber of reported aimual cases, reeme1° gence within mammalian hosts is associ­ ated with "tree farms" that often function as inland freshwater swan1ps. Nonetheless, EEEY disease occurs frequently in naive

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horses in southeastern habitats not associated with sylvatic field ecology, so a full understanding of the epizootic cycle still remains to be elucidated. Intense focal activity has been reported in Michigan, Wisconsin, Ohio, Massachusetts, and New Hampshire. In 2005, Massachusetts experienced a hun1an case affected rate more than five times that of the preceding 10 yr; affected people resided within Y2 mile of a cranberry bog or swamp associated witl1 forest habitat. In Central and South America, the principal vectors of MADY belong to Culex (Melanoconion) spp. These vectors feed on birds, rodents, marsupials, and reptiles, with rodent reservoirs possibly featuring more impo1tantly in this life cycle. Before the yeai· 2000, comparatively few epizootics of disease caused by MADY in horses were recorded in South America, with minin1al disease repo1ted in people. Furthermore, there are notable differences in vimlence between EEEY strains in South America vs in North America. In 2008 and 2009, larger outbreaks occurred in Central and South America. In northeastern Brazil, 229 horses were affected, with a case fatality rate of 73"/o and disease severity sintilar to that of EEEY in North America. WEE is transmitted primarily by C tarsalis, which is found just west of the Mississippi river and throughout the West. This mosquito breeds in sunlit marshes and in pools of inigation water in pastures. WEE can also be transmitted by the tick De1macentor ande1·soni. Epizootics of WEE are associated with increased rainfall in early spring followed by warmer than norn1al temperatures. Sylvatic VEE viruses are found through­ out North, Central, and South America in jungle or swampy areas, Two cycles occur with VEEY, the enzootic cycle and the epizootic cycle. The mosquitoes that serve as the primaiy vectors for the bird- or rodent-mosquito life cycle are members of tl1e subgenusMelanoconion (C cedecci). Epizootics ai·e associated with a mutation to a subtype I (AB, C, and possibly E), a chai1ge in manl.lllalian pathogenesis, and a change to several bridge vectors. The enzootic cycle centers around sylvatic rodents such as spiny and cotton rats, which have high natural infection rates and can develop viremia high enough to trat1S1nit VEEY to mosquitoes. Opossums, bats, and shore birds likely contribute to dispersal of the enzootic virus so that constant cycling occurs. When epizootics occur with mutation of the virus and this change in mosquito vectors, equine infection becomes

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS

a predominant feature in the maintenance of epizootic VEE. All mammalian hosts are capable of developing a high-titer viremia of -106 plaque-fom1ing units/mL for up to 5 days, but the horse is likely to be the most important manunalian host in tem1s of vector capacity. Flaviviruses: ln general, viruses belonging to the Flaviviridae and Bunyaviri­ dae families are less pathogenic than the Togaviridae; however, viral encephalomyeli­ tis caused by any of these pathogens is a potentially catastrophic illness for any vertebrate host. There are 53 species of flavivirus, and many are clinical pathogens for horses, including Japanese encephalitis, West Nile virus (WNV) encephalitis, Kunjin virus (KUN), and Murray Valley encephalitis virus. Overall, the diseases caused by the Japanese encephalitis serogroup are similar (see TABLE 3). All of these viruses are transmitted by a mosquito vector, with Culex spp usually the most efficient transmitter. KUN is actually a strain of WNV and is found in Australia, some southeast Asia countries, and New Guinea. Disease in horses caused by Murray Valley fever is geographically restricted to the South Pacific and is sporadic in occurrence. WNV has the widest geographic distribution of all of the flaviviruses. Prior to 1999, WNV was recognized in Africa, the Middle East, Asia, and occasionally in European countries. ln 1999, WNV infection was first recognized in North America. Since then, the virus hq.5 spread throughout the USA and parts of Canada and Mexico. WNV isolated from the outbreak in New York in 1999 appears to be closely related to an isolate recovered from geese in Israel in 1998. Since 2010, continued worldwide spread and reemergence of many flaviviruses, especially WNV, has occurred. As of 2014, WNV is recognized as having seven lineages, with lineage 1 (sublineage la, lb, and le) and lineage 2 affecting people and horses. Lineage la activity in the USA and Europe dominated much of the end of the 1990s until the mid-2000s, causing neuroinvasive infections in people and horses in Africa, Europe, Australia, Asia, North and Central America, and the Middle East. In 2012, a very large epizootic occurred in the USA, with 5,674 human and 690 equine cases reported. New emergences have occurred in Greece and Serbia, and the first lineage la case in lndia was detected in 2012. Lineage lb viruses are primarily represented by KUN, with Australia undergoing the largest epizootic of arboviral disease in 2011,

involving 900 horses. Although multiple pathogens were detected, including KUN, Murray Valley encephalitis virus, and Ross River virus, there was emergence of a new strain of KUN. The le viruses are fairly nonpathogenic and found in lndia. (This sublineage may soon be designated as lineage 5.) Lineage 2 strains, long consid­ ered African based and inducing mild disease in horses, is also expanding globally with increased neuroinvasive activity. Neuroinvasive disease due to lineage 2 has emerged across Europe in Hungary, Austria, Italy, and Greece, which had at least four epizootic cycles with cases of neuroinvasive disease identified in horses. Both wetland and terrestrial birds may be involved in the natural cycle of WNV, with migratory birds thought to introduce the virus into a geographic region. However, a wide range of infected birds ( -326) have high, sustained viremia and little or no clinical disease (passe1ines). Fatal infections among corvids (eg, crows, blue jays, and magpies) have been the hallmark of WNV infection in the USA. Ticks have been demonstrated to be infected with WNV, but their role in natural transmission is unknown. Experimentally, transmission has been documented between cohabitating birds and from oral exposure to WNV in drinking water in birds. Oral transmission has been demonstrated experimentally in several types of raptors. ln people, other important routes of infection include blood transfusions, organ donation, breast milk, and across the placenta. Sporadic infections and illness have also occurred in several other manunalian species, including dogs, cats, can1elids, sheep, and squirrels. Oral transmission has been demonstrated experimentally in cats. Farmed alligators have demonstrated disease and mortality due to WNV, and there has also been a report of WNV-induced disease in croco­ diles. Alligators are susceptible to oral infection. ln addition to birds, only alligators have consistently demonstrated high enough viremia (104-105 plaque-fanning units) to amplify virus, serve as reservoir hosts, and transmit virus back to mosqui­ toes. Most equine-associated flaviviruses are maintained in an enzootic transmission cycle between wild birds and mosquitoes, although tickbome encephalitis found in Eurasia can cause disease in horses. Many species of mosquitoes can transmit the equine virulent viruses, although Culex spp are principal vectors to maintain enzootic activity. C pipiens complex and C tarsalis

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS are thought to play the largest role in natural transmission in North America. In the eastern and Midwestern regions of the USA, C pipiens is one of the major vectors, whereas in the western regions of the USA, C tarsalis is thought to be one of the most efficient vectors. Bunyaviruses: Cache Valley virus (transmitted by mosquitoes and Culicoides sp an10ng rabbits), Main Drain virus (transmitted by Culicoides vaiipennis an10ng hares and rodents in the western USA), and snowshoe hare virus (transmit­ ted by Culiseta and Aedes mosquitoes among rabbits in southern Canada and northern USA) have all been identified, although infrequently, as the cause of encephalitis in horses.

Clinical Findings of Viral Encephalo­ myelitis in Equids: The initial clinical

signs are similar for the arboviruses; progression of clinical signs and severity of disease are the differentiating features. Initially, horses are quiet and depressed, with clinical neu.rologic signs generally occurring 9-11 days after infection. Compared with WEE and WNV disease, clinical signs of EEEV (and VEEV) encephalomyelitis more frequently include altered mentation, in1paired vision, ain1less wandering, head pressing, circling, inability to swallow, irregular ataxic gait, paresis and paralysis, seizures, and death. Spinal signs are often symmetric with ataxia in all limbs, rapidly progressing to quadriparesis, along with intensification of forebrain signs. Many horses progress to recumbence within 12-18 hr of onset of neu.rologic abnorn1ali­ ties. Most deaths occur within 2-3 days after the onset of signs. The clinical signs and course of disease are highly variable in WNV disease and other flavivirus encephalomyelitis. Presenting complaints most often include neu.rologic abnormalities; otl1er conunon initial complaints include colic, lameness, anorexia, and fever. Initial systemic signs include a mild fever, feed refusal, and depression. Neurologic signs are highly variable, but spinal cord disease and moderate mental aberrations are most consistent. Spinal cord disease manifests as asynunetric, multifocal or diffuse ataxia and paresis. Severe manifestations of WNV may occur independently in the fore- or hindlirnbs, unilaterally, or in a single limb. In all clinical studies published to date, for WNV, >90"A, of affected horses developed some type of spinal cord signs, whereas 40"h-60"A, developed behavioral changes

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characterized by periods of hyperesthesia, ranging from mild apprehension to overt hyperexcitability, wiili fractious reactions to aural, visual, and tactile stimuli. Fine and coarse tremors of the face and neck muscles are common, described in 600/o-90% of horses. Some horses have periods of cata­ plexy or narcolepsy that may render them temporarily or permanently recwnbent. Cranial nerve deficits can be seen in all arbovirus infections of horses; these include most cranial nerves with cell bodies located in ilie mid- and hindbrains. Weakness and/or paralysis of the face and tongue are most frequent. Horses with facial and tongue paresis can be dysphagic, and overt signs of quidding or even esophageal choke can develop. Many horses with severe mental depression and facial paresis will keep their heads low, resulting in severe facial edema. Occasionally, head tilt may be seen. Infrequently in WNV disease, urinary dysfunction ranging from mild straining to stranguria has been reported, making differentiation from equine herpesvirus 1 (EHV-1) more challenging. During ilie neurologic phase, horses frequently thrash and injure themselves. Sepsis from traw1ia in recwnbent horses also occurs. Prolonged recumbency leads to pulmonary infections, especially in foals, in which a long du.ration of slinging and treatment may be pursued more frequently than in large, recwnbent animals. Dyspha­ gia leads to decreased water and food intake, with renal daniage due to concurrent use of anti-inflan1matory drngs. Skin and muscle .necrosis are common in recwnhe.nt horses. Life-threatening trauma can also occur, including a ruptured diaphragm and fractures. Lesions: All necropsies on horses suspected of viral encephalitis should be perfonned with all participants wearing personal protective gear (ie, waterproof gown, boots, gloves, N-95 or N-99 mask, face shield, and hair covering). Gross lesions are most common with EEEV and severe VEEV disease and are characterized by widespread and prominent congestion of the meninges. In oilier infections, gross lesions are rarer and are limited to small multifocal areas of discoloration and hem­ orrhage throughout the brain and spinal cord. The brain should be examined microscopically for the presence of me.ningoencephalitis. In EEEV infection, a severe gliosis with necrosis of ilie .neuropil is seen in ilie cerebrwn and extending through the corona radiata through the hindbrain and cervical spinal cord.

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS

Although mononuclear cells are present, neutrophils a.re widespread and diffusely distributed. The gliosis is less nodular than in WNV, and when there are accumulations of cells, there is extensive necrosis and often frank microscopic hemorrhage within and around lesions. In milder cases and in WNV infections, microscopically there is a non-necrotizing lyrnphohistiocytic poliomeningoencephalitis. Slight to severe inflammation, characterized by perivascular cuffing of lymphocytes and monocytes, is usually present. In more severe cases, there can be extravasation of fluid and red blood cells from vessels. Often the distribution of lesions is rnultifocal, with more severe lesions present in grey matter. In the neuropil, dying neurons often are sur­ rounded by microglial cells. The most severe gliosis and perivascula.r cuffing is often in the midbrain (thalamus, hypothala­ mus) and hindbrain (pons and medulla), extending into the cerebellum. Lesions can be multi.focal in the spinal cord and can be more severe in the lumbar cord. Diagnosis: No consistent changes in clinical pathology have been found in equine viral encephalitis. With EEEV and WNV in horses, peripheral lymphopenia is common. Horses are frequently azotemic, likely from decreased food and water intake. In general, no pathognomonic signs distinguish flavivirus infection in horses from other CNS diseases, and a full diag­ nostic evaluatio11 should be performed. Confirmation of flavivirus infection with encephalitis in horses begins with assessment of 1) whether the horse meets the case definition based on clinical signs; (2) whether the horse resides in an area in which flavivirus has been confirmed in the cun-ent calendar year in mosquitoes, birds, people, or horses; and (3) lack of appropri­ ate vaccination. In terms of antemortem diagnostic testing, analysis of CSF can be a valuable acljunct to presun1ptive clinical assessment. CSF analyzed from horses with acute EEEV infection typically shows a neutrophilic pleocytosis with markedly increased total solids. Horses infected with EEEV that are partially itm11une may have predominantly mononuclear cells, but nondegenerate neutrophils are still present. Altl10ugh WNV-infected horses can have normal CSF, if the CSF is abnormal, there is a mononu­ clear pleocytosis with moderately to markedly increased total solids. In a few horses with acute infections, vi.Jus may be isolated from tl1e CSF. By the titne

neurologic signs are seen, viremia has ended and detection of vitus in the plasma of clinically affected horses is of no value. Serology is the key to antemortem diagnosis of recent alphavirus and flavivirus infection in horses showing clinical signs. lgM antibody rises sharply and is increased in 85%--90% of horses with clinical a.rboviral encephalitis. Thus, the lgM capture ELISA is the test of choice to detect recent exposure to these viruses. Neutralizing antibody titers (primarily IgG) develop slowly during this titne and stay increased for several months. Although neutralizing antibody tests will differentiate between subtypes of these viruses, and are thus considered the gold standard for confuma­ tory serology, paired serum samples are essential to detect recent exposure and to differentiate antibody response due to field infection from vaccine responses for any of these viruses. Because virus-neutralizing antibodies appear at tl1e end of viremia and may precede appearance of neurologic signs, paired samples may not show a 4-fold increase in horses while demonstrating neurologic signs. In horses that succun1b witl10ut premortem and postmottem testing, paired san1ples from febrile herdmates may be necessary to confirm presence of arbovirus activity within a locale. Maternal antibodies may interfere with neutralizing responses in young foals. This response is confounded by recent vaccination. The most common neutraliz­ ing antibody test formats are the classic plaque reduction neutralization test (PRNT) and a rnicrowell format test. Practical application of the microwell vs the PRNT indicates that the endpoint titer ill the rnicrowell test can be several logs higher than ill the PRNT, so results cannot be compared between samples. Several postmortem diagnostic assays are available and, al\;hough specific, they vary in sensitivity, dependmg on the vims. The midbrain and brain stern have the highest concentrations of encephalitic viruses, including rabies virus. In1munohis­ tochemistry and PCR testing for EEEV and EHV-1 are relatively straightforward compared with that for WNV. Diagnostic testillg continues to confirm the tmreliabil­ ity of detection of virus, even by PCR, because of the low viral load ill WNV mfection. Often, only a single neuron in one or two sections may yield positive virus staining ill the horse by in1munohistochern­ istry. When tested by PCR, the limited viral load dictates accurate testing of approptiate tissues consistillg of several locations, includmg thalan1us, hypothalamus, rostral

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS

colliculus, pons, medulla, and anatomically identified spinal cord. Viral isolation is still important for molecular epidemiology. Infectious and noninfectious causes of brain and spinal cord diseases should be considered as differential diagnoses. Infectious causes include alphaviruses, rabies, equine protozoal myeloencephalitis (seep 1309), and EHV-1; less likely causes are botulism and verminous meningoencephalo­ myelitis ( eg, Halicephalobus gingivalis, Setaria spp, Strongylus vul.garis). Noninfectious causes include hypocalcemia, tremorigenic toxicities, hepatoencephalopa ­ thy, and leukoencephalomalacia. Treatment: Treatment of viral encephali­

tis is supportive, because there are no specific antiviral therapies. Management is focused on controlling pain and inflanuna­ tion, preventing injuries associated with ataxia or recumbency, and providing supportive care. Intervention does not appear to significantly affect the outcome of most fulminate EEEV infections. For WNV, flunixin meglumine (1.1 mg/kg, IV, bid) early in the course of the disease decreases the severity of muscle tremors and fascicula­ tions within a few hours of administration. Recumbent horses that are mentally alert frequently thrash, causing self-inflicted wounds and posing a risk to personnel. Responses to tranquilizers and anticonvul­ sant medications are variable, depending on the virus and severity of disease. A sling and hoist may be used to assist horses that are recumbent and have difficulty rising; however, recumbent horses with EEEV generally are too comatose to sling. Dysphagic horses require fluid and nutritional support. Until equine protozoal myeloencephalitis is excluded, prophylactic antiprotozoal medications may be instituted. Other supportive measures ( eg, oral and parental fluids and nutrition for dehydrated and dysphagic horses) are also important. Broad-spectrum antibiotics should be given for treatment of wounds, cellulitis, and pneumonia. Horses with intermittent or focal neuropathies have a better prognosis than those with complete flaccid paralysis or that appear comatose. Efficacy of specific antiviral agents for treatment of naturally occurring WNV or EEEV infection is unknown, even in people. Recent work with passive immunotherapy indicates possible benefit after the onset of clinical signs in WNV models. Prognosis: Mortality of horses showing clinical signs from EEEV is 50%--900/o, from

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WEEV 200/o--500/o, from VEEV 500/o--75%, and from flavivirus infections 35%45%. Horses with clinical neurologic signs from alphavirus infection that recover have a high incidence of residual neurologic deficits, whereas many horses that recover from WNV disease have been reported to have no residual neurologic deficits. In EEEV infection, death is frequently spontaneous. With WNV disease, horses are euthanized for humane reasons, but spontaneous death does occur. In EEEV, most surviving horses exhibit longterm nemologic signs. In WNV disease, overt clinical signs in horses that recover can last from 1 day to several weeks; improvement usually occurs within 7 days of onset of clinical signs. Although 800/o--900/o of owners report that the horse returns to no1mal function 1-6 mo after disease, at least 10% of owners report longterm deficits that limit athletic potential and resale value. Deficits include residual weakness or ataxia in one or more limbs, fatigue with exercise, focal or generalized muscle atrophy, and changes in personality and behavioral aberrations. Prevention: Vaccination against alphaviruses and flaviviruses as core annual vaccines are considered the standard of care for all horses in the USA as endorsed by the American Association of Equine Practitioners. Formalin-inactivated whole viral vaccines for EEEV, WEEV, and VEEV are commercially available in bi- and trivalent forms, usually formulated with tetanus toxoid; several now include WNV. Nonvaccinated adult horses require the label priming two injections. For adult horses in temperate clin1ates, an annual vaccine within 1 mo before the start of the arbovirus season is recommended. However, for horses that travel between northern and southern areas affected by the virus, injections should be given two or even three times yearly in active arbovirus seasons. Mares should be vaccinated 1 mo before foaling to induce colostral antibody. If a pregnant mare is naive, the full priming series starting 2 mo before foaling is reconunended. However, some mares do not produce colostral antibody if vaccinated for the first time during gestation. In foals that have received adequate colostrum from vaccinated dan1s, vaccination should begin at 5-6 mo of age; foals should receive two additional vaccinations at 30 and 90 days after the first one. It is unclear whether maternal antibody interferes with vaccine responses in foals; however, epidemiologic evidence strongly indicates that horses between 4 mo

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EQUINE ARBOVIRAL ENCEPHALOMYELITIS

and 4 yr old are highly susceptible to EEEV. If there is early spring (March) activity in the southeastern USA, horses may require three injections throughout the year, especially in horses 200 recognized serovars. Leptospira serovars Grippotyphosa, Pomona, Canicola, and lcterohaemorrhagiae usually cause abortions in the last trimester, 2-6 wk after maternal infection. Serovar Hardjo is host adapted to cattle and can establish lifelong infections in the kidneys and reproductive tracts. In addition to third trin1ester abortions, serovar Ha.rdjo reduces conception rates in carrier cows and cows bred to carrier bulls. Although dams may show clinical signs of leptospirosis, most abortions are in other­ wise healthy cattle. Abortion rates vary from 5o/-400/oor more. The leptospires cause a diffuse placentitis with avascular, light tan cotyledons and edematous, yellowish intercotyledona.ry areas. The fetus usually dies 1-2 days before expulsion and therefore is autolyzed. Occasionally, calves are born a.Jive but weak. Fetuses infected with serovar Pomona may show icterus. There are no specific lesions, but placenta and fetus should be submitted to the laboratory for fluorescent antibody staining or PCR testing for Leptospira.

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ABORTION IN LARGE ANIMALS Although maternal titers are probably waning by the time of abortion, an initial titer of> 1:800 may be suspicious. Approxi­ mately one-third of cows aborting because of serovar Hardjo have titers of 89.6°F]) is associated with increased returns to estrus, increased embryonic mortality, decreased farrowing rates, and small litters. The effect is greatest if heat stress occurs at the time of breeding or implantation. Increased embryonic mortality and increased irregular return to estrus are seen in pigs bred during the summer. High ambient temperature may play a role, but there is evidence tl1at seasonal low progesterone levels are a major factor. The estrogenic mycotoxins zearalenone and zearalenol interfere with conception

1341

and implantation, causing infertility, embryonic death, and reduced litter size, but rarely, if ever, abortion. Another class of mycotoxins, the fumonisins, causes acute pulmonary edema in swine; sows tl1at recover from the acute disease often abort 2-3 days later. Other toxic causes of abortions or stillborn pigs include cresol sprays (used for mange and louse control), dicumarol, and nitrates. Nutritional causes of reproductive failure are not well defined. Vitamin A deficiency can cause congenital anomalies and possibly abo1tions. Riboflavin deficiency can cause early premature bitths (14-16 days), and calcium, iron, manganese, and iodine deficiencies have been associ­ ated with stillbirths and weak pigs. Carbon monoxide toxicity due to faulty propane heaters has been associated with increased numbers of stillbirths and autolyzed full-term fetuses. Fetal tissues are cherry red; the sows do not appear affected.

Infectious Causes The major infectious causes of reproductive failure in pigs include porcine reproductive and respiratory syndrome virus, porcine parvovitus, pseudorabies virus, Japanese B encephalitis virus, classical swine fever virus, Leptospira spp, and Brucella suis.

Porcine Reproductive and Respira­ tory Syndrome (PRRS): PRRS is caused

by an arterivirus. It is of major importance in the USA and tl1roughout most of the world. Most PRRS strains do not cross the placenta until after 90 days of gestation. Consequently, most abortions are near the end of gestation. Affected litters contain fresh and autolyzed dead pigs, weak infected pigs, and healthy, uninfected pigs that often develop respiratory disease within a few days of birth. The sows are often anorectic and feverish a few days before aborting. Concurrent respiratory disease and increased munbers of bacterial infections in the herd are common. Hemorrhage in the umbilical cord, when present, is the only gross lesion associated with PRRS abortions. Not all fetuses are infected, so multiple fetuses should be sampled. Viral antigen is most consistently present in the fetal thynms and in fluid collected from the fetal thoracic cavity. PCR testing of pooled thoracic fluid from three to five fetuses is the most reliable means of diagnosis. Herd management is important in control and prevention. Inactivated and modified-live virus vaccines are available. (See also p 729.)

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ABORTION IN LARGE ANIMALS

Porcine Parvovirus: Porcine parvovirus is ubiquitous in pigs in the USA and most of the world. Almost all females are naturally infected before their second pregnancy, and immunity is lifelong. Consequently, it is a disease of first-parity pigs. Gilts that are immunologically naive or have high passive antibody titers have the high.est risk of reproductive disorders caused by the vims. Wection before day 30 of pregnancy results in early emb1yonic loss. Fetal infection between 30 and 70 days of gestation can result in death of the fetus and sometimes mwnmification. Not all fetuses are infected at the same time, and death at different stages of pregnancy is typical. Some fetuses survive and are born alive but persistently infected. Most fetuses infected after 70 days of gestation mount an immune response, clear the virus, and are healtl1y at birth. Litters with dead fetuses of varying sizes, including mwnmified fetuses, along with stillborn and healthy pigs born to first-parity gilts, are the hallmark of porcine parvovirus. Diagnosis is by fluorescent antibody testing, virus isolation using lung from mwnmified fetuses, or demonstration of precolostral antibody in stillborn pigs. Boars shed virus by varying routes, including semen, for a couple of weeks after acute infection and can introduce the virus into a herd. Effective inactivated vaccines are available. Pseudorabies (Aujeszky Disease, Porcine Herpesvirus 1 Infection):

Pseudorabies is a: cause of CNS and respiratory diseases. Wection results in latency, and seropositive animals are considered infected. Wection early in pregnancy can result in.embryonic death and resorption of the fetuses. Wection later in pregnancy can result il1 abortion and birth of stillborn and weak pigs. Mununifica­ tion can occm but is uncommon. There are no gross lesions in most aborted pigs, but a few have pinpoint white foci of necrosis in the liver and tonsils. Diagnosis is by virus isolation, PCR, or fluorescent antibody staining. Effective gene-deleted vaccines that allow serologic differentiation of vaccinated and natW'ally infected pigs were developed for the eradication program in the USA, but after eradication from commercial pigs was completed in 2003, vaccination was discontinued. Feral pigs in multiple states harbor the virus, and since 2003 there have been sporadic outbreaks of pseudorabies in herds that have contact with feral pigs. These outbreaks are cmrently controlled by herd depopulation. (See also p 1300.)

Japanese B Encephalitis Virus Infection: Japanese B encephalitis is

an arthropod-borne disease that causes reproductive failme in pigs and encephalitis in people. The disease is reported p1imarily in southeast Asia, Indian subcontinent, Indonesia, and Australasian regions. Wected litters can contain dead pigs of vari­ ous sizes (including mw11.mies), stillborn pigs, weak pigs, and pigs with CNS signs. Hydrocephalus and subcutaneous edema are the most common gross lesions. Diagnosis is confim1ed by viral isolation and immunohistochemistry. Viral nucleic acid can be detected il1 tissue and blood samples using RT-PCR or nested RT-PCR. Pigs are the primary amplifyil1g host for the virus and are vaccinated not only to prevent reproductive failme but also to prevent hwnan infection. Classical Swine Fever (Hog Cholera):

Classical swine fever is caused by a pesti­ vilus eradicated from the USA but still a serious problem throughout much of the world. With highly vil1.tlent strains that cause se1ious maternal illness, ab01tion is common. Witl1 strains of moderate or low virulence, bilth of mummified and stillborn pigs, weak pigs, and persistently infected pigs are more common. Fluorescent antibody staining, vims isolation, and PCR are used for diagnosis. Both killed and modi­ fied-live vaccines are available, but their use in the USA is prohibited. (See also p 713.) Porcine Circovirus Infection: Porcine circovirus type 2 (PCV2) is found world­ wide, is ubiquitous in pigs, and is associated with several conditions, including sporadic outbreaks of late-term ab01tions and tenn litters with increased numbers of dead piglets. The dead piglets vaiy from small, mwnmified fetuses to stillbirths. Nonmwn­ mified fetuses typically have a large amount of serosanguineous fluid in their body cavities. Microscopically, there is myocar­ dial necrosis and/or fibrosis, and PCV2 is present in the heart and otl1er tissues. The incidence of PCV2 reproductive failme is very low; when it occurs the problem soon disappears, perhaps because most pigs are naturally exposed and immune before being bred. Diagnosis is based on presence of PCV2 DNA or antigen in precolostral serun1 san1ples from live born piglets. Inununohis­ tochemistJ.y and m situ hybridization are considered tl1e gold standard to detect the agent. Vaccines are available for grower and finisher pigs, but their efficacy in preventing reproductive failme is unlmown.

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ABORTION IN LARGE ANIMALS

Leptospirosis: Leptospira interrngans (especially serovar Pomona) is a major cause of reproductive failure in swine (infertility, abortion, stillbirths, and the birth of weak piglets). Although acute leptospiro­ sis occurs in adult swine, most cases are asymptomatic. Pigs infected with serovars Pomona and Bratislava can become chronic renal carriers. Abortion occurs 1--4 wk after infection, so the abortuses are autolyzed. Mummification, maceration, stillbirths, and weak pigs are also seen. Diagnosis is based on demonstration of leptospires in fetal tissues or stomach contents. However, severely autolyzed fetuses may result in poor fluorescent antibody and inununohis­ tochemistry results. PCR testing has better sensitivity and specificity. Vaccination with a multivalent bacterin every 6 mo helps prevent the disease. Streptomycin was formerly used to elinlinate the carrier state and to treat pregnant sows during an out­ break, but it is no longer available for use in food animals. Experimentally, high levels of injectable oxytetracycline, tylosin, and erythromycin and high levels of tetracy­ clines in the feed have elintinated the carrier state. However, field results indicate that Leptospira infection cannot be reliably elintinated with antibiotics. Leptospirosis is zoonotic. (See also p 646.) Brucellosis: Brucella suis infection in commercial swine has become rare in the USA as a result of state and federal control programs. However, it is present in feral pigs in multiple states; these represent a source of infection for conunercial pigs and people. The route of infection is oral in most cases, but venereal transmission is not uncommon. Infected sows can abort at any stage of gestation, and abmtions are not always accompanied by illness. Abortion is probably due to endometritis and fetal infection.There are few fetal or placental lesions, although some fetuses may be autolyzed. Diagnosis is by serology and isolation from the placenta and fetal tissues. No treatment has been uniformly effective. Control is based on test and slaughter. Brucellosis is one of the few venereal diseases recognized in swine. B suis causes a serious zoonotic disease. (See also p 1348.) Other Infectious Causes of Abortion:

Pigs with foot-and-mouth disease (see p 629), African swine fever (seep 711), and swine influenza (seep 1470) often abort, but they and their herdrnates also have clinical signs of those diseases. Enteroviruses and encephalomyocarditis virus have been

1343

reported to cause fetal losses in pigs, but they are not considered economically important. Blue eye paramyxovirus is an important cause of abortion, stillbirths, and mummified fetuses in parts of Mexico. Bacteria that cause sporadic abortions include Staphylococcus aureus, Streptococ­ cus spp, Erysipelothrix rhusiopathiae, Salmonella spp, Pasteurella multocida, T1ueperella (Arcanobacterium) pyogenes, Listeria monocytogenes, and Eschm·ichia coli.

ABORTION IN HORSES See also MANAGEMENT OF REPRODUCTION: HORSES, p 2187.

Noninfectious Causes

The most common noninfectious cause of abortion in horses is twinning. Most abo1tions related to twinning occur at 8-9 mo of gestation and may be preceded by premature lactation. Placental insufficiency ultimately causes abortion of twins. Umbilical cord abnormalities, such as torsion due to abnormal length (>100 cm), are conunonly diagnosed as a noninfectious cause of abortion, particularly in Thorough­ breds. Diagnosis of abortion due to cord torsion requires evidence of localized swelling or hemorrhage, because torsions occur in some normal births. Signs of fetal circulatory disturbances, such as subcuta­ neous edema, a swollen, soft liver, and microscopic mineralization of pl;i,centaJ vessels, are also signs of un1bilical cord obstruction.Various congenital fetal abnormalities have been reported in cases of noninfectious abortions.

Mare Reproductive Loss Syndrome:

In spring of 2001, horse farms in Kentucky and neighboring states experienced an explosive outbreak of early abortions and late-term abortions, stillbirths, and weak foals that died within a few days. Sinmlta.ne­ ously there was a large increase in fibrinous pericarditis and unilateral uveitis in horses of all ages and both sexes. Together these conditions became known as mare reproductive loss syndrome (MRLS). Analysis of records showed that MRLS had occurred in the area in earlier years. MRLS has since been diagnosed in other states, including New York ar1d F1orida An abortion storm with sinillar clinical signs and risk factors was recently reported from AusLralia. Most early abortions occur at 40---80 days of gestation, with some losses occurring as late as 140 days. A few affected mares have colic, fever; ancVor purulent vulvar

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ABORTION IN LARGE ANIMALS

discharge, but most remain clinically nonnal. Typically, the first sign is abortion or fincling a fetus dead in utero by ultrasound. Most fetuses are expelled within 2 days to 2 wk of dying and are autolytic. Neutrophilic placentitis and metritis are usually present. Most mares rebred during the same breecling season do not become pregnant, but conception is usually n01mal during the next breecling season. Late-term losses generally occur at 10 mo of gestation to term, and the mare usually does not display signs of impending parturition. Pathologic features of MRLS include the presence of amnionitis and funisitis, with only the amniotic portion of the umbilical cord affected. The placenta and umbilical cord are thickened, edema­ tous, and discolored light brown to yellow. Neutrophilic inflammation of the umbilical cord and placenta are usually present, with the neutrophilic funisitis being characteristic of the syndrome. A variety of bacteria can be isolated from the fetuses, regardless of when they abort, but are not considered causative. Pasture exposure to eastern tent caterpillars (Malacosoma americanum) is an in1portant risk factor, and both early and late-te1m abortions have been reproduced by oral administration of whole caterpillars or their exoskeletons but not their digestive tract. The mechanism causing abortion has not been confmned. It has been proposed that an unidentified toxin associated with the exoskeleton of these caterpillars is involved, and that bacte1ial infections are secondary. Alternatively, caterpillar hairs (setae) may penetrate the oral or intestinal mucosa and carry bacteria, resulting in bacteremia with localization in the uterns and other organs. (The horses in the Australian outbreak were exposed to processionary caterpillers [ Ochragasf,er lunifer]).

Prevention consists of pasture manage­ ment to control the numbers of eastern tent caterpillars and other procedures to prevent exposure of pregnant mares to eastern tent caterpillars. Fescue Grass Toxicosis: Ingestion of fescue infected by the endophyte Neotypho­ dium coenophialum causes prolonged gestation, agalactia, edema and premature separation of the placenta, and perinatal death. Abortion may occur in the last 2 mo of pregnancy due to severe edema and premature placental separation. The placenta is thickened and edematous and does not rnpturc nonnally at the cervical star. The chorioallantois precedes the foal through the birth canal instead of remaining attached to the uterus (red bag), resulting in anoxia and death of the fetus. The source of

the infected fescue can be pasture, hay, or bedding. (See also p 3016.) Infectious Causes

Infectious causes of abortion include viral diseases (such as equine rhinopneumonitis and equine viral arteritis) as well as bacterial and fungal infections. Equine Rhinopneumonitis (Equine Herpesvirus 1 Infection): Equine

rhinopneumonitis, specifically equine herpesvirus 1 (EHV-1) infection, is the most important viral cause of abortion in horses, although EHV-4 has also been isolated from some cases. The principal mode of transmission of the virus from horse to horse is by direct cont.act through nasal secretions, reproductive tract discharge, placenta, or the abo1ted fetus. Shor t -dis­ tance airborne spread of infection is possible. Abortion is usually after 7 mo of gestation and is not preceded by maternal illness. The placenta may be edematous or n01mal. Gross fetal lesions include subcutaneous edema, jaundice, increased volume of thoracic fluid, and an enlarged liver with yellow-white lesions -1 mm in dian1eter. Histologically, these lesions represent areas of necrosis containing intranuclear inclusions. Inclusion bodies are also found in necrotic lymphoid tissues. There is often a necrotizing bronchiolitis. Diagnosis is by fluorescent antibody, PCR, or virus isolation from fetal tissues. Prevention is based on vaccinating at 5, 7, and 9 mo of gestation as well as preventing exposure of pregnant mares to horses attencling shows or other equine events. Abortion may occur despite regular vaccination. (See also p 1444.) Equine Viral Arteritis (EVA): Abortion may follow clinical cases of EVA by 6---29 days. Abortion rates can approach 6QOA, in a naive population as the result of direct impaiiment of placental ftmction and severe fetal infection. Arteritis may be found in the fetal myocardium or placenta, but usually there are no fetal lesions. StaJlions can be persistently infected, and EVA can spread venereally (via natural cover or insemina­ tion with shipped cooled or frozen semen) or by aerosol. Diagnosis is by a history of EVA shortly before abortion, virns isolation or PCR of placenta and/or fetal tissues, or by seroconversion of the dam. Prevention of EVA is by management to minimize viral transmission in breeding populations and to prevent development of car1ier staJlions. In the USA, a licensed modified-live virns vaccine is available for use in nonpregnant

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ABORTION IN LARGE ANIMALS

mares. Antibody titers resulting from vaccination and natural infection cannot be clifferentiatecl, and the serologic status of horses can affect their in1port status. Therefore, the serologic status of breeding horses should be determined before vaccination, and all subsequent vaccina­ tions should be recorded. (See also p 701.)

Bacterial Abortion: Bacte1ial placentitis is by far the most conunonly diagnosed cause of ab01tion in many horse breeding areas. PlacenLitis is a significant cause of equine late-term abortion, premature deli.very, and neonatal death. Except for Leptospira spp and nocardioforn1 infections, most cases of bacterial placentitis are ascending. Ascending placentitis is character.izecl by premature udder development, increased uteroplacental thickness at the level of the cervical star, and mucopurulent vaginal discharge. If placentitis is untreated, placental function is comprorn.isecl and placental separation ensues, resulting in fetal death and expulsion. In chronic placentitis, the fetus may show intraute1ine growth retardation. Streptococcus equi subsp zooepidemicus, Escherichia coli,

Pseudomonas aeiuginosa, Enlembactei· spp, and K/,ebsiella pneumoniae are the

most frequent isolates from the vaginal discharge, uterus, placenta, and fetal stomach contents. Other bacteria have also been rep01ted to cause ascending placentitis in mares, including Streptococcus equisimi­ lis, Entei-obactei· agglomerans, a-hemolytic streptococci, Staphylococcus aureus, and Actinobacillus spp. Exanlination of the placenta shows an edematous and thicken.eel ch01ioallantois with fibrinonecrotic exudate at the level of the cervical star. Leptospira spp placentitis is character­ ized by diffuse lesions secondary to hematogenous spread. Leptospiral

Ascending placentitis in a mare. Note the congested and thick cervical star area. Courtesy of Dr. Ahmed Tibary.

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placentitis as a cause of abortion seems to be on the rise in Kentucky, Northern Ireland, En.gland, and South America. Several serovars of Leptospira inteirogans have been isolated from aborted equine fetuses (eg, Pomona, Grippotyphosa, Bratislava, Pomona type kennewicki, and Hardjo type hardjo-prajitno). In North America, the most conunon isolate is serovar Pomona type kennewick.i, which is carried by several wilcllife species, including the striped skunk, raccoon, whitetail deer, and opossum. Most leptospiral abortions occur between 6 and 9 mo of gestation. The placenta is thick, heavy, edematous, hemoIThagic, and occasionally covered with a brown mucoid mate1ial on the chorion.le surface. Funisitis has also been described in leptospiral abortion. The fetus may have mild to moderate icterus and liver enlargement, and fetal histopathologic lesions may include various degrees of nephritis and hepatitis. Diagnosis is by fluorescent antibody staining of placenta or fetal kidney, liver, or lung and by fetal serology. (See also p 652.) Nocardiofonn placentitis is a distinct type of equine placentitis first described in the USA in the late 1980s. Nocardioforn1 placentitis may result in abortion, stillbirth, or birth of weak foals at tenn. Some mares may exhibit prematlffe mammary gland development and lactation before abortion. Infection of the placenta is generally thought to be a sequela of hematogenous spread of microorganisms from a primary port of entry. The lesion is an extensive and· severe exudative, mucopurulent, and necrotizing placentitis, frequently located at the base of the uterine horns or at the junction between the body and horns of the placenta. The affected area is thickened, and its cho1ion.ic surface is covered with brown, necrotic, mucopurulent exudate and dotted with white or yellow granular structures. Underneath this mucoid material, the chorionic surface is reddish white, mottled, and roughened. Villous necrosis and adenomatous hyperplasia of the allantoic epithelium, and hyperplasia with or without squamous metaplasia of the chorionic epithelium are frequently seen. Various groups of gram-positive, filan1en­ tous, branching bacteria have been implicated as etiologic agents in mares with nocardioform placentitis, including Nocardia spp, Rhodococcits iubroperl'inc­ tus, Amycolatopsis spp, and Cmssiella equi. The fetus is often severely underdevel­ oped as a result of placental insufficiency and does not show any remarkable gross or histologic lesions.

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ABORTION IN LARGE ANIMALS

Potomac horse fever (seep 283), caused by Ehrlichia risticii, may be followed by abortion in mid- to late gestation. There is placentitis, and the placenta is often retained. E risticii has been isolated from fetal lymphoid tissues after abortion. Histologically, there is fetal colitis. Identifica­ tion of this colitis provides a preswnptive diagnosis. There is a vaccine for Potomac horse fever, but its efficacy in preventing abortion is not known. Equine Mycotic Placentitis: Mycotic placentitis in horses is also due to an ascending infection that causes placentitis with a thickened chorioallantois with vruiable exudate. Causative agents include Aspergillus spp, Mucor spp, Candida spp,

Histoplasma capsulatum, Coccidoides spp, and CriJptococcus neofonnans.

Fetuses abmted in late gestation may be fresh, with evidence of growth retardation. A pale, enlarged liver or dermatitis may be found. Hyphae are found in the placenta, liver, lungs, or stomach contents. ABORTION IN CAMELIDS

Pregnancy loss is a common complaint in crunelid practice. The general approach to diagnosis is similar to that in other species. However, crunelids have several unique features of placentation and pregnancy. In neru·ly all pregnancies, the fetal horn is the left uterine horn, and the placenta is epitheliochorial, microcotyledonary diffuse (such as in the horse), but·the allantocho­ rion adheres to the runniotic sac. Noninfectious Causes

Noninfectious causes of abortiort include fetal or placental abnormalities (twinning, wnbilical cord torsion, severe deformities, chromosomal abnormalities and placental insufficiency, uterine torsion), luteal insufficiency (hypoluteidism), environmen­ tal stressors (severe disease process; long, stressful trip; heat stress), or iatrogenic causes (administration of prostaglandin F2a, corticosteroids, 8-way vaccines). Recurrent loss due to luteal insufficiency has been associated with obesity and possibly hypothyroidism. Presence of large avillous areas suggest placental insuffi­ ciency. Twin conceptions are not rru·e, and most are reduced to singleton or lost by day 45. Abortion of twins is generally seen between 5 ru1d 9 mo of pregnancy. On a herd basis, severe losses may be seen with nutritional deficiencies (seleniwn, vitamin A, iodine), or toxicosis (copper,

iodine). Lactating and very young maiden females may have an increased incidence of embryo and fetal losses. Infectious Causes Viruses: Viral causes of abortion are

dominated by bovine viral diruThea virus (BVDV). However, abortions due to equine herpesvirus 1, equine ruteritis virus, and bluetongue virus have been reported. The most common BVDV serotype that affects alpacas and llan1as is noncytopathic BVDV-lb. Abortion may occur at any stage of gestation, or a weak, persistently infected (PI) cria may be born prematurely. The birth of a PI anin1al can have significant effects on a herd of anin1als. Diagnosis of BVDV infection is based on virus isolation from fetal blood, fetal tissues (lymph nodes), ru1d placenta. Immunohistochemistry may be performed on forn1alin-fixed tissues. PCR on whole blood san1ples is commonly used to screen newborn crias. Bacteria: The most commonly diagnosed infectious causes of pregnancy losses ru·e chlru11ydiosis and brucellosis (in some parts of tl1e world). Chlamydia spp have been identified as a cause of abortion and birth of weak crias in llrunas. C abortus has been associated with infertility and ovarian hydrobursitis in can1els. Brucellosis (Brucella abortus and B melitensis) is a common cause of abortion in crunelids in some areas of the world. Other reported bacterial causes of abortion in crunelids include leptospirosis (Le'J)tospira interrogans serogroups Icterohaemorrhagiae and Ballwn), listeriosis (Listeria monocytogenes), and can1pylobacteriosis (Campylobactmfetus fetus). Coxiellosis (Coxiella burnetii) abortion is suspected to occur but has not been diagnosed definitively. Nonspecific bacterial infections (Escheri­

chia coli, Stre'J)lOCOCCUS equi ZOOe'J)ide'lni­ cus) are often isolated from cases of abortion that were due to placentitis.

Protozoa: Reported protozoa! causes of abortion in crunelids include toxoplasmosis (Toxoplasma gondii), neosporosis (Neospora caninum), and sarcocystosis (Sarcocystis aucheniae and S cruzi). Trichomoniasis (Tritrichomonas foetus) has been isolated from crunels, but there is no strong evidence it is involved in abortion. Fungi: Sporadic cases of abortion due to

Ence'J)halitozoon cuniculi and Aspergillus spp have been reported.

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BOVINE GENITAL CAMPYLOBACTERIOSIS

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BOVINE GENITAL CAMPYLOBACTERIOSIS Bovine genital campylobacteriosis is a venereal disease of cattle characterized primarily by early embryonic death, infe1tility, a protracted calving season, and occasionally abortion. Distribution is probably worldwide.

Etiology and Epidemiology: The cause is the motile, gram-negative, curved or spiral, polar flagellated, microaerophilic bacteria Campylobacterfetus venerealis or Cfetusfetus. For many years, it was thought that C fetusfetus was generally an intestinal organism, only occasionally caused abortion in cattle, and was not a cause of infertility. However, Cfetusfetus can also be a.significant cause of the classic infertility syndrome usually att1ibuted to C fetiis venerealis. There are several strains of Cfetusfetus, and the only way to determine whether a strain is a cause of infertility is to test that possibility in a group of heifers. Campylobacter spp are very labile and are destroyed quickly by heating, drying, and exposure to the atmosphere. Unless cultured quickly after collection from the animal and grown under micro­ aerophilic or anaerobic conditions, Campylobacter spp will not grow. C fetus is transmitted venereally and also by contaminated instruments, bedding, or by artificial insemination using contan1i­ nated semen. Individual bulls vary in their susceptibility to infection; some become permanent carriers, while others appear to be resistant to infection. The primary factor associated with this variability seems to be the age-related depth of the preputial and penile epithelial crypts. In young bulls ( 3-4 yr old, the deeper crypts may provide the proper n1icroaerophilic environment required for chronic infections to establish. In cows, the duration of the carrier state is also vaiiable; some clear the infection rapidly, whereas otl1ers can carry Cfetiis for �2 yr. IgA antibodies are shed in cervical

mucus in significant amounts in -50"A, of cows for several months after infection and ai·e useful diagnostically. Although most of the genital tract may be free of infection when a cow eventually conceives, the vagina may remain chronically infected Uu·ough pregnancy.

Clinical Findings: Cows are systemically

normal, but there is a variable degree of mucopurulent endometritis that causes early embryonic death, prolonged luteal phases, i.ITegular estrous cycles, repeat breeding, and, as a result, protracted calving periods, assuming the breeding season is long enough to allow for complete clearance and a successful rebreeding. Observed abortions ai·e not common. In herds not managed intensively, disease may be noticed only when pregnancy examina­ tions reveal low or marginally low pregnancy rates but, more in1portantly, great variations in gestation lengths, especially when the disease has recently been introduced to the herd. In subsequent yeai-s, infertility is usually confined to replacement heifers and a few susceptible cows. Bulls are asymptomatic and produce nom1al semen.

Diagnosis: Cai11pylobacteriosis and trichomoniasis (seep 1384) are similai· syndromes, and investigations should be directed at both diseases. Systemic anti­ body responses ai·e not helpful, because they are often due to nonpathogenic Campylobacter spp . A vaginal mucus agglutination test (VMAT) is useful, but because of variability in individual responses, at least l()OA, of the herd or at least 10 cows should be sampled. An ELISA test has been developed for use on vaginal mucus and is said to be more sensitive and able to detect a wider range of antibody responses than the VMAT. Vaginal culture inm1ediately after abortion or infection can be used for diagnosis, but the number of organisms may be low; in addition, because C fetus is labile and requires special techniques for isolation, success is lin1ited. An accurate diagnostic method is to test-breed heifers and then exaniine them for infection, but tl1is is seldom practical. More often, the preputial cavity and fom.ix are either scraped and aspirated with an infusion pipette or infused with buffered

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BOVINE GENITAL CAMPYLOBACTERIOSIS

sterile saline, and the prepuce is massaged vigorously in the area of the fomix. The aspirate or sheath washing is then examined using a fluorescent antibody test and culture. C fetus will survive for only 6-8 hr after collection, but inoculation into Clark's or similar media will allow survival for >48 hr. For maximum accuracy, bulls should be sampled twice, -1 wk apart. Caution should be exercised when Cmnpylobacter spp are isolated from the placenta because of the possibility of contamination by nonpathogenic fecal Campylobacterspp. Conversely, failure to successfully isolate Cfetus from an infected aborted fetus or placenta often results from overgrowth of the colonies by contaminating organisms or the lethal effects of atmospheric oxygen. Treatment and Control: Vaccination

should start as soon as genital campylobac­ teriosis is diagnosed. Infected cows and cows at risk should be vaccinated. Vaccination of infected cows hastens the

elimination of C fetus and, although cows may remain caniers, fertility is greatly improved. In routine use, the vaccine should be given once, -4 wk before breeding starts; because antibody responses are sho1t-lived, cows should be revaccinated halfway tl1rough the breeding season. Bulls are vaccinated for the san1e reason as cows (ie, for b·eatment as well as for prophylaxis) but are given twice the dose used for cows, 3 wk apart. The infection can also be eliminated in bulls by 1-2 treatments witl1 streptomy­ cin at 20 mg/kg, SC, together with 5 g of streptomycin in an oil-based suspension applied to the penis for 3 consecutive days. For practical reasons, cows are not usually b·eated for genital campylobacteri­ osis. When practical, artificial insemination is an excellent way to prevent or conb·ol genital campylobacteriosis. Because Cfetus has been isolated from cows for >6 mo after the end of pregnancy, it has been suggested that artificial insemination should continue until all the cows in a herd have been wough at least two pregnancies.

BRUCELLOSIS IN LARGE ANIMALS Brucellosis is caused by bacteria of the genus Brucella and is characterized by abortion, retained placenta, and to a lesser extent, orchitis and infection of the accessory sex glands in males. The disease is prevalent in most countries of the world. It primarily affects cattle, buffalo, bison, pigs, sheep, goats, dogs (see p 1402), elk, and occasionally horses. The disease in people, sometimes referred to as undulant fever, is a serious public health problem, especially when caused by B melitensis.

BRUCELLOSIS IN CATILE (Contagious abortion, Bang's disease) Etiology and Epidemiology: The disease in cattle, water buffalo, and bison is caused almost exclusively by Brucella abortus; however, B suis occasionally is isolated from seropositive cows but does not appear to cause clinical signs and is not contagious from cow to cow. In some countries, the disease in cattle is caused by B melitensis. The syndrome is similar to

that caused by B abortus. B melitensis is not present in the USA. Wection spreads rapidly and causes many abortions in unvaccinated cattle. In a herd in which disease is endemic, an infected cow typically aborts only once after exposure; subsequent gestations and lactations appear normal. After exposure, cattle become bacteremic for a short period and develop agglutinins and other antibodies; some cattle resist infection, and a small percentage of infected cows spontaneously recover. A positive serum agglutination test usually precedes an abortion or a nom1al parturition but may be delayed in -15% of cows. The incubation period may be variable and is inversely related to stage of gestation at time of exposure. Organisms are shed in milk and uterine discharges, and the cow may become temporarily infertile. Bacteria may be found in the uterus during pregnancy, uterine involution, and infrequently, for a prolonged time in the nongravid uterus. Shedding from tl1e vagina largely disappears with the cessation of fluids after parturition. Some infected cows that previously aborted

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BRUCELLOSIS IN LARGE ANIMALS shed brucellae from the uterus at subse­ quent normal parturitions. Organisms are shed in milk for a variable length of time-in most cattle for life. B abortus can frequently be isolated from secretions of nonlactating udders. Natural transmission occurs by ingestion of organisms, which are present in large num­ bers in aborted fetuses, fetal membranes, and ute1ine discharges. Cattle may ingest contaminated feed and water or may lick contaminated genitals of other animals. Venereal transmission by infected bulls to susceptible cows appears to be rare. Transmission may occur by artificial insemination when Brucella-contaminated semen is deposited in the uterus but, reportedly, not when deposited in the midce1° vix. Brucellae may enter the body tJu·ough mucous membranes, coajunctivae, wounds, or intact skin in both people and animals. Brucellae have been recovered from fetuses and from manure that has remained in a cool environment for >2 mo. Exposure to direct sunlight kills the organisms within a few hours.

Clinical Findings: Abortion is the most obvious manifestation. Infections may also cause stillborn or weak calves, retained placentas, and reduced milk yield. Usually, general health is not in1paired in uncompli­ cated abortions. Seminal vesicles, ampullae, testicles, and epididy.mides may be infected in bulls; therefore, organisms are present in the semen. Agglutinins may be demonstrated in seminal plasma from infected bulls. Testicular abscesses may occur. Longstand­ ing infections may result in artluitic joints in some cattle. Diagnosis: Diagnosis is based on bacteriol­ ogy or serology. B abortus can be recovered from the placenta but more conveniently in pure culture from the stomach and lungs of an aborted fetus. Most cows cease shedding organisms from the genital tract when uterine involution is complete. Foci of infection remain in some parts of the reticuloendothelial system, especially supramanunary lymph nodes, and in the udder. Udder secretions are the preferred specin1ens for culture from a live cow. Senun agglutination tests have been the standard diagnostic method. Agglutination tests may also detect antibodies in milk, whey, and semen. An ELISA has been developed to detect antibodies in milk and serum. When the standard plate or tube serum agglutination test is used, complete agglutination at dilutions of 1:100 or more in

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serum samples of nonvaccinated animals, and of 1:200 of animals vaccinated at 4-12 mo of age, are considered positive, and the animals are classified as reactors. Other tests that may be used are complement fixation, rivanol precipitation, and acidified antigen procedures. Screening Tests: In official eradication programs on an area basis, the Bnicella milk ring test (BRT) has effectively located infected dairy herds, but there are many false-positive tests. The brucellosis status of dairy herds in any area can be monitored by implementing the BRT at 3- to 4-mo intervals. Milk samples from individual herds are collected at the farm or milk processing plant. Cows in herds with a positive BRT are individually blood tested, and seropositive cows are slaughtered to determine herd status. Nondairy and dairy herds in an area may also be screened for brucellosis by testing serum san1ples collected from cattle destined for slaughter or replacements through intermediate and tem1inal markets, or at abattoirs. Reactors are traced to the herd of origin, and the herd is tested. The cost of identifying reactors by this method is mini.nlal compared with that of testing cattle in all herds. Screening tests, including the brucellosis card (or rose bengal) test and plate test, may be used in markets and laboratories to identify presumptively infected animals, thus reducing the number of more expensive and laborious diagnostic tests. Brucellosis-free areas can be achieved and maintained, effectively and economi­ cally, by using the BRT on dairy herds and through market cattle testing. Adult cattle are sampled at the time of slaughter. Supplemental tests using sensitive screening methods may be used in cattle in which the brucellosis status is unclear. Use of a battery of these tests improves the probability of detecting infected cattle that have remained in some herds as possible reservoirs of infection. Supplemental tests are also used to clarify the results of plate or card tests, especially in serum samples from vaccinated cattle. These tests, which include complement fixation and rivanol precipitation, are designed to detect prin1arily the antibodies specifically associated with Brucella infection. Another supplemental diagnostic procedure is to test milk san1ples from individual udder quaiters by serial dilution BRT, which can be used to detect chronic infection in udders of cows tl1at may have equivocal serum test reactions.

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BRUCELLOSIS IN LARGE ANIMALS

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Control: Efforts are directed at detection

and prevention, because no practical treatment is available. Eventual eradication depends on testing and eliminating reactors. The disease has been eradicated from many individual herds and areas by this method. Herds must be tested at regular intervals tmtil two or three successive tests are negative. Non.infected herds must be protected. The greatest danger is from replacement animals. Additions should be vaccinated calves or nonpregnant heifers. If pregnant or fresh cows are added, they should originate from brucellosis-free areas or herds and be seronegative. Replacements should be isolated for -30 days and retested before being added to the herd. Vaccination of calves with Babortus Strain 19 or RB51 increases resistance to infection. Resistance may not be complete, and some vaccinated calves may become infected, depending on severity of exposure. A small percentage of vaccinated calves develop antibodies to Strain 19 that may persist for years and can confuse diagnostic test results. To minimize this problem, calves in the USA are mostly vaccinated witl1 a vaccine of Strain RB51. It is a rough attenuated strain and does not cause production of antibodies, which are detected by most serologic tests. Whole-herd adult cattle vaccination using Strain 19 or RB5 l has been practiced in certain high-incidence areas and selected herds in the USA with much success. Vaccination as tl1e sole means of disease control has been effective. Reduction in the munber of reactors in a herd is directly related to the percentage of vaccinated anin1als. However, when proceeding from a control to an eradication prograin, a test and slaughter program becomes necessary. Ba.bo1·t1is has been eradicated from cattle herds in the USA, and all states are considered free of brucellosis. Brucellosis is endemic in some nondo­ mesticated bison and elk herds in the USA. Transmission of Babortus to domestic cattle herds is rare but has occuffed in several cattle herds commingli..ng with infected elk in the greater Yellowstone Park area.

BRUCELLOSIS IN GOATS The signs of brucellosis in goats are similar to those in cattle. The disease is prevalent in most countries where goats are a significant part of the anin1al industry, and milk is a common source of hwnan brucellosis in many countries. The causal agent is Brucella melitensis. Wection occurs

primarily through ingestion of the organisms. The disease causes abortion at approximately the fourtl1 mo.nth of pregnancy. Arthritis and orchitis may occur. Diagnosis is made by bacteriologic examination of milk or an abo1ted fetus or by seru.n1 agglutination tests. The disease can be eliminated by slaughter of the herd. ln most countiies where B melitensis is endemic, vaccination with the Rev. l strain is common. Rev. l is an attenuated strain of Bmelitensis and is administered by SC or intraconjunctival routes. Bmelitensis is highly pathogenic for people.

BRUCELLOSIS IN HORSES Horses can be infected witl1 B1ucella abortus or Bsuis. Suppurative bursitis, most commonly recognized as fistulous withers or poll evil (seep 1064), is the most common condition associated with brucellosis in horses. Occasionally, abor­ tion has been reported. It is unlikely that infected horses are a source of tl1e disease for other horses, other animal species, or people. Brucellosis in horses is very rare in tl1e USA because of elimination of tl1e disease in cattle.

BRUCELLOSIS IN PIGS Clinical martifestations of brucellosis in pigs vary but are sinular to those seen in cattle and goats. Altl10ugh the disease is often self-li..nuting, it remains in some herds for years. Brucellosis caused by Brucella suis rarely occurs in domestic anin1als other than pigs. Epidemics of brucellosis in people have been reported among packing-house workers, and the usual source is infected pigs. The prevalence in the USA is sometin1es high among feral pigs. The incidence of swine brucellosis an1ong domesticated animals in tl1e USA is very low. CU1Tently there are no known infected domestic swine herds.

Etiology and Transmission: Bsuis

is usually spread mainly by ingestion of infected tissues or fluids. Wected boars may ti·ansnut tl1e disease during service; the orgaiusm can be recovered from semen. Pigs raised for breeding purposes are sources of infection. Suckli..ng pigs may become infected from sows but most reach weanling age without beconung infected.

Clinical Findings: After eiqiosure to B

suis, pigs develop a bacteremia that may persist for as long as 90 days. During and after the bacterenua, localization may occur

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BRUCELLOSIS IN LARGE ANIMALS in various tissues. Signs depend consider­ ably on tl1e site(s) of localization. Common manifestations are abortion, temporary or pem1anent sterility, orchitis, lameness, posterior paralysis, spondylitis, and occasionally meb.itis and abscess formation. The incidence of abortion may be 0-800/o. Abortions may also occur early in gestation and be undetected. Usually, sows or gilts that abort early in gestation return to estrus soon afterward and are rebred. Ste1ility in sows, gilts, and boars is common and may be tl1e only manifestation. Before attempting treatment for other diseases, it is logical to test for brncellosis in herds in which stelility is a problem. Steruity in sows is more frequently temporary but may be permanent. In boars, orchitis, usually unilateral, may occur, and fertility appears to be reduced. Diagnosis: The p1incipal means of diagnosis in pigs is tl1e brucellosis card (rose bengal) test; however, otl1er sernm agglutination tests or complement fixation tests have been used. It is generally accepted tl1at the tests have limitations in detecting brncellosis in individual pigs. Thus, entire herds or units of herds, ratl1er tl1an individual pigs, must be tested in any control program. Low agglutinin titers are seen in almost any size herd, regardless of infection status, and a few infected pigs may have no detectable titer. The card test is usually more accurate tl1an conventional agglutination tests. Supplemental tests designed for cattle may also be used for pigs. Prevention and Control: Caution should be practiced in tl1e purchase of individual pigs tl1at exhibit a low agglutinin titer unless tl1e status of tl1e entire herd of origin is known. Pigs should be isolated on return from fairs or shows before reenter­ ing the herd. Replacements should be purchased from herds known to be free of brucellosis, or tl1ey should be tested and isolated for 3 mo and retested before being added to tl1e herd. There is no vaccine for brucellosis in swine, and no practical recommendations can be made for treatment. Control is based on test and segregation as well as slaughter of infected breeding stock. Brucellosis remains a problem in feral swine and is a potential source of infection for domesti­ cated herds and people.

BRUCELLOSIS IN SHEEP Brucella melitensis infection in certain breeds of sheep causes clinical disease

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similar to tl1at in goats (see above). However, B ovis produces a disease unique to sheep, in which epididymitis and orchitis impair fertility-the principal economic effect. Occasionally, placentitis and abortion are seen, and there may be perinatal mortality. The clisease was first described in New Zealand and Australia and has since been reported from many sheep-raising areas of tl1e world. B ovis infection among sheep in tl1e USA is rare. There is no evidence that the disease is present in any oilier animal species. Rare natural and experimental infections in fai111ed red deer stags have been reported in New Zealand. Rains as young as 8 wk have been infected expelimentally by various nonvenereal routes. The disease can be transmitted ainong rains by direct contact. Active infection in ewes is unusual but has developed after mating with naturally infected rains. Contaminated pastures do not appeai· to be important in spread of the disease. Infection frequently persists in ran1s, and a high percentage shed B ovis intermittently for several years. Primary maiufestations ai·c lesions of the epididymis, tunica, and testis in rams; placentitis and abortion in ewes; and occasionally perinatal death in lambs. Lesions may develop rapidly. In rams, the first detectable abnormality may be a marked deterioration in semen quality associated with the presence of inflam­ matory cells and organisms. An acute systemic phase is rarely seen in naturally occurring infections. After regression of the acute phase-which may be so mild as to go unobse1ved-lesions may be palpated in the epididymis and scrotal tunics. Epididymal enlai·gement may be unilateral or bilateral. The tail of the epididymis is involved more frequently than the head or body, and the most prominent lesion is spennatoceles of variable size containing partially inspis­ sated spermatic fluid. The tunics fre­ quently become thickened and fibrous, and extensive adhesions develop between them. The testes may show fibrous atrophy; these lesions are usually permanent. In a few cases, palpable lesions ai·e transient, while in others, organisms may be present in semen over long periods without clinically detectable lesions. Because not all infected rams show palpable abnormalities of scrotal tissues (and not all cases of epicliclymitis ai·e clue to brucellosis), tl1e remaining rams must be exaininecl further. Rams shedding orgaiusms, but having no lesions, must

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BRUCELLOSIS IN LARGE ANIMALS

be identified by culture of semen. Repeated examinations may be necessaty to identify intennittent shedders. Microscopic examination of stained semen smeat'S may also be helpful; fluorescent antibody exatnination is a highly specific diagnostic aid. Serologic tests used for eradication of disease and certification of anin1als include indirect ELISA, complement fixation, hemagglutination inhibition, indirect agglutination, and gel diffusion. Incidence and spread of the disease may be reduced by regular exan1ination of ran1s before the breeding season and culling of those with obvious genital abnormalities. Because susceptibility in rams increases markedly with age, it is advantageous to keep a young ratn flock and isolaLe

noninfected ratns from older, possibly infected rams. Immunization of weaner rams with attenuated (Rev. 1) B melitensis has been recommended in some countries. Because infection in ewes apparently originates almost exclusively from service by infected rams, lamb losses through infection of ewes may be controlled economically by restricting vaccination to ratns. There is no recommended vaccina­ tion in the USA. Chlortetracycline and streptomycin used concurrently have effected bacteriologic cw·es. However, treatment is not economic except in especially valuable ran1s, and even if infection is eliminated, fertility may remain impaired.

CONTAGIOUS AGALACTIA First recognized in ltaly more than 200 yeat'S ago, contagious agalactia is primarily a disease of dairy sheep and goats and is characterized by an interstitial mastitis leading to a loss of milk production, atthritis, and infectious keratocortjunctivi­ tis. It is more often seen on farms practicing traditional husbandry. Contagious agalactia is principally caused by the wall-less bacteriwn Myeoplasma agalaetiae, but in recent years, M rnyeoides eapri (Mme; fom1erly known as LC), and, to a lesser extent, M eaprieolum eaprieolum (Mee) and M putrefaciens have also been isolated from goats with mastitis, arthritis, and occasionally, respiratory disease. The clinical signs of these infections are sufficiently sinlilar to those of contagious agalactiafor the OIE to include them as causes of this listed disease. Etiology and Epidemiology: Mycoplas­

mas that cause contagious agalactia can persist for > 1 yr after clinical recovery of infected aninlals, wllich are the main reservoir of the orgatlism. The introduction of such carriers into a susceptible flock can initially cause high morbidiLy and mortality. Once established in a herd, young rumi­ nants become infected while suckling. Adults are contanlinaLed via the milkers' hands, milking machines, or possibly by bedding. Other routes of transmission may include aerosols of infective exudates over

short distances and ingestion of contami­ nated water. Sheep and goats are equally susceptible to M aga.laetiae, but goats are additionally susceptible to Mee, Mrne, and M putrefa­ ciens. However these mycoplasmas may be found in both ailin1al species in regions where they graze together. In general, clinical disease is more pronounced in goats. Antibodies to Mee and Mme have been detected in South American can1elids, but no mycoplasmas have yet been isolated. Because alpacas, llatnas, and vicw1as develop polyarthr:itis, pnewnonia, and pleuritis, it is likely that mycoplasmas may eventually be found. Mme has also been isolated from cattle, although its role in disease in this species is hot clear·. Contagious agalactia has been reported in many countries swTounding the Mediterra­ nean, in particular Portugal, Spain, Greece, Italy, France, Tw·key, Israel, and North Africa, as well as in many parts of tl1e Middle East, most notably Iran, India, Mongolia, and parts of South America. Sporadic cases have been reported in the USA. Clinical Findings and Lesions: The

incubation period ranges from 1 wk to 2 mo and can be followed by either an acute disease with fever, neurologic signs, and occasionally deatl1 or, more commonly, a subacute or chronic disease characterized

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CONTAGIOUS AGALACTIA

by mastitis, arthritis, and infectious keratoconjunctivitis. The infection begins as an interstitial mastitis giving rise to a hot, swollen, and painful udder, followed by a sudden drop in the quantity and quality of milk production. The milk may appear discolored and granular, separating into watery and solid phases, or take on a thick, yellow consistency with milk clots obstructing the teat duct. After several days, the affected udder shrinks because of damage to secretory tissue. Abscesses within the udder and enlargement of the retromammary lymph nodes may also be seen. Generally the clinical condition improves after a few weeks, with partial restoration of udder function, but the quality of milk remains abnormal. In some cases, atrophy and fibrosis lead to permanent loss of milk production. The acute syndrome may lead to abortion and weak lambs as a result of ingestion of infected milk or starvation brought about by reduced milk production. Arthritis can be seen in adults and the young who find it difficult to keep up with the flock; affected animals may be seen limping or sitting on their carpal joints because of the discom­ fort. In these animals, the joints are hot, swollen, and painful. Conjunctivitis presents as a discharge of clear exudates from the eyes, followed by corneal opacity, keratitis, purulent exudation, and occasion­ ally ulceration and panophthalmitis. Severe cases may result in irreversible blindness. Necropsy often reveals generalized peritonitis among anin1als that die during the acute stage. The infected udder is grossly atrophic in either one or both halves. Microscopically, the chronic inflanlffiatory reaction in the stroma shows increased fibrosis and a reduced number of glandular acini. Infected joint capsules are edematous, and the synovium may contain clumps of fibrin. Articular surfaces may be eroded and occasionally ankylosed. In early stages of keratitis, the cornea is edematous and infiltrated with leukocytes; later, abundant purulent exudate infiltrates both the cornea and the ciliary body. M putrefaciens is common in milking goat herds in western France. It can be isolated from the milk of animals with or without clinical signs, and milk production is usually severely affected. The milk of affected animals has a characteristic smell of putrefaction. Diagnosis: When a flock is severely affected, clinical diagnosis is easy; the three major signs-mastitis, arthritis, and keratoconjunctivitis-are generally present,

1353

although rarely in the same animal. However, an acute forn1, in which there is septicemia without specific local signs, can confound the diagnosis. Laboratory diagnosis is the only means of confinnation. Preferred samples from living animals include milk and udder secretions, joint fluid from arthritic cases, eye swabs from cases of ocular disease, and serum for antibody detection. The ear canal is a rich source of pathogenic mycoplasmas. Isolation of mycoplasmas from the blood during the brief mycoplasmaemia stage of the disease is rarely successful. Samples from dead animals should include udder and associated lymph nodes, joint fluid, lung tissue (at the interface between diseased and healthy tissue), and pleural or pericardia} fluid. Samples should be kept moist and cool and sent promptly to a diagnostic laboratory. PCR tests, which can be performed directly on clinical samples, including milk, can be used to confirm the diagnosis. Identification of the organism is usually achieved by the growth inhibition or immunofluorescence tests using hyperim­ mune rabbit antiserum and, increasingly, by PCR tests that can be pe1formed directly on clinical samples, including milk, within hours. PCR, together with denaturing gradient gel electrophoresis, which can detect all causative mycoplasmas in a single reaction, has been described. Detection of antibodies in serum by ELISA provides rapid diagnosis of disease but may not be very sensitive in chronically affected herds and flocks. Indirect ELISA, some conunercially available, have been used routinely in control programs to screen herds for M agalactia.e but less so for Mme and Mee. Immuno (Western) blotting can be used to confirm suspect ELISA results and can distinguish field infection from vaccine antibody. In areas believed to be free of contagious agalactia, it is usually necessary to isolate and identify the causative organism to confinn infection. Serologic tests are not widely available for M putrefaciens. A number of other mycoplasmas such as M arginini, M bovigenitalium, and M bovis have occasionally been isolated from mastitic milk and joint fluids, but their role in disease is not known. M conjunctivae is a common cause of keratoconjunctivitis but does not affect the udder or joints. Other bacteria causing mastitis include staphylo­ cocci, streptococci, Escherichia coli, and J(lebsiella; caprine arth!itic encephalomy­ elitis virus and Erysipelothrix rhusiop­ athiae should also be considered in cases of arthritis.

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CONTAGIOUS AGALACTIA

Treatment, Control, and Prevention:

Regular laboratory monitoring of flocks/ herds and replacement animals may help to prevent spread or introduction of disease and can be done on serum and/or milk (including bulk tank milk) by serology, culture, or PCR. Culling or isolation of infected animals is generally advised, because udder damage is considered permanent. When this is not possible, hygienic measures, such as improved milking hygiene and pasteurizing milk before feeding to the young, should be implemented. Antibiotics that inhibit cell wall synthesis (eg, penicillins) are not effective against contagious agalactia. In vitro tests have shown that strains of M agalactiae are still sensitive to fluoroquinolones and mac­ rolides. These can bring about clinical in1provement, paiticularly if given early in the djsease, but there is always the danger of promoting carrier animals. Resistance to tetracyclines has been reported for some

strains of M agalactiae. The use of erytlu-omycin and tylosin can destroy milk­ producing tissue in small ruminants. In many disease-free countries and regions, a confirmed infected herd is always slaughtered. In countries bordeting the Mediterra­ nean, both attenuated and inactivated vaccines have been used with mixed success. Some have provided protection from clinical disease and have been useful in endemic areas; however, they do not prevent transmission of the mycoplasmas. Generally, the duration of immunity, particularly to the fonnalinized, inactivated vaccines that are used in Europe, is sho1t. Vaccines containing two or three of the causative agents are now available, but published data on their effectiveness is scarce. Zoonotic Risk: There is no evidence that contagious agalactia is transmitted to people.

CYSTIC OVARY DISEASE An10ng domestic animals, cystic ovary disease (COD) is most common in cattle, paiticularly the dairy breeds, but it occurs sporadically in dogs (seep 1395), cats, pigs, and perhaps mares. Cystic Ovary Disease and the Corpus Luteum: Three ovarian structures in cattle

may include the tem1 "cyst": follicular cysts, luteal cysts, and cystic corpus luteurn (CL). However, in contrast to the other two, the structure sometimes described as a cystic CL (a CL with a cavity or "lacunae") actually arises after normal ovulation. CL with a lacunae are a normal stage or variation of CL development ai1d ai·e found in nom1ally cycling and pregnant cows without concurrent abnonnal reproductive performance. The lacunae can be compared with the homogeneous, liver-like consist­ ency of the base of a typical CL. The CL may have an ovulation crown or papilla at its apex; however, 10%-200;6 of functional, nonnal CL fail to develop this feature. The two pathologic forms of bovine cystic ovary disease, follicular cysts and luteal cysts, are etiologically and pathophysiologi-

cally related but differ clinically. Both are characterized by the presence of a fluid-filled structure >25 mm dian1eter, persisting for> 7 days and associated with abnom1al reproductive perfonnance.

FOLLICULAR CYSTIC OVARY DISEASE (Cystic follicles, "Bulling")

Follicular cystic ovary disease may be defined on a number of levels. Essentially, all signs relate to the disruption of the nonnal endocrine events of the estrous cycle, through the failure of ovulatory events. Key features include the presence of a thin-walled, fluid-filled structure>25 mm diai11eter and present for> 7 days in the absence of a CL on ultrasonographic imaging of the ovary. Along with occasional behavioral signs of nymphomania, such as short inter-estrus intervals and excessive heat behavior, ai·e endocrine changes, including a suboptimal luteinizing honnone (LH) surge and persistently increased estradiol levels.

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CYSTIC OVARY DISEASE

Etiology and Pathogenesis: A hereditary predisposition has been implicated in dairy cattle. Cystic ovary disease or syndrome (COD) is commonly considered to be associated with negative energy balance and stress factors in dairy cows that are high milk producers. Genetic predisposition to partition glucose to the udder to prioritize lactose synthesis and milk production is characterized by insulin resistance in Holstein cattle. IGF-1 is a cytokine associated with metabolic influences on reproduction and hence COD. Incidence increases with age. Most cases occur within 3-8 wk of parturition at the first attempted postpartum ovulation, coinciding with peak daily milk production and rapidly decreasing body condition. The reported herd incidence is 5%-25% per lactation, or higher in some problem herds. Dming normal proestrus, regression of the CL coincides with development of a selected follicle, while the growth of any additional follicles is inhibited. In animals developing COD, ovulation fails to occur and the dominant follicle continues to enlarge. An important component of the etiology is the failure of positive feedback of follicular estrogen on the hypothalamus via estrogen receptor ex to release sufficient GnRH during estrus to trigger an LH surge. The end result is a failure of ovulation at the time of estrus. Moreover, other follicles may grow and form multiple cysts either bilaterally or unilaterally. Grossly, follicular cysts resemble enlarged follicles, generally defined as varying in size from25 mm to 50-60 mm in dian1eter. The size and fom1 of an affected ovary depends on the number and size of cysts present. The cystic ovary is capable, at least initially, of steroidogenesis, and its products vary from estrogens to progester­ one to androgens. The actions of the various hormones produced or the absence of the stabilizing action of high progesterone from the normal CL during -75% of the estrous cycle (or both) are responsible for the changes seen in the genital tract, body conformation, and general behavior. Clinical Findings: Behavioral aberrations range from frequent, intem1ittent estrus with exaggerated monosexual drive to bull-like behavior, including mounting, pawing the ground, and bellowing. This behavior may be accompanied by masculinization of the head and neck. Relaxation of the vulva, perineum, and the large pelvic ligaments, which causes the tail head to be elevated, can occur in chronic cases. Some affected cows show these

1355

signs, but others may be sexually quiescent; anestrous or subestrous cows are a common presentation. The affected ovaries generally are enlarged and rounded, but their size vaiies, depending on the number a11d size of cysts. Their surface is smooth, elevated, and blister-like. Cysts frequently are multiple and may approach 4-6 cm in diameter. Under the influence of honnones produced by the cystic ovary or the lack of hom10nes (especially progesterone) normally present during estrous cycles, the uterus undergoes palpable changes, which in turn vary with the duration of the cystic condition. Thus, during tl1e first week, the uterine wall is thickened and edematous as an extension of the preceding estrus. Toward the end of the first week, the uterine wall develops a sponge-like consistency. In chronic cases, atony and atrophy of the uterine wall are common. Occasionally, the uterine horns become markedly shortened. Some degree of mucoid to mucopurulent vaginal discharge is common. Hydrometra, a fluid-filled, extremely thin-walled uterus, is seen occasionally. Diagnosis: Palpation of the uterus may help differentiate a follicular cyst from a dominant preovulatory follicle; the estrous cow has a coiled, extremely turgid uterus and a follicle. As noted earlier, cystic cows fail to ovulate a preovulatory follicle after undergoing CL regression and, on exainination of the reproductive tract, they present with a large follicle, absence of a CL, and absence of a turgid uterus. Ultrasound technology per rectum can be used to differentiate cysts from corpora lutea and may help diagnose cyst type (ie, follicular cyst wall diameter has been described as 3 nun). Larger, multiple cysts are easily identified by rectal palpation. History, conformation, and uterine changes, when present, provide supplemental diagnostic evidence. Treatment: COD may be frustratingly unresponsive to therapy. Some cysts respond readily to an LH-type honnonal treatment. In the past, human chorionic gonadotropin (hCG) was commonly used. It is most effective at 10,000 USP units IM, although success with lower doses given IM or IV has also been reported. Hormone therapy with GnRH may be effective at 100 mcg and less antigenic than hCG. To hasten the onset of the first estrus after treatment, prostaglandin (PG) F2cx products can be given 7 days after hCG or

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CYSTIC OVARY DISEASE

GnRH. Ovulation synchronization protocols combine GnRH and PGF2o: to control follicular dynamics, luteolysis, and ovulation. They allow for fixed timed artificial insemination (TAI) of cattle without the need for estrus detection and have been successfully used to treat cows with cystic ovaries. This protocol consists of giving GnRH, then prostaglandin 7 days later, then a second administration of GnRH 48 hr later, and finally TAI 0-24 hr later. Breeding on the first estrus may reduce recurrence by establishing pregnancy as soon as possible. However, COD recurrence is a tisk. Manual rupture is used, but the poten­ tial danger of traumatizing the ovruy ru1d causing hemorrhage with subsequent local adhesions should not be overlooked. Prognosis: After therapy with an LH-type honnone, a normal, fertile estrus can be expected in 15-30 days. With GnRH therapy, 25% of cases required a second treatment, and 5% required a third. One-third of the cases treated for the third ti.me did not respond. Spontaneous recovery is possible and is most conrn10n in cases arising during the first 50 days after calving. Likewise, successful treatment encourages perpe­ tuation of the disease in the herd if the offspting ru·e used for breeding. Although COD in cattle clearly has a genetic component, it is unlikely that a single fann using artificial insemination can signifi­ cantly influence the incidence. In Sweden, progress has been made in reducing the condition through culling and selection procedures for bulls used in artificial insemination, but affected cows are often still treated.

LUTEAL CYSTIC OVARY DISEASE Luteal cystic ovary disease is charactetized by enlarged ovru·ies with one or more cysts, the walls of which ru·e thicker than tl10se of follicular cysts because of a lining of luteal tissue. Incidence ratios of follicular versus luteal cysts vary greatly because of diagnostic tendencies of individual vetetinarians. Classically, luteal COD is defined as the presence of a fluid-filled ovarian structure >25 nrn1 di3Jl1eter persisting > 7 days in the absence of a CL and with a wall diruneter >3 mm, usually associated with abnormal reproductive signs. Normal lacunae fonnation in CL may be incorrectly classified as luteal COD. Etiology and Pathogenesis: The basic causes of true luteal cysts ru·e believed to be

tl1e srune as for follicular cysts. The release of luteinizing honnone (LH) may be some­ what greater than that occurting when follicular cysts develop, and sufficient to initiate luteinization of follicles but inadequate to cause ovulation. Luteal cysts may be an extension of follicular cysts such that the nonovulatory follicle is partially luteinized spontaneously or in response to honnonal therapy. Clinical Findings: Luteal cysts are accompanied by nom1al conformation and anestrous behavior. Rectal palpation reveals a quiescent uterus charactetistic of tl1e luteal phase of tl1e estrous cycle. Luteal cysts are recognized as smooth, fluctuant domes protruding above the surface of the ovary. Usually, they are single structures. Luteal cysts ru·e differentiated from follicular cysts on the basis of palpable char­ acteristics of both the structurn and the uterus and, to some extent, on the cow's behavior. Progesterone assay and ultra­ sonography can help differentiate between follicular and luteal cysts, although with either method a final diagnostic decision remains somewhat subjective. On attempts to manually rupture the cystic structure, follicular cysts burst or rupture under minimal pressure whereas luteal cysts c3JU1ot be ruptured with reasonable force. Both types of cysts respond to LH or GnRH therapy, but PGF,cx will lyse some luteal cysts and generaily all diestrual CL structures. Treatment and Control: The treatment of choice is luteolytic doses of PGF2cx if a correct diagnosis can be asce1tained. A nom1al estrus is expected in 3-5 days. The major limitation of this treatment is the difficulty in accurately estin1ating the 3Jl1ount of luteal tissue present. If the structure being diagnosed as a luteal cyst is really a developing CL (as discussed above, sometimes called a cystic CL), it may not respond because dairy cows do not become highly responsive to the luteolytic action of PGF2o: until day 6 after estrus. Ultrasound ex3Jl1inati.on is increasingly conu11on and facilitates diagnosis of ovarian structures. Luteal cysts also respond to htunan chorionic gonadotropin and GnRH therapy that is effective in the treatment of follicular cysts, but the next estrus could occur 5-21 days after treatment. Mrumal rupture of luteal cysts is not recommended because of the risk of tratuna and hemonhage. Because of poor estrus detection practices on many dairy farms, the treatment of choice for both follicular and luteal cysts is intravaginal

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EQUINE COITAL EXANTHEMA

progesterone/prostaglandin (a fixed timed artificial insemination protocol) (see p 1355). Application of this protocol in affected cows promotes timely breeding after treatment.

CYSTIC OVARY DISEASE AS A HERD PROBLEM Individual herds may experience excep­ tionally high rates ( -50%) of cystic ovary disease (COD) over a period of months. Detemlining the cause of these multifacto1ial episodes is not easy, but the following questions should be addressed: 1) Is the diagnosis accurate, ie, are the structures being identified as cysts really cysts? This can be established via second opinion diagnoses, detemlination of milk or plasma progesterone levels, ultrasound exanli.na­ tion of the ovaries in suspected cases, observing ovarian changes and time of estrous activity after treatment with prostaglandin products, and/or improving diagnostic skills by continuing education. 2) Has the palpation exanli.nation schedule for the herd changed? Initiating routine postpartum examinations for all cows and increasing frequency of herd visits can result in an increased apparent incidence. 3) Has the herd incidence of peripaiturient complications and stress increased? Cows having problems around calving (such as twins, milk fever, dystocia, retained

1357

placenta, ketosis, etc) ai·e much more likely to develop cysts. Attempts to reduce these complications are indicated. 4) Have herd genetics been considered? It is well accepted that ovarian cysts are more common in certain lines. 5) Has the nutritional program of the herd been evaluated? Nutritional problems are frequently implicated as a risk factor for COD. Proper nutlitional manage­ ment of da.Lty herds is always warranted. Monitoring the effects of the nutritional prograin via a body condition scoring prograi11 should be done as part of the effo1t to reduce ovaiian cysts in problem herds. 6) Has management of cows around estrus changed? Social and environmental changes may cause stresses associated witl1 COD.

CYSTIC OVARY DISEASE IN MARES When diagnosing the reproductive status of mares, it must be remembered that follicles during estrus are normally 4--6 cm in diameter. Ovulation failure can also be seen in mai·es having irregular estrous cycles during the spring or fall transition phases of the reproductive cycle, but this state is not treated in the san1e way as the cystic ovary disease condition of cattle. The granulosa cell tw110r condition in mai·es causes marked enlai·gement of one ovary but differs from cystic ovaiy disease of cattle.

EQUINE COITAL EXANTHEMA (Genital horsepox, Equine venereal balanitis in stallions) Etiology and Epidemiology: Equine coi­ tal exanthema is a benign venereal disease of horses tl1at probably occurs worldwide. It affects both sexes and is caused by equine herpesvirus type 3 (EHV-3). Tlli.s virus has a single antigenic type but also has small and large plaque variants ill tissue culture, indicating that variation may occur in the severity of field outbreaks. Although the pril11ary route of transmission is venereal, outbreaks have been docmnented m which tra.I1Smission occurred via contanli.nated supplies and instruments or by the use of a single glove for rectal exainination of ma.Ily mares. It is probably for this reason that EHV-3 has also been isolated from horses that have not been bred.

Equine coital exa.I1thema is probably transmitted only in the acute phase of the disease; after the lesions have healed, horses do not appeai· to shed the virus. However, tile existence of a carrier state is unclear: the scai-s tliat persist after healing may identify potential carriers, but such asymptomatic carrie1-s have not been identified. Immwli.ty is short-lived, but evidence from stallions shows tllat recurrence is not likely within a single breeding season. Clinical Findings: Clinical signs in mares develop 4--8 days after sexual contact or veterinary exainination a.Ild are ma.Ili.fest by tile appeara.I1ce of multiple, circular, red

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nodules up to 2 mm in diameter on the vulvar and vaginal mucosa, the clitoral sinus, and perineal skin. These lesions develop into vesicles and then pustules and eventually rupture, leaving shallow, painful, ulcerated areas that may coalesce into larger lesions. Edema can develop in the perineum and may extend to between the thighs. Occasionally, ulcers will be found on the teats, lips, and nasal mucosa. Secondary bacterial infection of the ulcers by Streptococcus spp is common, causing the ulcers to enlarge and exude a mucopurulent discharge. In such cases, the horse may become febrile. Unless secondary bacterial infection occurs, skin healing is complete within 3 wk, but clitoral and vaginal ulcers heal more slowly. Skin lesions persist for long periods as unpigmented scars. However, pregnancy rates are not reduced. Lesions in stallions are similar to those in mares and are found on both the penis and prepuce. As a result, intromission is painful, and the stallion may be reluctant to copulate. If copulation does occur during the ulcerative stage, the ulcers may hemon-hage into the ejaculate, reducing sperm viability.

Diagnosis: A tentative diagnosis is based on clinical signs and confirmed by identifying (using electron microscopy) the virus in cells from the margin of ulcers. Typical intranuclea.r herpesvirus inclusion bodies can also be seen in cytologic or histologic preparations. Acute and convalescent samples for serum neutraliza­ tion or complement fixation tests can also be diagnostic, but these tests must be interpreted carefully because both EHV-1 and EHV-4 have also been isolated from genital lesions. Treatment and Prevention: Sexual rest

is essential to allow ulcers to heal and prevent spread of the disease. The use of antibiotic ointments to prevent secondary infections is also advisable. Affected horses should be isolated until all lesions have healed, and disposable equipment should be used for examinations. During the acute phase of the disease, mares should be bred only by attificial insemination. No vaccine is available. All horses should be examined carefully before they are allowed to breed, keeping in mind that the incubation period is up to 10 days.

MASTITIS IN LARGE ANIMALS Mastitis, or inflammation of the mammary gland, is predominantly due to the effects of infection by bacterial pathogens, although mycotic or algal microbes play-a role in some cases. Pathologic changes to milk­ secreting epithelial cells from the inflamma­ tory process often bring about a decrease in functional capacity. Depending on the pathogen, functional losses may continue into further lactations, which may reduce productivity and potential weight gain for suckling offspring. Although most infections result in relatively mild clinical or subclinical local inflanunation, more severe cases can lead to agalactia or even profound systemic involvement, resulting in death. Mastitis has been reported in almost all domestic mammals and has a worldwide geographic distribution. Climatic conditions, seasonal variation, bedding, housing density of livestock populations, and husbandry practices may affect the incidence and etiology. However, it is of greatest frequency and economic importance in species that

primarily function as producers of milk for dairy products, particularly dairy cattle. (See also UDDER DISEASES, p 1385.)

MASTITIS IN CATTLE Almost any microbe that can oppottunisti­ cally invade tissue and cause infection can cause mastitis. However, most infections are caused by various species of strepto­ cocci, staphylococci, and gran1-negative rods, especially lactose-fennenting orgatlisms of enteric origin, conunonly te1med coliforms. From an epidemiologic standpoint, the primary sources of infection for most pathogens may be regarded as contagious or environmental. Except for Mycoplasma spp, which may spread from cow to cow through aerosol transmission and invade the udder subsequent to bacteremia, contagious pathogens are spread during milking by milkers' hands or the liners of the milking unit. Species that use this mode of

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MASTITIS IN LARGE ANIMALS transmission include Staphylococcus aureus, Streptococcus agalactiae, and Corynebacterium bovis. Most other

species are opportunistic invaders from the cow's environment, although some other streptococci and staphylococci may also have a contagious component. Additionally, contagious transmission infrequently occurs for pathogens typically associated with environmental reservoirs, eg, through the development of host-adapted virulence factors (Escherichia coli) or by shedding of overwhelming numbers of bacteria from infected udders (Trueperella [formerly Arcanobacterium] pyogenes). The bedding used to house cattle is the primary source of environmental patho­ gens, but contaminated teat dips, intraman1mary infusions, water used for udder preparation before milking, water ponds or mud holes, skin lesions, teat trauma, and flies have all been incriminated as sources of infection. Intramanimary infections are often described as subclinical or clinical mastitis. Subclinical mastitis is the presence of an infection without apparent signs of local inflanimation or systemic involvement. Although transient episodes of abnormal milk or udder inflammation may appear, these infections are for the most part asymptomatic and, if the infection persists for at least 2 mo, are tem1ed chronic. Once established, many of these infections persist for entire lactations or the life of the cow. Detection is best done by examination of milk for somatic cell counts (SCCs) (predominantly neutrophils) using either the California Mastitis Test or automated methods provided by dairy herd in1prove­ ment organizations. SCCs are positively correlated with the presence of infection. Inflanimatory changes and decreases in milk quality may start with secs as low as 100,000 cells/mL. Although variable (especially if determined on a single analysis), an sec of �280,000 cells/mL in a cow indicates a >85% chance of being infected. Likewise, the higher the sec in a herd bulk tank, the higher the preva­ lence of infection in the herd. Herd SCCs 40.5 ° C [ 104.9°Fl). The concept that postpartum rectal temperatures >39.5° C (103.1 °F) predict early lactation problems must be questioned. Physiologic hyperthermia observed in lactating sows should not be confused with fever. Reduced appetite or anorexia, constipation, and depression may also be seen. Abnom1al and copious vaginal discharges may be seen in some sows (eg, cervicitis, endometritis). Cystitis, mettitis, vaginitis, constipation, or mastitis in the sow and diarrhea in neonatal piglets should be considered as a general syndrome (requiring an overall diagnosis) rather than as individual problems. Treatment and Control: Systemic or

local therapeutic intervention (antibiotics, NSAIDs) can sometimes be helpful but only

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PROLONGED GESTATION IN CATILE AND SHEEP

on a short-term basis. Flunixin meglurnine may help to counteract the effects of endotoxins. Antin1icrobial treatment is usually presc1ibed before susceptibility can be tested. A broad-spectrum antibiotic is therefore recommended. However, if antibiotics are used longterm, a dependence on them for puerperal fevers, acute mastitis, vaginitis, endometritis, or neonatal diarrhea can develop rapidly and lead to multire­ sistant bacterial infections. Oxytocin or prostaglandins (or both) can be useful in cases of prolonged farrowing or postpartum endomet1itis. By far the most effective method is to cross-foster the piglets from affected to healthy sows, as long as the health status of the litters are equivalent. Oxytocin (5-10 U/sow) is occasionally effective in reestablishing lactation if used 4 or 5 times at 2- to 3-hr intervals. In herds in which PPDS is a significant problem, incidence may be reduced by inducing paiturition with prostaglandin F2ac; this results in rapid induction of labor and dilata­ tion of the teats for a shorter period of time. However, the ainelioration is not constant

1377

an10ng herds and depends on fann circumstances. As many risk factors as possible should he identified and corrected or minimized. Systematic manual interventions during farrowing or uterine washings should be limited to only those that are necessary. There is no clear evidence that vaccines have a beneficial effect. Good sanitation tends to decrease the incidence of mastitis in the sow and diarrhea in the piglets, but PPDS is also common in herds in overall good health and with a high level of hygiene. For clu·onic mastitis, use of partially slatted fan·owing pens and cleaning with disinfectants between batches of sows in the farrowing and breeding ai·eas may be helpful. Cutting or grinding the piglets' teeth after farrowing is not considered a good way to control chronic mastitis. Indeed, it can lead to a high prevalence of mastitis, possibly ca.used by changes in the oral flora of the piglets or the failure of piglets to suckle as a result of sore mouths from careless cutting of teeth.

PROLONGED GESTATION IN CATTLE AND SHEEP Paiturition is induced by the fetus in both cattle and sheep. It is initiated by rising cortisol levels in the fetus that provoke a cascade of endocrine activity in the 40-60 breaths/min) with a shallow abdominal component. This is often associated with a purnlent nasal discharge that sometimes is tinged reddish brown or green. Milk yield is greatly reduced to zero in lactating animals. Thoracic auscultation reveals reduced lung sounds over affected consoli­ dated lung, with increased breath sounds over normal lung. In cows that aspirate ruminal contents as a consequence of becoming cast with hypocalcemia, toxemia is usually fatal within 1-2 days. Superficial consolidated lung and overlying lesions of fibrous pleurisy can readily be identified on ultrasound examination using either linear or sector probes connected to 5-MHz machines; pleuritic friction rubs are not audible on auscultation. In dogs and cats, clinical signs may be peracute, acute, or chronic. Cough, dyspnea, tachypnea, or exercise intolerance are seen most frequently. Thoracic radiographs generally show a bronchoalveolar pattern in gravity­ dependent ventral lung lobes (right cranial and middle and left cranial lobes); however, radiographic changes may not be seen until 24 hr after acute aspiration. Lesions: Aspiration pneumonia is usually in the anteroventral parts of the

lw1g; it may be unilateral in animals in which lateral recwnbency was the cause of aspiration, or bilateral and centered on airways. In early stages, the lungs are markedly congested with areas of interlobular edema. Bronchi are hyperemic and full of froth. The pneumonic areas tend to be cone-shaped, with tl1e base toward the pleura. Suppuration and necrosis follow. The foci become soft or liquefied, reddish brown, and foul smelling. There usually is an acute fibrinous pleuritis, often with pleural exudate. Animals tl1at survive develop chronic abscesses and fibrous adhesions between the visceral and parietal pleura. Prevention and Treatment: Broad­ spectrum antibiotics should be used in animals known to have inhaled a foreign substance without waiting for signs of pneumonia to appear; however, this rarely occurs in farm animals presented with severe clinical signs. A transtracheal wash can help identify the causative agent for which an antibiotic sensitivity can be obtained. Care and supportive treatment include NSAIDs such as flunixin meglumine. In small animals, oxygen therapy can be useful. Saline nebulization and coupage may assist witl1 generating a productive cough to facilitate clearance of the aspirated material. Despite all treatments, prognosis is poor, and efforts must be directed at prevention.

DIAPHRAGMATIC HERNIA A break in tl1e continuity of tl1e diaphragm allows protrusion of abdominal viscera into the tl1orax. Etiology: In small animals, automobile­ related trawna is a common cause of diaphragmatic hernia, altl1ough congenital defects of the diaphragm may also result in herniation (eg, peritoneopericardial hernia). In horses, diaphragmatic hernia may occur, less commonly, congenitally or after trawna, dystocia, or recent strenuous activity. Dia­ phragmatic hernias are extremely rare in cattle. Clinical Findings: The signs vary, depending on the duration and species

affected. Dogs and cats are characteristi­ cally dyspneic in tl1e acute case. The degree of dyspnea may vary from subclinical to incompatible with life, depending on the amount of herniated viscera. If the stomach is herniated, it may bloat and the animal may deteriorate rapidly. In chronic cases, systemic signs such as weight loss may be more prominent than respiratory signs. Physical examination findings may include the absence of lw1g sounds and/or the presence of GI sounds on auscultation of the thorax. Congenital peritoneopericar­ dial hernia is most frequently an incidental finding, although findings may be related to the respiratory or GI systems or due to compromised venous return to tl1e heart.

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LARY NG EAL DISORDERS

Horses most frequently present with acute, severe colic secondary to displaced intestines, or with respiratory signs and dyspnea. In cattle and water buffalo, diaphragmatic hernias may be associated with traumatic reticulitis and herniation of the reticulum.

Diagnosis: Careful physical exan1ina­ tion, including auscultation and percus­ sion, usually suggests the presence of thoracic disease. The definitive diagnosis is most frequently made from radiographs. Loss of diaphragmatic contour, abdominal viscera in the thorax, and displacement of viscera from the abdomen may be apparent. Radiographic contrast studies may be necessary to make the diagnosis. Barium may be given by mouth (GI series),

1419

or water-soluble contrast may be injected intraperitoneally (celiogram). Radio­ graphs may be difficult to obtain in horses and cows; ultrasonography is useful. San1ples from abdominocentesis and thoracocentesis, electrocardiographs, and blood work may be obtained, and surgical exploration of the abdominal cavity may be necessary for definitive diagnosis in these species.

Treatment: Surgical repair of the hernia

is the preferred treatment. Other areas of trauma may be present. Optimally, the animal should be stabilized before surgery. If the diaphragmatic tear is chronic, it is necessary to be especially careful with anesthesia, because reexpansion pulmo­ nary edema is likely fatal.

LARYNGEAL DISORDERS See a/,so LARYNGEAL f!EMJPLEGIA, p 1458.

Laryngitis, an inflammation of the mucosa or cartilages of the larynx, may result from upper respiratory tract infection or by direct irritation from inhalation of dust, smoke, or irritating gas; foreign bodies; or the trauma of intubation, excess vocaliza­ tion, or injury from roping or restraint devices (in livestock). Laryngitis may accompany infectious tracheobronchitis and distemper in dogs; infectious rhinotra­ cheitis and calicivirus infection in cats; infec­ tious rhinotracheitis and calf diphtheria in cattle; strangles, herpesvirus 1 infection, viral arteritis, and infectious bronchitis in horses; Fusobacterium necroplwium or Trueperella pyogenes infections in sheep; and influenza in pigs. Edema of the mucosa and submucosa is often an integral part of laryngitis and, if severe, the rima glottidis may be obstructed. Edema may also result from allergy, inhalation of irritants, or surgery in the area. Intubation for anesthesia, especially when attempted with inad­ equate induction or poor technique, is likely to provoke laryngeal edema. Brachycephalic and obese dogs, and dogs with laryngeal paralysis (seep 1420) develop laryngeal edema and laryngitis through severe panting or respiratory effort during excitement or hyperthermia.

In cattle, laryngeal edema has been seen in blackleg, urticaria, serum sickness, and anaphylaxis. In pigs, it may develop as a part of edema disease. In horses, cattle, and sheep, laryngeal edema may lead to arytenoid chondropathy. Laryngeal chondropathy is a suppura­ tive condition of the cartilage matrix 1hat principally affects the arytenoid cartilages; it is believed to result from microbial infection, often as a sequela of inhalation of initants or trauma to the area In herbivores, trawna can occur when administering medications by bolus or drench or by ingestion of rough foodstuffs; in dogs, trawna can occur from sticks or foreign bodies. Laryngeal chon­ dropathy is characterized by necrosis and ulceration of the laryngeal mucosa, over or just caudal to the vocal cords, and abscessa­ tion within the arytenoid cartilage. Initially, there is often acute laryngeal inflammation. Later, there is progressive enlargement of the cartilages that conunonly results in a fixed upper airway obstruction with stertorous breathing and reduced exercise tolerance. Laryngeal chondropathy is seen in horses, sheep, and cattle, most often young males. There is a distinct breed predisposition in Texel sheep and Belgian Blue cattle. Laryngeal contact ulcers are common in young feedlot cattle and often result in necrotic laryngitis and chondropathy.

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LARYNGEAL DISORDERS

Clinical Findings: A cough is the principal sign of laryngitis when edema is slight and the deeper tissues of the larynx are not involved. It is harsh, dry, and short at first, but becomes soft and moist later and may be very painful. It can be induced by pressure on the larynx, exposure to cold or dusty air, swallowing coarse food or cold water, or attempts to administer medicines. Vocal changes may be evident, especially in small animals. Stridor may result from swelling and reduced motion of the arytenoid cartilages in laryngeal chondropa­ thy. Halitosis and difficult, noisy breathing may be evident, and the animal may stand with its head lowered and mouth open. Swallowing is difficult and painful. Systemic signs ar·e usually attributable to the prin1ary disease, as in infectious bovine rhinotra­ cheitis, in which temperatures of 105 ° F (40.5° C) may occur. Secondary systemic signs due to inappetance and dehydration rapidly become apparent. Death due to asphyxiation may occur, especially if the animal is exerted. Edema of the larynx may develop within hours. It is characterized by increased inspiratory effort and stridor arising from the larynx. Respiratory rate may slow as the effort of breathing becomes exagge1° ated. Visible mucous membranes are cyanotic, the pulse rate is increased, and body temperature rises. Horses may sweat profusely. Dogs with obstructions of the conducting airways may show extreme disturbance of thermoregulation in hot weather; marked hyperthermia is not uncommon. Untreated animals with marked obstruction eventually collapse and often have signs of pulmonary edema. Diagnosis: A tentative diagnosis is based on the clinical signs, auscultation of the laryngeal region, and exacerbation of stridor by palpation of the larynx. Definitive diagnosis requires laryngos­ copy. In conscious horses and cattle, this can be achieved with a flexible endoscope passed per nasum; in dogs and cats, anesthesia or analgesia usually is required. The history and signs usually permit rapid identification of the primary disease and the associated laryngeal involvement. Bilateral laryngeal paralysis, laryngeal abscess, pharyngeal trauma and cellulitis, and retropharyngeal abscesses or masses can cause similar signs. Treatment: In laryngeal obstruction, a tracheotomy tube should be placed immediately; if a tracheotomy is not

possible, airway patency may be estab­ lished by passage of a pliable tube th.rough the glottis. Corticosteroids should be administered to reduce the obstructive effect of the inflan1mato1y swellings. Concurrent administration of systemic ar1tibiotics is also necessary. In cases in which c01ticosteroids cannot be used, NSAIDs can be given. Administration of diuretic drugs, eg, furosemide, may be indicated to resolve laryngeal edema and, if present, pulmonary edema. Identification and treatment of the primary disease is essential. Palliative procedures to speed recovery and give comfort include inhalation of humidified air; confinement in a warm, clean environment; feeding of soft or liquid foods; and avoidance of dust. The cough may be suppressed with antitussive preparations, and bacterial infections controlled with antibiotics or sulfona­ mides. Control of pain with judicious use of an arialgesic, especially in cats, allows the ar1inlal to eat, and thus speeds recovery. Subtotal arytenoidectomy is an effective remedy for laryngeal chondropathy of horses, although a return to full athletic capacity in competitive horses is unce1tain. Tracheolaryngostomies and permanent tracheostomies have been used success­ fully to salvage cattle and sheep with laryngeal chondropathy but carry significant anesthetic risk. A medical alternative for rwninants is prolonged antibiotic therapy, 14-21 days of parenteral lincomycin (5-10 mg/kg), plus initial, short-acting c01ticosteroids.

LARYNGEAL PARALYSIS Laryngeal par·alysis is common in clogs and rare in cats. Signs include a c!J.y cough, voice changes, noisy breathing that progresses to marked difficulty in breathing with stress and exertion, stridor, and collapse. Regtuc gitation and vomiting may occur. Progres­ sion of clinical signs is slow, usually taking montlis to year-s before respiratory distress is evident. It is a common acquired problem in middle-aged to older, large and giar1t breeds of dogs, eg, Labrador Retrievers, Irish Setters, and Great Dar1es. It is seen less often as a hereditary, congenital disease in Bouvier des Flandres, Leonbergers, Siberian Huskies, Bulldogs, and racing sled dogs. Diagnosis is based on clinical signs; laryngoscopy under light anesthesia is needed for confirmation. Laryngeal movements are absent or paradoxical with respiration. Electromyography shows positive sharp waves, dene1vation

VetBooks.ir

LUNGWORM INFECTION

potentials, and sometimes myotonia. Radiographs are not diagnostic. Denerva­ tion atrophy is seen on histologic sections of laryngeal muscles. Differential diagnoses include myositis, recurrent laryngeal or vagal nerve tumor, inflammation, myasthenia gravis, severe hypothyroidism, trauma, and more widespread generalized neurologic degen­ eration. Therapy is directed at relieving signs of airway obstruction. Tranquiliza­ tion and corticosteroids are effective temporarily in mild cases. Severe obstruc­ tion may require tracheotomy. Definitive

1421

therapy is surgical and directed at enlarging the glottic opening. Currently recom­ mended techniques include arytenoid cartilage lateralization, ventriculocordec­ tomy and partial arytenoidectomy, castellated laryngofissure, or permanent tracheostomy. Studies have demonstrated that bilateral ventriculocordectomy through a ventral median laryngotomy has had good longterm treatment success for surgical treatment of idiopathic laryngeal paralysis in dogs, and unilateral aryte-noid lateralization appeared to be a suitable method to treat laryngeal paralysis in cats.

LUNGWORM INFECTION (Verminous bronchitis, Verminous pneumonia) An infection of the lower respiratory tract, usually resulting in bronchitis or pneumo­ nia, can be caused by any of several parasitic nematodes, including Dictyocau­ lus viviparus in cattle, llamas, and alpacas; D filaria in goats, sheep, llan1as, and alpacas; D eckerti in deer; D arnfieldi in donkeys and horses; Protostrongylus rufe­ scens and Muellerius capillaris in sheep and goats; Metastrongylus apri, M puden­ dotectus, and M sal:mi in pigs; Oslerus osleri, Crenosoma vulpis, and Eucoleus aerophilus in dogs; andAelurostrongylus abstrusus and E a.erophilus in cats. Other lungworm infections occur but are less common. Species of Dictyocaulus belong to the superfamily Trichostrongyloidea and have direct life cycles. E aerophilus belongs to the Trichuroidea and is thought to have a direct life cycle. The others belong to the Metastrongyloidea and, except for O osleri, have indirect life cycles. Some nematodes that inhabit the right ventricle and pulmonary circulation, eg, Angiostrongylus vasorum and Dirofilaria immitis, both found in dogs in certain areas of the world, may be associated with pul­ monary disease. Clinical signs relating to a cardiac or a pulmonary syndrome or to a combination of both may occur.

Epidemiology: Diseases caused by the rurninantDictyocaulus spp are of most economic importance. The cattle lungworrn

D viviparus is common in northwest Europe and is the cause of severe out­ breaks of"husk" or"hoose" in young (and more recently, older) grazing cattle. The lungwom1 of goats and sheep, DJumia, is comparatively less pathogenic but does cause losses, especially in Mediterranean countries, although it is also recognized as a pathogen in Australia, Europe, and North America. DfiJ,aria and D vivipmus are less pathogenic in alpacas and llamas, although severe infections can cause coughing, dyspnea, depression, and loss of condition. D arnjieldi can cause severe coughing in horses and, because patency is unusual in horses (but not in donkeys), differential diagnosis with disease due to other respiratory diseases can be difficult. M capillaris is prevalent worldwide and, although usually nonpathogenic in sheep, can cause severe signs in goats. Other lungworrn infections cause sporadic infections in various animal species in many countries. Dictyocaulus spp: Adult females in the bronchi lay larvated eggs that hatch either in the bronchi (D viviparus, DfiJ,aria) or in host feces (D arnjieldi) after being coughed up and swallowed. The infective third-stage larvae can develop on pasture within 5-7 days in wann, moist conditions, but typically in sununer in temperate northern climates will require 2-3 wk. Once larvae are infective, transmission depends on their dispersal away from the fecal pats.

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LUNGWORM INFECTION

Dispersal mechanisms are, primarily, mechanical and include rain or, in the case of D viviparus and possibly D arnjieldi, by the sporangia of the fungus Pilobolus. A proportion of infective larvae survive on pasture throughout the winter until the following year but, in very cold conditions, most become nonviable. The principal source of new infections each year is from infected carrier animals, with overwintered larvae providing a secondary but not unin1portant contribution in some countries. In the case of D arnjieldi, donkeys are the prime source of pasture contamination for horses. Clinical disease in mminants usually develops on first exposure to sufficient infective larvae; the severity of disease and stin1ulation of an immune response is related to the number of larvae ingested. In cattle and sheep, this usually occurs during their first season at pasture; however, an increase in the number of older cattle affected has been reported and is attributed to the efficiency of some prophylactic anthelmintic regimens, which eliminates infection and prevents develop­ ment of a protective inm1une response. Because transmission of infection to horses requires infected donkeys (patent infections rarely occur in adult horses but may occur in foals and yearlings), first infections can occur at any age in that species. Once infected, adult mrninants generally become immune to further disease, but a proportion maintain subclinical infections during which they act as a source of further pasture contan1ination. Occasionally, when previously infected adults or groups that have not been exposed to reinfection for > 1 yr, and in which immunity may have waned, are exposed to an overwhehning level of infection, clinical disease may recur. In areas of Europe in which cattle are housed during winter and first grazing season calves turned out in late April or May, the first infections can be seen between mid June and late July, but most severe infections generally occur in previously unexposed calves after development of the second generation of infective larvae on pasture between August and early October. Other Species: Metastrongylus spp in pigs require an earthworm intermediate host; thus, infection is confined to pigs with access to pasture and may become more common in previously uncommon areas as a result of organic farming methods. M capillaris andPrufescens in sheep and goats require slugs or snails as intermedi­ ate hosts, which must be eaten for infection to occur. C vulpis is acquired by dogs

through ingestion of an infected terrestrial snail or slug intermediate host. A abstrusus is normally acquired by cats after ingestion of a paratenic host such as a bird or rodent that has previously eaten the infected slug or snail intermediate host. Adults of O osleri live in nodules in the trachea of dogs, and larvated eggs laid by adults hatch there. Larvae migrate up the bronchial tree and may pass in the feces; however, these are not active, are often dead or degenerat­ ing, and are not an important route of transmission. Infection in domestic dogs is mainly through saliva as the dam cleans her pups. E aerophilus in dogs likely has a direct cycle, with larvated eggs being ingested with food or water.

Pathogenesis: The pathogenic effect of lungwom1s depends on their location within the respiratory tract, the number of infective larvae ingested, and the animal's immune state. During the prepatent phase of D viviparus infection, the main lesion is blockage of bronchioles by an infiltrate of eosinophils in response to the developing larvae; this results in obstruction of the airways and collapse of alveoli distal to the block. Clinical signs are moderate unless large numbers of larvae are ingested, in which case the animal may die in the prepatent phase with severe interstitial emphysema and pulmonary edema. In the patent phase, the adults in the segmental and lobar bronchi cause a bronchitis, with eosinophils, plasma cells, and lymphocytes in the bronchial wall; a cellular exudate, frothy mucus, and adult nematodes are found in the lumen. The bronchial irritation causes marked coughing, and the entire reaction leads to increased airway resistance. A major component of the patent stage is develop­ ment of a chronic, nonsuppurative, eosinophilic, granulomatous pneumonia in response to eggs and first-stage larvae aspi­ rated into alveoli and bronchioles. This is usually in the caudal lobes of the lungs and is severe when widespread; in combination with the bronchitis, death may result. Interstitial emphysema, pulmonary edema, and secondary bacterial infection are complications that increase the likelillood of death. Survivors may suffer consider­ able weight loss. If the animal survives until the end of patency (2-3 mo for D viviparus), most or even all of the adult worms are expelled, and the cellular exudate resolves over the ensuing 4 wk. Most animals recover unless secondary infection develops in the

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LUNGWORM INFECTION

damaged lungs during the postpatent phase. In a few animals, clinical signs are exacerbated in the postpatent phase due to development of a diffuse, proliferative alveolitis characterized by hyperplasia of the type II alveolar epithelial cells. The cause is unlrnown, but it is seen much less often in cattle treated with anthelmintics with a persistent action against D viviparus such as the macrocyclic lactones ivennec­ tin, doramectin, eprinomectin, and moxidectin. DjUaria is similar to D viviparus, but interstitial emphysema is not a common complication. Bronchial lesions predomi­ nate in D arnfieldi infections; when an alveolar reaction occurs, as in donkeys or foals, there are lobular areas of overinfla­ tion due to intermittent obstruction of small bronchi. The pathogenic effect of the other lungwonns has a similar basis, but frequently such severe clinical signs are not produced, perhaps because of a more restricted localization in the lungs and less severe infections. The patent phase and the associated lesions last >4 mo for some lungworms (M apri and A abstrusus) but can be >2 yr (M capillaris). The lesions in pigs with metastrongylosis are a combina­ tion of localized bronchitis and bronchioli­ tis with overinflation of related alveoli, usually at the tips and midway along the diaphragmatic lobes. Associated with the mass of nematodes in the lumen is hypertrophy and hyperplasia of bronchi­ olar and alveolar duct smooth muscle with marked mucous cell hyperplasia. Near the end of the patent period (as adult worms are killed), gray-green lymphoid nodules (2-4 mm) are formed; fragments of dead worms may be seen microscopically in these nodules composed of lymphocytes and plasma cells surrounding a central zone of eosinophils. In M capillaris and P rufescens infections, chronic, eosinophilic, granu­ lomatous pneun10nia seems to predomi­ nate; the reaction is in the bronchioles and alveoli that contain the parasites, their eggs, or larvae. They are surrounded by macrophages, giant cells, eosinophils, and other immunoinflammatory cells, which produce gray or beige plaques (1-2 cm) subpleurally in the dorsal border of the caudal lung lobes. Small (1-2 mm), greenish, nodular lesions may also develop. The effect of these lesions in sheep is minor, perhaps because of tl1e predominantly subpleural location. This infection represents the lower end of the pathogenic spectrunl for lungworms.

1423

In cats, A abstr1tsus produces nodular areas of granulomatous pneumonia in the caudal lobes tl1at, if sufficiently generalized, can be clinically significant and occasionally fatal; a notable feature is the hypertrophy and hyperplasia of the smooth muscle in tl1e media of pulmonary arteries and arterioles. The nodules of O osleri, found in the mucous membrane of the trachea and large bronchi, can produce extreme airway irritation and persistent coughing. C vulpis infections result in chronic bronchitis and bronchiolitis, which leads to chronic coughing. E aerophilus infections in dogs are usually well tolerated but may ca.use chronic tracheitis and bronchitis. In adult animals not previously exposed to infection, the lesions and pathogenesis are the same as in young animals. However, in adults with some degree of inmmnity, reexposure to the parasite (eg, husk in adult cattle) can result in different lesions. Despite the immune response, many larvae reach the lungs before they are killed in the tem1inal bronchioles and alveoli. Larvae not killed in the terminal bronchi­ oles may reach the bronchi and cause a bronchitis characterized by marked eosinophilic infiltration of the bronchial walls and greenish yellow exudate in the lumen comprising eosinophils, other inflanm1atory cells, and parasitic debris. The reaction associated with this process can lead to severe clinical signs if the nodules are nwnerous and the eosinophilic bronchitis extensive; this is responsible for the reinfection phenomenon.

Clinical Findings: Signs of lungworm

infection range from moderate coughing with slightly increased respiratory rates to severe persistent coughing and respiratory distress and even failure. Reduced weight gains, reduced milk yields, and weight loss accompany many infections in cattle, sheep, and goats. Patent subclinical infections can occur in all species. The most consistent signs in cattle are tachypnea and coughing. Initially, rapid, shallow breathing is accompanied by a cough that is exacerbated by exercise. Respiratory difficulty may ensue, and heav­ ily infected animals stand with their heads stretched forward and mouths open and drool. The animals become anorectic and rapidly lose condition. Lung sounds are particularly prominent at the bronchial bifurcation. In adult dairy cattle, milk yield drops severely, and abnormal lung sounds are heard over the caudal lobes. The reinfection phenomenon in adult dairy cattle is usually seen in the fall; although

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1424

LUNGWORM INFECTION

less severe than in initial infections, the signs are widespread coughing and tachypnea and a marked drop in milk yield. The signs in llamas, alpacas, sheep, and goats infected with Dfilaria are similar to those in cattle. Pulmonary signs usually are not associated with M capillaris or P rufescens in sheep, but the former can affect goats similarly to Djilaria. D arnfieldi is associated with coughing, tachypnea, and unthriftiness in older horses but with few if any signs in foals or donkeys. The main clinical sign of metastrongylo­ sis in pigs is a persistent cough that may become paroxysmal. Coughing and dyspnea occur with A abstrusus infections in cats and O osleri or C vulpis infections in dogs. Fatalities are relatively uncommon with these lw1g­ wonns, although they do occur in kittens. Diagnosis: Diagnosis is based on clinical signs, epidemiology, presence of first-stage larvae in feces, and necropsy of animals in the same herd or flock. Bronchoscopy and radiography may be helpful. Larvae are not found in the feces of animals in the prepatent or postpatent phases and usually not in the reinfection phenomenon (D viviparus). ELISA tests are available in some countries. The test is mainly of use in detecting cattle that have not been exposed, rather than as a differential diagnostic tool in acute respiratory disease. In the early stages of an outbreak, larvae may be few in number. First-stage larvae or laivatecl eggs can be recovered using most fecal flotation techniques with the appropriate salt solutions; however, larvae will crenate if allowed to-sit for a long time on the slide before examination, making identification difficult. Bronchial lavage can reveal D arnfieldi infections in horses. A convenient method to recover larvae is a modification of the Baermann technique, in which large fecal samples (25-30 g) are wrapped in tissue paper or cheese cloth and suspended or placed in water contained in a beaker. The water at the bottom of the beaker is examined for larvae after 4 hr; in heavy infections, laivae may be present within 30 min. In domestic pets, detection of first­ stage larvae in the feces, either on flotation or with the Baermann technique, is still the diagnostic technique of choice. However, in dogs, cats, and horses, because of the relative infrequency of infection in many areas, lungworms may be considered only after failure of

antibiotic therapy to ameliorate the condi­ tion. Adults of Dictyocaulus spp and M apri ai·e readily visible in the bronchi during the patent phases of infection. However, examination of smears from bronchial mucus or histologic sections from lesions may be necessary to confirm the diagnosis during other stages of lungworm infection (and also for other lungworms). Bronchoscopy can be used to detect nodules of O oslmi or to collect tracheal washings (dogs and horses) to exanline for eggs, laivae, and eosinophils. Necropsy should include examination of the trachea, particularly at the bifurcation, for O osleri and the lesions they induce. Treatment: Several drugs are useful to treat lungworms (see TABLE 1). The benzimidazoles (fenbendazole, oxfenda­ zole, and albendazole) and macrocyclic lactones (ivermectin, doramectin, eprinomectin, and moxidectin) are frequently used in cattle and are effective against all stages of D v'iviparus. These drugs are also effective against lung­ worms in sheep, horses, and pigs. Levamisole is used in cattle, sheep, and goats, but treatment may need to be repeated 2 wk later because it is less effective against laivae during the early stages. Topical fonnulations containing moxidectin, selamectin, or emodepside and oral fenbendazole have been used successfully in cats for A abstrusus. O osle1i in clogs is a problem, but there is evidence that fenbendazole and ivermec­ tin ai·e effective if treatment is prolonged (fenbendazole). Injectible doramectin along with removal of as many nodules as possible is the current treatment of choice. E aerophilus in dogs and cats is similarly difficult to treat, but success has been reported with ivermectin, fenbenda­ zole, or selamectin. Animals at pasture should be moved off infected pasture, and supportive therapy may be needed for complications that can ai·ise in all species. Control: Lungworm infections in herds or flocks are controlled primarily by vaccination or anthelmintics. Oral vaccines are available in Europe for D viviparus (northeastern areas) and Djilaria (southeast). Two doses of irradiated infective larvae are given 4 wk apart, with the second dose given at least 2 wk before the start of grazing or exposure to probable infection. Used properly, they prevent clinical disease,

VetBooks.ir

MYCOTIC PNEUMONIA

IH=i•il

1425

RECOMMENDED TREATMENTS FOR LUNGWORMS

Parasite

Host

'Ireatment8

Dictyocaulus viviparus

Cattle

Ivem1ectin, doramectin, moxidectin, eprino­ mectin, fenbendazole, albendazole, levamisole

DfiJ,aria

Sheep, goat

Ivermectin, doramectin, moxidectin, eprino­ mectin, fenbendazole, albendazole, levamisole

D arnjieldi

Horse, donkey

Ivermectin, moxidectin

Metastrongylus spp

Pig

Ivem1ectin, doramectin, moxidectin, fenbendazole, levamisole

Aelurostrongylus abstrusus

Cat

Fenbendazole, emodepside, moxidectin, selamectin

Oslerus osleri

Dog

Fenbendazole, ivermectin, doramectin

Eucoleus aerophilus

Dog, cat

Fenbendazole (dog), selamectin (cat)b

Crenosoma vulpis

Dog

Febantel, fenbendazole, milbemycin oxin1e, moxidectin

a In severe cases, NSAIDs may also be helpful. b Anecdotal evidence for efficacy but no published evidence or label recommendations.

but some vaccinated animals may become mildly infected to the extent that larvae are excreted and perpetuate further infection. Anthelmintic prophylaxis has become feasible with the advent of anthelmintics with prolonged activity (eg, ivermectin, doramectin, moxidectin, eprinomectin). With persistent anthelmintics, two or three treatments during the grazing season, the timing of which depends on local grazing practice and epidemiology, are effective and may, by disrupting developing infections, stimulate

immunity to the parasite. The use of multiple treatments may delay immunity to D viviparus until the animal is adult, when infection (albeit usually less severe) can occur. However, these methods have become popular in that GI parasites are controlled simultaneously. Other more sporadic infections can be controlled more easily by man�gement, eg, avoidance of grazing horses with donkeys, indoor husbandry of pigs, and by not mixing sheep and goats on the same grazing.

MYCOTIC PNEUMONIA Fungal infection of the lung may result in an acute to chronic active, pyogranulomatous pneumonia. Etiology: Cr1.Jptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatiditis, Pneumocystisjiroveci, Aspergillus spp, Candida spp, and other less common fungi have been identified as causative

agents of mycotic pneumonia in immuno­ compromised hosts (see also FUNGAL INFECTIONS, p 632). Infection is typically caused by inhalation of spores, which can lead to hemolymphatic dissemination. Pulmonary tissues and secretions are an excellent environment for these organ­ isms. Aspergillosis is most commonly associated with sinonasal infection in dogs or sino-orbital infection in cats,

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MYCOTIC PNEUMONIA

with systemic infection being quite rare and seen only in immunocompromised individuals. Cryptococcosis most commonly affects the nasal cavity in cats, with CNS infection less commonly encountered in dogs and cats. The source of most fungal infections is believed to be soil-related rather than horizontal transmission.

Lesions: Multifocal to coalescing lesions of granulomatous to pyogranu­ lomatous inflammation are present in the lungs or other affected organs. Abscess fom1ation and cavitation may be seen in conjunction with yellow or gray areas of necrosis. Causative organisms are present within macrophages or areas of intense inflammation.

Clinical Findings: Mycotic pneumonia is more commonly seen in small animals than in large. The most common course of disease is chronic. A short, productive cough is often present. A thick, mucoid to mucopurulent nasal discharge may be present. As the disease progresses, dyspnea, emaciation, and generalized weakness become increasingly evident. Respiration may become abdominal, with crackles on auscultation. Generalized lymphadenopathy is common in dogs. Multiple cutaneous and subcutaneous nodules with draining tracts may be seen with blastomycosis in dogs. Blastomyco­ sis is often associated with emaciation and diarrhea in dogs, with skin lesions common in cats. Coccidiomycosis is often associated with severe bone pain due to osteomyelitis in dogs, with skin lesions common in cats. Uveitis or granuloma­ tous chorioretinitis may accompany dimorphic fungal infections. (See also FUNGAL INFECTIONS, p 632.)

Diagnosis: Thoracic radiographs often disclose a diffuse pattern with tracheo­ bronchial lymphadenopathy in dogs or large focal pulmonary granulomas in cats. If bone pain is present, skeletal radiogra­ phy shows osteolysis with periosteal proliferation and soft-tissue swelling at infected sites. Abdominal radiography may reveal granulomas or lymphadenopathy. The clinical diagnosis can be confinned with impression smears of cutaneous draining tracts, fine-needle aspirate of the lung, lymph node aspirates, or CSF tap (cryptococcosis). Special stains can be used to highlight the organisms. Treatment: Treatment of mycotic pnemnonia is often lengthy. Drugs of choice include itraconazole, fluconazole (cryptococ­ cosis), lipid-complexed amphotericin B, and terbinafine (aspergillosis). Newer generation azole antifungals such as voriconazole or posaconazole are more effective for resistant infections or systemic aspergillosis.

PHARYNGITIS Pharyngitis is an inflammatory condition of the walls of the oro- or nasopharynx. Pharyngitis may develop secondary to viral or bacterial infections of the upper respiratory tract, eg, strangles in horses and distemper in dogs. In most species, a common pharynx is present at times other than deglutition. The unique caudal pharyngeal-laryngeal anatomy of horses shows complete separa­ tion of the pharynx into two components, the nasopharynx and the oropharynx.

(See also PHARYNGEAL LYMPHOID HYPERPLASIA,

p 1459.)

Clinical Findings: Animals affected with

pharyngitis have a normal desire to eat and

drink but may have difficulty swallowing and appear dysphagic. Animals with secondary peripharyngeal cellulitis and abscessation may be acutely dyspneic secondary to pharyngeal obstruction. For example, foals affected with suppurative pharyngitis secondary to abscessation of the retropharyngeal lyn1ph nodes can become acutely dyspneic and require an emergency tracheotomy. Diagnosis: The diagnosis of pharyngitis can be made with a complete physical examination, radiography of the skull, endoscopic evaluation of the pharynx, and microbial cultures of draining

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PHARYNGITIS

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abscesses or nasopharyngeal swabs for viral isolation. In small animals, oral pain and resistance to having the mouth opened may indicate retropharyngeal abscessation and the presence of a penetrating foreign body or oral or tonsil­ lar neoplasia. Abnormal pharyngeal tissue should be biopsied and submitted for histopathology to exclude pharyngeal neoplasia. In small animals, oral examina­ tion and/or endoscopic examination is the best diagnostic tool for pharyngitis. In large animals, the diagnosis of pharyngitis is easily made by endoscopic examination of the upper respiratory tract. Treatment: Bacterial pharyngitis should

be treated with systemic antimicrobials based on microbial culture and sensitivity testing. Abscesses should be drained and lavaged when appropriate. Viral-induced pharyngitis should be managed with antimi­ crobials to prevent secondary bacterial infections. Animals affected with either bacterial or viral pharyngitis should be treated with NSAIDs. Pharyngitis second­ ary to foreign bodies should be resolved with removal of the offending object and effective surgical drainage accompanied by excision of necrotic tissue. Racehorses affected by pharyngeal lymphoid hyperplasia can be treated with topical and systemic anti-inflammatory agents such as flunixin meglumine, phenylbutazone, or dexamethasone. A commonly used topical anti-inflamma­ tory treatment includes prednisolone, DMSO, glycerin, and nitrofurazone. Large pharyngeal masses can also be treated with contact diode laser photoablation. Some veterinarians have also found hyperimmunization helpful in managing pharyngeal lymphoid hyperplasia. Calicivirus infections in cats may cause mild, moderate, or severe ulceration of the oropharyngeal mucosa. Although specific antiviral therapies are not available, affected cats should be treated with systemic antimicrobials to prevent secondary bacterial infection. Animals that cannot maintain their own hydration because of severe mucosa! ulceration may require nutritional and electrolyte supplementation either intravenously or by extraoral alimentation.

PHARYNGEAL TRAUMA Pharyngeal trauma in ruminants is not uncommon secondary to iatrogenic

Stylohyoid fracture in a horse. Courtesy of Dr. Sameeh M. Abutarbush.

causes, such as incorrect passage of balling guns or attempts to pass probangs per os. Affected cattle develop severe swelling of the head and proximal neck secondary to diffuse cellulitis caused by penetration of the pharyngeal mucosa. Feed frequently becomes impacted in these areas and can lead to acute dyspnea. Management of pharyngeal trauma in ruminants should include the placement of a temporary rumen fistula to provide extraoral alimentation while the pharyngeal defect heals. Treatment should also include systemic antimicrobi­ als and anti-inflammatory agents. Some affected animals may also require surgical drainage of accumulated feed anct abscessation secondary to the foreign material. In small animals, oropharyngeal foreign bodies are quite common in dogs but less so in cats. However, cats are prone to ingestion of linear foreign bodies, which may become entangled with the tongue and can be identified with a careful oral examination under sedation or general anesthesia. Penetrating foreign bodies include pins, needles, and pieces of stick or bone fragments. Small animals sus­ pected to have oropharyngeal foreign bodies should be evaluated with an oral examination while sedated or anesthe­ tized and with radiographs or ultra­ sound to identify all foreign material present. Once identified, pharyngeal foreign bodies may be removed directly via the oral cavity or approached externally.

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PULMONARY EMPHYSEMA

PULMONARY EMPHYSEMA Two major forms of pulmonary emphy­ sema are generally recognized. Alveolar emphysema is abnom1al permanent enlargement of air spaces distal to the terminal bronchiole and destruction of alveolar septa! walls without apparent fibrosis. Interstitial emphysema is the presence of air within the supporting connective tissue stroma of the lung (interlobular, subpleural, mediastinal, subcutaneous).

Epidemiology and Pathogenesis:

Emphysema affects -10% of people with chronic obstructive pulmonary disease; the main risk factors are tobacco smoke exposure and a,-antitrypsin deficiency. In animals, it typically occurs secondary to a primary obstructive pulmonary disease process. While the pathogenesis of pulmonary emphysema is not fully understood, at least three mechanisms have been suggested: 1) an in1balance between protease secreted by neutrophils and macrophages, and antiprotease activity results in destruction of alveolar walls and interstitial matrix; 2) inappropri­ ate maintenance of lung structure and repair follows injury; and 3) the condition develops secondary to obstruction of airways on expiration: due to chronic bronchitis/bronchiolitis or congenital abnormality of the airway wall. This creaLes a "check valve" lesion, in which air is able to enter alveoli on inspiration or through collateral ventilation but is unable to leave freely and causes air trapping. Recurrent airway obstruction, or "heaves" in horses (seep 1455), is associ­ ated with chronic bronchitis and bronchi­ olitis, resulting in alveolar hyperinflation by air trapping. The condition is partially reversible with bronchodilators; however, a small subset of horses develop alveolar emphysema presumably from chronic overdistention of alveolar walls and protease/antiprotease inlbalance associ­ ated with pulmonary inflammation. Congenital lobar emphysema of dogs (as seen in the Pekingese breed) occurs second­ ary to aplasia or hypoplasia of bronchiolar cartilage that collapses during expiration, leading to air trapping. Because of well­ developed interlobular septa and lack of collateral ventilation, cattle are particularly

susceptible to interstitial emphysema. Pulmonary diseases associated with airway obstruction and dyspnea, such as bovine respiratory syncytial virus infection, acute respiratory disease syndromes, such as acute pulmonary edema and emphysema (seep 1439), and moldy sweet potato toxicity (seep 1442) are commonly associated with interstitial emphysema. Severe interstitial emphysema can cause large gas bullae in all parts of the lung and subcutaneous emphysema as air dissects along fascial planes from the lungs through the mediasti­ mun and thoracic inlet to the subcutis of the back.

Clinical Findings and Diagnosis:

Clinical signs depend on the primary disease process. Often, affected animals present with labored breathing, and auscultation reveals abnormal breath sounds such as wheezes and crackles due to airway disease. The area of thoracic auscultation is typically enlarged due to lung hyperinflation. At necropsy, the lungs do not collapse and stay overinflated. Histology is the only method to differen­ tiate lung overinflation secondary to pulmonary emphysema from air trapping due to airway obstruction from chronic bronchiolitis or bronchitis. Air bubbles (bullae) of various sizes may be seen in the subpleural space and interstitium, as well as around the kidneys and pericardia! sac in cattle with emphysema. Pulmonary emphysema affects a small percentage of horses with recurrent airway obstruction ( -12%). Lesions may develop as subpleural bullae or emphysema localized to a lobe or diffused lesions. Minor degrees of emphysema may precede death if there was a prolonged struggle or exaggerated respiration. These agonal changes should be differentiated from antemortem lesions.

Treatment: Emphysema is an irreversible lung lesion; however, therapy directed toward the prinlary disease process may result in significant improvement of clinical signs, especially by targeting airway obstruction with administration of bronchodilator and anti-inflan1matory drugs.

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RESPIRATORY DISEASES OF CATTLE

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RESPIRATORY DISEASES OF CATTLE Respiratory disease is among the most economically important diseases of cattle in production on a worldwide basis.

bone lysis. Cytology of aspirated material from the affected sinus may reveal purulent material. Treatment: Sinusitis is treated by draining

Allergic rhinitis is an uncommon disease of cattle that, when chronic, may lead to granu­ loma formation. The etiology is an allergic reaction to pollen or fungal spores. Signs are seasonal and occur under warm, moist conditions; they include rhinorrhea, sneezing, and a sudden onset of dyspnea. In the chronic stage, multiple granulomas may fom1 on the mucosa.I surface of the nasal cavity. Cytologic examination of nasal discharges may reveal eosinophils. Treatment should focus on removing the allergen or removing the animal from the allergen. Treatment with cotticosteroids to block tl1e hypersensitivity reaction is a consideration.

Etiology: Sinusitis in cattle typically involves the frontal or maxillary sinus. Frontal sinusitis is usually associated with dehoming, and maxillary sinusitis with infected teeth. Numerous bacteria have been isolated from sinusitis infections in cattle. Clinical Findings: Frontal sinusitis may occur immediately after dehoming while the site is still open or months later after the dehoming site has healed. The condition is most often unilateral. Signs may include anorexia, pyrexia, unilateral or bilateral nasal discharge, changes in air flow through the nasal passages, and foul breath. Head carriage may be abnonnal. In longstanding cases of frontal sinusitis, there may be distortion of the frontal bone, exophtha.1mos, and neurologic signs. Diagnosis: Diagnosis can usually be made on the basis of clinical signs. Percussion may reveal a dull sound over the affected sinus. Radiographs may reveal fluid in the sinus, the presence of dental disease, or

the affected sinus. Trephine sites should be selected carefully, using approptiate anatomic landmarks. If an infected tooth is the cause of maxillary sinusitis, the tooth can be repelled through a sinusotomy site created with a trephine. Once drainage has been established, the sinus can be lavaged daily with antiseptic solutions. Treatment with parenteral antibiotics is indicated if systemic signs are present. NSAIDs can be given for pain relief, if needed. The prognosis is guarded. Control: The best control method is to

dehom calves at a young age using a closed dehoming technique. If this is not possible, close attention should be paid to disinfec­ tion of surgical instruments between animals, dust control, and fly control.

(Calf diphtheria, Laryngeal necrobacillosis) Fusobacterium necrophorum, a gram­ negative, nonsporefonning anaerobe, is a nonnal inhabitant of the alimentary, respiratory, and genital tract of animals. The organism is an opportwustic pathogen that causes several necrotic conditions in animals (ie, necrobacillosis), including necrotic laryngitis. Necrotic laryngitis is an acute or chronic Fnecrophorum infection of the laryngeal mucosa and cartilage of young cattle, characterized by fever, cough, inspirato1y dyspnea, and stridor. It occurs prin1arily in feedlot cattle 3--18 mo of age; however, cases have been documented in calves as young as 5 wk and in cattle as old as 24 mo. Cases are seen worldwide and year round but appear to be more prevalent in fall and winter. Etiology: Predisposing factors are not fully understood. F necrophorum, commonly isolated from laryngeal lesions of affected cattle, is unable to penetrate intact mucous membranes. Laryngeal contact ulcers, a common finding in slaughtered cattle, are thought to provide a portal of entry for F necrophorum.

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RESPIRATORY DISEASES OF CADLE

Transmission, Epidemiology, and Pathogenesis: Necrotic laryngitis is

most common where cattle are closely confined under unsanitary conditions or in feedlots. The prevalence in feedlot calves is estimated to be 1o/o-2%. Most cases are sporadic and occur year round, but disease peaks in fall and winter. Mixed upper respiratory tract infections (caused by infectious bovine rhinotra­ cheitis virus and parainfluenza-3 virus; Mycoplasma spp; and bacteria, including Pasteurella and Haemophilus), and the coughing and swallowing associated with these infections, may predispose feedlot cattle to develop laryngeal contact ulcers. These ulcers on the vocal processes and medial angles of arytenoid cartilages are thought to provide a portal of entry for

F necrophorum. F necrophorum causes inflammation,

necrosis, and edema in the laryngeal mucosa, resulting in variable narrowing of the rin1a glottidis and inspiratory dyspnea and stridor. If infection extends into the laryngeal cartilage, laryngeal chondritis develops, which may lead to a chronically defo1med larynx. Pharyngeal invasion by the organism causes discomfort character­ ized by painful swallowing motions. Systemic signs of illness have been attributed to the exotoxin produced by

F necrophorum.

Clinical Findings: Initially, a moist, painful cough is noticed. Severe inspiratory dyspnea, characterized-by open-mouth breathing with the head and neck extended, and loud inspiratory stridor are common findings. Ptyalism; frequent, painful swallowing motions; bilateral, purulent nasal discharge; and a fetid odor to the breath may also be present. Systemic signs may include fever (106° F [41.1 °Cl), anorexia, depression, and hyperemia of the mucous membranes. Untreated calves die in 2-7 days from toxemia and upper airway obstruction. Longterm sequelae include aspiration pneumonia and permanent distortion of the larynx, resulting in a clU"onic harsh cough and inspiratory dyspnea. Lesions: Lesions are typically located over the vocal processes and medial angles of arytenoid cartilages. Acute lesions are characterized by edema and hyperemia surrounding a necrotic ulcer in the laryngeal mucosa; lesions may spread along the vocal folds and processes to involve the cricoarytenoideus dorsalis muscle. In chronic cases, lesions consist of necrotic

cartilage associated with a draining tract swTounded by granulation tissue. Diagnosis: Clinical signs are usually

sufficient to establish a diagnosis. However, because numerous other conditions can cause signs of upper airway obstruction, the larynx should be visually inspected to confirm a diagnosis. This can be accom­ plished by means of an orally inse1ted speculum, laryngoscopy, endoscopy, or radiography, but care must be exercised to avoid fimher respiratory embarrassment. A tracheostomy should be performed before laryngoscopic or endoscopic exan1ination in cattle with severe inspira­ tory dyspnea. Differential diagnoses include pharyngeal trauma; severe viral laryngitis (eg, infectious bovine rhinotracheitis); actinobacillosis; and laryngeal edema, abscesses, trauma, paralysis, or tumors. Treatment and Control: Oxytetracy­

cline (11 mg/kg, IV or SC, bid, or 20 mg/kg of long-acting tetracycline, SC, every 72 hr) or procaine penicillin (22,000 U/kg, IM, bid) are the antin1icrobials of choice. NSAIDs (aspirin, 100 mg/kg, PO, bid; flunixin, 1.1-2.2 mg/kg, IV, once daily or divided bid; or ketoprofen, 3 mg/kg/day, IM or IV, for up to 3 days) are used to decrease the fever and laryngeal inflammation and edema. A single dose of dexamethasone (0.2-0.5 mg/kg, IV or IM) may be used to decrease laryngeal edema in aninlals with severe respiratory distress. A tracheostomy is indicated in cattle with severe inspiratory dyspnea. Good nursing care should be provided. Intravenous fluids may be required in dehy­ drated animals. The prognosis is good for early cases treated aggressively; chronic cases require surgery under general anesthesia to remove necrotic or granula­ tion tissue and to drain laryngeal abscesses. A 6()0A, success rate has been reported for surgical intervention in advanced cases. There are no specific control measures for necrotic laryngitis; however, the proposed pathogenesis suggests that control measures for common respiratory pathogens may be beneficial.

Tracheal edema syndrome is characterized by extensive edema of the mucosa and submucosa in the dorsal membrane of the lower trachea. The etiology is unknown. Proposed causes include respiratory viruses

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RESPIRATORY DISEASES OF CATILE and bacteria, trauma to the trachea f rom feed bunks, passive congestion and edema from excessive fat accumulation in the thoracic inlet, hypersensitivity reactions, and mycotoxins. The condition occurs in heavy feeder cat­ tle in the later two-thirds of the feeding period throughout North America but may be most severe in the summer in southern plains (USA) feedlots. Onset is sudden and appears to be associated with an increase in respirations stimulated by hot weather or exercise. The initial signs a.re a loud inspiratory noise (stridor) and the onset of dyspnea.. Forced movement ca.uses the respiratory distress to worsen. The cattle become cyanotic and typically collapse and die of asphyxiation in 104° F (40 °C). Antibiotics are indicated when fever persists beyond3-4 days or when purulent nasal discharge or pneumo­ nia is present. Prevention of influenza requires hygienic management practices and vaccination. Exposure can be reduced by isolation of newly introduced horses for 2 wk. Numer­ ous vaccines are commercially available for prevention of equine influenza. An intranasal modified-live influenza vaccine, designed to induce mucosal (local) antibody protection, has demonstrated protection against natural challenge. This vaccine is temperature sensitive and is not capable of replicating beyond the nasal passages (ie, inactivated by core body temperature). Most commercially available influenza vaccines are inactivated, acljuvanted vaccines recommended

primarily for IM administration. A recombi­ nant canarypox-vectored influenza vaccine has also been shown to be effective against influenza challenge. Because the duration of protection provided by current vaccines is limited, booster iltjections for at-risk adult horses should be administered every 6 mo. Sedentary horses can be vaccinated annually. Foals should be vaccinated with a single modified-live intranasal vaccine or a series of three inactivated vaccines beginnillg at 6 mo, with booster vaccination in 3----6 wk and again between IO and 12 mo of age. Broodmares should be vaccinated 4---6 wk before foaling.

EQUINE VIRAL ARTERITIS Equine viral arteritis (EVA) is caused by an RNA togavirus and produces clinical signs of respiratory disease, vasculitis, and ab01° tion. Horses with EVA infection present with fever, anorexia, and depression. The clinical signs of respiratory infection due to EVA are serous nasal discharge, cough, conjunctivitis, lacrimation, and palpebral, scrotal, and periorbital edema. Clinical signs of disease persist for 2-9 days. Treatment consists of supportive care (support bandages) and NSAIDs for fever and inflanrn1ation. Antimicrobial therapy is usually unnecessary. A carrier state occurs in most stallions after natural infection and is primarily responsible for persistence of the virus in the horse population through infectious seminal fluids. Vaccination (modified-live virus) is targeted toward prevention of venereal spread of EVA in breeding animals as opposed to prevention of respiratory disease (seep 701).

HENDRA VIRUS INFECTION (Equine morbillivirus)

Hendra virus (HeV) is tl1e prototype species of a new genus Henipavi1us within the subfamily Paramyxovirinae and was first identified in Australia in 1994. The viral agent is endemic in specific species of fruit bats (also called flying foxes), and close contact with these bats is suspected to have facilitated transfer of the HeV to horses. Horses are infected by oronasal routes and excrete HeV in urine, saliva, and respiratory secretions. There have been multiple, sporadic incidents of human and equine disease in Australia occurring in 1994, 1995, 1999, 2004, 2008, and 2009. The case fatality rate

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RESPIRATORY DISEASES OF HORSES in horses and people is high, with reports of 81 horses and 4 people succwubing to Hendra virus infection, including an equine veterinarian investigating an outbreak. Very close contact is required to transmit the virus an1ong horses and from horses to people, and the virus is not considered highly contagious. Equine veterinarians are considered at occupational risk of contractingHeV. Infected horses develop severe and often fatal respiratory disease, characterized by dyspnea, vascular endothelial dan1age, and pulmonary edema. Depression, anorexia, fever, respiratory difficulty, ataxia, tachycardia, and frothy, nasal discharge are common clinical signs. (See a.lso p 707.) A commercialHeV vaccine for use in horses is available ru1der a Minor Use Pem1it for release to veterinarians who have completed an online training program. Horses must have a microchip to be vaccinated, and the infonuation must be entered into theHeV Vaccine National Online Registry. The vaccine consists of soluble fom1s ofG glycoprotein ofHeV; it does not contain modified or inactivated virus.

PLEUROPNEUMONIA (Pleuritis, Pleurisy)

Pleuropnewuonia is defined as infection of the lru1gs and pleural space. In most instances, pleural infection develops secondary to bacterial pneumonia or penetrating tl10racic woru1ds. Spontaneous pleuritis (without accompanying pnellillo­ nia) is uncommon in horses. In the USA, -700/o of horses with pleural effusion have pleuropneWllonia. The prin1ary differential diagnoses for pleural effusion are neoplastic effusions, heart failure, and hydatidosis.

Etiology and Pathogenesis: Viral

respiratory infection, long-distance transportation, general anesthesia, and strenuous exercise are common predispos­ ing factors that impair pulmonary defense mechanisms, allowing secondary bacterial invasion. Head restraint results in bacterial contan1ination and multiplication within the lower respiratory tract within 12-24 hr and may be tl1e single most important predispos­ ing factor for development of pnew110nia associated with long-distance transport. Race and sport horses are particularly at risk. Most horses with pleuropneWllonia are atl1letic horses 2 sec), and tachycardia. Auscultation reveals a lack of breath sounds in the ventral lung fields and abnormal lung sounds (often crackles) in dorsal lung fields. Cardiac soru1ds may be muffled or absent or may radiate over a wider area. Although uncommon, pleural friction rubs are most prominent at end-inspiration and early expiration and are detected after thoracic drainage.

Diagnosis: In horses witl1 peracute pleuropnewuonia, laboratory findings reflect bacterial sepsis or toxemia and include abnormalities such as leukopenia,

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RESPIRATORY DISEASES OF HORSES

neutropenia, left shift, hemoconcentration, and azotemia. Horses with more stable disease have leukocytosis, mature neutrophilia, hyperfibrinogenemia, hyperglobulinemia (chronic antigenic stimulation), hypoalbuminemia (loss in pleural space), and anemia of chronic disease. Thoracic ultrasonography is ideal for investigation of pleural effusion and is indicated in horses with regions of poor to absent breath sounds, thoracic pain, and/or dull thoracic percussion. Transudative pleural fluid (neoplastic effusion) appears anechoic, whereas more cellular exudate appears echogenic. Gas echoes represent small air bubbles within pleural fluid, which may indicate an anaerobic pleural infection, a bronchopleural fistula, or iatrogenic introduction of air. Pulmonary atelectasis, consolidation, and abscessation can be identified if the lesions are located in periph­ eral lung fields. Ultrasonographic evidence of a large area of pulmonary consolidation, in cor\junction with serosangui:neous suppu­ rative plew·aJ effusion, is consistent with pulmonary infarction and necrotizing pneumonia. Adhesions of the visceral to parietal pleura can be visualized using thoracic ultrasonography, and these regions should be avoided during thoracocentesis. Ultrasonography should be performed before pleurocentesis to detennine the best site for maximal drainage and to avoid cardiac or diaphragmatic pw1cture. Thoracocentesis is perfom1ed for diagnos­ tic and therapeutic purposes in horses with pleuropneun10nia. Pleural fluid should be drained relatively slowly to avoid hypoten­ sion. The hemithorax that appears to contain the most fluid is drained first. Bilateral thoracocentesis is usually necessary. The chest tube may be removed inunediately after drainage of the thoracic cavity or may be secured in place to allow continual drainage. Thoracic radiography is indicated after pleurocentesis to evaluate pulmonary parenchyrnal lesions, mediasti­ nal structures, and the presence/severity of pnewnolhorax. Gross examination of pleural fluid includes evaluation of color, odor, volwne, and turbidity. Malodorous pleural fluid is associated with necrotic tissue and anaerobic infection and indicates a guarded prognosis. Cytologic evaluation of septic pleural fluid reveals purulent exudate (>90% neutroph.ils) with increased cellularity (25,000-200,000 cells/µL) and increased total protein (>3 g/dL). Intracellular and extracellular bacteria may be seen, and Gram stain exanlination is used to direct

initial antimicrobial therapy. Bacterial culture and sensitivity should also be perfonned on transtracheal aspirate san1ples, which yield positive bacterial cultures more frequently tl1an pleural fluid san1ples. Treatment: Management of horses with pleuropnewnonia includes daily ultrasound exanlination to monitor fluid production, evaluate effective drainage, identify isolated fluid pockets, and assess periph­ eral pulmonary disease. The volume and character of pleural fluid will determine whether single, intemtittent, or continual drainage is indicated. Continual drainage is preferable in cases with fibrinous, cellular, malodorous, and/or large volmne of effusion. A one-way (Heimlich) valve allows constant drainage of pleural fluid witl1 nlininlal risk of development of pneumothorax. An indwelling chest tube should remain in place as Jong as drainage is productive. Medical therapy includes broad-spectrum antibiotics, NSAIDs, analgesics, and supportive care. Broad­ spectrum antimicrobial therapy targeting common aerobic and anaerobic bacteria (eg, penicillin, gentanlicin, metronidazole) should be instituted pending results of culture and sensitivity. Intrathoracic fibrinolytic therapy has been reported to reduce fibrin deposition and pleural fluid accunmlation. In some horses, the pleural infection does not resolve despite weeks to montl1S of antimicrobial tl1erapy and drainage via indwelling chest tubes. Thoracostomy allows manual removal of organized fibrinous material and necrotic ltmg; however, tllis technique should be limited to horses with chronic, stable, tutilateral disease with resolving infection in the contralateral henlithorax. Complications associated with pleuro­ pneun10nia include thrombophlebitis, lami.Ilitis, bronchopleural· fistula, pulmo­ nary abscess, and cra.ilial thoracic mass. The prognosis for horses with pleuro­ pneumonia has greatly improved tlrrough­ out the past 20 yr because of early recognition, advancements in diagnostic testing, and aggressive therapy. The survival rate is reported to be as high as 900A, by some investigators, with a 60% chance of return to athletic performance. The duration of hospitalization is not indicative of outcome; however, a delay in initiation of appropriate therapy by >48 hr promotes development of anaerobic infection and, ultimately, poor response to treatment. Placement of an indwelling chest tube does not limit the prognosis for return to athletic function.

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RESPIRATORY DISEASES OF HORSES Horses with hemon-hagic necrotizing pneumonia respond poorly to conventional therapy and have a low survival rate.

RHODOCOCCUS EOUI PNEUMONIA Rhodococcus equi is the most serious

cause of pneumonia in foals 1-4 mo old. It is not the most common cause of pneumonia in this age group; however, it has significant economic consequences because of mortality, prolonged treatment, surveillance progran1s for early detection, and relatively expensive prophylactic strategies. Clinical disease is rare in horses >8 mo old. Compelling epidemiologic data indicate pulmonary infection probably originates within the first week of life. (See also p 679.)

Etiology and Pathogenesis: R equi is a gran1-positive, facultative intracellular pathogen that is nearly ubiquitous in soil. Inhalation of dust particles laden with virulentR equi is the major route of pnemnonic infection. Development of clinical disease is related to immunocompe­ tency of individual foals; foals that produce little to no detectable 'I interferon (IFN-'I) are at risk of developing pnemnonia. Manure from pneurnonic foals is a major source of virulent bacteria contaminating the environment. Foals with pulmonary infections swallow sputun1 laden with R equi, which readily replicates in their intestinal tract. The pathogenicity of R equi is linked to its ability to survive intracellu­ larly, which hinges on failure of phagosome­ lysosomal fusion in infected macrophages and failure of functional respiratory burst upon phagocytosis of R equi. Clinical Findings and Lesions: R equi

infection is slowly progressive, with acute to subacute clinical manifestations. Clinical signs of disease are difficult to detect until pulmonary infection reaches a critical mass, resulting in decompensation of the foal. Pulmonary lesions are relatively consistent and include subacute to chronic suppurative bronchopnemnonia, pulmonary abscessation, and suppurative lymphadeni­ tis. At the onset of clinical signs, most foals are lethargic, febrile, and tachypneic. Diarrhea is seen in one-third of foals with R equi pnemnonia and may be caused by colonic microabscessation. Cough is a variable clinical sign; purulent nasal discharge is less common. Thoracic auscultation reveals crackles and wheezes with asymmetric/regional distribution.

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Pulmonary regions with marked consoli­ dation Jack breath sounds and exhibit dull resonance on thoracic percussion. In foals with subclinical infections, small to moderate-sized abscesses (< 10 cm) may resolve spontaneously. Immune-mediated polysynovitis (eg, stifle and hock effusion) is often seen in affected foals at presentation. Intestinal and mesenteric abscesses are the most common extrapulmonary sites of infection. Foals with abdominal involvement often present with fever, depression, anorexia, weight loss, colic, and dian-hea. Intestinal lesions are characterized by multifocal, ulcerative enterocolitis and typhlitis involving Peyer's patches with granulomatous or suppurative inflammation of the mesenteric and/or colonic lymph nodes. The prognosis for foals with abdominal forms of R equi is less favorable than for those with pulmonary disease. Septic physitis and osteomyelitis are Jess conm1on extrapulmonary sites of infection. Vertebral osteomyelitis may result in pathologic vertebral fracture and spinal cord compression and is a devastating mani­ festation of R equi osteomyelitis. Panoph­ thalmitis, guttural pouch empyema, sinusitis, pericarditis, nephritis, nonseptic uveitis, and hepatic and renal abscessation with R equi have been reported.

Diagnosis: Routine laboratory evalua­ tion of CBC and serum chemistry reveals nonspecific abnormalities consistent with infection and inflammation. Neutrophilic leukocytosis and hyperfibrinogenemia are common, and the severity of these finrungs relates to prognosis. Thoracic radiographic evaluation may reveal a pattern of perihllar alveolization, consolidation, and abscessa­ tion. The presence of nodular lung lesions and mediastinal lymphadenopathy in foals 1-4 mo old is highly suggestive of R equi. Bacterial culttu·e of transtracheal wash samples is required for definitive diagnosis. Cytologic evaluation of transtracheal wash samples reveals intracellular coccobacilli, indicating that appropriate antimicrobial therapy should be started pending culture results. Treatment and Prognosis: The combination of erythromycin (25 mg/kg, PO, qid; esters or salts) and 1ifampin (5-10 mg/kg, PO, bid) has historically been the treatment of choice for R equi infection in foals. These antinticrobials may be bacteriostatic, but their activity is synergis­ tic, and the combination has markedly in1proved survival of foals with R equi pnetm1onia. Rifampin is lipid soluble (able

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RESPIRATORY DISEASES OF HORSES

to penetrate abscess material) and is concentrated in phagocytic cells. Erythro­ mycin is concentrated in granulocytes and alveolar macrophages; however, its anti­ microbial activity is somewhat inhibited by intracellular pH. Adverse reactions are relatively common in foals treated with the erythromycin-rifampiil combination. Diarrhea, idiosyncratic hyperthemlia, tachypnea, anorexia, bruxism, and salivation can occur with erytlu·omycin administration, and antimicrobial resist­ ance of R equi to erythromycin-rifampin has been reported. Claritlu·omycin is the macrolide of choice for foals with severe disease, given the most favorable nlinimwn inhibitory concentra­ tion againstR equi isolates obtained from pneumonic foals (900/o of isolates are inhibited at 0.12, 0.25, lllld 1 mcg/rnL for clarithromycin, erythromycin, and azithromycin, respectively). In foals with R eqiLi pnewnonia, the combination of claiithromycin (7.5 mg/kg, PO, bid) and rifan1pin is superior to erythromycin­ rifampin and azithromycin-rifampin. Foals treated with clarithromycin-rifampin have improved survival rates and fewer febrile days than foals treated with e1ythromycin­ rifampin and azithromycin-rifampin. Reported adverse events of clarithromycin­ rifampin include diatThea in treated foals. The duration of antimicrobial therapy typically is 3---8 wk. Supportive therapy includes provision of a clean, comfortable environment and highly palatable, dust-free feeds. Judicial IV fluid therapy and saline nebulization facilitates expectoration of pulmonaiy exudates. NSAlDs should be administered as needed to maintain rectal temperature 14,000 cells/µL should be further evaluated via ultrasonographic examina­ tion for R equi. Administration of hyperim­ mune plasma might reduce tile incidence and severity of R equi witilin the herd, but it is not completely effective in preventing disease. Hyperimmune plasma (1 L) is administered IV within the first week of life, followed by a second liter at -25 days of age. Foals with low IFN--y production in tile first month of life appear more susceptible to development of clinical disease. Adnlinis­ tration of a nonspecific inununostimulant may enhance IFN--y production and protect this susceptible population. Mass treatment of foals witil subclinical infection has resulted in marcolide- and rifampin­ resistant strains and should be avoided.

ACUTE BRONCHOINTERSTITIAL PNEUMONIA IN FOALS Acute bronchointerstitial pnewnonia is a sporadic, rapidly progressive disease of foals characte1ized by acute respiratory distress and high mortality.

Etiology, Epidemiology, and Patho­ genesis: The etiology of acute bronchoin­

terstitial pneun1onia in foals is not clear. It may result from different insults ratiler than a single factor, initiate a cascade of events, and result in a final common response of severe pulmonaiy damage and acute respiratory distress. Warm weather (>85 °F [29.4 °C]) is a common epidemiologic factor. Many foals have a history of antimicrobial therapy when clinical signs developed. No virus is consistently isolated, and no bacterial agent has been consistently identified. Enteric gran1-negative organisms,

Rhodococcus equi, Pseudomonas aeruginosa, and Pneumocystis jiroveC'i

have been cultured from the lungs of affected foals.

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RESPIRATORY DISEASES OF HORSES

Clinical Findings and Lesions: The age of affected foals ranges from 1 wk to 8 mo. Acute bronchointerstitial pneumonia has an acute or pcracute onset and is accompanied by high fever. The disease is rapidly progressive and may result in sudden death due to fulminant respiratory failure. Foals are unable or reluctant to move and are usually cyanotic. Severe respiratory distress is the most striking clinical sign. Clinico­ pathologic evaluation of foals with acute respiratory distress should include arterial blood gas, CBC, serum chemistry analysis, and thoracic radiographs. Hypoxemia, hypercapnea, and respiratory acidosis are consistent findings. These arterial blood gas findings quantify the severity of respiratory in1pairment and are used to monitor response to therapy. The hypoxemia of bronchointerstitial pneumonia is relatively resistant to supplemental oxygen therapy. Bronchointerstitial pneumonia is similar to bacterial pneumonia in that hyperfibrino­ genemia and neutrophilic leukocytosis are seen in most foals. Diagnosis: Physical exan1ination and clinicopathologic findings may appear sin1ilar to those of foals with severe R equi pneumonia (seep 1451), and thoracic radio­ graphic exan1ination may be the most valuable diagnostic test to differentiate R equi pneumonia from bronchointerstitial pneumonia. Interstitial pneumonia appears as diffuse to caudodorsally distributed inter­ stitial and bronchointerstitial pulmonary opacities. With advanced disease, the radio­ graphic pattern progresses to include patches of a coalescing alveolar nodular pattern with air bronchograms. Transtra­ cheal aspiration may be prohibitively dangerous to pe1forn1 on a dyspneic foal but should be done when the foal becomes more stable to obtain samples for bacterial culture/sensitivity, cytologic evaluation, and virus isolation. Cytologic evaluation of tracheal aspirates reveals acute neutrophilic inflan1mation with or without evidence of sepsis. Bacterial organisms are often recovered from transtracheal aspiration samples or necropsy of foals with bronchointerstitial pneumonia; however, no single organism is consistently recovered. Necropsy examination reveals diffusely enlarged lungs that fail to deflate upon opening of the thoracic cavity with rib impressions on the visceral pleural surface. The cut surface of lung is mottled, with dark red lung interspersed with more normal­ appearing lung tissue and edematous separation of lobules. The most prominent histopathologic findings are severe, diffuse,

1453

necrotizing bronchiolitis, alveolar septa! necrosis, and neutrophilic alveolitis. Surviving foals develop a proliferative epithelial and interstitial response, including bronchiolar and alveolar epithelial hyperpla­ sia, type II cell hyperplasia, and hyaline membrane formation. Treatment: Because the cause of bronchointerstitial pneumonia is unknown, therapy is symptomatic. Treatment includes anti-inflan1matory therapy, broad-spectrum antibiotics, thennoregulatory control, bronchoclilation, supplemental oxygen, and supportive care. Anti-i.nflan1111atory therapy with corticosteroids (eg, dexan1ethasone 0.1 mg/kg/clay, IV) appears to in1prove survival. An alcohol bath, an air-conditioned stall, and/or a fan are used in conjunction with NSAlDs to maintain rectal temperature 2%of total cells); or3) eosinophilic inflammation (5%-40% of total cells). The mixed inflammatory profile likely results from environmental irritation or the consequences of a previous infectious disease. Treatment: The type of inflan1mation

in bronchoalveolar fluid will dictate the therapeutic plan. Regardless of the cytologic profile, all horses with IAD should receive aerosolized bronchodilator therapy before exercise to avert exercise­ or irritant-induced bronchoconstriction. In horses with a mixed inflammatory cytologic profile, administration of low-dose interferon-a is recommended for immunomodulation and antiviral activity. Interferon-a reduces tracheal exudate and improves cytologic profiles in horses with mixed inflanirnatory IAD. Eosinophilic bronchoalveolar fluid likely represents a Type I hypersensitivity reaction. In addition to tracheal exudates, peripheral eosinophilia, miliary pulmo­ nary opacities, and eosinophilic pulmo­ nary granulomas may be seen in affected horses. If such fluid is identified, parasitic pulmonary disease should be considered in addition to hypersensitivity pneumoni­ tis. Systemic corticosteroid therapy is recommended to reduce pulmonary inflammation in horses with eosinophilic IAD. Mast cell inflammation likely represents a local pulmonary hypersensi-

1457

tivity response and may represent an early form of recurrent airway obstruc­ tion (seep 1455). In IAD-affected horses with increased mast cells in bronchoal­ veolar fluid, aerosol administration of an inhaled corticosteroid preparation (beclomethasone or fluticasone) improves clinical signs of respiratory disease.

EXERCISE-INDUCED PULMONARY HEMORRHAGE (Epistaxis, "Bleeder") Exercise-induced pulmonary hemorrhage (EIPH) is seen in most racehorses and in many other horses used in equine sports (eg, polo, ban·el racing,3-day events) that require strenuous exercise for short periods of tinle. Epistaxis is seen in a small proportion ( -5%) of horses with EIPH. Blood in the tracheo­ bronchial tree is identified in 45o/1r-75% of racehorses via endoscopic examination, and hemorrhage is detected by cytologic examination of bronchoalveolar lavage in >90% of racehorses.

Etiology: The proposed pathophysiologic mechanism for pulmonary hemorrhage includes high pulmonary vascular pressures dU1ing maximal exercise, with resultant thickening of pulmonary vein walls and decreased lunlinal diameter and increased intravascular pressure at the level of the pulmonary capillaries. Diagnosis: Endoscopic observation of blood in the airways 30-90 min after exercise provides definitive evidence of EIPH. Other sources of hemorrhage in the upper airway, particularly guttural pouch mycosis (seep 1463) and ethmoid hematoma (seep 1462), must be excluded during endoscopic exanlination. If EIPH is suspected and the horse cannot be exan1ined after exercise, cytologic examination of bronchoalveolar lavage fluid for semiquantitative assessment of hemosiderophages is diagnostic. Stains that highlight iron-containing pigments (Prussian blue) facilitate recognition of these cells. Thoracic radiography demonstrates alveolar or mixed alveolar­ interstitial opacities in the caudodorsal lung fields; however, radiographic examination of the thorax has little impact on the diagnosis or management of EIPH. Treatment and Control: Furosemide

reduces the incidence and severity of

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EIPH in Thoroughbred racehorses. Horses with and without EIPH demon­ strate equal improvements in race performance after administration of furosemide, indicating that the drug may enhance performance via mechanisms unrelated to EIPH. Application of nasal dilator bands reduces RBC counts in bronchoalveolar fluid from affected horses running on a treadmill by 33%. Alternative treatments, including procoagulant agents (eg, vitamin K, conjugated estrogens, aminocaproic acid), antihypertensive drugs, rheologic agents (pentoxyphylline), bronchodila­ tors, prolonged rest, dietary supplements (hepseridin-citrus bioflavinoids), and anti-inflammatory drugs, have not demonstrated therapeutic benefit.

LARYNGEAL HEMIPLEGIA (Roaring, Left laryngeal hemiplegia)

Left recurrent laryngeal hemiplegia is characterized by paresis or paralysis of the left arytenoid cartilage and vocal fold. It manifests clinically as exercise intolerance and inspiratory respiratory noise ("roaring") during exercise. Right-sided hemiplegia and bilateral (paraplegia) arytenoid dysfunction are uncommon. Etiology and Pathogenesis: Progres­ sive loss of the large myelinated fibers in the distal portion of the recurrent laryngeal nerves results in neurogenic atrophy of the intrinsic laryngeal mus­ culature, the most crucial of which is the cricoarytenoideus dorsalis muscle. Axonal dystrophy of the left recurrent nerve occurs more commonly than the right, perhaps due to its extended length around the base of the heart. Left laryngeal hemiplegia is likely heritable. Less common causes include direct trauma to the recurrent laryngeal nerve, accidental perivascular injection of irritating substances, and plant (eg, Cicer arietiniim [chick peasJ and Lathyrus spp) and chemical intoxications. Lead toxicity should be suspected in horses with bilateral laryngeal paralysis. The peroneal nerve (similar length to the left recurrent laryngeal) may be affected with toxic insults, and axonal dystrophy of the peroneal nerve may manifest as stringhalt (seep 1137). Although all breeds are affected, prevalence is higher in males and long-neckeclllarger breeds. The prevalence in young Thoroughbreds presented for sale is estimated to be ---3%---5%.

Loss of neuromuscular control of the abductor muscle results in collapse of the arytenoid cartilage and vocal fold, which reduces the glottal cross-sectional area. The resistance to airflow necessitates greater respiratory effort. Because of the pliable nature of the glottis, the exaggerated subatmosphe1ic pressure in the airway results in further collapse of the arytenoid cartilage and exacerbation of the imped­ ance to airflow. Upon inspiration during strenuous exercise, the affected side is drawn across the midline (by negative pressure in the airway) until it abuts the abducted normal arytenoid, effectively occluding the airway (dynamic collapse). The characteristic inspiratory whistle results from resonance within the open ventricle on the affected side. The harsher stridor, or roar, is produced by vortex shedding from the edges of the arytenoid cartilage and vocal fold. Clinical Findings and Diagnosis: The principal clinical signs are inspiratory noise during exercise and exercise intolerance. Affected horses are asyn1ptomatic at rest but may have an unusual whinny. Diagnosis is confirmed by endoscopic observation of reduced or absent mobility of the arytenoid cartilage and vocal fold. With laryngeal hemiplegia, the arytenoid cartilage and vocal fold are located in a median position within the laryngeal lumen and are in1111obile. Asynchronous movements of the laryngeal cartilages occur commonly, with variable clinical relevance. Horses with laryngeal asynchrony, exercise intolerance, and respiratory noise during exercise should have their laryngeal function evaluated endoscopically during treadmill exercise to confirm laryngeal dysfunction. Differential diagnoses include other pharyngeal conditions that produce upper

Endoscopic image demonstrating grade IV paralysis of the left arytenoid from a horse with left laryngeal hemiplegia at rest. Courtesy of Dr. Bonnie R. Rush.

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RESPIRATORY DISEASES OF HORSES airway obstruction and exercise intoler­ ance. Most of these conditions are easily differentiated from laryngeal hemiplegia during endoscopic examination. Although arytenoid chondritis may be confused with laryngeal hemiplegia, misdiagnosis can be avoided by observation of the shape and size of the arytenoid cartilages. In arytenoid chondritis, the arytenoids thicken transversely and lose their characteristic "bean" shape. Abduction and adduction are usually limited. The axial (medial) surface of the arytenoid cartilage may be distorted with granula­ tion tissue protruding through the mucosa, and a contact (kissing) lesion may be present on the contralateral arytenoid cartilage. Arytenoid chondritis should always be considered if motility of the right arytenoid is reduced. Radio­ graphic examination of the pharynx may reveal mineralization within the arytenoid cartilages in cases of chondritis. Treatment: Prosthetic laryngoplasty can

stabilize the affected side of the larynx during inspiration and prevent dynanlic collapse of the airway during exercise. Laryngeal vent1iculectomy perfom1ed via laryngotomy, or ventriculocordectomy performed via transendoscopic laser, rm proves airflow and reduces the "roaring" sound during exercise. Prosthetic laryngoplasty is commonly done in racing horses and is the only technique that satisfactorily reduces the impedance to inspiratory flow. Postoperative complica­ tions include chronic cough, chronic aspiration of feed, implant failure, and in1plant infection. Athletic performance will improve after surgery; however, horses are more likely to experience inflan1matory airway disease and exercise-induced pulmo­ nary hemorrhage, have fewer race starts, and are unlikely to develop their predicted perfom1ance potential.

PHARYNGEAL LYMPHOID H YPERPLA SIA (Pharyngitis)

Pharyngeal lymphoid hyperplasia is a common condition of the dorsal pharyngeal wall seen in young horses (l--3 yr old). Horses do not have discrete masses of lymphoid tonsillar tissue; rather, they have many small foci or follicles of lymphoid tissue spread diffusely over the roof and lateral walls of the pharynx. In mature horses, these follicles blend with mucosa!

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Endoscopic photograph of grade 3.5/4 pharyngeal lymphoid hyperplasia. Courtesy of Dr. Jan Hawkins.

tissue and are unnoticeable. In yom1g, matming horses, lymphoid follicles appear as prominent, raised nodules on the surface of the pharyngeal roof and extend down the lateral walls of the pharynx and cranially into the nasopharynx. Although PLH was once believed to be an important cause of poor perfom1ance in racehorses, its clinical significance is now questionable. Virtually all young horses develop hyperplasia of pharyngeal lymphoid follicles; in most cases, this represents a normal immuno­ logic event. Occasionally, follicles may enlarge and coalesce with surrounding follicles. In these situations, follicles may appear hyperenlic or inflamed and may exude mucoid or mucopurulent material. These cases likely represent a mild or subclinical viral infection and may be associated with in1paired performance. Signs of pharyngeal pain include reduced appetite and frequent swallowing. Treatment is not necessary in the vast majority of cases; however, rest and NSAID administration are warranted in horses demonstrating pharyngeal pain.

DORSAL DISPLACEMENT OF THE SOFT PALATE Dorsal displacement of the soft palate (DDSP) is a performance-limiting condition of the upper respiratory tract and is a relatively common cause of upper respiratory noise during exercise. Dwing DDSP, the caudal free margin of the soft palate moves dorsal to the epiglottis,

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creating a functional obstruction within the airway. The cross-sectional area of the pharynx is reduced, and airflow resistance and turbulence are increased.

Etiology and Pathogenesis: DDSP may result from several pathophysiologic mechanisms. Inflammation of the upper respiratory tract due to infection may cause neuropathy of the pharyngeal branch of the vagus nerve as it traverses the floor of the medial compartment of the guttural pouch, resulting in neuromuscular dysfunction of the pharyngeal muscles that control the soft palate. The retropharyngeal lymph nodes are in direct contact with the pharyngeal branch of the vagus nerve, and retropharyn­ geal lymphadenopathy may result in compression and irritation. Clinical signs can be induced by local anesthesia of this nerve. Congenital hypoplasia of the epiglottis may contribute to DDSP due to insufficient epiglottal tissue to maintain the position of the caudal border of the soft palate ventral to the epiglottis. Horses that have undergone laryngoplasty for left laryngeal hemiplegia are more likely to develop DDSP. Clinical Findings: DDSP creates a characteristic gurgling respiratory noise, primarily during expiration, due to vibration of the soft palate. Horses may make no noise at the onset of exercise but displace their palate during high-speed exercise, causing them to "choke down." Head position (flexed) may contribute to displacement. Treatment: The most effective

treatment for DDSP in young horses (2-yr-olds) and horses with evidence of upper respiratory tract infection is rest and anti-inflammatory therapy. Caudal retraction of the tongue elevates the soft palate and pushes the larynx caudally, both of which may predispose to DDSP. Placing a tongue tie during exercise reduces caudal retraction of the tongue. Sternothyrohyoideus myectomy per­ formed in horses prone to DDSP to alter the anatomy of the upper respiratory tract is successful in -50% of horses. Soft palate resection (staphylectomy) is frequently performed in horses with DDSP and also has a success rate of -50%; however, the mechanism of improvement after surgery is unclear. Success has been attributed to reduction in the mass of soft palate obstructing the airway, easier replace­ ment of the shorter soft palate to the subepiglottic position, and firming of the

caudal edge of the soft palate to keep it ventral to the epiglottis. Palatal sclero­ therapy via endoscopic-guided sodium tetradecylally sulfate injection has demonstrated success in a small nwnber of horses, resolving respiratory noise in 7 of 8 horses and improving performance in 6 of 8 horses. A laryngeal tie-forward procedure can be performed to alter the position of the larynx with respect to the caudal edge of the soft palate.

EPIGLOTTIC ENTRAPMENT Epiglottic entrapment is a less common cause of respiratory noise and exercise intolerance. In this condition, the aryepiglottic fold completely envelops the apex and lateral margins of the epiglottis. The general shape of the epiglottis is visible, and the position (dorsal to the soft palate) is appropriate. However, the distinct serrated margins of the epiglottis and the dorsal epiglottic vascular pattern are obscured by a fold of aryepiglottic mucosa. Clinical signs of epiglottic entrapment include inspiratory and expira­ tory respiratory noise during exercise and poor exercise performance. Less common signs include cough, nasal discharge, and headshaking. In mature nonracehorses, cough is the most consistent presenting complaint. Diagnosis is determined by endoscopic examination. Surgical correction of epiglottic entrapment is axial division of the aryepiglottic fold to free the epiglottis. Axial transection of the aryepiglottic fold may be performed by transendoscopic contact Nd:YAG laser, transnasal or transoral transection via curved bistoury, or direct excision through a laryngotomy or pharyngotomy. Surgical transection is generally curative, with a relapse rate of 5%. Some affected horses can race successfully with the condition.

SUBEPIGLOTTIC CYST Subepiglottic cysts are an uncommon cause of respiratory noise in young horses. They are likely present from birth but remain undetected until the horse begins exercise training. These cysts are suspected to arise from remnants of the thyroglossal duct. Clinical signs include respiratory noise and exercise intolerance. Large cysts may produce coughing, dysphagia, and aspiration in foals. Diagnosis is determined by endoscopic examination of the upper respiratory tract. The cyst appears as a smooth-walled, fluctuant mass that contains

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RESPIRATORY DISEASES OF HORSES thick, yellow, mucoid material. Occasionally, the mass is not visible in the nasopharynx, and oral examination under general anesthesia may be required to identify it. Histologically, subepiglottic cysts are lined with a combination of stratified squamous and pseudostratified columnar epithelium. Treatment involves complete removal of the secretory lining of the cyst. Rupture of the cyst results in immediate decompression, but recurrence is common. The most common approach is ventral laryngotomy, although transendoscopic Nd:YAG laser surgery has been used for complete excision.

FOURTH BRANCHIAL ARCH DEFECT (Rostral displacement of the palatopharyngeal arch)

The extrinsic structures of the larynx, such as the wing of the thyroid cartilage, cricothyroid muscle, and upper esophageal sphincter, develop from the fourth branchial arches. Aplasia or hypoplasia of one or more of these structures may occur mtilaterally or bilaterally. Right-sided defects are more conunon than bilateral or left-sided defects. The severity of clinical manifestation ranges broadly and is based on the degree of the defect. The most common clinical sign is respiratory noise, although mild dysphagia, eructation, and cough have been reported. Palpation of the larynx reveals absence of one or both wings of the thyroid cartilage, resulting in failure of the cricothyroid articulation and a palpable space between the cricoid and thyroid cartilages. Radio­ graphic evidence of a fourth branchial arch defect includes dilation of the cricopharynx with a continuous column of air from the pharynx to the cervical esophagus. Rostral displacement of the palatopharyngeal arch may or may not be detected during endoscopic examination. Endoscopic examination during treadmill exercise may reveal dynamic collapse of the vocal folds. Affected horses are unlikely to become effective athletes. Pa.itial arytenoidectomy may in1prove airway dynan1ics sufficiently for pleasure riding.

DISEASES OF THE NASAL PASSAGES Nasal Septum Diseases of the nasal septum are ra.i·e. Most nasal septal disorders are congenital abnor­ malities that remain undetected tmtil the horse is exercised. Traumatic injury to the

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bridge of the nose as a juvenile can produce nasal septal deviation and thickening. Other less common diseases of the nasal septum include amyloidosis, fungal infection, and squamous cell carcinoma. Thickening or deviation of the nasal septum causes low-pitched stertorous breathing dwing exercise. Facial defonnity may be seen. Septal abnonnalities may be detected by palpation, visual inspection, and endoscopic examination. Dimensions of the nasal cavity a.i·e difficult to appreciate via endoscopic exan1ination; however, abnormalities of the mucosa are easily identified. Precise dorsoventral radiographs of the skull provide definitive evidence of septal defonnity, deviation, and thickening. Histologic examination of any nodules or discrete lesions on the septum will identify twnors, amyloidosis, or fungal infections. Surgical resection of the nasal septum is the only treatment option in most cases. The entire diseased portion of the septum ca.ii be excised using obstetrical wire by transect­ ing the septum on the dorsal, ventral, and caudal border. Hemorrhage is substantial dming tlus procedure (4-8 L), a.i1d the nasal passages are packed with sterile gauze soaked in saline or in 1: 100,000 epinephrine solution to minimize blood loss. Before the horse recovers from anesthesia, a trache­ otomy is performed. Postoperative ca.i·e includes parenteral antibiotics and NSA!Ds. The packing and tracheotomy tube should be removed 48--72 hr after surgery. All incisions heal by second intention within 3 wk. Horses should be rested for -2 mo before returning to nom1al activity. After surgery, most horses make a respiratory noise during work, although less than before surgery, and exercise tolerance is improved. Shortening of the upper jaw, incisor malalignrnent, or nostril collapse can develop if the procedure is performed in inunature horses. Ideally, the surgery should be delayed until maturity.

Nasal Polyps Nasal polyps are pedtmculated growths tl1at arise from the rnucosa of the nasal cavity, nasal septum, or tooth alveolus. Polyps are usually unilateral and single but can be bilat­ eral and multiple. They form in response to chronic inflanunation by hype1trophy of the mucous mernbra.i1e or exuberant prolifera­ tion of fibrous connective tissue. There is no age, breed, or gender predilection. Clinical signs are poor airflow through the affected nasal passage; inspiratory dyspnea; unilateral, malodorous, mucopurulent nasal discharge; and low-volume epistaxis. The

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mass may extend rostrally until it protrudes beyond the nostrils. Polyps are detected via endoscopic and radiographic exanlination, and histopathologic evaluation of biopsy samples provide a definitive diagnosis. Stugical excision is perfom1ed via an incision in the false nostlil, a trephine opening, or a bone flap. Choanal Atresia Choanal atresia is caused by persistence of the bucconasal membrane that separates the primitive buccal or oral cavity from the nasal pits dilling embryonic development. Bilateral and unilateral cases have been described in horses. Clinical signs are evident immedi­ ately after birth in f oals with bilateral disease, because dyspnea is severe and air cannot be detected passing through the nostrils. An endoscope or stomach tube passed through the ventral meatus will be obstructed at the level of the medial canthus of the eye. Bilateral complete choanal atresia is a life-threatening condition, and a trache­ otomy must be performed immediately after birth. It may be possible to perforate a thin membrane by electrocoagulation or laser or by excision through bilateral flaps centered along the midline. Indwelling tube stents should be inserted through both choanae and left in place for 6 wk. DISEASES OF THE PARANASAL SINUSES The maxillary sinus is the largest paranasal sinus and is divided by a thin septun1 into caudal and rostral parts. The frontal sinus has a large communication with the dorsal conchal sinus at its rostral end, thereby fomling the conchofrontal sinus. The conchae or ttubinates are delicate scrolls of bone that are attached laterally in the nasal passage and contain the conchal sinuses. The caudal and rostral maxillary sinuses have separate openings into the middle nasal meatus, and the caudal maxillary sinus communicates with the frontal sinus through the large frontomaxillary opening. Diseases that originate in one sinus cavity may extend to and involve others. Most diseases of the paranasal sinuses cause mucoptuulent or bloody nasal discharge. Drainage is unilateral, in con­ trast to disease of the lungs, pharynx, and gutttual pouches, because the sotuce of discharge is rostral to the caudal border of the nasal septum. Unilateral facial swelling, epiphora, dull percussion of the sinuses, and inspiratory noise are common manifestations of disorders of the sinuses.

On endoscopy, ptuulent material, a mass, or blood can be seen in the nasal passage originating from the nasomaxillary opening. Lateral and dorsoventral radiographs of the skull may reveal fluid lines, sinus cysts, solid masses, or lytic/proliferative changes associated with dental disease and neoplasia. Oblique projections in a dorsal to ventral direction may be required to improve views of the tooth roots. CT is useful, particularly f o r ventral conchal sinus disease. Centesis of the maxillary or frontal sinuses is performed to obtain fluid for bacterial culture, sensitivity testing, and cytologic examination. With sedation and local anesthesia, the sinuses can be examined in the standing horse by insertion of an arthroscope (4 mm). A second portal could be used to insert an instrument into the sinus to obtain specinlens, debride tissue, and lavage the sinus cavity. Sinusitis Primary sinusitis occurs subsequent to an upper respiratory tract infection that has involved the paranasal sinuses. It usually involves all sinus cavities but can be confined to the ventral conchal sinus. This cavity is difficult to detect radiographically and access stugically. Secondary sinusitis can result from tooth root infection, fracture, or sinus cyst. The first molar, fotuth premolar, and third premolar (in decreasing frequency) are the most likely to develop tooth root abscesses. Clinical signs of secondary sinusitis closely resemble those of primary sinusitis, including unilateral mucoptuulent nasal discharge and facial defomlity. Tooth root abscesses typically produce a fetid nasal discharge. Treatment of primary sinusitis involves lavage of the sinus cavity and systenlic antinlicrobial therapy based on culttue and sensitivity results. Second6 yr old. Low-grade, spontaneous, intermittent, unilateral epistaxis is the most common clinical sign. Horses with extensive masses may have reduced airflow through the affected nasal passage and fetid breath. In longstanding cases, the mass may protrude from the nares. In most instances, the lesion can be seen extending into the nasal passages on endoscopic examination, and the extent of the mass can be determined radiograph­ ically. Conservative management includes intralesional injection of the mass with 4% formaldehyde. Formalin is injected into the mass using a guarded endoscopic needle. The mass typically regresses rapidly, but recurrence is common. Neurologic signs have been reported after intralesional formalin injection, associ­ ated with communication of the hema­ toma into the calvarium. Surgical excision is achieved via frontonasal bone flap. Sinus Cysts Sinus cysts are single or loculated fluid-filled cavities with an epithelial lining. They develop in the maxillary sinuses and ventral conchae and can extend into the frontal sinus. A congenital form has been described. Sinus cysts are typically found in horses 9 yr old. The primary clinical signs are facial deformity, nasal discharge, and partial airway obstruction. Radiographs are more likely to identify a sinus cyst than endoscopic exan1ination. Multiloculated densities and fluid lines in the sinuses are observed radiographically; occasionally, dental distortion, flattening of tooth roots, soft-tissue mineralization, and deviation of the nasal septunl are seen. Treatment involves radical surgical removal of the cyst and associated conchal lining. Prognosis for complete recovery is good, and the recurrence is low. Some horses may have a permanent, mild mucoid discharge after surgery.

GUTTURAL POUCH DISEASE Empyema Guttural pouch empyema is defined as the accumulation of purulent, septic exudate in the guttural pouch. The infection usually develops subsequent to a bacterial (primarily Streptococcus spp) infection of the upper respiratory tract. Clinical signs include intermittent purulent nasal discharge, painful swelling in the parotid area, and in severe cases, stiff head carriage and stertorous breathing. Fever,

1463

Empyema of guttural pouch, horse, radiograph. Courtesy of Or. Ronald Green. depression, and anorexia may or may not be seen. Diagnosis is determined by endoscopic examination of the guttural pouch. Radiographs of the pharynx demonstrate a fluid line in the guttural pouch and may allow identification of an associated retropharyngeal mass. Systemic antimicrobial therapy alone rarely resolves the infection; guttural pouch lavage is necessary. Penicillin gel (prepared using sodium penicillin) can be administered directly into the guttural pouch and may enhance bacterial clearance. Retropharyngeal abscesses can be resolved by rupturing the abscess into the guttural pouch using an endoscopic blade. If endoscopic rupture into the guttural pouch is unsuccessful, surgical drainage is necessary for retropharyngeal abscessation. Guttural pouch empyema may compress the dorsal pharynx and produce upper airway obstruction. Tracheotomy may be necessary to provide a temporary alternative airway in these cases. If guttural pouch empyema is not treated, chondroid material may form in the guttural pouch and serve as a source of chronic infectious exudate. A small number of chondroids can be removed endoscopically, but accumulations of exudate, chondroid material, or unre­ solved retropharyngeal abscesses require surgical drainage. Guttural Pouch Mycosis Mycotic plaques in the guttural pouch are typically located on the caudodorsal aspect of the medial guttural pouch, over the internal carotid artery. In some instances, fungal plaques may be multiple or diffuse. The most common fungal organism associated with guttural pouch mycosis is Aspergillus spp (seep 633). Clinical signs arise from damage to the cranial nerves and

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the arteries within the mucosa! lining of the guttural pouch. The most common sign is epistaxis, due to fungal erosion of the wall of either the internal carotid artery (most cases) or branches of the external carotid artery. Hemorrhage is spontaneous and severe, and repeated bouts may precede a fatal hemorrhagic episode. Dysphagia, Homer syndrome, and dorsal displacement of the soft palate may develop in response to fungal damage to cranial ne1ves and the sympathetic nerve that superficially traverse the guttural pouch. Dysphagia is a poor prognostic indicator and is highly correlated with nonsurvival. Diagnosis is detennined by endoscopic examination of the guttural pouch. Treatment consists of topical and systemic antifungal therapy, based on sensitivity testing. Topical antifungal therapy is administered directly on the lesion via infusion through the biopsy channel of an endoscope. A fatal hemorrhagic event can be prevented by occluding the affected arteries along their course through the guttural pouch by means of a balloon-tipped catheter or a coil embolus. It is necessary to occlude the arteries proximal and distal to tl1e lesion to prevent retrograde bleeding from the circle of Willis. Guttural Pouch Tympany Guttural pouch tympany is seen in horses ranging from birth to 1 yr of age and is more common in fillies tl1an in colts. A genetic basis of disease has been identified in Arabian ar1d Gem1an warmblood breeds. In some cases, the condition is acquired due to inflan1IDation of the upper respiratory tract. The affected guttural pouch is distended with air and fonns a characte1istic nonpainful swelling in the parotid region. Breathing may become ste1torous in severely affected anin1als. Tympany may result from inflanrn1a­ tion or malfom1ation of the pharyngeal orifice of the eustachian tube, which then acts as a one-way valve by allowing air to enter the pouch but preventing its return into the pharynx. Diagnosis is based on clinical

signs and radiographic examination of the skull. Severely affected ar1in1als may develop a secondary empyema. Tympany is usually unilateral, but bilateral cases have been reported. Medical management with NSAIDs and az1timicrobial therapy resolves most cases due to upper respiratory tract inflan1mation. Surgical intervention is warranted in horses witl1 malformation of the guttural pouch opening and involves fenestration of the membraz1e that separates the affected guttural pouch from the normal one. This provides a route for air in the abnormal guttural pouch to pass to the nonnal side and be expelled into the pharynx. The postoperative prognosis is good. Rupture of the Long us Capitis Muscle Traumatic rupture of the longus capitis is the second most common cause (after mycosis) of severe hemorrhage from the guttural pouch. The longus capitis muscle is one of the ventral straight muscles of the head. It inserts on the basisphenoid bone at the base of the skull. The point of rupture occurs at the inse1tion of the muscle dorsal to the guttural pouch. Rupture results from traumatic poll injury (rearing over backward) az1d produces profuse hemorrhage. Hemorrhage into the retropharyngeal space can cause asphyxia az1d death. On endoscopic exaz11ination, swelling az1d hemorrhage caz1 be seen in the most rostral ar1d medial aspects of the guttural pouch by retroflexion of the endoscope. On lateral radiographic exaz11ination, az1 avulsion fracture of the basisphenoid bone may be seen overlying the guttural pouch region. Significaz1t neurologic deficits are often seen with this fracture. Treatment involves stall rest for 4-6 wk; broad-spectrum az1tibiotics are given for 5-7 clays for az1y infection at the site of muscle rupture. Prognosis for full recovery is good, but persistent neurologic signs or recurrent hemorrhage worsens the prognosis.

RESPIRATORY DISEASES OF PIGS Respiratory diseases of pigs can be classified into two broad categories based on the extent az1d duration of overt disease: those that affect lar,ge numbers of pigs az1d

may be serious but of limited duration, ar1d those that persist in a large number of pigs for indefinite periods. Diseases in the first category caz1 be costly, but tl1e losses are

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RESPIRATORY DISEASES OF PIGS limited rather than ongoing. They include swine influenza (seep 1470), classical swine fever (seep 713), the pneumonic forms of pseudorabies (seep 1300), porcine circovirus-associated disease (seep 723), and porcine reproductive and respiratory syndrome (seep 729). The causal viruses may persist in a herd, but outbreaks of overt disease tend to be self-limiting. The most impmtant syndromes in the second category are mycoplasmal pneumonia and pleuropneumonia (see p 1467). Atrophic rhinitis, once considered to be a significant cause of respiratory disease in swine, has declined substan­ tially as a result of eradication programs. Salmonellosis and Ha.emophilus pamsuis infections may be significant problems in some herds. Moderate levels of atrophic rhinitis caused by Bordetella bronchisep­ tica alone may not be too significant but, when coupled with toxigenic strains of Pasteurella, are an important cause of economic loss due to decreased rate of growth and reduced feed conversion in young pigs. Enzootic pneumonia, when caused by mycoplasma alone, is of little consequence; however, when it is combined witl1 secondary infection, eg, Pasteurella mullocida, the resulting condition may be severe. Actinobac'illw; pleuropneumoniae may be associated with considerable losses in some herds. Migrating worm larvae or the infections listed in the first category often lead to severe problems when they occur with the infections in the second category. The severity and economic importance of diseases in tl1e second category also are related to population density and to the type and size of herd. They may be of little importance in weanling pig operations but become of major importance in high-density feeder-pig units. Although mortality usually is low, economic damage results from an adverse and uneven effect on growth rate, decreased feed efficiency, and additional costs of drugs, particularly medicated feed. However, when stress can be avoided by proper management, such diseases may result in only minimal losses. Finally, it must be stressed that respira­ tory disease problems in pigs are frequently the result of multiple agents (co-infection) and rarely due to the effects of a single pathogen. It is possible to set up herds free of diseases in the second category by techniques such as SPF repopulation or segregated early weaning, or by buying pigs from a pneumonia-free herd. The latter method is the least expensive, but because

1465

the etiology of diseases in the second category is complex, all the pigs should be purchased from one source. This is also true when purchasing weaned pigs for feeder-pig units. It is difficult to keep herds free of respiratory diseases. Aerosols have been suspected as sources of pathogen entry onto naive farms. Organisms such as Mycoplasma hyopneumoniae have been postulated to be transmitted over distances of as far as 2 miles, depending on climate, terrain, and density of pigs in the locality; however, this assun1ption is based on speculation and use of mathematical models rather than on experimental data. Closed herds, ie, buying in no live animals (using artificial insemination or embryo transfer to bring in new genetic mate1ial), help establish in1munity to present organisms and avoid introduction of new infections, strains, or serotypes. Multiple site production or an "all-in/all-out" policy, in which the entire barn or air space is emptied before refilling, can very effectively minimize the potential effect of chronic pneun10nia. Respiratory disease is endemic in many herds. The main control factors are stress management, stocking density, ventilation, temperature control, and freedom from mixing and moving. Multiple site production or "all-in/all-out" and closed-herd manage­ ment practices greatly decrease the need for preventive and therapeutic medication.

ATROPHIC RHINITIS Atrophic rhinitis is characterized by sneezing, followed by atrophy of the turbinate bones, which may be accompanied by distortion of the nasal septum and shortening or twisting of the upperjaw. Its significance has declined substantially, and it is no longer considered a major health risk to swine herds. Etiology: The etiology is complex and involves at least two organisms. Various infections (eg, inclusion body rhinitis and pseudorabies) and noninfectious agents (eg, dust or high ammonia levels) cause sneezing and tear-staining, usually without leading to atrophic rhinitis. Bordetell.a bron­ chiseptica has long been implicated as a major cause. This bacterium is not host-specific, although strains that cause atrophic rhinitis are generally isolated only from pigs. Dogs, cats, rodents, and other species may harbor B bronchise'J)lica for long periods, but their role in the spread of atrophic rhinitis in pigs is unce1tain.

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appear below the medial canthi of tl1e eyes. Some severely affected pigs may develop lateral deviation or shortening of the upper jaw, whereas others may suffer some degree of turbinate atrophy with no apparent outward distoition. The degree of distortion can be judged from the relationship of the upper and lower incisors if breed variations are considered. In addition to the above clinical signs, outbreaks frequently impair growth rate and feed conversion. The severity of atrophic rhinitis in a herd depends largely on tl1e presence of toxigenic strains of P multocida, the level of management, and the in1mune status of the herd. The latter is related to both vaccination status and the parity distribu­ tion of the sow herd, because younger sows tend to shed more organisms and produce less lactogenic in1rnunity for their nursing piglets than do older multiparous sows.

Atrophic rhinitis in a pig. The nasal turbinate bones have been completely destroyed after natural infection with type D toxigenic

Pasteurefla multocida. Courtesy of the Department of Pathology, University of Guelph.

Toxigenic strains of Pasteurella multocida (type D), often acting withB bronchisep­ tica, cause permanent turbinate atrophy and nasal distortion. Both organisms can cause clinical atrophic rhinitis. The disease has been divided into two forms: nonprogressive atrophic rhinitis, due Lo B bronchiseptica, is mild and transient and probably does not greatly affect the animal's growth and performance; progressive atrophic rhinitis, due to toxigenic P multocida, is severe, perma­ nent, and usually accompanied by poor growth. Outbreaks of disease usually follow either the introduction of infected pigs or mixing of pigs from different sources. Piglets may be affected at any age, especially with P multocida, which also may infect mature animals. Crowding, inadequate ventilation, mixing and moving, and other concurrent diseases are important contributory factors in intensification of the disease. Clinical Findings: Acute signs, which usually appear at 3-8 wk of age, include sneezing, coughing, and inflanm1ation of the lacrin1al duct. In more severe cases, nasal hemorrhage may occur. The lacrin1al ducts may become occluded, and tear stains then

Lesions: The degree of atrophy and distortion is best assessed by examining a transverse section at the level of the second premolar tooth (the first cheek tooth, up to 7-9 mo of age); some recommend additional parallel sections. In the active stages of inilan1rnation, the mucosa has a blanched appearance, and purulent material may be present on the surface. In later stages, the nasal cavities may be clear, but there may be variable degrees of softening, atrophy, or grooving of the turbinates; deviation of the nasal septum; and asyrrunetric distortion of the surrounding bone structure.

Diagnosis: The signs and lesions are commonly the basis for diagnosis; how­ ever, the presence of toxigenic strains of P multocida should be confirmed. Routine monitoring is done in some breeding herds by measuring tl1e degree of turbinate atrophy and giving the herd an atrophy score. Atrophic rhinitis. must be differenti­ ated from necrotic rhinitis (seep 1468). Control: It is rarely possible to keep herds entirely free from mild outbreaks of sneezing, and a low level of aberrant turbinates and nasal bones at necropsy is con1rnon, even in herds that show no clinical signs of rhinitis. When atrophic rhinitis rises to an unacceptable level in a herd, control measures are usually strategic: chemopro­ phylaxis, vaccination, temporary closure of the herd to introduction of new pigs, and improved management (eg, better ventilation and hygiene, less dusty feed). Chemopro­ phylaxis usually includes administration of antibacterial drugs to all sows, particularly before farrowing, as well as programs of

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RESPIRATORY DISEASES OF PIGS

repeated medications for newborn piglets and sometimes for newly weaned pigs. Medi­ cation of weaner and grower rations, and sometimes sow rations, is often helpful. Drngs commonly used are ceftiofur, sulfonamides, tylosin, and tetracyclines. Bacterins against toxigenic P multocida and B bronchiseptica have been devel­ oped. Both toxoid vaccines and bacterin­ toxoid mixtures are available againstP multocida; although both give satisfactory results in most herds, infection can be best prevented with bacterin-toxoid mixtures. Typically, sows are vaccinated 4 and 2 wk before farrowing, and the young pigs at 1 and 4 wk of age. However, vaccination schedules recommended by the manufac­ turer should be followed. A high level of colostral immunity is acquired by piglets nursing vaccinated sows. An intranasal vaccine using modified-live strains of B bronchiseptica is also available for young pigs.

MYCOPLASMAL PNEUMONIA (Enzootic pneumonia)

Mycoplasmal pneumonia is a chronic, clinically mild, infectious pneumonia of pigs, characterized by its ability to become endemic in a herd and to produce a persistent dry cough, retarded growth rate, sporadic "flare-ups" of overt respiratory distress, and a high incidence of lung lesions in slaughter pigs. It occurs worldwide. Clinical outbreaks of mycoplasmal pneumonia may in1pair growth rate and feed conversion. This effect is enhanced when large numbers of pigs are closely confined in poorly ventilated buildings under poor husbandry conditions. The effects of the disease are uneven and unpredictable and place limits on the efficiency and flexibility of large production units. However, in swine units with good disease control measures, mycoplasmal pneumonia may remain largely subclinical and is of little economic importance. Etiology and Epidemiology: The terms "viral pneumonia" and "enzootic pneumonia" are frequently used to describe a characteristic disease syn­ drome now known to be caused primarily by Mycoplasma hyopneumoniae. The pleomorphic organism is fastidious, smaller than most bacteria, and difficult to see clearly under ordinary light micro­ scopes. It can be cultured in specially prepared media, but isolation from field

1467

cases is difficult. It is rapidly inactivated in the environment and by disinfectants, but it may survive longer in cold weather. It appears to be host-specific. Mycoplasmal pneumonia is also frequently complicated by other mycoplasmas, bacteria, and viruses, which affect the severity of the disease. Certain strains of M hyorhinis, and perhaps some viruses, may themselves act as primary agents to produce a syndrome resembling the pneumonia ca.used by M hyopneumoniae. In most countries tl1a.t use modem pig-farming methods, the lungs of30%-80% of the pigs slaughtered show pneumonic lesions of the type associated with mycoplasmal infection. Pigs of all ages are susceptible, but within a herd, pigs become infected in the first few weeks of life either by their darn or by other young pigs after mixing. Transmission to lactating piglets can occur from sows of all parities but is most prevalent in first-parity (gilt) litters. In addition, witl1 the adaptation of segregated (rnultisite) production, llie onset of the disease has been delayed and may be most evident in the finishing stage at -18---20 wk of age. The incidence of lung lesions is highest in pigs3-5 mo old. Immunity develops slowly, followed by regression of the lw1g lesions. Older growing and mature pigs may recover completely. Clinical Findings: In herds in which the

disease is endemic, morbidity is high, but clinical signs may be minimal and mortality is low. Coughing is the most common sign and is most obvious when pigs are roused. Individual pigs or groups sporadically develop severe pneumonia.. A conunon predisposing factor is a change of weather, but other stresses (eg, transient viral infections, parasitic migration, and mixing pigs) may also ca.use outbreaks. The disease is usually more severe when it first enters a naive herd. Lesions: Affected lungs are gray or purple, most commonly in the apical and cardiac lobes. Old lesions become clearly demarcated. The associated lyn1ph nodes may be enlarged. Histologically, inflamma­ tory cells are present in the bronchioles; there is pe1ivascular and peribronchiolar cuffing and extensive lyn1phoid hyperplasia Diagnosis: Clinical, pathologic, and epi­ demiologic findings a.re usually adequate for diagnosis. M hyopneumoniae can be demonstrated in impression smears of

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RESPIRATORY DISEASES OF PIGS

the cut surface of affected lung, identified by fluorescent antibody technique, and sometimes isolated and identified in culture. Serologic tests, principally the complement fixation test, and ELISA are occasionally used on a herd basis, but results may be difficult to interpret. A PCR test to detect M hyopneumoniae in nasal and bronchial swabs has been developed and appears to be very sensitive and specific. Control: When the disease first enters a

herd, mass treatment with antibiotics (eg, tylosin, lincomycin, tiamulin, or a tetracy­ cline) helps to control the severity of signs. When disease increases in endemic herds, treatment of individual pigs with antibiotics usually results in remission, presumably by controUing secondary bacteria. Inactivated mycoplasmal cultures have been developed as bacterins and consist of whole-cell preparations as well as new subunit bacterins. These induce exceUent protection against development of gross lesions and significantly reduce clinical signs (coughing) in growing pigs. Data indicate that prefarrowing vaccination of sows with M hyopneumoniae vaccines significantly reduces colonization of suckling piglets. The economic effects of the disease can be reduced, and sometimes eliminated, by improvements in housing and husbandry, particularly ventilation and overcrowding, along with medication and vaccination. "All-in/all-out" management of pi.gs from birth to market is extremely effective at reducing negative effects of disease; following this practice improves growth performance and reduces lung lesions. In large intensive units, starting with foundation stock free of mycoplasmal pnew11onia and adopting strict precautions against direct and indirect contact witll pigs from other herds is advisable. Unfortu­ nately, many herds set up in this way do not remain free of mycoplasmas for very long, particularly in areas with a high density of pigs. Field observations suggest that infection can be windborne for at least a mile between large herds in cold, wet weather. In the USA and parts of Europe, most herds free of mycoplasmal pneumonia were established by the pig repopulation technique. More recently, some have been established by segregated early weaning. The biggest problems with these herd programs are the breakdown rate and the difficulty of monitoring

herds that claim to be free of mycoplas­ mal pneumonia. Hypotheses for these outbreaks suggest that the organism may never have been successfully eliminated in certain herds, but rather coexisted within the population at an undetectable level for extended periods. Use of nasal swab PCR technology has demonstrated presence of the organism in pigs free of clinical signs, lesions, and antibodies. Analysis of tracheal sections from these pigs by electron microscopy has indicated presence of the organism on the cilia.

NECROTIC RHINITIS (Bullnose)

Necrotic rhinitis is an uncommon, sporadic disease of young pigs characterized by suppmation and necrosis of the snout, arising from wounds of tl1e oral or nasal mucosa. Confusion exists in the literature because of the use of the misnomer "bullnose" to also describe atrophic rhinitis (seep 1465). Etiology: Pusobacterium necrophorum is commonly isolated from the lesion and undoubtedly contributes to tl1e disease, but other types of organisms are frequently present. They gain entry through damage to the roof of the mouth, often as a result of clipping the needle teeth too short or using blunt clippers. Clinical Findings and Lesions: Signs include swelling and deformity of the face, occasionally hemorrhage, snuffling, sneezing, foul-smelling nasal discharge, sometimes involvement of the eyes with lacrirnation and pw11lent discharge, loss of appetite, and emaciation. Generally, only one or two pigs in a herd are affected. The facial swelling usually is hard, but incision reveals a mass of pinkish gray, foul-smelling necrotic tissue, or greenish gray tissue debris, depending on the age of the lesion. The nasal and facial bones become involved, and facial defonnity may be marked. Diagnosis: Necrotic rhinitis is readily differentiated from atrophic rhinitis by the bulging type of facial distortion seen in the fom1er. The character of the exudate and its location within the tissue of the snout or face are also distinctive of necrotic rhinitis. Prevention and Treatment: Prevention is directed toward avoiding ir\juries to the

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RESPIRATORY DISEASES OF PIGS mouth and snout, improving pig processing techniques, and improving sanitation. When the disease occurs repeatedly, needle teeth should be clipped carefully. If the condition is advanced, treatment may not be advisable. Early surgical intervention and packing the cavity with sulfonamide or tincture of iodine may be useful. In young pigs, sulfamethazine given PO is of value.

PASTEURELLOSIS Pasteurellosis is most commonly seen in pigs as a complication of mycoplasmal pneumonia (seep 1438), although swine influenza, Aujeszky disease, Bordetella bronchiseptica, or Haemophilus parahaemolyticus may also cause changes in the lungs that lead to disease caused by Pasteurella spp. The causative organism usually is P multocida. A normal inhabitant of the porcine upper respiratory tract, it produces an exudative bronchopneumonia, some­ times with pericarditis and pleuritis. Primary, sporadic, fibrinous pneumonia due to pasteurellae, with no epidemio­ logic connection with mycoplasmal or other pneumonia, may also be seen in pigs. In both primary and secondary forms, chronic thoracic lesions and polyarthritis tend to develop. Diagnosis is based on necropsy findings and recovery of pasteurellae from the lesions. Nontoxigenic strains of capsular type A are the predominant isolates from cases of pneumonia. Toxigenic strains of P multocida, in the presence of B bronchiseptica, are now associated with atrophic rhinitis (seep 1465). Septicemic pasteurellosis and meningi­ tis occasionally occur in piglets. Mann­ heimia haemolytica has been recovered from aborted fetuses, and septicemia may also occur in adult pigs. There are no distinctive lesions, and the pathogenesis is obscure. Porcine strains of M haemo­ lytica are often untypeable and do not belong to the common ovine and bovine serotypes. However, some outbreaks in the UK have been associated with close contact with sheep. Control of the secondary, pneumonic form of the disease is generally based on prevention or control of mycoplasmal pneumonia. Early and vigorous therapy with antibiotics, or in combination with sulfonamides, is indicated to prevent chronic sequelae of all forms of the disease. An increasing resistance to some antibiotics has been noted among the pasteurellae.

1469

PLEUROPNEUMONIA Pleuropneumonia is a severe and conta­ gious respiratory disease, primarily of young pigs ($;6 mo old), although in an initial outbreak, adults also may be affected. It has a sudden onset, short course, and high morbidity and mortality. It occurs world­ wide and appears to be increasing in incidence, although some reports suggest that severity is declining in countries where it has been long established. Etiology: The causal organism is

Actinobacillus pleuropneumonia.e. To

date, 15 serotypes have been identified; they vary widely in virulence and significance across countries. Historically, serotypes 1, 5, and 7 have been prevalent in the USA. Transmission is mainly by nose-to-nose contact, and many recovered pigs are carriers. Clinical signs develop within 4-12 hr in experimental infections. Aerosol transmission is limited.

Clinical Findings: Onset is sudden, and in herds that have not been infected previ­ ously, spread is rapid. Some pigs may be found dead without having shown clinical signs. Respiratory distress is severe; there are "thumps," and sometimes open-mouth breathing with a blood-stained, frothy nasal and oral discharge. Fever up to 107°F (41.5° C), anorexia, and reluctance to move are typical signs. Although primarily a disease of growing pigs, A pleuropneumoniae infection may be fatal in adults or cause sows to abort. The course of the disease varies from peracute to chronic. Morbidity may reach 50"Ai, and in untreated cases, mortality is high. Survivors generally show reduced growth rates and persistent cough. Once established in a herd, the disease may be evident only as a cause of reduced growth rate and pleurisy at the abattoir, although acute disease exacerbations may occur. However, severe lesions may not always be accompanied by equally severe clinical signs. Deaths in transit and carcass condemnation may result. Concurrent infection with mycoplasma, pasteurellae, porcine reproductive and respiratory syndrome, or swine influenza virus is common. Lesions: The pneumonia is usually bilateral. The characteristic lesion is a severe fib1inonecrotic and hemorrhagic pneumonia with accompanying fibrinous pleuritis. Fibrinous pleuritis and pericarditis may be severe. In acute cases, the lungs are

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dark and swollen and ooze bloody fluid from the cut surface; hemorrhagic, even necrotic, bullae of various sizes may be present. The trachea may contain blood­ stained froth. In chronic cases, the lesions are more organized and localized. Extra.tho­ racic lesions are uncommon. Diagnosis: An explosive disease onset is suggestive and, when combined with clinical signs and gross lesions, often justifies a tentative diagnosis. Concurrent infections, eg, with pasteurellae, may complicate diagnosis. In herds that have been exposed and have developed at least a degree of immunity, the pattern may be less distinctive. Many serologic tests, including complement fixation and ELISA, have been used to confirm a herd diagnosis or detect carriers, but results are not always straightforward. A definitive diagnosis depends on isolation and identification of A pleuropneumoniae, a gram-negative coccobaciltus that requires V factor (NAD) supplementation for growth. A Staphylo­ coccus aureus nurse colony can provide the necessary factor. PCR testing is also available and provides better sensitivity than direct culture. Treatment and Control: Rapidity of

onset and persistence in infected herds make treatment difficult. Ceftiofur, tilmicosin, tetracyclines, synthetic penicillins, tylosin, and sulfonantldes have been used. The first treatment should be parenteral, followed by medication given in water or feed, which also may protect contact pigs. Because survivors frequently remain carriers, control is difficult, afthough good results are being claimed for some vaccines. Segregated early weaning, "all-in/all-out" management, reduced stocking rates when possible, and in1proved ventilation are recommended. In herds free of the disease, replacements should be purchased from herds free of A pleuropneumoniae; if the disease proves difficult to control, herd depopulation and repopulation should be considered. Serologic testing effectively detects previously infected herds but may not identify carrier animals.

SWINE INFLUENZA (Hog flu, Pig flu)

Swine influenza is an acute, highly contagious, respiratory disease that results from infection with type A

influenza virus. Field isolates of variable virulence exist, and clinical manifesta­ tion may be determined by secondary organisms. Pigs are the principal hosts of classic swine influenza virus. (Human infections have been reported, but porcine strains of influenza A do not appear to easily spread in the human population. However, deaths have occurred in immunocompromised people.) In 2009, a pandemic strain of HIN1 influenza A virus spread globally; it infected people, swine, and poultry, as welt as a small number of dogs, cats, and other animals. The disease in swine occurs commonly in the midwest­ ern USA (and occasionally in other states), Mexico, Canada, South America, Europe (including the UK, Sweden, and Italy), Kenya, China, Japan, Taiwan, and other parts of eastern Asia. Etiology: Swine influenza virus (SIV) is an orthomyxovirus of the influenza A group with hemagglutinating antigen H l and neurantlnidase antigen N1 (ie, H l N 1 ). Recently, new subtypes of SIV have been reported (H3N2, H1N2, and H2N3). Influenza B and C viruses have been isolated from pigs but have not caused tlle classic disease. The classic type A infection with isolates of mild virulence may favor replication of pseudorabies virus (seep 1 300), Haemophi­ lus parasuis (Glasser's disease, seep 720), AclinobaciUus pleuropneumoniae (see above), and Mycoplasma hyopneumoniae (seep 1467), any of which may complicate outbreaks. The ntlxing of carrier and noninunune pigs is an important predispos­ ing factor. The virus is unlikely to survive outside living cells for >2 wk except in cold conditions. It is readily inactivated by disinfectants. Transmission and Epidemiology:

In North America, outbreaks are most common in fall or winter, often at tlle onset of particularly cold weatller. In warmer areas of the world, infection may occur at any time. Usually, an outbreak is preceded by one or two individual cases and then spreads rapidly witltln a herd, mainly by aerosolization and pig-to p - ig contact. The virus survives in carrier pigs for up to 3 mo and can be recovered from clinically healthy animals between outbreaks. In antibody­ positive herds, outbreaks of infection recur as in1111unity wanes. Up to 40% of herds may contain antibody -positive pigs. Carrier pigs are usually responsible for the introduction of SIV into previously uninfected herds and countries.

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RESPIRATORY DISEASES OF SHEEP AND GOATS

Pathogenesis: The spectrum of infection ranges from subclinical to acute. In the classic acute form, the virus multiplies in bronchial epithelium within 16 hr of infection and causes focal necrosis of the bronchial epithelium, focal atelectasis, and gross hyperemia of the lungs. Bronchial exudates and widespread atelectasis, grossly appeaiing as plum-colored lesions affecting individual lobules of apical ai1d intennediate lobes, are seen after 24 hr. The lesions continue to develop until 72 hr after infection, after which the virus becomes more difficult to demonstrate. Losses in reproduction associated with prinlary outbreaks appear to be secondary, because vims has been recovered only rarely from the fetus. Clinical Findings: A classic acute outbreak is chai·acterized by sudden onset a11d rapid spread through the entire herd, often within 1 -3 days. The main signs are depression, fever (to l08° F [42° C]), anorexia, coughing, dyspnea, wealrness, prostration, and a mucous discharge from the eyes and nose. Mortality is generally 1o/o 4 - %. The overt course of the disease is usually 3-7 days in uncomplicated infections, with clinical recovery of the herd almost as sudden as the onset. However, vims may continue to cycle an10ng pigs when clinical signs are suppressed by immune responses. Some pigs may become chronically affected. In herds that are in good condition, the principal economic loss is from sttmting and delay in reaching market weight. Some increase in piglet mortality has been reported, and effects on herd fertility, including abortions in late pregnancy, may follow outbreaks in nonirnmune herds. Lesions: In uncomplicated infections, lesions usually are confined to the thoracic cavity. The pnemnonic areas are clearly demarcated, collapsed, and purplish red. They may be distributed ttu·oughout the

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lungs but tend to be more extensive and confluent ventrally. Nonpnemnonic areas are pale and emphysematous. The ai.tways contain a copious mucopurulent exudate, and the bronchial and mediastinal lymph nodes are edematous but rarely congested. There may be severe pulmonary edema, especially of interlobular septae, or a serous or serofibrinous pleuritis. Histologically, the lesions, when fully developed, are prinlarily those of an exudative bronchiolitis with some interstitial pneumonia. Diagnosis: A presumptive diagnosis can be made on clinical and pathologic findings, but confirmation depends on detection of viral RNA via PCR, molecular sequencing, or demonstration of vims-specific antibody. Virus can be isolated from nasal secretions in the febrile phase or from affected lung tissue in the early acute stage. A retrospec­ tive diagnosis can be made by demonstrating a rise in vims-specific antibodies in acute and convalescent serum sainples using the hemagglutination inhibition test. Both H3 and H l subtype antigens should be included. This test is also used for herd surveys. To diagnose uncomplicated influenza infection, conditions such as pasteurellosis, pseudora­ bies, porcine reproductive and respiratory syndrome, and chlanwdial and Haemophi­ lus infections must be excluded. Treatment and Control: There is no effective treatment, although antimicrobials may reduce secondary bacterial infections. Expectorants may help relieve signs in. severely affected herds. Vaccination and strict in1port controls are the only specific preventive measures. Good management practices and freedom from stress, particularly due to crowding and dust, help reduce losses. Commercially available killed vaccines that contain both H l N2 and H3N2 subtypes appear to induce a strong protective in1111une response.

RESPIRATORY DISEASES OF SHEEP AND GOATS Upper Respiratory Tract: Diseases of the upper respiratory tract of sheep and goats include sinusitis caused by the larvae of Oestrus ovis, nasal foreign bodies, and nasal tun10rs. Clinical signs associated with

sinusitis may include some or all of the following: tutilateral or bilateral, serous to mucopurulent nasal discharge; decreased or lack of ai.tilow through one or both nostrils; coughing; sneezing; and mild to severe

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respiratory distress. The types of nasal neoplasms reported include adenopapillo­ mas (nasal polyps), adenomas, adenocarci­ nomas, lymphosarcomas (goats), and squamous cell carcinomas (sheep). Enzootic nasal tumor is caused by an exogenous retrovirus referred to as enzootic nasal tumor virus (ENTV). It can be transmitted experimentally by tumor homogenates, which would explain the widespread occurrence of this condition within some flocks. This type of tumor generally affects mature animals (2-4 yr old), although it has been reported in animals as young as 4 mo old. The lesion may be unilateral or bilateral, resulting in either unilateral or bilateral serous, mucoid, or mucopurulent nasal discharge. Advanced unilateral tumors may cause deviation of the nasal septum, resulting in bilateral nasal discharge. Affected animals show progressive signs of dyspnea (inspiratory), including open-mouth breathing, decreased airflow as measured at the nares, dullness on percussion over the turbinates, sneezing, and head-shaking. Strid or may also b e caused by compression of the larynx by enlarged retropharyngeal lymph nodes associated with abscessation of the head. Laryngeal chondritis also results in inspiratory dyspnea of varying severity. With advancing tumor growth, exophthal­ mos and facial deformity may occur. Metastatic spread is uncommon. Outcome depends on the tumor type, condition of the animal, and extent of the lesion, but in most commercial situations the animal is culled for animal welfare and commercial reasons. Surgical removal of a noninvasive tumor is rarely undertaken. The most common probleIRs associated with the pharynx are trauma and abscessa­ tion. Pharyngeal trauma usually results from overly aggressive use of equipment used to administer boluses. Injuries may result in the fom1ation of discrete abscesses or extensive and diffuse cellulitis, both of which can interfere with swallowing and possibly lead to respiratory difficulty or distress. Bacteria commonly isolated after an incident of phaiyngeal trauma include

Trueperella, Pasteurella mullocida, Mannheimia haemolytica, and F'usobacte­ rium. Laryngeal chondritis is an obstructive upper respiratory tract disease charactet" ized by severe dyspnea most commonly encountered in meat-breed rai11s 18--24 mo old. Acute onset of severe respiratory distress with marked inspiratory effort and stertor is caused by edema of the arytenoid

cartilages of the laiynx, resulting in narrowing of the lumen. Affected sheep stand with the neck extended, head held lowered with flared nostrils, and mouth open; they are reluctant to move because of dyspnea. Delayed identification and/or inadequate duration of antibiotic therapy may result in abscess formation within the arytenoid cartilages. Lower Respiratory Tract: The most common problem associated with the lower respiratory tract is pneumonia. Pneumonias can be caused by viruses, bacteria, or parasites. They can be acute, chronic, or progressive. Viruses associated with acute pneu­ monia include pai·ainfluenza type 3 (PI-3), adenovirus, and respiratory syncytial virus. These viral pneumonias most often affect lambs and kids. Pl-3 is an enveloped RNA virus (family Pai·amyxoviridae) that induces a mild interstitial pneumonia. Clinical signs may include coughing, serous nasal and/or ocular discharge, fever (104°-106°F [40°-41°C]), and an increased respiratory rate. The single PI-3 serotype for sheep that has been identified is distinct from the bovine PI-3 serotype. Infection with this vims can be confirmed by its isolation from nasal swabs from affected anin1als, or by comparison of acute and convalescent semm antibody levels. Treatment is usually not warranted in mildly affected animals. In severely affected animals in which secondary pathogens are suspected, antimicrobial therapy is recommended using dmgs with efficacy against the most likely organisms, such as P mullocida, M haemolytica, and Mycoplasma sp. There are no PI-3 vaccines specifically designed for use in small ruminants. Chronic, progressive viral pneumonia is most common in adults and includes progressive interstitial retroviral pneumonia (in sheep, ovine progressive pneumonia or maedi [seep 1475]; in goats, pneumonia induced by arthritis encephalitis virus [seep 747]) and ovine pulmonary adenocarcinoma (seep 1477), also known asjaagsiekte or the conta­ gious lung tumor of sheep and, infre­ quently, of goats. Chronic, progressive, proliferative changes in the lungs are usually associated with the lentiviruses (family Retroviridae), or so-called slow-virus infections. In both progressive pnewnonia and pulmonary adenocarcinoma, the entire lung can change in a gradual process of abnormal cellular

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RESPIRATORY DISEASES OF SHEEP AND GOATS proliferation. In affected sheep, the loss of functional lung tissue results in progressive dyspnea, anorexia, and weight loss.

M haemolytica, P rnullocida, Myco­ plasrna spp, Chlarnydia pneurnoniae, and Salrnonella spp are associated with either

primary or secondary bronchopneumonia in sheep and goats. BothP rnultocida and M haemolytica, can be cultured from the upper respiratory tract of nom1al sheep and goats. Not all factors predisposing to acute respiratory diseases are known, but acute viral infections in a susceptible population can alter the protective mechanisms in the respiratory tract so that certain bacteria may invade lung tissue, multiply, and cause serious disease. An initial infection with PI-3 virus may predispose an animal to infection with pathogenic M haemolytica. Also, Myco­ plasrna ovipneurnoniae alone can cause a mild bronchopneumonia; however, it is often isolated along withM haernolytica from sheep and goats with severe pneumonia, suggesting that the Myco­ plasrna may predispose the lung to invasion by this organism. Additionally, introduction of new animals, high-density stocking, poor ventilation, and a sudden change to a high plane of nutrition can act as stress factors that predispose to development of pneumonia. Caseous lymphadenitis (seep 63) caused by Corynebacteriurn pseudotuberC'ulosis may result in abscessation of the lungs and mediastinal lymph nodes. This can result in a progressive debilitation in sheep and goats with or without obvious clinical signs of respiratory disease. Parasitic or verminous pneumonias of sheep and goats are most commonly caused by infection with Dictyocaulus.fua1ia, Muellmius capillmis, or Protostrongylus rufescens. (See also p 1421.) In contrast to the acute viral and bacterial pneumonias, which result in a bronchopneumonia affecting the anterior ventral po1tion of the lungs, vem1inous pneumonia affects the margins of the diaphragmatic lung lobes. Dictyocauliis has a direct life cycle, whereas Protostrongylus and Muellerius have indirect life cycles and rely on a variety of snails and slugs to serve as intermediate hosts. Adult forms of Dictyocaulus and Protostrongylus live in bronchi but rarely cause clinical signs. AdultMuellmius live in alveoli and lung parenchymal tissue and are considered the least pathogenic of the three lungwonns. Muellm"ius appears to cause more problems for goats than for sheep. Diagnosis of lungwonn infection requires Baem1ann exanlination of fecal material

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(See also p 1619). Treatment for lungwonn infection is rarely indicated; however, it is likely that sheep with such infections will also carry other nematodes that will cause parasitic gastroenteritis and limit produc­ tion. SHEEP NOSE BOT The sheep nose bot fly, Oestrus ovis, is a cosmopolitan parasite that, in its larval stages, inhabits the nasal passages and sinuses of sheep and goats. Its geographic distribution is worldwide. The adult fly is grayish brown and -12 mm long. The female deposits larvae in and about the nostrils of sheep without alighting. These small, clear-white larvae (initially 9 wk old should be vaccinated twice, with a3-wk interval. Kittens should be vaccinated at intervals of3-4 wk until they are 2!12 wk old. In adult cats, revaccination with a single dose every 1-3 yr is indicated. The second type of vaccine is administered to healthy cats by instillation into the coqjunc­ tival cul de sacs and nasal passages. Owners should be advised that cats inoculated oronasally may sneeze frequently for 4--7 days after vaccination. Kittens vaccinated when 12 wk old; younger kittens should be revaccinated when they reach 16 wk. All should be revaccinated annually. These vaccines are indicated in catteries or on premises where CJelis infection has been confmned. The chlamydia! vaccines are available in combination with FVR-FCV and panleu­ kopenia vaccines. Systematic vaccination and control of environmental factors (such as exposure to sick cats, overcro­ wding, and stress) provide good protec­ tion against upper respiratory disease.

LUNG FLUKES Paragonimus kellicolli and P weste1mani usually are found in cysts, primarily in the lungs of dogs, cats, and several other domestic and wild animals. They also have been found rarely in other viscera or the brain. Infection is most common in China,

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southeast Asia, and North America. P wes­ te1mani is a parasite of people and other

animals in China and other countries in the Far East. The adult flukes are fleshy, reddish brown, oval, and -14 x 7 mm. The eggs are golden brown, oval, distinctly operculated, and -100 x 60 µm. The eggs pass through the cyst wall, are coughed up, swallowed, and passed in the feces. The life cycle includes several snails as the first intermediate host, and crayfish or crabs as the second. Dogs and cats become infected by eating raw crayfish or crabs that contain the encysted cercariae. After penetrating the intestinal wall and wandering in the peritoneal cavity, the young flukes pass through the diaphragm to the lungs, where they become established. Infected animals may have a chronic, deep, intermittent cough and eventually become weak and lethargic, although many infections pass unnoticed. Finding the characteristic eggs in feces or sputum is diagnostic. The location in the lungs is ascertained by radiography. Aberrant infections can be identified serologically. Fenbendazole (50 mg/kg/day, PO, for 10-14 days) or less preferably albendazole (25 mg/kg, PO, bid for 14 days) reduce the number of eggs deposited and eventually kill the parasites. Praziquantel (25 mg/kg, PO, tid for 3 days) may also eliminate lung flukes in dogs.

LUNG NEMATODES See also LUNGWORM INPECTION, p 1421. Aelurostrongylus abstrusus Aelurostrongylus abstrusus, the most

common lungwom1 of cats, is found in many parts of the world, including the USA, Europe, and Australia. They are small parasites (males 7 mm, females 10 mm), deeply embedded in the lung tissues. The eggs are forced into alveolar ducts and adjacent alveoli, where they fom1 small nodules and hatch. Once tl1e larvae escape, they are coughed up, swallowed, and passed in the feces. The larvae seen in the feces of infected animals are tightly coiled, have an undulating tail with a spine, and are 600/o are carcinomas, of which adenocarcinoma is the most common. In dogs, the ethmoturbi­ nates tend to be the site of predilection. Dolichocephalic and mesocephalic breeds appear to be at higher risk than brachyce­ phalic breeds. In cats, 2'90% of nasal twnors are malignant, the most conunon being lymphoma and the second most common being carcinomas. Tumors of the nose and paranasal sinuses typically are very invasive locally and metastasize infrequently; metastasis is more likely in carcinomas and usually occurs late in the disease. Common sites of metastasis are regional lymph nodes, lungs, and brain. Invasion of the paranasal sinuses tends to be greater in dogs than in cats. In general, survival of untreated animals is 3--5 mo after diagnosis. Chronic nasal discharge is the most corrunon clinical finding; it may be mucoid, mucopurulent, or serosanguineous. Initially, discharge is unilateral but often becomes bilateral. Periodic sneezing, epistaxis, and respiratory stertor may occur. Facial and oral deformities result from destruction of bony or soft-tissue sinonasal structures. Retrobulbar extension of these twnors results in exophthalrnos

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RESPIRATORY DISEASES OF SMALL ANIMALS and exposure keratitis. Secondary epiphora may occur ifthe nasolacrimal duct is blocked. Late in the disease, CNS signs (eg, disorientation, blindness, seizures, stupor, and coma) may develop ifthe tumor extends into the cranial vault. Diagnosis is based on history and clinical findings and elimination ofother causes of nasal discharge, sneezing, or facial deformation. Nasal radiographs or CT typically show increased density ofthe nasal cavity and frontal sinuses as well as evidence ofbone destruction. CT is vastly superior to plain radiography in diagnosis of chronic nasal diseases. Definitive diagnosis is based on biopsy oftumor tissue, either with blind biopsy based on CT lesion localization or on rhinoscopic visualization with direct biopsy. Nasal hydropulsion using a high-pressure saline infusion into the nose often yields diagnostic samples and, iflarge volumes oftwnor tissue break free, nasal obstruction will be relieved inunediately. Treatment largely depends on tumor type and extent ofdisease. The treatment of choice for canine nasal adenocarcinoma is radiation therapy. Aggressive surgical excision, chemotherapy, radiation therapy, or combinations for other tumor types afford a more favorable prognosis when diagnosis is made early. Tumors of the Larynx and Trachea Tumors ofthe larynx and trachea are rare in dogs and cats. Tumors ofthe larynx most frequently reported in dogs are oncocy­ toma, squamous cell carcinoma, mast cell twnor, melanoma, and osteosarcoma; in cats, they are squamous cell carcinoma, lymphosarcoma, and adenocarcinoma. Benign inflanm1atory polyps ofthe larynx also are seen in dogs and cats. Tumors ofthe trachea are particularly rare. Osteochondral dysplasia ofthe trachea (osteochondroma) is a benign tumor ofthe trachea prin1a1ily seen in dogs d y.r old. Other benign mesenchymal tumors, carcinomas, and sarcomas are occasionally seen. The most common signs oftumors ofthe larynx include inspiratory dyspnea, stridor, voice change (hoarse bark or loss ofvoice), coughing, and exertional dyspnea. Findings typically associated with tumors ofthe trachea are coughing, dyspnea, stridor, and rarely hemoptysis. Laryngeal and tracheal tumors may be associated with signs of fixed upper airway obstruction (inspiratory and expiratory dyspnea). The degree of dyspnea often relates to the degree of luminal obstruction.

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Diagnosis is made from the history and clinical findings and by etinlinating other causes ofupper airway obstruction or coughing. The twnor mass may be seen radiographically or on laryngoscopy or tracheoscopy. Definitive diagnosis is made on biopsy. Surgical excision and resection is the treatment ofchoice. Radiation therapy may be palliative for radiosensitive tumors such as squamous cell carcinoma, mast cell tumor, and lymphoma. Surgical resection of tracheal osteochondral dysplasia in dogs is cw·ative. Primary Lung Tumors Primary tung tun1ors are rare in dogs and cats; however, tl1e reported incidence of lung carcinomas has increased at least 100% during the last 20 y.r. This is attributed to an increased average life span, better detection and awareness, or possibly increased exposure to environmental carcinogens. Most prin1ary lung tumors are diagnosed at a mean age of10-12 y.r in dogs and 12 y.r in cats. There is no consistent breed or sex predilection in either species. Primary lung tumors usually originate from t11e terminal bronchioles and alveoli; they occasionally develop as a second coincidental tmnor, which may make differentiation between primary and metastatic disease difficult. Ofthe primary lung tumors in dogs and cats, �8()0A, are malignant. Adenocarcinoma and alveolar carcinoma are the most common types. Primary lung sarcomas and adenomas are rare in both species. Metastatic spread ofprimary tw1g twnors is generally to other areas ofthe lungs, tracheobronchial lymph nodes, bone, and brain. Intrapulmonary spread via the airways occurs in -500A, ofdogs with adenocarcinoma. Metastatic spread to the pleurae, pericardium, heart, and diaphragm may occur; miscellaneous extrathoracic sites include liver, spleen, and kidney. Dogs with papillary (bronchoalveolar) adenocar­ cinoma have a better prognosis than those with other lung twnors; however, histologic grade and detection ofclinical signs are the most important determinants ofprognosis and survival. Both recurrence and metastasis tend to occur earlier and with greater frequency in dogs with moderately or poorly differentiated tumors. Clinical Findings: Primary lung tumors have variable manifestations, which depend on the location oftwnor, rapidity oftumor growth, presence ofprevious or concurrent pulmonary disease, and awareness ofthe

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owner. Common signs include cough, inappetence, weight loss, reduced exercise tolerance, lethargy, tachypnea, dyspnea, wheezing, vomiting or regurgitation, pyrexia, and lameness. The most common clinical findings in dogs are cough, dyspnea, lethargy, and weight loss, although 25% of dogs with primary lung tumors have no clinical signs related to the tumor. Coughing is uncommon in cats; nonspecific signs, such as inappetence, weight loss, and tachypnea and dyspnea, are more common. In either species, tachypnea or dyspnea indi­ cates massive tun1or burden or pleural effusion. Pleural effusion is particularly common in cats with primary lung tumors. Lameness may be due to hypertrophic osteopathy (unusual in cats) or to metasta­ sis to bone or skeletal muscle. Thoracic auscultation may be nonnal, reflect increased breath sounds compatible with pulmonary airway disease, or be muffled because of pulmonary consolidation or pleural effusion.

Diagnosis: One-third or more of primary lung tun1ors are recognized incidentally during radiography for other problems, or at necropsy. Thoracic radiographs are essential for a tentative diagnosis in those animals exhibiting compatible clinical signs. Prinlary lung tumors in dogs may occur as single or multiple circun1scribed mass lesions, as a diffuse lung pattern, or as a lobar consolidation. In cats, single circumscribed mass lesions are less common, whereas a diffuse lung pattern or lobar consolidation is more frequent. Pleural fluid accunmlation is common in cats and less frequent in dogs. In either species, chest wall involvem�nt and hilar lymphadenopathy may be seen. Tentative diagnosis can be made by excluding other causes of pulmonary disease with similar radiographic lung patterns. Definitive diagnosis requires biopsy. Treatment: Surgical resection of tumor

via lobectomy of diseased lung lobes is the treatment of choice. Inoperable lesions or metastatic disease may be controlled with chemotherapy. Overall median survival time for dogs having surgical treatment for primary lung tumor is 120 days. Mean survival time for operable primary lung tumors without node involvement in dogs is 12 mo; if the lymph nodes are involved or multiple tumors are found at the tinle of diagnosis, survival time is only 2 mo. Recurrence or metastasis of tumor is a common cause of death.

Metastatic Tumors of the Lungs A localized tun1or may extend to the lungs by dissemination through hematogenous or lymphatic routes or by direct extension of tumor cells. Certain primary tumors, such as mammary adenocarcinoma, osteo­ sarcoma, hemangiosarcoma, and oral melanoma, most commonly metastasize to the lungs. The lungs may be the only site of metastasis, or there may be concurrent metastasis in other organs; in the forn1er, the diagnostic approach is to identify an occult prinlaiy tumor or to cai·efully review the medical history for disclosure of previous tumor removal. Because pultno­ nary metastasis occurs late in the clinical course of a malignant tumor, prognosis is poor. The signs of metastatic pultnonary disease are sinliiai· to those of prinlary !wig twnors except that coughing is less common. Seve1ity of signs depends on the anatomic location of the tun1or and whether the lesions are solitary or multiple. Establishing a diagnosis is sinlilar to that for primary lung tumors. Because of the limitations of routine radiography, small lesions (53 mm in diaineter), which are present in �4()0A, of cases with pultnonary metastasis, may not be seen. Thoracic CT can identify lesions not seen radiographl­ cally. Radiography of the chest should precede removal of tumors with a known high incidence of metastatic spread to the lungs. The major goal of cancer therapy is prevention of metastasis rather than cancer eradication. Slow-growing or solitary metastatic lesions are best treated by surgical excision. Chemotherapy or radiation therapy may be useful with certain tumor types not an1enable to surgical resection. Overall, the prognosis for aninlals with pulmonary metastasis is poor.

PNEUMONIA Pnewnonia is an acute or chronic inflanima­ tion of the lungs ai1d bronchi characterized by disturbance in respiration and hypox­ emia and complicated by the systemic effects of associated toxins. The usual cause is primary viral infection of the lower respiratory tract. Canine distemper virus, adenovirus types 1 and 2, parainfluenza virus, and feline calicivirus cause lesions in the distal airways and predispose to secondary bacte­ rial invasion of the lungs. Parasitic invasion of the bronchi, as by Filaroides, Aeluros-

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RESPIRATORY DISEASES OF SMALL ANIMALS trongylus, or Paragonimus spp may result in pneumonia. Protozoan involvement, eg, by Toxoplasma gondii (seep 685) or Pneumocystis jiroveci, is rarely seen. Tuberculous pneumonia, although uncommon, is seen more often in dogs than in cats. The incidence of mycotic granu­ lomatous pneumonias is also higher in dogs than in cats. Cryptococcal pneumonia has been described in cats. Injury to the bronchial mucosa and inhalation or aspiration of irritants may cause pneumo­ nia directly and predispose to secondary bacterial invasion. Aspiration pneun1onia (seep 1417) may result from persistent vomiting, abnom1al esophageal motility, or improperly administered medications (eg, oil or barium) or food (forced feeding); it may also follow suckling in a neonate with a cleft palate. Clinical Findings: The initial signs are usually those of the primary disease. Lethargy and anorexia are conunon. A deep cough is noted. Progressive dyspnea, "blowing" of the lips, and cyanosis may be evident, especially on exercise. Body temperature is increased moderately, and there may be leukocytosis. Auscultation usually reveals consolidation, which may be patchy but more commonly is diffuse. In the later stages of pneumonia, the increased lung density and peribronchial consolidation caused by the inflanunatory process can be visualized radiographically. Complications such as pleuritis, mediastini­ tis, or invasion by opportunistic organisms may occur. Diagnosis: Analysis of bronchoalveolar lavage fluid is valuable for the diagnosis of bacterial infections. Cytologic examina­ tion can demonstrate the animal's immune response and indicate the intracellular or extracellular location of bacteria. Bacterial culture and sensitivity testing is required and may include anaerobe and mycoplasma culture, especially in refractory cases. A viral etiology generally results in an initial body temperature of 104°-l06° F (40°-41°C). Leukopenia, often expected, may not be seen in many viral respiratory infections (eg, canine infectious tracheobronchitis, feline calicivirus pneumonia, feline infec­ tious peritonitis pneun1onia). A history of recent anesthesia or severe vomiting indicates the possibility of aspiration pneumonia. Acutely affected aninlals may die within 24-48 hr of onset. Mycotic pneun1onias are usually chronic in nature. Miliary nodules seen at necropsy may suggest protozoa! pneumonia.

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Treatment: The aninlal should be placed

in a wam1, dry environment. Anemia, if present, should be coITected. If cyanosis is severe, oxygen therapy may be used, administered by means of an oxygen cage, with a concentration of 30%--500/o. Empirical antinlicrobial chemotherapy should be i.Jlitiated and changed if needed based on results of culture of bronchoalveolar lavage fluid. Supportive therapy should be instituted as needed and may include oxygen supplementation, pulmonary physiotherapy (nebulization and coupage), and bronchodilators. If no response is seen after 48--72 hr of therapy, the treatment plan should be reassessed. Antimicrobial chemotherapy should be continued l wk after clinical and radiographic signs resolve. Anin1als should be reexamined fre­ quently. Chest radiographs should be repeated at regul.ar intervals to monitor recurrence or note a primary underlying disease process and to detect complications such as lung consolidation, atelectasis, or abscessation.

PULMONARY THROMBOEMBOLISM See also THROMBOSIS, EMBOLISM, AND ANEURYSM, p 141. Pulmonary thromboembolism (PTE) is an obstruction of one or more pulmonary vessels by a blood clot. The actual incidence of PTE is uncertain, although in critically ill aninlals or in tllose with certain disease states (eg, immune-mediated hemolytic anemia, corticosteroid administration, bacterial infections, protein-losing enteropathy or nephropathy, neoplasia, trauma, feline infectious peritonitis, diabetes mellitus, hyperadrenocorticism, hypothyroidism, dissenlinated intravascular coagulation, dirofilariasis) the incidence is considerable, and PTE is underdiagnosed. Mortality rates of PTE in aninlals are uncertain but probably significant. Survival depends on early diagnosis and early appropriate therapy. Thromboemboli in the venous circulation become trapped in the pulmonary vasculature and, if occlusion is substantial, pulmonary and hemodynamic sequelae result. Animals with preexisting cardiac or respiratory compromise may be affected earlier or more severely. The acute pulmonary consequences of PTE include ventilation-perfusion mismatch, hypox­ emia, hyperventilation, and bronchocon­ striction. Hemodynamic consequences of PTE are related to the magnitude of the

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obstrnction and presence of coexisting cardiopulmonary disease. Myocardial ischemia, a.rrhytlrn1ias, or right ventricular failure may result. Decreased cardiac output may ensue with severe obstrnction to pulmonary arterial blood flow as a result of decreased venous cardiac return. In dogs, PTE is associated with protein­ losing neph.ropathy, hea.itwonn disease, endoca.i·ditis, cardiomyopathy, necrotizing pancreatitis, hypercortisolism, immune­ mediated hemolytic anemia, sepsis, diabetes mellitus, neoplasia, atherosclero­ sis, trauma, and major surgical procedures. Cardiomyopathy a.t1d neoplasia are most commonly associated with PTE in cats.

Clinical Findings: Clinical signs are nonspecific a.t1d most often subclinical or may be mild to profound, reflecting the severity of cardiorespi.ratory compromise. Dyspnea, tachypnea, a.11d depression are commonly seen. Coughing, cyanosis, hemoptysis, collapse, shock, a.11d sudden death ca.11 occur. Diagnosis: Diagnosis is often difficult because PTE ca.11 resemble many other conditions, including pneumonia, pulmo­ nary edema or hemorrhage, neoplasia, or pleural effusion. Routine diagnostic tests such as thoracic radiography or arterial blood gas a.11alysis are nonspecific a.11d ra.i·ely confirm diagnosis. Arterial blood gas a.11alysis will identify hypoxemia present in 800;6 of dogs, although response to oxygen is variable. Thoracic radiographs ca.11 be normal in 9%-27% of dogs a.t1d in 9% of cats with PTE. Abnonnal radiographic findings with PTE include alveola.i· or inLersLiLial pulmona.iy infiltrates or regional ll.ypovas­ cula.i· lung a.i·eas. However, thoracic radiographs that underestimate the degree of clinical respiratmy compromise should raise suspicion of PTE. Blood gas a.11alysis may reveal hypoxemia and hypocapnia, indicating inefficient gas excha.11ge, but the presence of normal blood gas values does not exclude PTE. Echocardiography ca.11 aid in assessment, demonstrating cha.11ges suggestive of PTE a.11d pulmonary hyperten­ sion (dilation of the right ventricle, pulmonary artery, inferior vena cava; right ventricula.i· hypokinesis; tricuspid regurgitation; abnormal septal wall motion). A normal echoca.i·diogra.in does not exclude diagnosis of PTE. Spiral CT a.11giography or selective pulmonary a.11giography remain gold standards for diagnosis of PTE in people, but these adva.11ced imaging studies are available at few veterinary institutions.

Treatment: Therapy should begin as soon as possible a.11d include suppo1t of respirato1y a.t1d cardiovascular systems, prevention of thrombus development and recurrence, a.11d possibly thrombolysis. Oxygen supplementation a.t1d bronchodila­ tors are indicated when dyspnea is evident or when a.iterial oxygen saturation is 600A, of their clay foraging. The remainder of their time is spent resting (standing or lying down), grooming, or engaging in another activity. This san1e pattern is seen under barn conditions; even with free choice of grain, horses will eat mru1y small meals a day. Horses are highly social ru1imals that require contact with others for nom1al daily ma.intenru1ce ru1d well-being. Isolating horses can lead to development of problems. The ma.in goal of managing behavior problems in horses is to identify the deviation from nom1al equine behavior and con-ect it.

Aggression Aggression is a common problem in horses and includes chasing, neck wrestling, kicks a.I1d bites, and other threats. Signs of aggres­ sion include eru·s flattened backwru·d, retracted lips, rapid tail movements, snaking, pawing, head bowing, fecal pile display, snoring, squealing, !evade (rearing with deeply flexed hindquarters), ru1cl threats to kick. Submissive horses respond by avoiding, lowering the neck and head, clan1ping tl1e tail, and turning away from the aggressor.

Aggression to People: This behavior is

seen mostly in stalls in which the horse feels confined in a small space that is also easily

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defended. The varieties of aggression toward people include fear, pain induced, sexual (honnonal), learned, and dominance related. Some horses, especially young ones, play with each other while showing signs of aggression such as kicking and biting. Although benign to other horses, this can be dangerous to people. The first step in managing equine aggression is identifying the cause, and if possible, removing it. Training and positive reinforcement to establish control over the horse are also used, along with desensitiza­ tion and counterconditioning. Dominance­ related aggression in horses is different from canine status-related aggression (also known as dominance aggression) in that it is not context-dependent. Environmental management is important as well; good management should include sufficient resources such as space, food, and water. Some horses are considered to have pathologic dominance aggression; they will attack other horses and people that are near them. These horses should be separated completely from other people or horses and have a poor prognosis. Aggression Toward Other Horses: Aggression toward other horses is mostly associated with sexual competition, fear, dominance, or territory (protecting the group and resources). As with aggression toward people, some horses may be pathologically aggressive toward other horses. The first step is separation of aggressive horses from other horses, and keeping subordinate away from dominant horses. Separation is achieved by solid walls or two fences to avoid kicks through the fence. Horses should have sufficient resources, and desensitization and counterconditioning is the best treatment approach. In cases of sexually related aggression, castration and progestins (eg, medroxyprogesterone 70-80 mg/300 kg/day) can help. Adverse effects of such treatment should be weighed carefully, and the horse should be monitored closely. Adding tryptophan to the daily ration or administering selective serotonin reuptake inhibitors (SSRis) may be helpful in some cases. Punishment should be avoided. Maternal Aggression: Aggression by mares toward people is normal during the first few days after paiturition. This behavior is hormonally driven and usually wanes with time. Mares should be fainiliarized with their caretakers before delivery and have minimal contact with

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other people after delive1y. No treatment is required in most cases. Aggression While Breeding: Stallions that are aggressive when used for breeding are often overused or used out of season. Stallions cai1 develop preferences for mating and may not be compatible with the chosen mai·e; changing the mare may help. If stallions were stabled with mares when they were colts, they may have some social inhibition for mating, and forced mating can result in aggression. The goal of treatment is to treat the main cause of aggression; chai1ging the mare (because of preferences) or artificial breeding can also be attempted. Physical restraint (eg, hobbles) and desensitization can help as well. Clicker training has been used successfully to desensitize stallions with this problem. Stereotypic Behaviors Compulsive behaviors in horses can be divided into movement-related behaviors and oral behaviors. They can be called stereotypic because they are repetitive, occupy a large part of the daily activity, and serve no function. Confmement and poor management practices are the prinlaiy contributing factors. In addition, bedding, feed, and social contact influence stereo­ typic behaviors. Horses that have more social contacts, are fed more roughage and more than one type, are fed two or more tin1es daily, and are bedded on straw are less prone to these behaviors. Cribbing and wood chewing are exainples of oral behaviors, whereas weaving, stall walking, and pawing are exan1ples of locomotor stereotypies. Horses with one stereotypic behavior are likely to exhibit another. In Thoroughbreds, these behaviors ai·e conunonly seen in mares and 2-yr-old foals. Cribbing {Aerophagia, Windsucking): When cribbing, the horse usually grasps an object in the stall (such as the water bucket) with its incisors, flexes its neck, and sucks air into the pharynx. Some horses will aspirate or swallow the air. In some cases, horses will suck air with­ out grasping any object. Feeding highly palatable food (eg, grains, molasses) is associated with cribbing. Lack of exercise is also associated with cribbing; endurance horses are less likely to do it than race or dressage horses. Thoroughbreds are more prone to cribbing than other horses. The rate of cribbing is higher in confined horses; however, even if the horse is turned to pasture once the behavior is

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and covering fence edges with wires and taste repellents can also help minimize wood chewing.

established, it will persist. It is possible that GI discomfort can lead to cribbing. One of the major complications of cribbing is damage to the incisors. Other problems include gastroduodenal ulcers and epiploic foran1en entrapment. In most cases, cribbing is a benign behavior that does not affect the horse's welfare and does not require treatment. Close to 10% of foals 20 wk of age will start cribbing when weaned and placed in stalls. Those kept on pasture will not start. It has been speculated that horses can learn cribbing by watching other horses; however, no clear evidence exists. Cribbing can be diagnosed by finding U-shaped pieces missing from fences and horizontal surfaces in the stall, and worn incisors and enlarged neck muscles in horses that crib. In some cases, the caretaker may directly observe the behavior. Management should include more roughage, exercise, and social contact. Turning confined horses to pasture may help, and providing toys and stimula­ tion is also advocated. Placing a strap around the horse's neck behind the poll will apply pressure each time the horse tries to flex its neck. This essentially punishes the horse for cribbing, with the punishment associated with the behavior and not the caretaker. Alternatively, an open-end muzzle can be applied. This will allow the horse to eat and drink but prevent it from grasping objects to crib on. Some horses find a way to crib with the muzzle (eg, grasping a linear object, such as a stick), and most horses seem to tolerate the strap better than the muzzle. Keeping stalls free of horizontal surfaces and objects that tile horse can grasp can help minimize cribbing. A variety of surgeries have been suggested to manage cribbing; however, the varying success rates and negative impact on animal welfare are significant disadvantages.

Stall Walking and Weaving: These behaviors are seen in confined horses, serve no purpose, are hard to interrupt, and are usually slower than other types of movement. Horses that stall walk usually walk in circles in the stall, and when released to a larger space ( eg, pasture or barn) continue to circle in a small area. Tying the horse to prevent walking will only transfonn the behavior into weaving, ie, lifting the legs and shifting weight and head position from side to side in the same spot. Possible causes of stall walking include lack of exercise and social contact and claustrophobia. Stress and anxiety appear to aggravate the problem. Treat­ ment should focus on increasing exercise and stimulation, providing social contact, and turning the horse to pasture. Providing tllick bedding and feeding more than twice daily can help as well. In extreme cases, SSRis might be necessary to control the problem. Providing a large mirror in the stall in front of the horse can help decrease weaving.

Wood Chewing (Lignophagia): Like a horse that cribs, a wood-chewing horse will grasp pieces of wood with its incisors, but unlike in cribbing, it will swallow the pieces. The definitive cause of wood chewing is lack of roughage in tile diet. Confinement, high-concentrate diets, and lack of exercise and stimulation increase incidence of wood chewing. Horses on pasture normally spend 8-12 hr/day grazing, while confined horses spend 80 but that have normal histologic morphology. The reason for this is unknown. In general, plasma enzyme levels decrease due to sample deterioration. Uncommonly, atrophy or fibrosis of an organ may result in unusually low plasma activities of the relevant enzymes.

Additional Tests: Further tests may be added to the basic panel, according to the principal presenting signs, to create panels for polydipsic animals, collapsing anin1als, etc. These panels are structured so that the patterns of abnormalities typical of all the likely differential diagnoses applicable to the situation can be discerned. For example, a polydipsia panel may add calcium, glucose, and cholesterol. Calciw11 allows recognition of hyperparathyroidism and other causes of hypercalcemia (which causes polydipsia and renal insufficiency), glucose may indicate diabetes mellitus and contributes to the pattern characteristic of hyperadrenocorticism, and cholesterol also adds to the appreciation of the "Cushing pattern." Renal failure is covered by the tests already included in the basic panel. In contrast, in a panel for a "collapsing aninlal," calcium and glucose may be added to screen for hypocalcemia or hypoglyce­ mia. Sodium and potassiWll are included to screen for hypoadrenocorticism or hypokalemia. Analytes that might be consid­ ered for incorporation in such expanded profiles are described below. Sodium level increases due to Conn syndrome (hyperaldosteronism), restricted water intake, vomiting, and most causes of dehydration. It decreases due to hypoad­ renocorticism, loss of any high-sodiun1 fluid such as some fon11s of renal disease, and insufficient sodiWll provision during IV fluid therapy. Potassium level increases due to hypoadrenocorticism and severe renal failure (especially ternlinal cases). It

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decreases due to Conn syndrome, chronic renal dysfunction, vomiting, diarrhea, and insufficient potassium provision during JV fluid therapy. Congenital hypokalemia occurs in Bunnese cats. Chloride level increases in acidosis, and in parallel with increases in sodiw11 concentration. It decreases in alkalosis, vomiting (especially after eating), and in association with hyponatremia. Total C02 (bicarbonate) level increases in metabolic alkalosis and decreases in metabolic acidosis. It is less useful to assess respiratory acid/base disturbances. Calcium level increases due to dehydra­ tion (which is also associated with increased albwnin), primary hyperparathy­ roidism (neoplasia of parathyroid gland), primary pseudohyperparathyroidism (neoplasms producing parathonnone­ related peptide [PRP], usually perianal adenocarcinoma or some fonn of lyrnpho­ sarcoma), bone invasion of malignant neoplasms, thyrotoxicosis (uncommon), and overtreatment of part1.11ient paresis. It decreases due to hypoalbtuninemia, parturient paresis, oxalate poisoning, clu·onic renal failure (secondary renal hyperparathyroidism), acute pancreatitis (occasionally), surgical interference with parathyroid glands, and idiopathic (autoimrntme) hypoparathyroidism. Phosphate level increases due to renal failure (secondary renal hyperparathy­ roidism). Decreases are seen in some downer cows and as part of the stress pattern in horses and small anin1als. Magnesium level increases are rarely seen, including dllling acute renal failure. It decreases in ruminants due to dietary deficiency, either acute (grass staggers) or chronic, and diarrhea (unconm1on). Glucose level increases due to high­ carbohydrate meals, sprint exercise, stress or excitement (including handling and sampling stress), glucocorticoid therapy, hyperadrenocorticism, overi.nfusion with glucose/dextrose-containing JV fluids, and diabetes meUitus. It decreases due to insulin overdose, insulinoma, islet cell hyperplasia (unconm1on), acetonemia/pregnancy toxemia, acute febrile illness, and idiopathi­ cally (in certain dog breeds). 13-Hydroxybutyrate level increases in diabetes mellitus. It is a major component of ketoacidosis and as such is also increased in acetonemia/pregnancy toxemia and extreme starvation. It can be measured in both blood and urine. Bilirubin level increases due to fasting (benign effect in horses and squirrel

monkeys, may be caused by hepatic lipidosis in cats), hemolytic disease (usually mild increase), liver dysfunction, and biliary obstruction (intra-or extraliepatic). Theoretically, hemolysis is characterized by an increase in uncoajugated (indirect) bilirnbin, whereas hepatic and post-hepatic disorders are characterized by an increase in conjugated (direct) bilirubin; however, in practice this differentiation is unsatisfac­ tory. Better appreciation of the source of the jaundice is gained from bile acid measure­ ments. Bile acid levels increase when hepatic anion transport is impaired, usually during liver dysfunction (bile acids are more sensitive than bilirnbin to hepatic impair­ ment) and in the presence of a po1tosys­ temic shunt (congenital or acquired). The latter condition is characterized by a marked increase in bile acid concentration after feeding, from a fasting concentration that may be normal. It also increases in bile duct obstruction; very little increase is seen in feline infectious pe1itonitis or mild cases of hepatic lipidosis. Very high levels can sometimes be seen without structural histologic changes. The reason for this is not known. Cholesterol level increases due to fatty meals, hepatic or biliary disease, protein­ losing nephropathy (and other protein­ losing syndromes to some extent), diabetes mellitus, hyperadrenocorticism, and hypothyroidism. It decreases in some cases of severe liver dysftmction and occasionally in hype1thyroidism. Lactate dehydrogenase is a ubiquitous enzyn1e with a nwnber of isoenzymes; electrophoretic separation of isoenzymes is necessary to locate the source of increased activity. It is therefore of very limited value in general clinical practice. Sorbitol dehydrogenase level increases in acute hepatocellular damage in horses but is a very labile analyte. ex-Amylase level increases in acute pancreatitis but in dogs is also increased in chronic renal dysftmction. It is therefore of limited use in the diagnosis of pancreatitis. Pancreatic lipase inlmunoreactivity is now the test of choice for diagnosis of pancreati­ tis in dogs and cats. Amylase is not a useful indicator of pancreatitis in cats. Lipase level increases in acute pancreati­ tis in dogs (longer half-life than amylase) and also occasionally in chronic renal dysfunction. Lipase (routine assay) is not a useful indicator of pancreatitis in cats. Immunoreactive trypsin (trypsin­ like immunoreactivity) level decreases

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DI AGNOSTIC PROCEDURES FOR THE PRIVATE PRACTICE LABORATORY

in exocrine pancreatic insufficiency in dogs. It will also increase (irregularly) in pancreatitis. Tests for Pancreatic Disease: Pancreatitis: Serum amylase and lipase activities have been used for several decades to diagnose pancreatitis in both people and dogs. Unfortunately, neither of these tests is botl1 sensitive and specific for pancreatitis in dogs. In one study, significant serun1 amylase and lipase activities remained after total pancreatec­ tomy, indicating there are somces of semm amylase and lipase activity other tl1an the exocrine pancreas. Also, clinical data suggest a specificity for pancreatitis of only -500/o for both of these markers. Many nonpancreatic diseases, such as renal hepatic, intestinal, and neoplastic dis�ases can lead to increases in sernm amylase anci lipase activities. Steroid administration can also increase serum lipase activity and cause variable responses in serum an1ylase act1V1ty. Thus, in dogs, measurement of serum amylase and lipase activities are of lilnited usefulness for diagnosis of pancreatitis. Serum amylase and/or lipase activities that are 3-5 times the upper lilnit of the reference range, in animals with clinical signs consistent with pancreatitis are suggestive of such a diagnosis. Howe�er, it 1s important to note that -500/o of dogs that fulfill these criteria do not have pancreatitis. ln cats, serum amylase and lipase activities are of no clinical value for diagnosis of pancreatitis. Altl10ugh cats with experin1en­ tal pancreatitis can show an increase in serum lipase activity and a decrease in senun amylase activity, these changes are not consistent in cats with spontaneous pancreatitis. In one study of 12 cats with severe forms of pancreatitis, not a single cat had serum lipase or an1ylase activity above the upper limit of the reference range. Serum trypsin-like immunoreactivity (TLI) concentration measmes mainly trypsmogen, the only fonn of trypsin circulating in the vascular space of healthy md1V1duals. However, trypsin, if present in the serun1, is also detected by these assays. Senun TLI concentrations can be measmed by species-specific assays that have been developed and validated for both dogs and cats. ln healtl1y animals, senun TLI is low, but dming pancreatitis an increased amount oft_rYPsinogen leaks into the vascular space, which can lead to an increase in serum TLI concentration. Trypsin that has been prematmely activated may also contribute to this increase. However, both trypsinogen

1593

and trypsin are quickly cleared by the kidneys. ln addition, any prematurely activated trypsin is quickly removed by prnteinase inhibitors, such as a,-proteinase . mhib1tor and o:2-macroglobulin. In tum, 0:2-macroglobulin-trypsin complexes are removed by the reticuloendothelial system. Thus, the serum half-life for TLI is short and a significant degree of active inflanm1ation is required to increase serum TLI concentra­ tion. Because of tl1e limited sensitivity of serum cTLI and ITLI concentrations for canine and feline pa.ncreatitis, respectively, and because only a limited number of laboratories measure these assays routinely, serum TLI concentration is of limited usefulness for diagnosis of pancreatitis in dogs and cats. Pancreatic lipase immunoreactivity (PLI) concentration measmes the concentration of classical pancreatic lipase m the senun. This is in contrast to serum lipase activity, which measures the enzymatic activity of all triglyceridases present in the serum, regardless of their cellular origin. Assays to measure PLI in canine (cPLI) and feline (f'PLI) serum have been developed and validated and are commercially available. Serum PL! is highly specific for exocrine pancreatic function. Also, serum PLI is far more sensitive for diagnosis of pancreatitis than any other diagnostic test cmrently available. A pati.ent-side.selniqua.ntitative assay for . diagnosis of canme pancreatitis is also available. A test spot that is lighter in color tl1an the reference spot suggests tl1at pancreatitis can be excluded. A test spot darker in color than the reference spot raises the suspicion of pancreatitis and should prompt the clinician to measme a serum cPLI concentration in the laboratory. Other tests for diagnosis of pancreatitis in dogs and cats have been evaluated including plasma trypsinogen activation peptide (TAP) concentration, mine TAP concentration, mine TAP:creatini.ne ratio, serum o: 1 -proteinase inhibitor trypsin complex concentration, and serum armacroglobulin concentration. However, none has been shown to be of clinical usefulness. Exocrine Pancreatic Insufficiency: In the past, several fecal tests have been used to diagnose exocrine pancreatic insufficiency (EPI). Microscopic fecal examination for fat and/or tmdigested starch or muscle fibers are at best useful to suggest maldigestion. However, in light of wide availability of tests to diagnose EPI, microscopic fecal exan1ination is no longer justified. Fecal proteolytic activity had been used to

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diagnose EPI in small animals for several decades. Most of these methods, particu­ larly the radiographic film clearance test, are unreliable. One method, which uses pre-made tablets to pour a gelatin agar, is considered most reliable. However, false-positive as well as false-negative results have been reported. The clinical use of fecal proteolytic activity is limited to species for which more specific assays to estimate pancreatic function are not available and in areas where the more accurate and sophisticated tests are not available. Serwn TLI concentration is the diagnostic test of choice for EPI in both dogs and cats. Assays forTLI measure trypsino­ gen circulating in the vascular space. In healthy animals, only a small amount of trypsinogen is present in serum. However, in dogs and cats with EPI, the number of pancreatic acinar cells is severely decreased. Serum TLI concentration decreases significantly and may even be undetectable. The reference range forTLI in dogs is 5.7-45.2 mcg/L with a cut-off value of 500/mL in dogs generally indicate a significant increase. Normal synovial fluid contains -2 cells/high­ powered field (400X magnification). In the vast majority of cases where there is a.11 increased cell content, cell nun1bers are either low (up to 4 or 5 cells/high-powered field) in degenerativejoint disease or very high in septic or autoimmune arthritis. Inter­ mediate equivocal results ai·e extremely unconunon. Cell types includejoint mononuclear cells, which are a mixttll'e of circulating monocytes, tissue macrophages, and synovial lining cells. It is not possible, or even necessaiy, to differentiate these cells, because they all have a sinlilai· morphology ai1d all react to sinillai· stimuli. Cytoplasmic vacuolation of these cells, and especially the presence of phagocytosis of debris or RBCs, indicate activation, a feature not seen in

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DIAGNOSTIC PROCEDURES FOR THE PRIVATE PRACTICE LABORATORY

nom1al joint mononuclear cells. In degenerative joint disease, synovial fluid usually contains only macrophages, occasionally with extremely low nwnbers of neutrophils. Hemorrhage is common in synovial preparations but is frequently an artifact. True hema.rthrosis provides a synovial fluid san1ple that is unifonnly contaniinated with blood at the time of sampling. If the blood contamination occurs at the very end of the san1pling procedure with clear fluid initially, tllis is most likely artifact. In addition, in true hema.rtlu·osis, RBCs may be seen in the cytoplasm of macrophages. Artifactual blood contanlination will also introduce WBCs, such as neutrophi.ls, making interpretation of inflan1matory cells in the san1ple difficult, although blood contanlina­ tion still gives only a low cell nwnber. Neutrophils a.re present in large nwnbers in both septic arthritis and autoimmune joint disease. These two conditions can usually be differentiated by the clinical llistory. In septic arthritis, bacteria a.re sometimes found within the cytoplasm of phagocytic cells. The absence of bacteria, either within cytology preparations or by culture, does not exclude bacteria as a cause of a.rt1u;tis. False-nega­ tive results for bacteria a.re not uncommon. Lymphocytes a.re often present in very small nwnbers in inflan1matory processes but a.re not specific for a particular cause. Osteoclasts are very occasionally seen when there has been erosion of tl1e articular cartilage with exposure of the underlying bone. Neoplastic cells in joint fluid a.re rare, although joints can be the site of both primary and secondary tumors. Macrophages increase with any damage to a joint, especially in cases of degenerative joint disease. Cytoplasnlic vacuolation of these cells, and especially the presence of phagocytosis of debris or RBCs, indicate macrophage activation, a feature not seen in nom1al joint mononuclear cells. In degenerative joint disease, synovial fluid often contains only macrophages. Nasal Cavity: The cytology of nasal flush preparations is similar to that seen with BAL preparations. A small nwnber of respiratory epithelial cells a.re usually flushed out along witl1 exudate. A predomi­ nance of eosinophils may indicate i.nllaled allergens, parasites, or fungi and may occasionally indicate bacteria or neoplasia. The presence of eosinophi.ls in the nasal cavity therefore is less indicative of a specific process than in some other sites, eg, the trachea or bronchi.

1607

Neutrophi.ls a.re the most common exudative cell but, as with BAL, often indicate secondary infection. In the case of intranasal neoplasia, cells with neoplastic cha.racte1istics (seep 1601) may be present, but absence of these cells does not exclude neoplasia Only a minority of neoplastic processes erode the overlying respiratory epitheliun1 and allow exfoliation of neoplastic cells. Similarly, absence of fungal hyphae within the preparation does not exclude fungal infection. Unless fungal plaques a.re sampled directly for both cytology and culture, false-negative results are conu11on. Viral inclusions are rarely seen. Vaginal Cytology: This can be used to identify tile vrufous stages of the canine estrous cycle, but results must be inter­ preted in cortjw1ction with the animal's behavior. A sample of exfoliated cells is obtained from the vaginal vault crrulial to the urethral 01ifice wiU1 a cotton-tipped swab or glass rod. Cells ru·e gently rolled onto a glass slide, air dried, and stained. Features to be identified include neutro­ phils, bacteria, RBCs, and the types of epithelial cells. Epithelial cells (in increasing order of differentiation) a.re pa.rabasal, small and Iru·ge intem1ediate cells, and superficial cells. Para.basal cells are small, with central round nuclei, indistinct nucleoli, a relatively narrow band of cytoplasm, and a nucleus:cytoplasm ratio of -1: l . Small intennediate cells have a similar nucleus but a much larger an1ount of cytoplasm. Large intem1ediate cells have a similar nucleus with very large amounts of cytoplasm and an angular, irregular outline. Superficial cells also have large an1ounts of cytoplasm, but their nuclei are pyknotic (small and contracted) or absent. The stages of the estrous cycle change gradually. If a preparation does not conform exactly to a specific pa.rt of the cycle, judgment must be made regarding what stages are present. In proestrus, all types of epithelial cells ru·e present along with neutrophils, RBCs, and mucus. As proestrus progresses, the epithelial cells increasingly approach temlinal differentiation (superfi­ cial cells), and neutrophils slowly decrease. Bacteria a.re often present in lru·ge nwnbers. In estrus, >900Ai of epithelial cells a.re superficial cells, with no background mucus. There ru·e large nwnbers of bacteria, but no neutrophils. In di.estrus, pa.rabasal and intermediate cells a.re >80% of the total epithelial cells. Variable nun1bers of neutrophils and bacteria ru·e present but usually fewer than in proestrns. It cru1 be difficult to differentiate some stages of

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proestrus from diestrus. In anestrus parabasal and intermediate cells prectomi­ nate. Neutrophils and bacteria are rare. RBCs do not help differentiate the stages of estrus. Cerebrospinal Fluid: Interpretation of CSF cytology is difficult, because it can be hard to obtain enough well-prese1vecl cells for exan1ination before the satnple deteriorates. Cell counts in nom1al CSF are low (0-5 cells/µL in dogs and 0 8- cells/µL in cats). However, there is a large variation in cell counts between individuals; counts can also vaiy between cystemal and lumbar taps in the san1e individual. Because the albunlin level of CSF is -20A, of that found in serum, the cells that are present rapiclly degenerate. Cell counts should ideally be clone and morphology exanlined within 1 hr of collection. Because of the low cell numbers, the use of an automated cell counter is usually not appropriate. A hemocytometer cat1 be used for cell counts, and a cytocentrifuge for cytology preparations. A simplified sedimentation technique ( description of which is beyond the scope of this discus­ sion) to concentrate cells onto a slide is suitable for practice use. The presence of more than one or two nucleated cells in a plain smear of CSF should be considered potentially significai1t. In CSF, an increase in nucleated cells is called pleocytosis. There is tremendous variation ai1d overlap in both the degree of pleocytosis and the types of cells present in both infectious and noninfectious conditions in the CNS. Interpretation should be integrated with the other clinical details of the case. If neutrophils and/or macrophages are present, the cytoplasm of the cells should be searched for bacteria and fungi. The absence of organisms or pleocytosis does not exclude infection, and noninfectious conditions in the CNS can also produce a neutrophilic pleocytosis. Apart from lymphoma, it is rare to find neoplastic cells in CSF. If noninflainmatory cells are present in the CSF, they should be interpreted using the basic principles detailed above. Urine Cytology: U1ine can be exainined as a wet preparation or as a dried cytology smear. Because of the absence of staining in a wet preparation, these are better limited to exatnination for crystals and RBCs. Although nucleated cells may be seen, in most cases they caimot be identified and are better exan1ined using a dried cytology smear.

There are at least 10 common forms of urinaiy crystals. Identification is not discussed here but may be readily accomplished by use of good reference illustrations. (See also UROLITHIASIS, p 1525.) Because cells in urine rapiclly degenerate, _ particularly if bacteria are present, centrifuged preparations of urine sai11ples should be exanlined rapiclly after satnpling. If this 1s not possible, boric acid is often added to urine to prevent degeneration and bacterial overgrowth, although its effect may be very limited. If a delay between satnpling ai1d exatnination is likely, a better preservation method is the addition of a few drops of formalin; however, the traditional Romanowsky stains caimot then be used. H&E stain is a better alternative for sainples. formalin fixed Nonna! urine usually has very few nucleated cells. Single urothelial cells are occasionally present. Squatnous epithelial cells are also seen in urine and come from the tem1inal urethra, vagina, vulva, and preputial epitheliun1. Squatnous metaplasia of bladder epitheliwn after chronic inflammation is very rare. Neoplastic cells in urine sainples are almost always epithelial. They are rounded polygonal cells, often clun1ped, with marked variation in morphology, especially the nucleus:cytoplasm ratio. Uniform cells are more likely to be nmmal. Mi.Icily pleomor­ P_hic cells can be associated with hyperpla­ Sia (eg, some cases of polypoid cystitis). _ The inflainmatory cells seen in cystitis are almost exclusively neutrophils. Eosinophils are seen in some rare, specific inil=atory conditions, but macrophages are very uncommon even in chronic conditions. By far the most common cause of inflan1IDation is infection, so the cytoplasm of the neutrophils should be exanlined carefully for bacteria. It is very uncommon to see a significant neutrophil component accompa­ nying neoplasia or calculi. . R �Cs are commonly seen with neoplastic and inflanm1atory diseases of the bladder but ai·e also often seen without an indication of other pathology. This can be a sainpling artifact but is also a common finding in cases of interstitial cystitis. In cats, this tem1 is often used synonymously with feline urologic syndrome but interstitial cystitis also is seen 'in dogs and people, suggesting other unknown pathogenic factors that can cause this condition. Persistent hematuria without cytologic evidence of neoplasia or inflainmation may indicate interstitial cystitis. See also URINALYSIS, p 1615.

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liver Cytology: Although cytology is a popular method to investigate liver disease, there is disagreement on its usefulness. Blood contamination is found in most samples and may overshadow inflammatory infiltrates by introducing circulating WBCs. Diagnosis of many hepatic diseases relies on architectural features and the distribu­ tion of the changes within the liver rather than on the morphology of individual cells. Finally, in some hepatic disorders, hepatocytes proliferate without significant changes in their individual morphology (see below). These factors limit the amount of information that can be obtained from cytology of liver tissue. Sampling methods are similar to those used for other organs. San1pling is usually performed under guidance of ultrasound, but blind sampling can be performed at the tenth intercostal space at the level of the connection of rib to rib cartilage. Bleeding during this procedure is not a significant risk In the healthy liver, hepatocytes are plun1p, polygonal rounded cells with a diameter of 25-30 microns. Nuclei are central and round with a single large, prominent nucleolus. A few cells are binucleated. There is a large amount of blue-staining cytoplasm that usually appears granular. Changes in the metabolism of liver cells can be seen within the cytoplasm. The presence of nun1erous small, discrete vacuoles or one large vacuole indicates accun1ulation of fat. This has several potential causes and is prominent in feline hepatic lipidosis syndrome, starvation, pregnancy, and diabetes mellitus. Enlarged hepatocytes with a pale granular-staining cytoplasm but no discrete vacuoles are characteristic of excess glycogen storage. This is most often caused by increased levels of circulating steroids. Bile stasis and pigment accumulation (eg, iron) can also be assessed by examination of the cytoplasm. Hepatocytes nom1ally accumulate lipofuscin pigment, noted as small, fairly unifom1, dark-staining granules, whereas bile and often hemosid­ erin tend to appear as slightly larger dark-staining bodies within the cytoplasm. Bile accumulation within the canaliculae (canalicular plugs) can also occasionally be seen. These appear as black 1ibbons on the surface of hepatocytes. Cytologic interpretation of inflammation is difficult because of the inevitable blood contan1ination of samples. Inflan1mation should be considered significant only if it is present wiiliin clusters of hepatocytes.

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Although the individual inflammatory cells can be recognized, it is not possible to indicate which part of the liver is principally affected. Neutrophils can be seen in diffuse hepatitis and also in more focal cholangitis. Small, mature inflammatory lyn1phocytes are usually seen in periportal inflammatory conditions, such as lyrnphocytic pericholan­ gitis in cats and chronic active hepatitis in dogs. Macrophages can also be seen in the chronic inflammatory conditions and also in certain infections. Phagocytic cells should be investigated for the presence of organisms within the cytoplasm, but tlus is uncommon in liver disease. Primary proliferative nodular hepatocel­ lular lesions include regenerative hyperpla­ sia, nodular hyperplasia, adenoma (hepatoma), and hepatocellular carcinoma. Biliary proliferations can appear as cysts, adenomas, or carcinomas. Bile duct cells tend to be smaller than hepatocytes with less cytoplasm. They are cuboidal or low columnar cells that occasionally produce tubular structures within cytology samples. The cytoplasm is also more uniformly pale staining and not significantly granular. Nucleoli are smaller and less distinct. Significant cell harvest from cystic bile ducts is uncommon because most of these lesions are sin1ply cystic space rather than cellular. If a significant nwnber of biliary epithelial cells are obtained, neoplasia is most likely. However, malignant bile duct cells are more commonly uniform in size and shape and, therefore, do not always show the morphologic features usually associated with malignancy. Hepatocellular proliferation is a difficult area of interpretation, because hepatocytes in benign proliferative lesions are very similar to those in well-differentiated carcinomas and indeed often cannot be differentiated even from normal hepato­ cytes. Only in cases with poorly differenti­ ated pleomorpluc cells can an adequate interpretation of malignancy be made. The benign and non-neoplastic proliferations always have the same morphology as nonnal hepatocytes. Therefore, false-nega­ tive results for proliferative lesions within the liver are common. Cytology is thus of limited value for nodular hepatocellular lesions. Cytology can be a useful technique for diagnosis of round cell tumors in the liver. Even with severe inflarrm1atory lesions, lymphocytes are present in low numbers and are generally small, mature lympho­ cytes. A large population of medium and large lymphoid cells indicates lymphoma. No other condition will give this result.

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The other common round cell tumor that can affect the liver (particularly in cats but also occasionally in dogs) is mast cell tumor. The granules within mast cells are metachromatic, facilitating diagnosis. Aspirates of normal liver may contain a few mast cells, but in neoplasia they are usually present in large numbers. lf other cells are obtained from cytology preparations, they should be interpreted using the principles described above.

Kidney Cytology: Normal renal aspirates have almost a pure population of renal tubular cells. These are unifom1, mediun1sized cells of -17-20 microns with central nuclei, small indistinct nucleoli, and a moderate amount of pale-staining cytoplasm. In cats, lipid droplets within the cytoplasm are a common, nom1al feature. The cells can be present either singly or in clusters and can occasionally be seen as tubular structures. They sometimes contain small, dark granules within the cytoplasm. Renal lymphoma is the most common neoplastic disease of the kidney in cats and dogs. Because the cells are usually widely distributed within the tissue, false-negative results with cytologic examination are uncommon. Diagnosis can be made using the criteria described above. Primary renal tumors are unconunon. Cystic lesions include renal cysts, most commonly seen in cats but also occasionally in dogs, and hydronephrosis. In both disorders, cell harvest is usually low, with a large amount of fluid. The cellular component of the sample is .rarely helpful in identifying further the nature of the cystic structure. Most inflan1111atory lesions in the kidney are chronic and produce fibrous connective tissue. Cell harvest from these lesions is usually exceedingly low, and cytology is not typically a useful technique. Pyogenic inflanunation can sometimes be diagnosed. Cytology may help diagnose feline infectious peritonitis, although diagnosis using serologic techniques is more common. Because of the usually severe and widespread nature of the inflammation, cell harvest is usually high. The wide mixture of inflanunatory cells present in feline infectious peritonitis, with a predominance

MCV (fL)

of neutrophils, along with an appropriate history, are typical of the disorder.

Mammary Cytology: Cytology is useful to differentiate inflan1111atory from neoplastic nodular lesions within mammary tissue. Man1111ary tumors are not commonly inflamed. It is less useful to differentiate the neoplastic conditions. Neoplastic lesions must be interpreted using the criteria listed above (seep 160 1). The criteria most useful to detem1ine the behavior and prognosis of a man1111ary tumor are local tissue and vessel invasion, not cell morphology. These are best assessed histologically rather than cytologically. Therefore, cellular morphology is not necessarily a good guide to tumor behavior. In cats, malignant cells are often uniform and do not exhibit the normal malignant features; the size of the malignant tun1or is the most useful prognostic indicator. CLINICAL HEMATOLOGY Hematology refers to the study of the numbers and morphology of the cellular elements of the blood-theRBCs (erythro­ cytes), WBCs (leukocytes), and platelets (thrombocytes)-and the use of these results in the diagnosis and monitoring of disease. (See also 1-IEMATOPOIETIC SYSJ'EM INTllODUCTIO , p 4.)

Red Blood Cells: ThreeRBC measure­

ments are routinely done: packed cell volume (PCV), the proportion of whole blood volun1e occupied byRBCs; hemo­ globin (Hgb) concentration of whole lysed blood; andRBC count, the munber ofRBCs per unit volun1e of whole blood. Although these are separate estimations, they are in effect three ways to measure the same thing, and it is incorrect to attempt to interpret them as separate variables. Inasmuch as they do vary in rel.ation to each other, they allow calculation of two further meaningful parameters, mean corpuscular volume (MCV) and mean corpuscular hemo­ globin concentration (MCHC). MCV varies widely between manunalian species, from -15 fL in goats to -90 fL in people. Avian and reptilian red cells are even larger, up to 300 fL. Nevertheless,

= PCV(decimal fraction) x 1, 000 RBC(x 1012 /L)

MCHC (g/1)

= whole blood hemoglobin concentration (g/1) PCV(decimal fraction)

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MCHC varies little with species (or erythrocyte size), at -330 g/1. Several artifacts can cause significant and potentially misleading alterations to measured RBC paran1eters: 1) old samples cause RBCs to swell, thus increasing PCV and MCV and decreasing MCHC; 2) lipemia causes a falsely high Hgb reading, and hence a falsely high MCHC; 3) hemolysis causes PCV to decrease while Hgb remains unchanged, again leading to a falsely high MCHC; 4) underfilling of the tube causes RBCs to shrink, causing PCV and MCV to decrease and MCHC to increase; 5) auto­ agglutination causes a falsely low RBC cotmt, and hence a falsely high MCV. Visual description of RBC morphology on a Romanowsky stain also provides useful diagnostic infom1ation. The most common tenns include 1) nonnocytic--cells are of normal size; 2) macrocytes-abnormally large cells, usually polychromatophilic; 3) microcytes-abnormally small cells, usually caused by a lack of hemoglobin precursors; 4) anisocytosis-variation in size of cells due to macrocytes, microcytes, or both; 5) nonnochromic--cells are of normal color; 6) polychromasia-variation in color of the cells, which usually describes the appearance of large, juvenile, bluish­ staining polychromatophilic macrocytes (these broadly correspond to the "reticulo­ cyte" seen with new methylene blue staining, in which the reticulum represents the remnants of the nucleus); 7) hypochro­ masia-decrease in staining density of the cells, usually due to a lack of hemoglobin precursors, especially iron; and 8) annulocyte--extreme form of hypochromic cell with only a thin rin1 of hemoglobin. PCV is the variable usually used to assess the basic status of the erythron-increased in polycythemia, decreased in anemia­ although if a sample is too hemolyzed to allow measurement of PCV, a meaningful Hgb measurement may still be obtained. RBC count as such should not be inter­ preted clinically. An abnormally high PCV (polycythemia) may be relative, due to a change in the proportion of circulating RBCs to blood plasma without any change in the size of the erythron, or absolute, due to a real increase in erythron size. Absolute polycythemia may be prinlary (eg, polycythemia vera or, rarely, erythropoietin-producing tumors) or secondary (a consequence of disease in another organ system). (See also POLY­ CYTHEMIA, p 43.) Polycythemia vera and erythropoietin­ producing tumors should be suspected only when PCV is very high, nmrnally >0. 7. The

1611

former is characterized by normal, mature RBCs and a norn1al (or low) erythropoietin concentration, whereas the latter may show a regenerative RBC picture with high erytlrropoietin concentration. Relative polycythemia may also be associated with very high PCV values, and norn1al, mature RBCs. Secondary polycythemia generally shows a more modest increase in PCV, often with evidence of regeneration (more so when the cause is pulmonary or cardiac, less so when the cause is hormonal). It is often possible to make the differential diagnosis of polycythemia on clinical grounds. Abnonnally low PCV (anemia) may be caused by loss of blood (hemorrhage), breakdown of RBCs in circulation (hemolysis), or lack of production of RBCs by the bone marrow (hypoplasia or aplasia). Presentation varies according to whether the condition is acute or chronic. Aplastic anemia is always chronic in onset, because anemia occurs gradually as existing cells reach the end of their lifespan. (See also ANEMIA, p 7.) In acute hemorrhagic anemia, external blood loss is easily appreciated clinically, but blood loss into a body cavity may be detennined only on paracentesis. Initially, all hematologic parameters may be normal, because it may take 12 hr for fluid shifts to produce a decrease in the PCV. Within a few days, RBCs become regenerative, with juvenile fonns appearing in circulation (except in horses, in which circulating evidence of regeneration is not readily appreciable). These consist of polychro­ matophilic macrocytes and normoblasts (nucleated RBCs). Late normoblasts have a small, nonviable nucleus and a moderate amount of cytoplasm colored sinillarly to that of the polychromatophilic macrocytes, whereas early normoblasts have a larger, viable nucleus and scanty cytoplasm. These are most easily distinguished from lympho­ cytes by their more densely staining nucleus. If substantial amounts of blood have been lost from the body, the RBC picture may become hypochrornic. Thus, this type of anemia shows an increase in MCV and a decrease in MCHC. If bleeding is into a body cavity, hypochromasia may not be evident because hemoglobin precursors will be recycled. However, slight jaundice may be seen as the sequestered cells are broken down. Some sequestered cells may also be returned to the circulation intact, if somewhat misshapen. In acute hemolytic anemia, PCV will decrease in1lllediately, and in the early stages some jaundice will be evident. In the

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very early stages, even a sample collected with extreme care may be markedly hemolyzed. As with hemorrhagic anemia, theRBCs will become regenerative within a few days, with polychromatophilic macrocytes and nucleatedRBCs evident. Because hemoglobin precursors are not lost from the body, true hypochromasia is not seen. Chronic hemorrhagic anemia may be difficult to appreciate if blood is lost in the feces or urine, or due to bloodsucking ectoparasites. Anemia may be severe, and theRBC picture will be regenerative on presentation. Hypochromasia is usually very marked. In very longstanding conditions, depletion of iron and other hemoglobin precursors can become so marked that most of the cells are micro­ cytic, and MCV may paradoxically decrease. Intermittent intra-abdominal hemorrhage leads to a somewhat different picture, because blood shed into the peritoneal cavity can be returned to the circulation. PCV may therefore recover quickly (until the next episode), and signs of depletion of hemoglobin constituents do not emerge. In chronic hemolytic anemia,RBCs a.re regenerative on presentation, except that some cases of autoimmune hemolytic anemia (AIHA) paradoxically show little or no regeneration unW treatment has been initiated. Hypochromasia. is less marked than in hemorrhagic conditions, and misshapenRBCs (including target cells and folded cells) are more common. The spherocyte, in which the erythrocyte loses its classic biconcave shape, is essentially pathognomonic for AIHA. Jaundice may be absent, because the products of the destruction of theRBCs may be cleared by the reticuloendothelial system and the liver as quickly as they are fom1ed. Hypoplastic and a.plastic anemia may be mild ifRBC production is merely depressed secondary to some other disease. Protein, mineral, or vitamin deficiencies may cause hypoplastic anemia, but these are more likely to be secondary to another disease (eg, chronic hemorrhage or malabsorption) than sin1ple dietary deficiency. Other diseases may cause depression of erythro­ poietin production, eg, renal failure, deficiencies of hormones that usually stimulate erythropoietin production (eg, hypothyroidism, hyperadrenocorticism), and chronic, debilitating conditions (eg, chronic infections, chronic parasitism, and neoplasia.). RBC morphology is nonregen­ erative and may be hypochromic if a deficiency state is involved. Paradoxically, vitan1in B,2 and/or folic acid deficiency

produces a macrocyticRBC picture due to early maturation arrest of the erythrocytes. Neoplasia of the bone marrow may ca.use severe anemia as erythropoietic elements are crowded out, but some regeneration may be seen as the remaining bone marrow attempts to compensate. In this case, other bone marrow cell lines will also be affected. True a.plastic anemia refers to a failure of the entire bone marrow. The shorter-lived granulocytes and platelets decrease first, followed by a progressively severe anemia that is nom1ocytic and nom10chromic.

White Blood Cells: The WBCs consist

of the granulocytes (neutrophils in most manunals, called heterophils in rabbits, reptiles, and birds [ and these look like eosinophils in smears]; eosinophils; and basophils) and the agranulocytes (lympho­ cytes and monocytes). Although ea.ch type is traditionally counted by detennina.tion of its percentage of the total WBC population, meaningful interpretation requires that the absolute nwnber of ea.ch type be calculated by multiplying the total WBC count by the fraction attributable to the individual cell type. Percentages of ea.ch cell type alone are not helpful. An increased percentage that is due to an absolute decrease in another cell type is not an increase at all. Mature neutrophils have a. lobula.ted nucleus, but when demand is high, immature cells witl1 an unlobulated band nucleus (no constriction of the nucleus is more than half the width of the nucleus) may be released into circulation. They function as phagocytes and are important in infectious conditions and in inflammation. Increased neutrophil counts (neutrophilia) are caused by inflan1mation, bacterial infection, acute stress, steroid effects, and neoplasia. of the granulocytic cell line (granulocytic leukemia can be difficult to differentiate from a simple neutrophilia. without special stains or bone marrow biopsy). Decreased neutrophil counts (neutropenia) are caused by viral infections, toxin exposure (including foodbome toxins), certain drugs (eg, carbimazole and methimazole), autoirnmw1e destruction of neutrophils, bone marrow neoplasia not involving the granulocytes, and bone marrow aplasia. Eosinophils a.re characterized by prominent pink-staining granules on a Romanowsky stain. They inactivate histamine and inhibit edema fom1ation. Increased eosinophil counts (eosinophilia) are ca.used by allergic/hypersensitivity reactions, parasitism, tissue ir\jwy, mast cell tumors, estrus, and pregnancy or

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days, but many are long-lived. The nwn­ ber in circulation is a balance between populations in the blood, lymph, lymph nodes, and splenic follicles and does not necessai·ily reflect changes in lymphopoie­ sis. An increased lymphocyte coW1t (lymphocytosis) may occur for physiologic reasons, especially in cats, but significant increases usually indicate leukemia. Immatw-e or bizarre cells may also be recognized. Decreased lymphocyte counts (lymphopenia) are usually due to an effect of corticosteroids, either endogenous (stress or Cushing disease) or therapeutic, and may also accompany neutropenia in some viral infections, especially the pai-vovimses. Lymphopenia may also be a feature of solid-organ lymphosarcomas, when leukemia is absent.

Platelets: Manu11alian platelets are pale blue granular fragments (much smaller than RBCs) shed from multinucleate megakaryo­ cytes in the bone marrow; avian and reptilian platelets are true cells with nuclei. They maintain the integrity of the endothe­ liwn and act as part of the clotting process to repair dainaged endotheliwn, where they ensure mechanical strength of the clot. Increased platelet cotmts (thrombocyto­ sis) occur as a reaction to consW11ption after injury, when large juvenile platelets may also appear; after splenectomy, as splenic stores are liberated to the circula­ tion; after vincristine treatment, which increases platelet shedding from megakary­ ocytes; and in megakaryocytic leukemia. Decreased platelet counts (thrombocyto­ penia) are caused by autoin1mW1e reactions, thrombotidthrombocytopenic purpura, bone mairow suppression and aplasia, bone marrow neoplasia, and equine infectious anemia. Signs ai·e petechiation and ecchyrnosis more than frank hemorrhage, and little may be seen until the platelet count is 0.4: 1 in cats is considered abnom1al. A semiquantitative microalbwninuria test is available to detect urinary albwnin in the range of 1-30 mg/dL. It uses ELISA technology specific for canine or feline albwnin. Because of minor species differences in albru11in, there are different kits for dogs and cats. The microalbwnin­ uria test detects lower concentrations of albumin than a standard dipstick test pad. Hematuria must be macroscopic to increase the microalbwninU1ia or UP:UC; however, pyw'ia increases both. Glucose: Glucose is detected by a glucose

oxidase enzymatic reaction that is specific for glucose. Glucosuria is not present normally because the renal threshold for glucose is>180 mg/dL in most species and >240 mg/dL in cats. With euglycemia., the a.mow1t of filtered glucose is less than the renal threshold, and all of the filtered glucose is reabsorbed in the proximal renal tubules. Glucosuria can result from hyperglycemia (clue to diabetes mellitus, excessive endogenous or exogenous glucocorticoids, hepa.tocutaneous syndrome, or stress) or from a proximal renal tubular defect (such as p1irnary renal glucosuria. or Fanconi syndrome). If glucosuria is present, blood glucose concentration should be dete1mined. False-negative results can occur with high urinary concentrations of ascorbic acid (vitamin C) or with formaldehyde (a metabolite of the urinary antiseptic, methena.mine, which may be used for prevention of bacterial urinary tract infections). False-positive results may occur if the sample is contaminated with hydrogen peroxide, chlorine, or hypochlorite (bleach).

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Ketones: Ketones are produced from fatty acid metabolism and include acetoacetic acid, acetone, and 13-hydroxybutyrate. The ketone test pad detects acetone and acetoacetic acid, but not 13-hydroxybutyrate (which can be measured in blood and urine using a point-of-care instmment or a biochemistry analyzer). The test pad contains nitroprus­ side that reacts with acetoacetic acid and acetone to cause a purple color change; it is more sensitive to acetoacetic acid than acetone. Ketonuria is associated with primary ketosis (ruminants), ketosis secondary to diabetes mellitus (small animals), consumption of low-carbohydrate diets (especially in cats), and occasionally with prolonged fasting or starvation. A false­ positive reaction can occur with presence of reducing substances in urine. Bilirubin/Urobilinogen: When hemoglobin is degraded, the heme portion is converted to bilirubin, which is conju­ gated in the liver and excreted in bile. Some conjugated bili.rnbin is filtered by the glomerulus and excreted in urine. In dogs, but not cats, the kidney can metabolize hemoglobin to bilirubin and secrete it. Male dogs have a higher secretory ability than females. Dipstick reagent pads use diazoniurn salts to create a color change and are more sensitive to conjugated bilimbin than unconjugated bilirubin. Bilirubinuria occurs when conjugated bilirubin exceeds the renal threshold as with liver disease or hemolysis. 1n dogs with concentrated urine, a small amount of bilirubin can be normal. Pigmenturia and phenothiazine may result in a false-positive reaction; false-negative reactions may occur with large amounts of urinary ascorbic acid (vitamin C). Urobilinogen, formed from bilirubin by intestinal microflora, is absorbed into the portal circulation and excreted renally. A small amount of urinary urobilinogen is nom1al. Increased urinary urobilinogen occurs with hyperbilimbinemia; a negative test may be seen with biliary obstmction. However, the test is not specific enough to be clinically useful. Occult Blood: The occult blood test pad

uses a "pseudoperoxidase" method to detect intact RBCs, hemoglobin, and myoglobin. A positive reaction can be due to hemorrhage (hematuria), intravascular hemolysis (hemoglobinuria), or myoglobin­ uria. The latter two processes can be distinguished by examination of plasma: plasma will appear pink to red after intravascular hemolysis, whereas myoglo-

1617

bin is rapidly cleared from plasma, resulting in clear plasma. As with other colorimetric test pads, discolored urine may yield false-positive results. A positive result should be interpreted with microscopic exan1ination of urine sediment.

Urine Sediment Microscopic examination of urine sedin1ent should be pa.rt of a routine urinalysis. For centrifugation, 3-5 mL of urine is trans­ ferred to a conical centrifuge tube. Urine is centrifuged at1,000-1,500 rpm for -3-5 min. The supernatant is decanted, leaving -0.5 mL of urine and sediment in the tip of the conical tube. The sediment is resuspended by tapping the tip of the conical tube against the table several ti.mes. A few drops of the sediment are transferred to a glass slide, and a cover slip is applied. Examination of unstained urine is recommended for routine san1ples. Microscopic examination is performed at lOOX (for crystals, casts, and cells) and400X (for cells and bacteria) magnifications. Contrast of the san1ple is enhanced by closing the iris diaphragm and lowering the condenser of the microscope. Stains such as Sedistain® and new methylene blue can be used to aid in cell identification but may dilute the specin1en and introduce artifacts such as stain precipitate and crystals. Use of a modified Wright stain increases the sensitivity, specificity, and positive and negative predictive values for detection of bacteria. For some tests, air dried, stained smears are necessary.

Red Blood Cells: 1n an unstained preparation, RBCs are small and round and have a slight orange tint and a smooth appearance. Nmmal urine should contain 10 min. Intrathoracic or abdominal hemon-hage may be dfficult to detect and may be exacerbated when blood pressure and circulation are restored. The focused abdominal sonography for trauma (FAST) technique may be used to rapidly identify free abdominal fluid, focusing tl1e probe on tl1e ventral midline caudal to the xiphoid, over tl1e urinary bladder, a.i1d on the right and left dependent flank regions. A fom0quadrant abclominocentesis C3.Il be pe1fom1ecl if ultrasound is not immediately available. The TFAST may be used to identify pleural fluid as well. Ongoing abdominal hemorrhage is initially managed by small volume fluid resuscitation to low-normal endpoints and abdominal counterpressure (seep 1667). Ongoing intrathoracic hemorrhage should

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EVALUATION AND INITIAL TREATMENT

be managed with thoracocentesis or a thoracostomy tube to evacuate the blood and to allow measurement of the volume Jost. Exploration of these body cavities may be required for assessment and definitive hemostasis if a coagulopathy is not present. PCV of thoracic or abdominal fluid the same or higher than that of peripheral blood confinns hemorrhage. Significant volumes of cavitary hemorrhage may be collected in sterile, empty fV bags or blood transfusion bags for autologous blood transfusion, if necessary. lntravascular Volume Replacement:

Intravenous or intraosseous catheters are used, with multiple catheters placed for rapid, large-volume infusion in dogs >30 kg body wt. Isotonic crystalloids can be administered by repeated Jow-volw11e boluses (10-15 mLJkg) until desired endpoints of resuscitation are reached (eg, low-n01mal cardiovascular parameters). However, the interstitiwn is at risk of fluid overload with crystalloids alone. The concurrent use of colloids and crystalloids can reduce the an10unt of c1ystalloid required, rapidly expand the intravascular space with a smaller volume of fluid infused, and reduce the amount of fluid extravasat­ ing into the interstitial spaces of vital organs (eg, lung, brain). Isotonic crystalloids are given with hydroxyethylstarches (eg, hetastarch) or stroma-free hemoglobin. Whole blood, stroma-free hemoglobin, or packed red cells are necessaiy during initial volume resuscitation when hemorrhage has been significant. Small volume resuscitation to low­ normal endpoints (measured perfusion paraineters) is used to avoid volun1e overload or hypertension and is ideal for aninlals with head irtjwy, pulmonaiy edema or contusions, abdominal or intra.thoracic hemorrhage, heart disease, and all cats in hypovolemic shock. Isotonic crystalloids are given (10-15 mUkg, fV), followed by hetastarch or stroma-free hemoglobin (dogs 5 mUkg, fV; cats 1-5 mUkg, fV, slowly), repeating the colloid infusion, to effect. The least an10unt of crystalloids and colloids possible are used to obtain and maintain a systolic blood pressure of 90 mrnHg, restore a normal heart rate, and improve CRT and pulses. For an in-depth explanation, seep 1675. Pain Control: Analgesia is provided during initial fluid resuscitation for optimal cai·diovascular response and relief of anxiety. Narcotics are administered systemi­ cally, and local anesthetics can be infiltrated into the affected area. (See also p 2104.)

Warming: Animals in shock should be warmed dwing fluid resuscitation until rectal temperatures ai·e >98° F. This is best accomplished by increasing the environ­ mental temperature using warm air blowers or hot water bottles with blallkets, warm water blankets, and fV fluid line warmers. Gastlic, pelitoneal, or urinary lavage may be needed for severe hypothermia. Surface wam1ing is instituted only after initial volun1e resuscitation has provided enough intra.vascular volume to offset the peripheral vasodilation. Care must be taken in animals with cardiogenic shock or pericai·dial disease to avoid excessive peripheral vasodilation, because this may exacerbate a relative hypovolemia (due to decreased cardiac output). Corticosteroids: Corticosteroids are administered when a deficiency is suspected (ie, Adclisonian crisis, critical illness-related corticosteroid insufficiency). High-dose steroid administration has not been proved to reduce mortality in hypo­ volemic, septic, or cai·diogenic shock and has been associated with increased morbidity, so it is not reconunended. Cardiovascular Support: Phannaco­ Jogic agents (positive inotropes, systemic vasodilators, and vasopressors) can be used when fluid infusion has adequately replaced intra.vascular volwne (ie, central venous pressure >5-8 cm H20) but fails to restore blood pressure and perfusion, or when poor cardiac contractility is thought to contribute to hypotension. A positive inotropic agent can be administered to increase cardiac contractility in diseases such as sepsis and dilated cardiomyopathy (eg, dobutarnine, initially at 2-5 mcg/kg/rnin, and the dosage titrated for optimal cardiac output). Stroma-free hemoglobin (dogs 5 mUkg; cats 1-3 rnL per cat, slowly) can be adminis­ tered, and repeated as indicated, for its colloid effect as well as its mild vasopressor effect; it is particularly useful in animals with concurrent anemia. The initial resuscitation doses may be followed by a slow constant-rate infusion (dogs 10-15 mLJkg/day; cats 1-3 rnllhr up to 5 mLJkg/day) to maintain perfusion if the initial dose was successful and further support is anticipated. Pressor agents delivered as an fV constant-rate infusion such as dopamine (5-20 mcg/kg/min), norepinephrine (0.05-2 mcg/kg/min) or vasopressin (extra-label, 1-4 mU/kg/rnin) are other options to support blood pressw·e; they should be delivered in the smallest dosage needed to maintain arterial systolic pressure >90 mmHg. The blood flow to the

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EVALUATION AND INITIAL TREATMENT

kidneys and GI tract, as well as other organs, may have been significantly impaired during shock. Urine output, heart rate, blood pressure, ECG, pulse intensity, and mucous membrane color should be closely monitored, because fmther vasocon­ striction can worsen organ blood flow and function. If organ function declines or if arrhythmias become a problem, the IV cl.tip should be stopped. Hindlimb and Abdominal Binding: When ongoing abdominal hemorrhage is suspected from trauma, hindlimb and abdominal counterpressure can improve perfusion. This procedure compresses the arteries and arterioles within the bound regions, increasing regional vascular resistance, and produces abdominal tamponade, thereby effectively slowing or arrestmg hemorrhage and redirecting blood flow from the venous capacitance vessels in the caudal half of the body to the more central (core) circulation. Hindlimb and abdominal counterpressure can be perfonned by placing a rolled towel or rolled cotton between the legs and along the ventral midline of the abdomen. Th.is prevents the wrap from in1pairing ventila­ tion or fracturing the spleen or liver. If time pennits, a urinary catheter is placed. The h.indlimbs and abdomen are then fumly wrapped with padded bandage material or towels, beginning at the toes of the hindlimb and moving cranially toward the xiphoid, taking care not to in1pede respiration. The bandage should be secured with tape or stretch bandage material wrapped in a spiral pattern starting caudally and moving crarually. Abdominal binding should be avoided in cases of intrathoracic or intracranial hemorrhage. Once perfusion has stabilized, the wrap is removed slowly by sections (releasing one section every 15 min) from the abdomen, starting at the most cranial portion and moving caudally. Any signs of decompensation wan·ant rapid rebinding of the region last unwrapped.

SECONDARY SURVEY The secondary survey of emergency patients is the process of obtaining significant and thorough historical information, perfonning a complete physical examination, and collecting general diagnostic info1mation. These data are used to direct the fo1mulation of a specific diagnostic, therapeutic, and monitoring plan. The history should be recorded in a concise forn1at. The presenting complaint is obtained from the owner, who can provide

1667

information such as when the aninlal was last completely normal. A chronology of the daily progression of abnormalities since the onset of signs can be useful. Background inforn1ation includes past medical problems, toxicities, medications, drug and food sensitivities, blood transfusions the date of last vaccinations, and other preventive care. Other organ systems not seemingly involved should also be historically evaluated. Details of the specific disease process are obtained and may help direct diagnostics and care. A complete physical examination should be performed, working from head to tail. Particular attention is given to heait and lung auscultation for abnom1alities, and to abdominal, rectal, and joint palpation for pain or enlargements. A complete neurologic and orthopedic exainination is often warranted. Acute abdominal pain requires localization of tl1e pain and auscultation of the abdomen for bowel sounds to localize tl1e problem to the reticuloendothelial reproductive, urinary, or GI systems; the pentoneal space; or the muscle, skin, nerves, or fat around the abdominal wall. Fever of unknown migin directs exanlination to tl1e peritoneal cavity and to the reproductive minary, pulmonary, and cardiovascular systems. An initial minimum database should consist of a PCV, total solids, glucose, and BUN. Other important diagnostics include urinalysis (before fluid administration), venous or arterial blood gas, an electrolyte panel, a CBC, and a serum chemistry pan.el. When coagulation disorders are suspected or surgery is anticipated, blood smears to estimate platelet number, buccal bleeding time _to evaluate platelet ftmction, and a clottmg profile such as an activated clotting tune or prothrombin time and activated partial thromboplastin time are warranted. A deficit in any of the first tlu·ee compo­ nents of tile primary swvey (ie, airway, breatlling, circulation) will quickly result in anaerobic metabolism due to poor oxygen delivery to the tissues. This can rapidly result in a type A lactic acidosis. Lactate can be accurately, easily, and rapidly meas­ ured with several point-of-care analyzers. Nonna! lactate values in dogs and cats are 180 bpm in dogs), if ventricular premature contractions are multiform, or if there are prefibrillatory rhytluns (R on T phenomenon, torsades de pointes, ventriculai· flutter).

Abdominal Trauma The extent and severity of abdominal injuries are often not initially apparent, unless there is visceral herniation outside the body cavity. The abdominal surface should be examined closely for evidence of bruising, abrasions, lacerations, protrusions, localized swelling, hernfa­ tions, distention, and pain. Animals with evidence of abdominal pain that are in shock are considered to have intra­ abdominal hemorrhage until proved otherwise. Rupture or laceration of the spleen or liver are the most common sources of intra-abdominal hemorrhage. However, all abdominal organs are susceptible to the shearing forces from blunt trauma. Other common sources of abdominal bleeding include avulsed mesenteric vessels, dan1aged muscle, or avulsion of the kidneys in the retro­ peritoneal space. Approximately 40 mUkg Uust less than half of the circulating blood volume) is necessary before free blood in the abdominal cavity will be evident by palpation or visual inspection; this volume is associated with signs of poor perfusion (shock). Smaller volumes of abdominal fluid may be apparent with radiographs, abdominocentesis, or ultrasound of the abdomen. Abdominal distention from hemorrhage may become apparent if

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1670

SPECIFIC DIAGNOSTICS AND THERAPY

aggressive fluid resuscitation increases blood pressure and disrupts one or more blood clots that provided hemostasis. Small volume fluid resuscitation to achieve a low-normal blood pressure endpoint (90 mmHg systolic) is indicated to avoid sudden increases in arterial or venous pressures. When ongoing abdominal hemorrhage is confirmed, hindlimb and abdominal binding (see p 1667) is indicated early to reduce the amount of hemorrhage until hemostasis is accomplished. After irtjury of any abdominal organ, clinical signs of organ dysfunction or hollow viscus rupture typically develop over a period of hours but may be longer or shorter depending on the nature of the irtjury. Acute abdominal pain is a key physical finding. Survey abdominal radiographs can demonstrate organ displacement, disten­ tion, rotation, or free abdominal gas or fluid. Fluid can be recovered by fow0quadrant abdominocentesis. Using the f ocused assessment with sonography technique (FAST, seep 1665), even small amounts of free fluid in the abdomen can be identified and aspirated using ultrasound guidance. When free fluid is not readily identified, a diagnostic pe1itoneal lavage can be done. A fenestrated catheter is placed into the peritoneal space, and warm isotonic saline (20 milkg) is in.fused into the abdomen. The fluid is allowed to dwell for several minutes and distribute throughout the abdomen; it is then drained and evaluated. Clear fluid indicates.that the possibility of significant abdominal hemorrhage is minimal. Fluid with a 1% PCV indicates mild abdominal hemorrhage, whereas fluid with a PCV >5% indicates significapt abdominal hemorrhage that warrants careful monitoring. Fluid obtained from the abdomen should be examined cytologically for evidence of WBCs, plant or meat fibers, and free or intracellular bacteria. Biochemical evaluation for creatinine and potassium, bilirubin, amylase, and phosphorus help identify urinary system rupture, gallbladder rupture, pancreatic irtjury, or ischemic bowel, respectively. Abdominal fluid glucose that is 20 mg/dL or more below peripheral blood glucose is characteristic of a septic peritonitis and warrants exploratory surgery. The a.bdominocentesis, peritoneal lavage, or FAST scan can be repeated in several hours if fluid from the first assessment did not indicate a significant problem but the clinical signs continue or progress. Retroperitoneal, fascia!, or intramuscular

(body wall) hemorrhage or hemorrhage into the GI system can be more challenging to identify. Criteria. for emergency exploratory Japa.rotomy include ongoing hemorrhage; inability to stabilize shock; organ rotation, entrapment, or ischemia; diaphragmatic hernia; and evidence of organ rupture or peritonitis. Some simple bladder ruptures may be amenable to medical management and placement of a tuinary catheter. Surgery to repair a diaphragmatic hernia should not be delayed, particularly with gastJic displacement into the thoracic cavity, respira­ tory compromise, or ongoing hemorrhage. Retroperitonea.l, severe fascia! compait­ ment hemorrhage (associated with pelvic fractures), or hemorrhage into a hollow viscus is suspected in acutely t1·aun1a.tized animals that still have signs of a declining PCV/tota.l solids, nonresponsive hemor­ rhagic shock, and no significant findings on abdominocentesis, peritoneal lavage, or FAST scan. Radiog:raphs typically show expansion and loss of detail in the retJ·operi­ toneal space. An IV pyelogran1 should be done to help delineate disruption in the renal vasculai· supply or in the retroperito­ neal portion of the ureter before proceeding with exploratory surgery in this situation.

CARDIOPULMONARY RESUSCITATION The success of cardiopulmonary resuscita­ tion (CPR) efforts depends on many factors, including the underlying ca.use of the arrest, the timeliness and effectiveness of the intervention, and the preparedness of the team adniinisteri.ng CPR. Overall prognosis of recovery from cardiopulmonary arrest (CPA) with CPR effo1ts is as high as 35%-44%; however, only 60 mmHg (systolic >90 mmHg). In hypotensive animals with adequate cardiac function, treatment consists of intravascular volume infusion (seep 1675), oxygen administration, and pain control. Hypotension unresponsive to intravascular volume repl;icement can be due to one or more of the following: hypoglycemia, acidosis, alkalosis, electrolyte disorders (eg, potassium, calcium, magnesium), brain-stem pathology, cardiac arrhythmias, metabolic toxins (eg, hepatic, renal), ongoing fluid loss, relative hypoaclrenocorticism (eg, cortisol deficiency), heart or pericardia! disease, excessive vasodilation, and excessive vasoconstriction. The need for cardiac support with positive inotropes should be assessed. An experienced ultrasonographer may be able to assess ventricular and/or capacitance vessel size to provide an estimate of preloacl and contractility. Once intravascular volwne (central venous pressure >8 cm H,0) and cardiac function are assessed as adequate, vasopressor therapy with CRI of dopamine (5-15 mcg!kg/rnin) or norepinephrine (0.05-2 mcg!kg/min), beginning at the lower encl of the dosage range and increasing by increments of 0.2-0.5 mcg, is recommended. Stroma-free hemoglobin can be infused for its pressor effects.

Objective measurements of global perfusion may also include lactate monitoring; animals with a significantly increased lactate concentration may have a poorer prognosis. Studies have demon­ strated that serial lactate monitoring as pathology is treated is more useful than a single measurement. Central venous oxygen measurement is another objective measurement of global perfusion; nonnal values are 70-80 mmHg, whereas lower values may indicate increased oxygen extraction. Hypertension is a relatively uncommon condition in veterinary medicine, but it can lead to catastrophic problems such as retinal cletaclunent or neurologic derange­ ments from intracranial hemorrhage. Hypertension can exacerbate proteinuria in animals with chronic kidney disease. Moderate to severe hypertension can be treated with oral antihypertensive agents such as angiotensin-converting enzyme inhibitors (eg, benazepril), calcium channel blockers (eg, amlodipine), direct arterial dilators (eg, hydralazine), or systemic injectable antihypertensive agents such as nitroprusside (0.5-10 mcg!kg/min), titrated to effect. Blood pressure must be monitored constantly to assess response to therapy with nitroprusside. Chronic hype1tension that is rapidly decreased may result in decreased renal perfusion. The A.nlerican College of Vete1inary Internal Medicine classifies risk of target-organ dan1age from hype1tension into four categories based on systolic blood pressure: I: 180 nunHg = severe risk.

Heart Rate, Rhythm, Contractility, and Myocardial Injury: The electrical

and mechanical systems of the heart should be evaluated separately. Specific antiar­ rhythmic drug therapy should be instituted based on an accurate ECG diagnosis when perfusion is compromised by an ar-rhythmia and the first-line therapy of oxygen supplementation and analgesics has been unsuccessful in controlling the atThythmia. Arrhytlunias can occur for a variety of reasons, such as SIRS diseases, splenic disease, organ torsion (eg, gastric dilatation­ volvulus), and electrolyte abnormalities (eg, hyperkalemia); the underlying condition must be treated/investigated as well. Some ventricular rhythms (such as ventricular premature contractions and accelerated idioventricular atThythmias) may not necessarily require irnmediate

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MONITORING THE CRITICALLY ILL ANIMAL

therapy. Indications for treatment of a ventricular rhythm include tachycardia (rates >160-180 bpm), clinical signs of poor perfusion (low blood pressure, poor pulse quality, etc), multifonn arrhytlunias, and R-on-T phenomenon. Other tachyarrhyth­ mias may respond to class I, II, III, or IV antiarrhytlunics; bradyarrhythmias can be challenging to treat medically and may require pacemaker placement. An echocardiogran1 can be perfom1ed to evaluate cardiac contractility in SIRS diseases and to detect underlying cardiac diseases. If cardiac contractility is decreased, dobutamine at 5-10 mcg/kg/rnin (dogs) or 2.5-5 mcg/kg/min (cats) should be considered to provide inotropic support if there is evidence of poor cardiac output. Recent studies have demonstrated that dogs with mitral valve disease and dilated cardiomyopathy have a poorer prognosis if their cardiac troponins ( cTnI) and/or natriuretic peptide (NT-pro-BNP) is increased. However, these tests are not available in all hospitals and do not necessarily direct therapy, or diagnose or differentiate disease processes. Temperature: Body temperature is considered part of the initial clinical database and should be measured regularly in every critically ill aninlal. A variety of diseases can result in increased or decreased body temperature. Temperature is measured most accurately and consis­ tently with a rectal thennometer. Increased temperatures can be seen with environmental exposure (eg, heat stroke), increased activity (eg, exercise, excite­ ment), and infectious, inflammatory, or neoplastic diseases. Severe increases of temperature (>105.5° [40.8°C]), particularly when prolonged, can lead to severe metabolic disease such as hemorrhagic diathesis, disseminated intravascular coagulation, and SIRS diseases, which may lead to multiorgan dysfunction. Effective means of cooling animals include fluid therapy, using wet towels with fans, and placing alcohol in paw pads. Animals should not be inunersed in cold water, because this causes peripheral vasocontriction and decreases core heat dissipation. Fever of unknown origin warrants a systemic evaluation (seep 1015). Hypothermia is most comnunonly associated with anesthesia in small animals; however, severe systemic disease (particu­ larly in cats) and environmental exposure may be contributing factors. Mild hypother­ mia can be a common sequela of severe cardiovascular disease and is a prognostic

1689

marker in ca.ts with limb thromboembolism. Temperature is a vital parameter to monitor and treat in ca.ts with clinical signs of shock, and active wa.m1ing is an essential component of therapy. Therapeutic hypothennia. may have some neuro-sparing effects in animals with trawnatic brain injw-y or in postresuscitation (CPR) care; however, fwther investigation is needed. In animals with induced hypothermia, blood flow to most organs can be significantly decreased, and coagulation may be affected. Altered body temperature is part of the definition of SIRS-type diseases; oilier paran1eters include an increased or decreased heart rate, increased or decreased WBC count, and an increased respirato1-y rate. Coagulation: Disseminated intravascula.r coagulation (DIC) can develop in any aninlal tl1at has w1dergone a period of relative vascular stasis as occurs during shock, severe tissue or capillary damage such as that whi::h occurs with trawna, exposure of capillary endothelial cells to circulating inflammatory mediators as occurs during sepsis or SIRS, or moderate to severe alterations in body temperature. In the early stages of DIC, tllere may be few or no clinical signs. However, as DIC progresses, its effects are obvious and catastrophic. The goal is to detect DIC in tl1e early stages and to slow or prevent its progression. Early DIC is characterized by a hyperco­ agulable stage in which serum antithrombin (AT) levels are decreased and tl1e coagula­ tion cascade is activated by any of the precipitating causes. Activation of tlle coagulation cascade throughout the body rapidly depletes the clotting factors and the blood platelet cow1t as platelets are incorporated into tl1e clots. At tllis stage, the protlu-ombin time and partial thromboplas­ tin time may be decreased, but this is a challenging stage to identify and diagnose. However, tllis rapidly progresses to a hypocoagulable stage as the coagulation factors are conswned. In this late stage, the prolhrombin time and partial tllromboplas­ tin tin1e (or activated clotting time) are prolonged, and fibrinogen degradation products a.re increased. Treatment of DIC focuses on treating the underlying disease and removing the stimulus for continued activation of tlle coagulation cascade. In tlle early hyper­ coagulable stages, treatment focuses on maximizing tlle function of AT, which is the most abundant natural inhibitor of tlle se1ine proteases of tlle coagulation cascade. When AT levels a.re adequate, heparin can

VetBooks.ir

1690

MONITORING THE CRITICALLY ILL ANIMAL

be administered SC (50-100 U/kg, tid). If AT levels are 2 mm Jong. Vitreal and retinal hemorrhage and retinal detachments are likely. Ophthalmic ultrasonography and orbital radiology are most helpful to assess pellet location and the integrity of the intra.ocular and orbital tissues. Anterior Jens laceration and rupture is also a common sequela of cat claw injuries in young dogs. Penetration of the anterior lens cap­ sule (lacerations >2 mm) requires Jens removal as soon as possible, because escape of Jens material causes gradually intensifying lens-induced uveitis that often progresses to secondary glaucoma and phthisis bulbus. The posterior segment changes usually resolve provided the retina eventually reattaches. Focal retinal degeneration in the area of retinal penetration and detachment is common. Prognosis is guarded and based, in part, on the response to therapy and gradual clearing of the intraocular media. Therapy is directed at controlling the post-traumatic inflammation and maintain­ ing normal levels of intraocular pressure. Mydriatics and topical and systemic antibiotics and corticosteroids are administered to control the uveitis. Intraoc­ ular hemorrhage is allowed to resolve, with anterior chamber hemorrhage usually disappearing in -1-2 wk and the vitreal hemorrhage resolving in 3-6 mo.

DEEP STROMAL CORNEAL ULCERS, DESCEMETOCELE, AND IRIS PROLAPSE Most cornea.I ulcerations readily heal with appropriate antibiotic, antiproteinase (often topical serum), and mydriatic therapy. However, cornea.I ulcers detected late in the disease process, complicated by other ocular diseases, or given inadequate topical therapy can progress. These require surgical intervention using a conjunctiva.I graft or, more recently, the commercially available porcine small-intestinal submucosa or experimental anmiotic membranes. Deep cornea.I ulcers, descemetocele, and iris prolapse are seen with some frequency in dogs, cats, and horses. These conditions require immedi­ ate surgical support of the weakened cornea, because they can threaten or seriously compromise corneal integrity. Brachycephalic breeds and dogs with keratoconjunctivitis sicca are most

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1698

OPHTHALMIC EMERGENCIES

vulnerable. These corneal defects often develop in the center of the cornea and can markedly impair vision. Important diagnostic aids are the Schirmer tear test to measure aqueous tear production and topical fluorescein to determine the extent of the corneal ulcer. Corneal culture and cytology can assist in choosing topical and systemic antibiotics. Secondary anterior uveitis with aqueous flare, miosis, ocular hypotony, and hypopyon is common. Corneal ulcer depth must be accurately estimated using magnification, focal illumination using a slit-beam, and topical fluorescein. Central corneal ulcers are more vulnerable, because they require more time for the healing response and vasculariza­ tion. Adequate ulcer deb1idement is essential for successful adherence of a cortjunctival graft. The corneal ulceration (stromal, descemetocele, or iris prolapse) is covered with the bulbar cortjunctival graft (360°, 180°, bridge, or pedicle) that appears most appropriate. For full-thickness corneal ulcers with iris prolapse, cortjunctival grafts are also used, but the postoperative corneal opacity is usually larger and more dense. Postop­ erative therapy includes topical and systemic broad-spectrum antibiotics, systemic NSAlDs or corticosteroids, and mydriatics. Treatments are gradually tapered and administered for 4-8 wk. Postoperative complications include variable corneal scar and pigmentation, anterior and/or posterior synechiae, secondary cataract formation, and rarely bacterial endophthalmitis.

CORNEAL LACERATIONS Corneal lacerations are seim most frequently in dogs and horses and infre­ quently in cats. Bites, self-inflicted trauma, and other accidents can partially or totally penetrate the cornea. Partial-thickness corneal lacerations are usually highly painful and require apposition with simple interrupted absorbable sutures to the healthy cornea. Excision of the lacerated section is not recommended. For full-thickness corneal lacerations, signs usually include pain, blepharospasm, tearing, a corneal defect, and variable iris prolapse. Marked aqueous flare, hyphema, miosis, and distortion of the pupil are common. Often, tl1e size of the iris prolapse is much larger than the underlying corneal laceration. Prognosis depends on size and position of the corneal laceration, other ocular tissue involvement, gender (horse), age of the animal, duration of the irtjury, and

other systelnic irtjuries. If the entire eye cannot be examined directly, B-scan ultrasonography is used. The corneal laceration is apposed with simple interrupted 7-0 to 8-0 absorbable sutures. To provide additional protection and support, the sutured laceration may be covered with a third eyelid flap, bulbar cortjunctival graft, or partial temporary tarsorrhaphy. Postoperative therapy to control the secondary iridocyclitis consists of topical and systemic antibiotics, systemic NSAlDs, and mydriatics. Postoperative complications include variable and often dense corneal scarring, cataract formation with posterior synechiae, secondary glaucoma, phthisis bulbus, and bacterial endophthahnitis.

GLAUCOMA Animals are usually presented with high-pressure glaucoma because intraocular pressure (IOP) >40-60 mmHg results in clinical signs of buphthalmia, mydriasis, corneal edema, episcleral venous congestion, and variable ocular pain. The underlying glaucoma may be either open or narrow-closed angle, and either acute or chronic. Dog breeds most often affected with primary glaucoma include the American Cocker Spaniel, Basset Hound, Chow Chow, Akita, Chinese Shar-Pei, Norwegian Elkhound, and San1oyed. In cats, glaucoma is often associated with anterior uveitis, whereas in horses the risk factors are age > 10 yr old, anterior uveitis, and breed (Appa­ loosa). Although globe enlargement (buphthalmia) is detected fairly early in dogs, buphthalmia in horses and cats is often missed until the glaucoma has progressed. Diagnosis depends on clinical signs and accurate tonometry. The Tono-Pen® and TonoVet® applanation tonometers are the most versatile. Gonioscopy and other diagnostic methods are used to evaluate the anterior chamber angle and the posterior segment, including the optic neive head. The goals of therapy are to rapidly lower IOP and to preseive as much vision as possible. Immediate referral to a veteri­ nary ophthalmologist is often helpful. Short-term treatment includes mannitol (1-2 g/kg, IV), topical 13-blockers and carbonic anhydrase inhibitors, systemic carbonic anhydrase inhibitors, and either prostaglandin analogues or miotics (pilocarpine or demecariun1). The beneficial effects of the topical medica­ tions are not usually apparent until IOP is

VetBooks.ir

OPHTHALMIC EMERGENCIES 5 days after the initial wounding a.re considered to be secondary closure. This implies that granulation tissue has begun to fom1 in the wound before closure.

Open Wound Management: When a wound cannot or should not be closed, open wound management (ie, second-intention healing) may be appropriate. Such wounds include those in which there has been a loss of skin that makes closure in1possible or those that a.re too grossly infected to close. Longitudinal degloving i.Itjuries of the extremities a.re especially amenable to open wound management. Open wound management enables progressive deb1ide­ ment procedures and does not require specialized equipment (such as may be needed with skin grafting). However, it increases cost, prolongs time for healing, and may create complications from wound contracture. Open wound management is based on repeated bandaging and debridement as needed until the wound heals. Traditional therapy calls for wet-to-dry dressings initially. The initial wide meshed gauze dressings help with mechanical debride­ ment at every bandage change. Until a granulation bed f01ms, the bandage should be changed at least once daily. In the early stages of healing, the bandage may need to be changed as often as twice daily. After granulation tissue develops, the bandage should be changed to a dry, nonstick dressing so the granulation bed is not disrupted. Both the granulation bed and the early epithelium a.re easily damaged, and disruption of the granulation bed delays wound healing. With the concept of moist wound healing, bandaging is combined with autolytic debridement to promote wound healing. The use of moist wound dressings keeps white cells healthier, allowing them to aid in the deb1idement process. A variety of

dressings is available. Alginate dressings a.re commonly used in the exudative wound to stimulate granulation tissue. Hydrogels a.re used to maintain moisture levels in drier wounds. Foam dressings may be used to absorb excessive exudate or protect granulation beds. These newer dressings are changed only every 2-5 clays. Sugar Dressings: Sugar has been used as an inexpensive wound dressing for more than three centuries to control odor and infection. The use of sugar is based on its high osmolality drawing fluid out of the wound and inhibiting the growth of bacteria. The use of sugar also aids in the debridement of necrotic tissue while preserving viable tissue. Granulated sugar is placed into the wound cavity in a layer 1-cm thick and covered with a thick dressing to absorb fluid drawn from the wound. The sugar dressing should be changed once daily or more frequently whenever "strike-through" is seen on the bandage. During the bandage change, the wound should be liberally lavaged with wann saline or tap water. Sugar dressings may be used until granulation tissue is seen. Once all infection is resolved, the wound may be closed or allowed to epithelialize. Because a large volume of fluid can be removed from the wound, the animal's hemodynamic and hydration status must be monitored and treated accordingly. Hypovolemia and low colloid osmotic pressure a.re complications that may be associated with this therapy. Honey Dressings: Honey has also been used for wound dressings over the centuries. Honey's beneficial effects a.re thought to be a result of hydrogen peroxide production from activity of the glucose oxidase enzyme. The low pH of honey also may accelerate healing. Honey used for wound healing must be unpasteurized, and tl1e source of the honey appears to be a factor in its effectiveness. Manuka honey may be the best option for wound ca.re. The contact layer wound dressings should be soaked in honey before application. The bandage should be changed daily or more frequently as needed.

DRAINS Drains a.re used to direct fluid out of a wound or body cavity. Passive drainage techniques require gravity or capillary action to draw fluid from the wound or cavity. Penrose drains a.re soft, flat, commonly used passive drains made from latex. These drains must be placed in

VetBooks.ir

WOUND MANAGEMENT

gravity-dependent locations to ensure proper function. A firmer drain can be constructed from a red rubber or silicone tube. Active drains require some type of negative pressure to pull fluid from the wound. Red rubber or silicone drains can be used with a closed system, and low-pressure suction maintained with the intennittent use of low-pressure pumps or handheld rechargeable devices. Negative-pressure wound therapy is based on this theory to remove purulent debris and speed closw·e of an open wow1d. The use of active, closed-drain systems decreases the likelihood of ascending infection that can be associated with passive drains. Drains should be left in place until the draining fluid decreases in quantity and no longer appears purulent. The fluid can be evaluated by cytologic examination.

BANDAGES The goals of bandaging include limiting hemorrhage, immobilizing the area, prevent­ ing further trauma or conta.Jnination of the wound, preventing wound desiccation, absorbing exudate, controlling infection, and aiding in mechanical debridement of the wound. When constructing bandages, several principles must be followed to avoid complications. The bandages should be sufficiently padded, applied evenly and snugly, composed of three layers (primary, secondary, and tertiary), and placed to avoid traumatizing the newly fonned granulation tissue or epitheliun1. The first or primary layer directly contacts the wound to allow tissue fluid to pass tlrrough to the secondary layer. The first layer may be adherent or nonadherent. A nonadherent bandage is usually a fine mesh or foam, nonstick material and is indicated when a healthy granulation bed has developed. This layer prevents tissue desiccation and causes minimal trauma. An adherent bandage uses a wide mesh material that allows tissue and debris to become incorporated into the bandage. This debris is then removed with the bandage change. Adherent bandages are classified as dry to dry, wet to dry, or wet to wet based on the composition of the primary layer. Dry-to-dry bandages consist of dry gauze applied to the wound. The bandages are painful to remove but enable excellent tissue debridement. Wet-to-dry bandages are made with saline-moistened gauze placed directly on the wound. They are also painful to remove but result in less tissue desiccation than dry-to-dry bandages. Wet-to-wet bandages tend to damage the

1705

tissue bed by keeping it too moist. Newer bandage materials may be in1pregnated with various materials, such as silver, to help control infection. The secondary layer of a bandage absorbs tissue fluid, pads the wound, and supports or inlmobilizes the limb. This layer is frequently composed of cast padding or roll cotton. The tertiary layer functions to hold the primary and secondary layers in place, provide pressure, and keep the inner layers protected from tl1e environment. This layer is composed of adhesive tape or elastic wraps.

SURGICAL TECHNIQUES Advancement flaps can be used to move skin and relieve tension. The sin1plest type of advancement flap involves sliding skin to cover an adjacent defect. These flaps are elevated without regard to their vascular supply. Flap survival depends on the subder­ mal vascular plexus from the flap base and revasculaiization from tl1e recipient bed. Witl1 subdennal plexus flaps, the vascular supply is affected by the width of the flap base. A high length/width ratio decreases the likelillood of survival, because blood supply will not reach the distal end of the flap. Any flap placed in tension carries a high risk of failure. The basic advancement flap technique is known as the single pedicle advancement flap. Two slightly divergent incisions are made perpendicular to the defect. The tissue is undennined, advanced, and sutured to close the original defect. For larger wounds, two single pedicle flaps are safer than one large flap. Two advancement flaps are combined to form the "H" plasty. There are several other well-described flap techniques, including the bipedicle advance­ ment flap and the "V-Y'' advancement flap. In each of these techniques, the coverage depends on stretching the skin over the defect. For this reason, tile use of these techniques may be limited by vascular supply or the regional anatomy, such as tile area around the eyelids. Flaps designed to incorporate a direct cutaneous artery are known as axial pattern flaps (arterial pedicle grafts). The flaps can be used to cover a large area of tissue and carry along a new blood supply to ensure flap survival. Muscle-based pattern flaps can also be used to reconstruct a body wall defect in addition to covering a loss of skin. The surviving area of axial pattern flaps is 50"A, greater than a corresponding subdennal plexus flap and therefore allows coverage of a Jai·ger ai·ea. Because axial pattern flaps are based on arteries, they

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WOUND MANAGEMENT

must have consistent landmarks and do not cover all regions of the body. The best described of the axial pattern flaps is based on the caudal superficial epigastJic artery. Based in the caudal aspect of the abdominal wall, this flap can extend cranially to include mammary glands 2 through 5. Other commonly used flaps include the thoraco­ dorsal, omocervical, and deep circumflex iliac artery flaps. Free skin grafts are used for cases with massive tissue loss such as large burns or degloving i.rtjuries. The grafts are best used as a split mesh. This allows drainage and helps prevent seroma formation. Skin grafts will not remain viable if laid over squamous epithelium, denuded bone, cartilage, or tendon. The grafts must have a healthy, vascularized bed. Initially, nutJition for the flap is maintained because capillary action pulls semm into the dilated capillaries of the

Appearance of a free skin mesh graft 24 hr after surgery. Courtesy of Dr. Kevin Winkler.

skin graft, creating graft edema. Anastomo­ sis with recipient bed vessels (inosculation) begins within 48--72 hr of surgery. The edema may worsen immediately after inoscuJation, because ruterial supply is established before venous rettu11. The edema should resolve as norn1al blood flow rettul1s to the flap by day 4-6 after surgery. All skin flaps and grafts require a clean, healthy recipient bed for survival. This is especially inlportant for subdern1al plexus flaps and free tissue transfers, because they do not contain a direct cutaneous arterial supply. The recipient bed must be free of debris, infection, and necrotic tissue. Although flaps may have well-described anatomic markers, determining their viability may not be as easy. The simplest, but least accurate, methods to assess a flap's viability are subjective measures, including the assessment of color, wrumth, sensation, and bleeding. Purple color cannot be used as a predictor of viability. Contused, purple skin is often viable. Progression from deep purple to black indicates necrosis. Skin temperature may be affected by the state of vasoclilation and is therefore not an accurate method to assess viability. Viable flaps may bleed from a cut suiface, as may nonviable flaps that still have some arterial function but poor or no venous retUJ11. After a flap is moved, it may develop edema for the first few days ui1til venous vascuJariza­ tion is completed. Newer techniques and medications being developed for woui1d care include platelet-tich plasma, extJ·acor­ poreal shock wave therapy, stem cell therapy, microcurrent stimulation, and a variety of growth factors. Their efficacy has not yet been completely demonstrated.

FACTORS THAT INTERFERE WITH WOUND HEALING

Appearance of a free skin mesh graft 3 wk after surgery. Courtesy of Dr. Kevin Winkler.

Factors that interfere with wound healing may be divided by source into physical, endogenous, and exogenous categories. Physical factors that affect wound healing include temperature and mechani­ cal forces. Temperattrre affects the tensile strength of wounds. Ideal conditions allow woW1d healing to occur at 30° C. Decreasing the temperature to l2° C results in a 200A, loss of tensile wound strength. Mechanical forces include pressure ai.1d sheer force. Pressui·e can compromise blood flow in the region, decreasing oxygen levels in the tissue. Sheer forces result in tearing of the vessels. Because adequate oxygen levels ru·e required for appropriate woW1d healing, anything that interferes with blood flow will

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WOUND MANAGEMENT

slow wound healing. Low levels of oxygen interfere with protein synthesis and fibroblast activity, causing a delay in wound healing. Oxygen levels may also be compromised by other physical factors, including hypovolemia, the presence of devitalized tissue, hematomas, and excessively tight bandages. Endogenous factors typically reflect the overall condition of the anin1al. Anemia may inte1fere with wound healing by creating low tissue oxygen levels. Nub.ition has a significant overall effect on the body. Although the ideal nub.itional level for wound healing is unknown, hypoproteinemia delays wound healing when the total senun protein content is 100

>4

>50

>8

>4

>4

++

Ongoing losses are difficult to estimate, because losses from the GI tract are hard to measure. The equine GI tract secretes and resorbs the equivalent of the extracellular fluid volume (-30%of body wt) on a daily basis. If small-intestinal ileus or obstruction is present, the amount of gast1ic reflux obtained can be easily quantitated to gauge losses. If the large intestine is not resorbing water (eg, diarrhea), fluid losses can be significant but difficult Lo measure. With severe diarrhea, -500;6 of the extracellular fluids can be Iost daily. The formula to calculate volume of fluid to administer provides only a crude estimate of needs; volumes administered should be adjusted based on responses to treatment, such as heart rate, pulse quality, capillary refill time, urine production, PCV, serum total protein, creatinine, and lactate. Reassessment is required to adjust the daily fluid requirements for any horse receiving supplemental fluids, and the timing should be dictated by the horse's clinical condition. In horses in severe shock, cardiovascular parameters may need to be monitored continually (eg, every 15 min) until improvement is noted. In horses with severe ongoing fluid losses (eg, diarrhea, anterior enteritis), cardiovascular parameters should be reassessed every 4 hr and laboratory paran1eters measured as frequently as 4 times a day until ilie horse stabilizes. After determination of volwne required, the type of fluid to be administered should be selected. Fluid choices include crystalloids (fluids containing substances that freely cross the capillary membrane) and colloids (fluids retained in ilie vascular space for a certain number of hours because of their larger molecular size). Crystalloids

D1y/Red Dry/Cyanotic

are most commonly used for replacement fluid therapy, whereas colloids are more often reserved for resuscitation pwvoses. (See also FLUID THERAPY, p 1675.) Two general types of crystalloids are available: balanced electrolyte solutions (BES), which are solutions of electrolytes in concentrations similar to those in plasma, and saline solutions, which contain only sodium chloride. Although considered a crystalloid, dextrose solutions are rarely used alone, and are usually added as a supplement to a BES when indicated by ilie needs of the individual horse. The decision to choose BES or saline can be based on a serum chemistry profile. Saline is chosen if the sodium concentration is 5.9 mEq/L (eg, acute hyperkalemic periodic paralysis, uroabdomen). ln most emergent cases, however, a BES is used. The addition of colloids to a fluid therapy regimen serves two purposes: it prevents edema formation caused by hypoproteine­ mia, and it maintains the intravascular fluid volume. Plasma products iliat contain an ti.bodies to treat or prevent a variety of conditions (including endotoxemia, Rlwdococcus equi pneumonia, West Nile virus infection, clostridial diseases, and snake envenomation) are also available. Colloid solutions are available in natural or synthetic forms. Natural colloids are plasma, serwn products, or albtuni.n. In general, fresh or fresh frozen plasma is selected when an increase in colloid oncotic pressure is needed, and coagula­ tion factors or specific anticoagulants such as antiilirombin III are required. Albwnin solutions are not commonly administered to horses, because the intravascular half-life of albumin in diseases witl1

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EQUINE EMERGENCY MEDICINE

compromised vascular permeability is short. They also do not have the added benefits of whole plasma. Synthetic colloids include dextran and hydroxy­ ethyl starch. The synthetic colloid most commonly administered to horses is hydroxyethyl starch (hetastarch). It is used to increase plasma oncotic pressure, and its effect is best evaluated by clinical response (decreased edema) or increased oncotic pressure (measured by colloid osmometry). A refractometer that measures total protein cannot be used to monitor the effect of synthetic colloid administration. The goal of fluid therapy for treatment of shock is to rapidly expand circulating blood volwne to improve tissue pe1fusion and oxygen delive1y. Isotonic crystalloids should be administered at a dosage of up to 60-80 mUkg in the first hour ( equal to the circulating blood volwne) for maximal benefit. This fluid rate, the "shock dose," should be given in boluses of 20 mllkg (approximately 10 Lat a time), and the horse should be reassessed between each bolus to determine whether additional boluses are needed. Because of the large volwnes of BES required, hypertonic fluids or colloids may be given first to immediately support the circulation until the shock dose of c1ystalloids can be administered. At a dosage of 2-4 mllkg, hypertonic saline (7.5%) can rapidly expand the circulating volwne by redistributing extravascular fluids into the vascular space. Because of redistribution, hypertonic solutions have a short duration of effect (-45 min) in horses. Colloid solutions can be used for a more sustained effect. Hydroxyethyl starch has been reported to increased oncotic pressure for up to 24--36 hr. However, dosages of colloids >10 mllkg/day have caused coagulopathies. For resuscitation, a combination of hypertonic saline ( 4 mVkg) and hetastarch ( 4 mllkg) may have the most beneficial and sustained effects. The flow rate of fluids through an administration set is directly proportional to the diameter of the line and inversely proportional to the viscosity of the fluid and the length of the infusion set. Polytetrafluor­ oethylene or polyw·ethane 14--gauge catheters are routinely used in horses. A rate of 7 llhr can be achieved when fluids are >2 feet above tl1ejugular vein, and faster rates can be achieved through gravity flow if the fluid bags are raised even higher. For more rapid flow, 10- or 12-gauge catheters with large-bore connection sets can be used, but 10-gauge catheters are more thrombogenic. Other ways to increase fluid

administration rates include cannulating bothjugular veins or using a pressure bag system or peristaltic pwnp. Complications of pe1istaltic pwnps are endothelial damage and an increased 1isk of venous tl1rombosis. An alternative route of fluid administra­ tion is use of an indwelling nasogastric tube. Case selection is key, and horses that are in shock, are >8% dehydrated, or have positive net gastric reflux are not candidates for oral fluids. Equine electrolyte solutions are prefen-ed, or a homemade mixture can be formulated using 5.27 g sodiun1 chloride, 0.37 g potassiwn chloride, and 3. 78 g bicarbonate per liter of water. The daily fluid rate is divided into boluses and administered using a bilge pump. The horse should be checked for reflux before administration. Volw11es 12 hr old. If the spleen is accidentally punctured, centrifugation of the sample reveals a PCV the san1e or higher than the peripheral PCV. In internal hemorrhage, the blood in the sample is hemolyzed, there are no platelets, and erythrophagocytosis may be seen. When centrifuged, the supernatant will remain reddish. Abdominal ultrasound will reveal fluid swirling on the abdomen. If vascular compromise of the bowel occurs, hemolysis of RBCs that leak from damaged capillaries will result in a serosanguineous fluid, with a reel supernatant after a spin. Abdominal surgery increases the total protein and WBCs in the abdominocentesis. With a sterile peritonitis, the WBC cotmt will remain increased for up to 2 wk, and cell counts of 40,000 cells/clL have been reported at 6 days after surgery. Neutrophils will appear nondegenerate on cytology, and there are no bacteria The total protein peaks at 6 g/dL 6 days after surgery and may remain increased for 1 mo. After an enterotomy, or resection and anastomosis, degenerate neutrophils and occasional bacteria may be seen in the first 12-24 hr but should resolve in time. lf septic peritonitis is present, clinical signs will be consistent

with bacterial infection (eg, fever, depres­ sion, anorexia, ileus, colic, endotoxemia). The WBC and total protein in the abdomino­ centesis will be markedly increased. On cytology, >900150 mg/clL or a peritoneal fluid pH 60 breaths/min but should decrease to 30-40 breaths/nun within a few hours. Auscultation of the thorax shortly after birth reveals a cacophony of sounds as airways are gradually opened and fluid is cleared. End-expiratory crackles are consistently heard in the dependent lung during and after periods of lateral recun1bency. It is not unusual for a newborn foal to appear slightly cyanotic during the adaptation period, but this should resolve within a few minutes of birth. Similarly, the heart rate of a healthy newborn foal has a regular rhytl1m and should be at least 60 bpm after the first minute. Occasionally, arrhythmias (atrial fibrillation, wandering pacemaker, atrial or ventricular premature contractions) may be ausculted but should resolve within 15 min after birth. A continuous holosystolic, or machinery, murn1ur heard for the first few days after birth over the left side of the heart is consist­ ent with patent ductus arteriosis. Various other systolic murmurs, thought to be flow murmurs, may be heard during the first week of life. Murmurs that persist beyond the first week of age, those that are loud (>2/6), or murmurs that cause exercise intolerance or hypoxemia should be investigated more thoroughly. Foals are normally nonresponsive to stimulation while in the birth canal. This lack of responsiveness has led to the presumption of fetal death during dystocia. Diagnostics, including palpation

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EQUINE EMERGENCY MEDICINE

of a pulse in the tongue, neck, or limb, or palpation and auscultation of the thorax for a heartbeat should be performed to confirm the foal has died. If the foal's nose is accessible during parturition, nasotra­ cheal intubation will allow measurement of C02 tension in the expired gas. A long endotracheal tube (size 7 12 - mm outer diameter) with an inflatable cuff should be used. The tube is passed blindly into the ventral meatus using a finger to guide the tube. Proper placement can be determined by palpation of the throat. The cuff is inflated, and manual ventilation is peifom1ed with either100% oxygen or room air. C02 tension is measured continuously with a capnograph or a single-use end tidal C02 monitor. End-tidal C02 varies in foals during parturition, depending on cardiac output and ventilation frequency, but it should be consistently >20 mmHg and is usually closer to 30 mmHg. Once manual ventilation of a living foal is established, it must continue until the foal is delivered. The righting reflex is present as the foal exits the birth canal, as is the withdrawal reflex. Cranial ne1ve responses are intact at birth, but the menace response may take as long as 2 wk to fully develop. Absence of a menace reflex should not be considered diagnostic of visual deficits in newborn foals. The suckle reflex should be strong by 10 min of birth. Within1 hr of birth, healthy foals demonstrate auditory orientation with unilateral pinna control. The normal pupillary angle is ventromedial in the newborn; this angle gradually becomes dorsomedial throughout the first month of life. Foals may attempt to rise within 20 min of birth; most should stand on their own within 1 hr and nurse by 2 hr. Some foals defecate shortly after standing, but many will not attempt to defecate until after successfully suckling, about 3 hr after birth. First urination is more variable, with

l&H•ill

fillies usually urinating before colts. It is not unusual for colts not to "drop" their penis when urinating for the first few days of life because of the persistence of a norn1al tissue frenulum within the prepuce. The penis should not be forced from the prepuce; the frenulum will resolve without treatment. The gait of the newborn foal is hypermet­ ric, with a wide-based stance. Extreme hypennetria of the forelimbs, usually bilateral but occasional unilateral, has been seen in some foals associated with perinatal hypoxia and ischemia, but this gait abnormality usually resolves without specific therapy within a few days. Spinal reflexes tend to be exaggerated in the neonate. Foals also exhibit an exaggerated response to external stinluli (eg, noise, sudden movement, touch) for the first few weeks of life.

Dystocia and Resuscitation Most newborn foals make tl1e transition to extra-uterine life easily. However, for those with difficulties (eg, dystocia, premature placental separation), it is of utmost importance to recognize and institute appropriate resuscitation procedures. A modified Apgar scoring system has been developed as a guide to initiate resuscita­ tion and estimate the level of fetal compromise (see TABLE11). A brief physical examination should also be peiforn1ed before starting resuscitation, because of humane issues concerning resuscitation of foals with serious birth deforn1ities (such as severe limb contracture and hydroceph­ alus, among others). The initial assessment begins during the presentation of the foal in the birth canal. Although tl1e following applies primarily to the birth of a foal froi:n a high-risk pregnancy, quiet and rapid evaluation can be performed during any attended birth.

MODIFIED APGAR SCORE FOR EQUINE NEONATES

Clinical Evaluation (first 20 sec of life)

Score:!

Score:2

Score:3

Heart rhythm and rate

Regular, >60 bpm

Irregular, 3,500 species; Caudata (salamanders, newts, and sirens) with -375 species; and Gymnophiona (caecilians) with -160 species.

ENVIRONMENT AND HUSBANDRY Captive an1phibians require proper environmental conditions to remain healthy. Natural stressors, including temperature

change, food availability, and habitat loss, combined with anthropogenic stressors, such as exposure to pesticides, fertilizers, heavy metals, nitrogenous wastes, and acidification, likely increase an1phibian susceptibility to disease, contributing to the large population losses documented in recent years. As ectotherms, amphibians them10regulate by shuttling back and fort.h between different temperatures in their environment. The range of temperatures necessary for proper metabolism, called the preferred optimal temperature zone

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AMPHIBIANS (POTZ), varies among species. Metabolism, including the regulation of immune function and digestion, can be adversely affected if animals are kept at temperatures outside of their POTZ. Infectious diseases and malnutrition are common problems in tropical amphibians kept at suboptimal temperatures. Amphibians require moisture to prevent desiccation. Aquatic amphibians may be accommodated in aquariums with appro­ priate areas for swimming. Terrestrial amphibians need a shallow container of water in the enclosure. Moisture may also be provided by incorporating small streams, watelfalls, or ultrasonic humidifiers into enclosures, or by misting frequently witl1 a spray bottle. Because an1phibians have a semipem1eable skin that readily absorbs potentially ham1ful substances, the water must be clean and free of toxins such as chlo1ine, anm1onia, nitrite, pesticides, and heavy metals. Chlorine can be removed from tap water by placing the water in a barrel and circulating it through a carbon filter for �24 hr before use. Some numicipal water supplies may include chloran1ines. The chloramine bond must be split with specific dechlo1inizing agents, after which water can be filtered to remove the chlorine. External canister filters or tmder-gravel filters help maintain water quality in tank waterfalls, strean1s, and ponds. Substrates that can be used include gravel, soil, sphagnum moss, and mulch. Gravel should be either too large to be swallowed or small enough to be easily passed in the feces. Soils with chemical additives such as fungicides must not be used. Substrates such as sphagnum moss, untreated hardwood mulches, and leaf litter can be used, but cedar and pine mulches have toxic oils and should be avoided. Some an1phibians cannot tolerate low pH and may develop skin iJTitation if they come into contact with peat moss and sphagnun1 moss. Heating soils to 200° F for 30 n1in is reconu11ended to kill aithropods, such as trombiculid mites, and heln1inth pai·asites. Freezing substrates at 10,000 zoospores) appears to be associated witl1 mortality. Some amphib­ ians, including tl1e bullfrog (Rana catesbei­ ana) and the African clawed frog (Xenopus laevis) are less susceptible to Bd and may serve as reservoirs for the disease. Mobile zoospores contribute to the loss of whole

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AMPHIBIANS

populations of amphibians. Clinical signs include abnormal posture, anorexia, lethargy, dehydration, hyperemia, excessive shedding of skin, pupillary miosis, and muscle incoordination. These signs may be mild to absent in infected caudates, emphasizing the in1portance of performing diagnostic tests. Visualizing the spherical, single-celled organisms in skin scrapings stained with Wright-Giemsa or Gram stains using a light microscope is diagnostic, but the organisms are not always readily seen. Real-time PCR performed on swabs of the i.ntegmnent or pieces of skin is diagnostic and provides rapid assessment of presence and quantity of zoospores. This is useful in screening and management of amphibian populations at risk, such as those tmdergo­ ing transp01t or quarantine. On histopathol­ ogy, zoosporangia containing zoospores are associated with hyperkeratosis and u.nderlying dermal infection. Treatment includes the topical administration of itraconazole (0.01% bath for 5 min/day for 10-11 days) and maintaining animals well within their normal them1al range. The use of terbinafine (0.01% bath buffered using bicarbonate to a pH of 7.2-7.4 for 5 min/day for 5 days) may also be effective. If appropri­ ate for the species, raising environmental temperatm-es for captive populations to >23° C may help halt the i.nfection while medicated baths are used to eliminate Bd. Systemic antifungal drugs appear to be ineffective in treating this infection of the epidermis. Bd is a World Organization for Anin1al Health (OIE) notifiable disease. Saprolegniasis refers to disease caused by several genera of opportunistic fungi or "water molds" that infect the gills and/or skin of aquatic and larval amphibians. When in water, newly affected animals appear to have a whitish cotton-like growth on their skin. As the fu.ngal mat ages, it may become greenish due to the presence of algae. Once removed from water, the fu.ngal mat collapses and is difficult to see. Other signs include lethargy, respiratory distress, anorexia, and weight loss. Skin ulcerations may occm· as the infection progresses. A diagnosis of saprolegniasis is made by finding hyphae and the thin-walled zoospores in a skin scrape. Treatment with a malachite green dip (67 mg/L for 15 sec, once daily for 2-3 days) or copper sulfate (500 mg/L for 2 min, once daily for 5 days, then once weekly u.ntil healed) may be effective. Treatment of eggs with methylene blue may be effective. Secondary bacterial and parasitic infections may be present in animals with dermal ulcers. Poor water quality conditions should be c01Tected.

1739

Chromomycosis is caused by pign1ented or black fu.ngi from several genera (eg, Cladosporium, Fonsecaea, Phialophora, Ochroconis, Rhinocladosporium, and Wangiella ). These fu.ngi may be fou.nd in organic substrates such as topsoil and decayi.ng plant matter. Disease is either cuteaneous or disseminated systemic; both have been seen in captive and wild populations of an1phibians. Signs may include anorexia, weight loss, granuloma­ tous skin lesions or ulcers, coelomic distention, and neurologic disease. Diagnosis is usually made postmortem by finding disseminated granulomas with pigmented fu.ngal cells and hyphae. Culture is frequently u.nsuccessful; histopathology may be necessary to confirm tl1e diagnosis. Treatment using itraconazole (10 mg/kg/day, PO, for 30 days) may be given, but the prognosis is poor once the infection is disseminated. Zygomycosis, caused by fu.ngi of the class Zygomycetes (Mucor spp, Basidi­ obolus sp, and Rhizopus spp), affects both wild and captive populations of anurans. Clinical signs include lethargy and multifocal hyperemic nodules with fungal growth on the ventrum. Disease progresses rapidly and results in mortality within 2 wk. Zygomycetes are fou.nd in the environment, especially soils and decaying matter, and are a normal component of the an1phibian's GI tract. Successful treatment has not been reported, but advanced antifungal agents may be tried. Mesomycetozoans are fungus-like microrganisms at the animal-furrgal boundary. Those reported in the literature to infect amphibians include Amphibio­ lhecum (previously Dermosporidium), Amphibiocystidium, and Ichthyopho­ nus; however, continued molecular characterization of these organisms is ongoing, resulting in nomenclature changes and taxonomic reorganization. Amphibiothecum and Amphibiocyst­ idium are spore-forming organisms that typically produce a nonlethal infection in anurans. Clinical signs include multifocal nodules and pustules, usually on the ventrum, that resolve in 4-8 wk. Micro­ scopically encysted spores contain large cytoplasmic vacuoles. Jchlhyophonus is pathogenic to salamanders and frogs living in the eastern half of the USA. Pre­ and post-metamorphic life stages are infected. Clinical signs include muscle swelling in the thigh, rump, and tail and may appear nodular, especially in tadpoles. Debilitation may lead to mortality, especially in adults. Diagnosis

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AMPHIBIANS

is based on histopathology or finding characteristic spores through micro­ scopic examination of material from the lesions. There is no treatment other than supportive care. Parasitic Diseases: Many of the protozoa and metazoa found in and on amphibians are not associated with disease unless the host amphibian is stressed or imrnunocom­ promised. Recently caught or transported an1phibians are particularly susceptible to parasitism, as are those kept in poor hygienic conditions and outside their POTZ. Parasites with indirect life cycles tend to die out when wild-caught amphibians are brought into captivity if the intermediate or final host is not present. Conversely, infections by parasites with a direct life cycle may be magnified in a closed environment. Excellent hygiene is essential for parasite control and includes the routine removal of sloughed skin, fecal material, uneaten food, and carcasses from animal enclosures. External parasites may be found by close examination of an1phibians using magnifica­tion and a bright, cool light. A skin scrape or biopsy may be required to identify parasites causing nodules or epidermal lesions. Internal parasites are often identified tluough examination of fresh fecal samples. Some small frogs are translucent enough to allow the visualization of nematodes using transillumination. In some cases, metazoan and protozoan parasites are fom1d only at necropsy. Finding flagellates, ciliates, and opalinids in the feces is nonnal and does not require treatment in healthy amphibians. Although many larval nematodes found in the feces are nonpathogenic, treatment is reconunended because pathogenic and nonpathogenic species cannot be readily distinguished. Most protozoans found in the GI tract, including ciliates, opalinids, and flagellates, are commensals. The ciliate Tetrahymena, although norn1ally nonpathogenic, has been associated with mortality of salamanders. Trichodinids may be found in the urinary bladder or on the skin of amphibians and require treatment. Hemoflagellates are occasionally found and generally nonpatho­genic but can result in anemia. Greater-than­nonnal loads of GI flagellates and other protozoa may be found in debilitated an1phibians and require treatment aimed at restoring balance and not eliminating the protozoa. External dinoflagellates ( eg, Piscinoodinium) and flagellates ( eg, I chthyobodo) can cause significant mortality, especially in larval amphibians.

Fecal samples collected by placing the amphibian on clean, moist paper towels helps to prevent contamination from free-ranging protozoa. Cloacal wash, gill clips, and skin scrapes are also diagnostic. Treatment using metronidazole is often effective for external and GI organisms. Sporozoans such as coccidia (Eimeria and Isospora) and microsporidians (Micro­ sporidium, Pleistophora, and Alloglugea) may be incidental findings or parasitic. Clinical signs are nonspecific and include poor body condition and wasting. Myxozoa occasionally cause disease in an1phibians and result in specific host/disease agent lesions. Treatment efforts are focused on providing supportive care. Metazoa parasites include myxozoa, helminths, and arthropods. Myxozoa infections in an1phibians generally do not cause mortality. Helminths that are pathogenic to amphibians include trema­ todes (Ribeirola, Clinostomum) and nematodes (Rhabdias, Strongyloides, Pseudocapillaroides ). Arthropods, such as the common fish parasitesArgulus and Lernaea, may infect amphibian aquatic life cycle stages, whereas ticks and mites affect postmetamorphic terrestrial aninlals. Larval dipterid flies may consume an1phibian eggs and embryos and feed on the tissues of adults. 'I\vo of the most significant metazoan infections in captive amphibians are caused by Rhabdias sp and Pseudocap­illaroides xenopi. Rhabdiasis, caused by the lungworm Rhabdias sp, commonly causes pulmonary damage and secondary infections in captive an1phibians. This nematode has a direct life cycle with free-living phases. Adult worms live in the lungs, where they deposit larvated eggs that are coughed up, swallowed, and then excreted into the environment. Infective L3 larvae then burrow through the skin of a new host, where they mature and migrate to the lungs. Affected animals may appear anorectic, thin, and generally debilitated. A premortem diagnosis may be made by finding ova or worms in oral and nasal secretions. Infection should be suspected when nematode larva and larvated eggs are found in fresh feces from an animal with clinical signs. When rhabdiasis is suspected, treatment using fenbendazole (100 mg/kg/ day, PO, for2 days then repeated 12-14 days later) or ivern1ectin (200-400 mcgfkg, PO, once, repeated 12-14 days later) is recommended. After the second of each 2-day fenbendazole treatment or each dose of ivermectin, the anin1als should be moved into a newly established environment to

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AMPHIBIANS

prevent reinfection from free-living life stages. Some reactions to fenbendazole have been reported, so animals should be monitored closely and treatment discontin­ ued if necessary. The capillarid nematode Pseudocapillar­ oides xenopi buffows into the skin and is known to affect colonies of the aquatic African clawed frog. Signs include discoloration, roughening, pitting, and ulceration of the skin. As the infection progresses, lethargy, anorexia, and skin sloughing occur. Diagnosis is made by finding small, white nematodes beneath the mucus on the skin; skin scrapings may show larvae and ova. Treatment by adding thiabendazole (0.1 g/L) to the water may be effective. Levamisole and other anthel.min­ tics may also be effective. Frequent water changes with removal of shed skin containing the parasite are required to prevent the amplification and spread of infection to cage mates.

Viral Diseases: Renal adenocarcinomas (Lucke tumors), caused by ranid herpesvi­ rus-1, are relatively common in leopard frogs (Rana pipiens) wild-caught in the northeastern and north central USA. Few frogs with tumors are seen in the summer, because viral replication is temperature­ dependent. Virus particles and intranuclea.r inclusion bodies are seen when frogs are in hibernation, at 41°-50°F (5°-10°C). Metastasis of the tumor to liver, lungs, and other organs is common; both the primary and metastatic tumors can become very large. There is no treatment. The neoplasm is a model of herpesvirus-induced cancer. Ranaviruses, which are DNA-based viruses in the genusRanavirus, family lridoviridae, have been identified as the cause of mass mortality in wild populations of anurans and caudates across the world. Environmental conditions, reservoir species, persistence in the environment, direct and indirect transmission, stress, and host immunity contribute to the impact of ranaviruses on amphibian populations. Species of Ranavi?'us that infect amphib­ ians include frog virus 3 (FV3) and FV3-like viruses, Bohle iridovirus, andAmbysloma tigrinum virus. These viruses are highly virulent and may produce 900/6 mg/L, then the organic load is excessive, and sanitation practices should be evaluated. KMn04 has little impact on biofilters when applied at s2 mg/L. Potassium permanganate is more toxic as salinity of the water increases, and use in marine systems is not recommended. Food fish must undergo a 7-day withdrawal period after treatment before harvest.

Diquat: Diquat (Reward®), first registered as a contact herbicide (pesticide), has been used for many years to control columnaris disease (F columnare) in fish. Only recently has it come under greater FDA scrutiny and become an INAD for control of Flavobacte­ rium species associated with bacterial gill disease and columnaris disease. Withdrawal times for harvestable food fish species are 5 days for channel catfish, muskellunge, tiger muskellunge, and northern pike, and 30 days for all other fish species. Diflubenzuron: Diflubenzuron (Dimilin®), a chitinase inhibitor used to control crustacean parasites, is a restricted use pesticide that can be applied only by licensed pesticide applicators. Dimilin is labeled for control of anchorworn1s on ornamental fish and baitfish commercially produced in ponds and tanks. Fish being raised for hmnan consLUnption should not be exposed to diflubenzuron. Anesthetics/Sedatives Tricaine Methanesulfonate (MS-222, TMS): Tricaine methanesul­

fonate (approved product Tricaine-S® ) is a benzocaine derivative and is the only FDA-approved fish anesthetic. TMS is approved for the temporary immobiliza-

1753

tion of fish, amphibians, and other aquatic, cold-blooded animals. In fish intended for human consumption, TMS can only be used in members of the Ictaluridae, Salmonidae, Esocidae, and Percidae, and water temperature should not exceed 10°C (50° F). Withdrawal period if used in these species is 21 days.

Eugenol: Eugenol (Aqui-S20E®, active

ingredient J()OA, eugenol), one component of several found naturally in clove oil, is an lNAD intended for use as an anesthetic/ sedative. Although eugenol is not approved, it is currently allowed for use in freshwater fisheries work as a zero-withdrawal fish anesthetic. However, if used in aquaculture, the withdrawal tin1e is 72 hr. A related compound, isoeugenol (Aqui-S®), is not allowed for use in tl1e USA because of carcinogenicity concerns.

Metomidate: Metomidate hydrochlo­

ride (Aquacalm®) is a fish sedative on the FDA-CVM Index of Legally Marketed

Unapproved New Animal Drugsfor Minor Species (the Index), labeled for the sedation and anesthesia of ornamental finfish. It is not legal for use in food fish species.

Spawning Compounds Chorionic Gonadotrogin: Chorionic

gonadotropin (Chorulon ) is FDA approved for use as an aid to improve spawning function in male and female brood finfish. This is the only spawning aid ap]i)roved by the FDA for use in food fish species. There is no withdrawal time if used according to label instructions on broodfish. Veterinar­ ians may work as part of a team for fish hatcheries and may be asked to help obtain spawning hormones. Cho1ionic gonadotro­ pin is a prescription drug and is restiicted to use by or on the order of a licensed veterinarian.

Gonadotropin-releasing Hormone (sGnRHa) + Domperidone: Salrnonid

GnRH analogue + domperidone (Ovaprim®) is on the Index and labeled for use as a spawning aid in ornamental finfish brood­ stock. This product carmot be used in food fish species.

INFECTIOUS DISEASES Some fish pathogens may be more common in or adapted to a given species, genus, or family; however, many are ubiquitous and have broad host ranges. Enviromnental factors, including type of rearing system and

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production method, influence pathogen variety and prevalence within a given unit and facility. Many pathogens can infect fish regardless of rearing system and production method, but the following sections describe pathogens that may be more problematic under certain conditions.

Ponds: Most production ponds are outdoor and earthen (dirt or clay lined) and, over time, become high in organic loading as a consequence of feeding, fish growth, waste accumulation, and other related processes. In Florida, smaller ponds facilitate periodic cleaning, whereas much larger catfish ponds in the southeast are logistically much more difficult to clean. Although fish in production ponds are ce1tainly susceptible to a wide spectrum of parasites, high organics favor sessile ciliates, includingHete ropolmia/Epistylis, Apiosoma, andAmbiphyra, which attach to fish but feed on bacteria and other nutrients in the water column. Other protist parasites that thrive in 1ich, organic environ­ ments include the trichodinids (eg, Trichoclina, Tripartiella), and Tetrahy­ mena. Uronema, the marine counterpart to Tetrahymena, also thrives in highly organic waters. Fish cultured in outdoor ponds are much more susceptible to infection by melazoan parasites with indirect life cycles because of the presence of final hosts and intermediate hosts that pennit completion of the life cycle. These include digeneans, myxozoa, nematodes, and cestodes. The presence of birds and snails facilitate infestations by digeneans, requiring fish and snails as intermediate hosts and aquatic birds as the final host. Bolbophorus damnijicus is an important digenean parasite of channel catfish, the final host of which is the American white pelican, and the intennedi­ ate hosts a.re the ram's horn snail and the fish. Centrocestusformosanus, another in1portant digenean parasite infecting the gills of nun1erous fish species, uses a wading bird, such as the green heron or great egret, or the cone snail (Melanoides tuberculata) to complete its life cycle. Oligochaetes, annelid worms, are also much more prevalent in highly organic waters. Henneguya iclaluri, a myxozoan parasite and the causative agent of prolifera­ tive gill disease in channel catfish, requires the oligochaete Dero digitata to complete its life cycle. Eustrongylides, a nematode parasite that infects wading birds as adults, has an indirect life cycle that may involve either an oligochaete worm and a fish or just a fish. Juvenile, pond-reared fish can be

adversely affected when heavily infected with this organism. Other fish, reptiles, or amphibians may serve as paratenic hosts by feeding on infected fish and carry or transport the parasite. Bactetial diseases, such as those caused by Edwardsiella ictalU1i and Streptococ­ cus spp, as well as viral diseases may be more difficult to control once they infect a pond population because of logistical challenges with pond disinfection.

Recirculating Aquaculture Systems:

Recirculating aquaculture systems (RASs), by contrast,a.re situated within enclosed facilities with more limited access by potential final or intermediate hosts. Parasites with direct life cyclesa.re more conunon and dangerous in an RAS, because RASs used in production tend to have greater fish densities and by definition recycle water, which results in closer fish-to-fish contact and greater buildup of parasite nw11bers within the system. Once a parasite infects a fish within an RAS, it becomes magnified, and disease can spread rapidly. Ichthyophthi?ius multifiliis ("ich"), C1yptocaryon irritans ("salt water ich"), andAmyloodinium (marine velvet disease) can spread rapidly within an RAS. Similarly, egg-laying monogeneans such as Dactylogyrus sp and Neobenedenia sp, the capillarid nematodes (which have direct life cycles), and microsporidia also can spread rapidly within an RAS. Bacterial and viral diseases a.re also much more problematic in RASs, partly because microbial flora can be much less diverse and skewed than in more natural pond systems. Mycobacteriosis and streptococcosis have caused significant morbidity and mortality in RASs, which can favor their growth, amplification, and fom1ation of reservoirs. Certain environmental conditions promote mycobacterial growth, including warm water temperatures, low dissolved oxygen levels, acidic pH, high soluble zinc, high fulvic acid, and high hwnic acid. Many of these conditions-especially the low dissolved oxygen, low pH, and an organi­ cally tich environment-a.re present in intensive aquaculture systems. Closed conditions and higher stocking densities enhance the potential for spread and an1plification. Biofilms on the tanks, in pipework, and in filtration systems, as well as organics, inaccessible or overlooked mortalities, and detritus, can serve as reservoirs.

Net Pens/Cage Culture: Open ocean net pens, or cage culture systems within

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AQUACULTURE

large rese1voirs or lakes, have their own unique challenges. Under ideal conditions, "open" access through the net or cage structures is intended to make use of the vast surrounding water body and allow for dilution of solid and dissolved wastes. However, this "open" access also facilitates direct or indirect contact with pathogens endemic to the water body. Smaller wild fish or other organisms may directly enter and intenningle with the farmed species, or pathogens themselves may flow directly into the stmcture tlu-ough the water or on otl1er vectors. The higher densities found in net pens and cages can then magnify the disease through close contact and facilitate spread. Salmonid producers, during marine grow-out phases, can have significant losses caused by sea lice and infectious salmon anemia, among others. Neobened­ enia and other monogeneans are a major problem in warmwater marine systems. Bacterial diseases such as vibriosis are common in net pens, and emerging viral diseases, including those caused by iridovi­ mses (including megalocytivinises) and betanodaviruses, are of increasing concern in marine open ocean systems because of potential for transmission from wild populations.

PARASITIC DISEASES Protists Infecting Gills and Skin: For infonnation on protists infecting the gills and skin offish, seep 1799. Wormation presented here is relevant tofish reared in intensively cultured systems. As previously mentioned, trichodinids are indicators of poor sanitation and/or overcrowding. These organisms are commonly found in cultured fish, especially in systems with high stocking densities, high organic loads, and minin1al (or no) in-line sanitation (eg, UV or ozone). When fish are heavily infested, losses will occur. ln these cases, chemical treatment alone may not be adequate for complete control. Addressing management problems that favor infestation should be incorporated into the treatment plan. Decreasing organic material is essential for treatment efficacy, because these organisms can be protected from chemical treatment by "hiding" within organic debris. Ambiphyra and Apiosoma are sessile ciliates found on the skin, gills, and fins of fish. These are common in pond-reared fish and also have a predilection for organically rich environments. They are not generally found on marine fish. In high numbers,

1755

these parasites can cause significant epithelial damage, predisposingfish to opportunistic pathogens in the environ­ ment and compromising respiration and osmoregulation. Infested fish demonstrate flashing, decreased appetite, loss of condition, and hyperplasia of infested epithelial surfaces. Severe infestation of the gills is particularly damaging. These organisms can be controlled with a single treatment of formalin, copper sulfate, potassium permanganate, or a salt dip. Excessive crowding and poor sanitation are frequently associated with heavy infestations and should be corrected. For identification of protists affecting external surfaces of cultured fish, see p 1799. Control strategies are detennined by the species affected and their intended use, the type of system the fish is housed in, cost of treatment, and environmental considera­ tions. Internal Protistan Parasites: For inforn1ation on flagellated parasites ( diplomonads such as Spironucleus, and kinetoplastids such as C1yptobia iubilans), see INTERNAL PROTISTAN PARASITES, p 1803. These parasites are also conu-non in the GI tract of susceptible aquaculture species. The use of chemical treatment to control these organisms is not feasible in food fish; however, improvements in environmental conditions and husbandry will decrease morbidity and mortality. Opalinids, larger "cilate-like" parasites commonly found in tl1e GI tract, may be found occasionally in kissing gourami, discus, some catfishes, and other species. Considered commensal by some, these may or may not be associated with disease. Internal Metazoan Parasites: Myxo­

sporean (Myxozoa) diseases significant in aquaculture include whirling disease and proliferative kidney disease (PKD) of salrno­ nids and proliferative gill disease ("han1burger gill disease") of channel catfish. Whirling disease is caused by Myxobolus cerebralis. Fish are infected as fingerlings when the parasite infects cartilage in the vertebral colunm and skull, resulting in visible skeletal defonnities. Affected fingerlings typically show rapid tail-chasing behavior (whirling) when startled. The disease is also sometimes called "blacktail," because the peduncle and tail may darken significantly. Recoveredfish remain carriers. Adults do not show behavioral signs, but skeletal defonnities associated with infection do not resolve. The disease can be prevented by purchasing uninfected

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breeding stock and maintaining them in an environment free of the inte1mediate hosts (tubifex wonns). A presumptive diagnosis of whirling disease is made by detection of spores from skulls of infected fish. Diagnosis may be confirmed histologically or serologically. Whirling disease is of regulatory concern in some states. PKO is one of the most economically important diseases affecting salrnonid industries of North Ame1ica and Ew·ope. Rainbow trout are particularly susceptible. PKO is caused by Telracapsuloides b1yosalmonae, a myxosporidian with four distinct polar capsules. It occurs most commonly in the swmner when water temperatures are> 12 °C, and the parasite p1ima.rily infects yearling and yow1ger fish. Clinical signs include lethargy, darkening, and fluid accumulation indicated by exophthalrnos, ascites, and lateral body swelling. Wected fish are frequently anemic, resulting in gill pallor. Grossly, the posterior kidney appears gray, mottled, and significantly enlarged. Presumptive diagnosis can be based on obseivation of suspect organisms, 10-20 µm in diameter, in Giemsa-stained wet mounts of kidney tissue. Histologic examination of infected tissue, stained with H&E, and in1mw10histo­ chemistry are required for confirmation. There is no treatment, but fish tl1at recover from the infection are resistant to subse­ quent outbreaks. Wected stocks in nonendemic areas should be depopulated, the premises sanitized, and disease-free stock obtained for replacement. Avoidance is the best preventive measure. Proliferative gill disease ("hamburger gill disease") is a myxosporean infection of channel catfish caused b:t Aurantiactino­ my:1:on iclaluri. The organism has a complex life cycle, with the oligochaete worn1 Dero digitata serving as the intennediate host. Channel catfish may be aberrant hosts for A ictalU1i, and the disease usually occurs in new ponds or previously infected ponds tl1at have been drained and refilled. Although proliferative gill disease can cause catastrophic mortality approaching 1000/o, losses may be as low as 1%. Disease occurs at water temperatures of 16°-26°C, and mortality is exacerbated by poor water quality, paiticularly low dissolved oxygen or high levels of un-ionized anunonia. Gills of affected fish are severely swollen and bloody. A presun1ptive diagnosis can be made from a wet mount of infected tissue, in which filai11ents appeai· swollen, clubbed, and broken. Cartilaginous necrosis is strongly supportive of a diagnosis of proliferative gill disease;

however, histology is required for confirmation. Quantitative PCR has also been used diagnostically. Platyhelminthes (Flatworms): Flat­ w01ms (Platyhelminthes: monogenea, digenea, leeches, turbellaria, seep 1807) are also of concern in aquaculture. Monogeneans, including gyrodactylids, dactylogyrids, ancyrocephalids, and capsalids, have all been identified in nun1erous aquacultured species. Ch.J1-odaclylus salaris is a rep01table disease of salrnonids but has not been repo1ted in tl1e USA. Any gyrodactylid found on a salmonid species should be identified well enough to determine whetl1er it is G sala1is. Neobenedenia and Benedenia are in1portant monogeneans in marine aquaculture. Although treatments will vaiy depending on the aquaculture setting and species of parasite and fish host, formalin is approved for use in food fish. Hyposalinity for marine species, including freshwater dips, can help reduce loading on fish, but environmental reseivoirs (eg, eggs) will need to be controlled as well. Neobeneden'ia was controlled in one study when salt levels were reduced to ,14%) and high temperatures (>27°C) being significant risk factors. Affected trout may have a grossly distended abdomen, and necropsy findings reveal a hepatoma or hepatic carcinoma. Liver lesions have been reported after exposure to concentrations as little as 1 mg/kg. Disease has been induced experin1entally in tilapia at higher concentrations and/or extended exposme periods. In one study, tilapia fed 10 mg/kg for 8 wk had liver pathology and when fed 100 mg/kg for 8 wk, hepatic necrosis and mmtalities were seen. In another study, tilapia fed 0.245 mg/kg over the course of 20 wk demonstrated reduced growth and liver pathology. Presence of the toxin can be confirmed using high-performance liquid chromatogra­ phy (HPLC) or ELISA. Commercial test kits are also available.

VIRAL DISEASES The identification and characterization of previously undescribed viral diseases in aquaculture is increasing because ofrecent technologic advances and increasing expertise in the aquatic veterinary field. Virnses (seep 1812) may also affect susceptible species in aquacultme settings. Again, management options are linlited but vary depending on the type and pathogenic­ ity of the virus, species susceptibility, reportability, and whether the virus is

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considered endemic or exotic. In general, no approved or effective treatments exist for viral diseases in aquaculture species. Temperature manipulations are problematic, especially because of concerns over latency and potential recrudescence. Vaccine development for economically important virnses is ongoing, and some vaccines exist for some viruses either in the USA or interna­ tionally. Additional virnses of importance to aquaculture are described below. Herpesviruses (Alloherpesviruses) Herpesviruses (alloherpesvirnses) are also important pathogens in aquaculture (see also p 1812). Herpesvirnses have been identified in a nW11ber of different aquacultured species, including cyprinids and various cichlid species. Channel Catfish Virus Disease: Channel catfish virus (CCV) disease is an acute, virnlent herpesvirus infection of fry and fingerling channel catfish that can cause mortality of >80% at water tempera­ tures ;,,25 °C in small fish (5:5 cm). As fish age, mortality decreases, and clinical infec­ tion in fish > l yr old is rare. Acute infection often includes a recent history of a stress­ ful event such as handling or transport, low dissolved oxygen, or chemical treatment. Infected fish show signs of ascites, exoph­ thalrnos, and hemorrhages in fins. The cell line of choice for virus isolation is channel catfish ovary, followed by serum neutraliza­ tion to confirm identification. Typical cyto­ pathic effects include "cell fusion, syncytia formation, and intranuclear inclusions. There is evidence for vertical transmission of CCV; consequently, survivors of an epizo­ otic should not be used for liroodstock. Although CCV can cause severe mortality when an outbreak is in progress, the an­ nual number of cases of CCV in the catfish industry is relatively low. Novirhabdoviruses Infectious Hematopoietic Necrosis: Caused by a novirhabdovirus in the family Rhabdoviridae, infectious hematopoietic necrosis is listed as an OIE notifiable disease. It is endemic in salmonid (Onco­ rhynchus spp) populations in the Pacific Nortllwest and Alaska and has been reported in Atlantic, chum, chinook, sockeye, and kokanee salmon and in cutthroat, steelllead, and rainbow trout. Lake trout and Arctic char, members of the genus Salvelinus, appear resistant. The disease has also been reported in parts of Europe and Asia. Most

epizootics have been attributed to importa­ tion of infected eggs or fry. Acute disease in fry 90'/o) with few external signs. Disease usually occurs at water temperatures of l ()0-l2°C, although outbreaks occasionally occur at temperatures > l5°C. 1ypical signs include lethargy witl1 sporadic hyperexcit­ ability, including whirling. Sick fish may be darkened with distended abdomens, exophthalmia, pale gills, and mucoid fecal casts. Important differential diagnoses include infectious pancreatic necrosis and viral hemorrhagic septicemia Hematopoietic tissue in the kidney and spleen are most severely affected by necrosis. Risk factors include age (fish 40 different species of primarily marine fish worldwide. Susceptible species include red drum, cobia, barran1undi, tuna, groupers, flatfishes, surgeonfishes, lemonpeel angelfish, the orbicularis batfish, and tilapia. The resulting disease is also known as viral nervous necrosis (VNN) and viral encepha­ lopathy and retinopathy. A few freshwater species have also been reported as suscep­ tible. Betanodaviruses can infect tropical, subtropical, or cold-temperate species, with species susceptibilities and optimal temperature ranges varying depending on the strain of the virus. Four different genotypes are currently recognized, and VNN is reportable to USDA-APHIS and the OIE. As a group, betanodaviruses can infect fish at temperatures ranging from approxi­ mately 15° -30° C. Younger life stages (larvae, fry, fingerlings) are more frequently affected, although older, market-size fish may become affected. Losses can range from 15o/ 12 mg/1. The concentration of C02 in solution in ground water is typically 38%, and can add sigrtificant quai1tities of nitrogen to a system. Nitrogen is eliminated from fish by passive diffusion of anm10n.ia (NH3) from gill capillaries. Once NH3 is released into tl1e water, it enters the nitrogen cycle, a natural process in which bacterial populations chai1ge ainmonia to nitrite (N02) and then to nitrate (N03). Nitrate is most commonly removed from aquariums by water changes. In large, commercial systems, discharge of salt water to mtmicipal water supplies is not allowed, and nitrate accun1Ulates. It can be removed by anaerobic filtration, which converts N03 to nitrogen gas (N2), which is volatile and quickly leaves the system. These anaerobic filters are expensive and can be challenging from the design perspective, so they are not conunon except in very large exhibits. Plants or algae, if present in a system, will use nitrogen products directly. Toxicity of each of these paraineters is discussed below. NH3 is highly toxic and frequently limits fish production in intensive systems. It is also dynamic, and when it enters the aquatic system, an equilibrium is established between NH3 and anunon.iwn (NH/). Of the two, NH3 is fai· more toxic to fish, and its formation is favored by high pH (> 7) and water tempera­ ture. When pH exceeds -8.5, any NH3 present can be dangerous. In general, a norn1ally functioning aquatic system should contain no measmable NH3 because as soon as it enters the system, it should be remov�d by aerobic bacteria in the environment. Ammonia test kits do not typically measure NH3 directly but instead measure the combination of NH3 and NH, +, referred to as total anm10n.ia nitrogen (TAN). A TAN 8.5. However, if the ainount of NH3 is increased, an explanation should be sought. The ainount of toxic NH3 present can be calculated using the TAN, pH, and water temperature. When NH3 levels exceed0 .05 mg/1, dan1age to gills becomes apparent; levels of2 mg/Lare lethal for many fish. Fish exposed to an1mon.ia may be lethargic and have poor appetites. Acute toxicity may be suggested by neurologic signs such as spinning, disorientation, and convulsions.

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AQUATIC SYSTEMS

Overfeeding or malfunction (death) of a biologic filter are common causes of increased NH3. If possible, a water change (�500Ai) should be done as soon as high NH3 levels are detected. When changing water to alleviate NH3 toxicity, it is in1perative to consider whether source water contains chloramines, because this can contribute to increased NH,1 concentrations. If TAN is extremely high (ie, >5 mg/1) and pH is acidic (ie, 20 mg/1), extremely low pH (usually 10, killing all fish present. Correct liming of ponds is mentioned briefly below. C02 released into an aquatic system enters the carbonate cycle: H,O + C02 H2C03 + H + HC03- 2H + + CO}-. The process is driven by the presence of carbonate (CO}-) in the system, which is measured by testing the total alkalinity (TA). For most fish, water should be of moderate alkalinity, 100--250 mg/L. When TA is 25-100 g, depending on species, the caudal vessels of the caudal pedW1cle, the duct of Cuvier (common cardinal vein), and the dorsal and ventral aortas are easily accessible. For smaller specimens that are to be euthanized, blood can be collected in a hematocrit tube immediately after euthanasia by severing the caudal pedW1cle and exposing the caudal vessels. Use of hematology and sernm chemistry is limited, because normal values for manyfish species are not readily available; however, the inforn1ation may still be clinically useful. Lithium heparin is the anticoagulant of choice for mostfish species, although EDTA is preferred for ictalmid catfishes, and plasma may be used for biochemistry tests. Serology may be diagnostic in certain cases (eg, heavy metal toxicity). Whole blood (1-2 drops) can be incubated in brain heart infusion broth at room temperature on an electric rotator. If cloudiness indicative of bacterial growth develops, a loop of the blood-broth mix can be used to attempt primary isolation of a systemic bacterial pathogen.

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Fish should be euthanized and opened under sterile conditions. A ste1ile swab of posterior kidney, or other organ of interest, may be shipped to a laboratory in transport media, but primary isolation directly onto an enriched media (eg, tryptic soya agar enriched with 5% sheep blood) is preferable. Altl1ough blood agar supplemented with salt is helpful for ma.tine fish, it is not necessary if an eruiched blood agar is used. Ordal's or similar cytophaga media should be available

IM:i!ii

for isolation of myxobacteria (slime bacteria, includi.ngFlavobacterium columnare). Sabouraud agar is an excellent all-purpose media for isolation of fungal agents. Lowenstein-Jensen or Middlebrook media is recommended for isolation of Mycobacterium spp. Mueller-Hinton is the media of choice for susceptibility testing of most common bacteria isolated from fish. U abscesses or other obvious anomalies are visible, those sites should also be cultured.

FISH DISEASES OF REGULATORY CONCERN IN THE USA

Disease

Causative Agent

Susceptible Species

Viral hemorrhagic septicemia (Egtved disease)

Novirhabdovirus

Prin1ary: salmonids (Oncorhyn­ chus spp), turbo, herring and spat (Clupea spp ), Japanese flounder Secondary: grayling, whitefish, pike, Atlantic and Pacific cod, haddock, many freshwater, marine, and estuarine species

Infectious hematopoietic necrosis

Novirhabdovirus

Primary: cultured salmonids (Oncorhynchus spp); lake trout and char (Salvelinus spp) are resistant

Vesiculovirus

Primary: carp (including koi, goldfish), sheatfish (European catfish), orfe, tench

Epizootic hematopoietic necrosis

Ranavirus

Primary: redfin perch Secondary: rainbow trout (wild and farmed fish)

Red sea brea.in iridoviral disease

Megalocytivirus

Red sea brean1, many other estua.i·ine species, other marine species

Spring viremia of carp

Fan1ily: Rhabdoviridae

Fan1ily: Rhabdoviridae

Fa.inily: Rhabdoviridae

Fan1ily:lridoviridae

Iridoviridae

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AQUARIUM FISHES In general,bacte1ial or fungal cultures taken from fish tissue should be incubated at room temperature (25°C). Some agents of concern will not grow at all at 37°C,the standard temperature for incubation of cultures taken from mammals. Agents of zoonotic concern,such as Mycobacteriurri,, can be dual incubated at both 25°C and 37°C. An acid-fast stain should be available for bench-top staining of granulomatous material which,when positive,is strongly

1787

suggestive of Mycobacterium. If fish are seen spinning or showing other behavioral indications of neurologic disease before death,brain cultures are indicated. If viral disease is suspected,appropriate tissues may be collected. Specin1ens should include both fresh tissues placed in reagent ethanol and frozen tissues. Several viral diseases are of regulatory concern to veterinarians practicing fish medicine in the USA (see TABLE 6).

FISH DISEASES OF REGULATORY CONCERN IN THE USA (continued)

Clinical Signs and Pathology

Temperature Range °

Status in USA

Acute form: nonspecific hemo,� rhaging (eyes,fins, skin), darkening,exophthalmia,ascites Chronic forn1: few signs Neurologic form: spinning/ flashing Gross: enlarged spleen,ascites, necrotic kidney Histologic: focal necrosis of kidney liver,spleen; hemorrhage in muscle

9 -12 c (48 -54 F) op tin1at

Present in wild populations,sporadic, limited distribution; endemic in Pacific Northwest and Alaska (wild salmonids, haddock,and cod); emerging disease in Great Lakes region

Rapidly increasing mortality (fish l5°C (59"F)

Present in western USA, sporadic,limited dist1ibution; endemic in Pacific Northwest and Alaska (wild salmonids); also present in parts of Europe ang Asia

Nonspecific: darkening,exoph­ thalmic, pale gills,distended abdomen,ascites,hemorrhage (gills,skin,eye),petechiae in organs (including swim bladder), protruding vent with thick mucoid fecal cast Coinfection with Aeromonas or other bacteria common

12°�22°c (54°-72°F)

USA is free (last occurred in captive fish in 2004, wild fish in 2007); occurs in eastern Europe,Russia,China, and Middle East

Acute and high mortality of redfin perch; darkening,ataxia,lethargy, hemorrhage around nares; morbidity and mortality of rainbow trout less severe Histologic: necrosis,renal hematopoietic tissues

Redfin perch: >l2°C Has never occurred in (M°F) USA; endemic in Rainbow trout: 11°- l 7 °C Australia (52°-63 °F) Experin1ental: 8°-21 °C (46 °-70°F)

Severe anemia,lethargic,pate gills,enlarged spleen

°

°

°

Has never occurred in USA; occurs in Japan and Taiwan

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AQUARIUM FISHES

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FISH DISEASES OF REGULATORY CONCERN IN THE USA Disease

Causative Agent

Infection with HPRIsavirus Family: Orthomyxovirideleted or HPRO Infectious salmon anemia dae

(continued)

Susceptible Species Atlantic salmon Brown trout, sea trout, rainbow trout

Infection with salmonid alphavirus (pancreas disease or sleeping disease)

Alphavirus

Family: Togaviridae

Atlantic salmon, rainbow trout, brown trout

Koi herpesvirus

Herpesviridae Cyprinid herpesvirus-3

Common carp and hybrids, including koi and ghost carp

Epizootic ulcerative syndrome (mycotic granulo�atosis)

Aphanomyces invadans

Atlantic menl1aden, striped mullet, many oilier freshwater and estuarine species; snakeheads, barbs (Puntias spp) sensitive; gouramis, goldfish and oilier ornan1entals susceptible; tilapia resistant

Monogenea

Atlantic salmon, rainbow trout, brook trout, North American lake trout, brown trout, grayling arctic char

Gyrodactylus (Gyrodac­ tylus salaris only)

Gyrodactylus salaris

only

Tissue sections no larger ilian 1 cm3 should be placed in 10% neutral buffered formalin for histopathology. After 24 hr of fixation, iliey should be removed and placed in reagent alcohol in case molecular diag­ nostic techniques will be required.

Therapeutic Considerations · Therapy for pet and ornamental fish is often based on environmental management followed by ilie use of targeted ilierapy to control specific pailiogens. Use of prophylactic medication in ilie absence of diagnostic testing is strongly discouraged and may contribute to resistant bacte1ial infection and oilier complications. Drug ilierapy can be provided via several routes of administration, including expo­ sure by baili (adding medication to water), medicated feed, irtjection, or topical administration. Generally speaking, bath and topical treatments are most useful for external infections, whereas medicated food and irtjection are most appropriate for internal infections. Using a baili treatment requires accurate measurement of the volume of water to be treated. Volume of a rectangular tank is

calculated by multiplying measurements of the length, widili, and depili. Volwne of a circular tank is calculated by multiplying 3.14 by the radius squared by ilie depth. To calculate directly into liters, measurements should be in cm and multiplied by 0.001. lf the measurements are made in feet, the result will be in cubic feet; cubic feet can be converted to gallons by multiplying by 7.481. If ilie container is oddly shaped, volume may be calculated mathematically, but it may be easier to purchase a flow meter to measure ilie volw11e required to fill ilie tank. Alternatively, t11e volume of inflowing water per minute can be measured by detennining how long it takes to fill a 1-L graduated cylinder (or 5-gal. bucket). Using that inforn1ation, detennin­ ing how long it takes to fill a tank or ornan1ental pond can provide a fairly accurate assessment of volume. Some medicated feeds can be purchased commercially for aquaculture or pet fish. Custom-made medicated feeds can be prepared for use in ornamental fish. Flake, pellet, or gel diets can be used as a base for medicated food for pet fish. Cooking oil spray is an effective binder for use wiili

AQUARIUM FISHES

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FISH DISEASES OF REGULATORY CONCERN IN THE USA (continued)

Clinical Signs and Pathology

Temperature Range

Status in USA

Pale gills, severe anemia (PCV 1 wk), and treated water should be retainedfor28 days and then run ttu·ough a carbon filter before discharge. Metronidazole is used to control intes­ tinal protozoans and can be delivered in a medicated food or as a bath when fish are anorectic. Although very effective against

1795

Spironucleus spp, metronidazole does not

seem to be effective against gastric infections with Ciyptobia iubilans. A concentration of -7 mg/L( -250 mg metronidazole dissolved in 10 gal. of water) can be administered daily for5 days. A daily water change a few hours after treatment is recommended. Metronida­ zole can be administered in medicated feed at50 mg/kg, PO, for5 days. Metronidazole may not be used in food fish in the USA. Fenbendazole has been used to control intestinal helminths in fish. A dosage of25 mg/kg, delivered infood for 3 --5 days, has been commonly recommended, but efficacy has not been evaluated in controlled trials. When fenbendazole has been used in a bath treatment, high mortality has occurred. Consequently, this use is not recommended. Levamisole administered in a bath treatment at a concentration of2 mg/L is also used by some clinicians. These compounds may not be used in food fish in the USA. Praziquantel is selective for flatwom1s, so consequently is used to control cestodes and external monogeneans. The most common use of praziqua.ntel is as a prolonged bath in large maiine aquaria for control of capsalid monogeneans. It is applied at a concentration of5 mg/L and may remain active for several weeks. Treated water should be run through an activated carbon filter before discharge. Praziquantel can also be administered PO at a dosage of 35-125 mg/kg for up to 3 days or as a short-tern1 bath treatment at a concentration of 10 mg!L for 3 hr. Efficacy has been demonstrated in yellowtail ki.ngfish fed praziquantel at a dosage -1.2"Ai calciun1, whereas laying birds require 3.5%--6% calciwn because of the nutritional demand for laying eggs (a typical egg requires -2 g of calciwn). However, it is important for adult layers to have adequate calciwn to avoid osteoporosis (cage-layer fatigue) and thin-shelled eggs.

LAYING AND REPRODUCTION For laying hens, nest boxes just large enough to fit one "seated" hen are desirable. If eggs are to be collected for conswnption, efforts need to be made to decrease broodiness in the hens. The tenn "broody" refers to a hen that stops laying eggs in order to sit on the eggs, even when no eggs are present. As soon as this behavior is noticed, the hen should be moved to a wire cage. Broody hens can have an aggressive temperament, and caution must be taken during handling. Most hens put into cages become less broody in 2-3 days. Without intervention, hens may remain broody for 3--4 wk. Backyard flocks raised under natmal light will stop laying once hours of daylight become shorter and undergo a molt period lasting 3--4 mo or longer. Artificial lighting may be used for layers to lay eggs during the winter months, which will increase the nun1ber of eggs laid during that period but not the total munber of eggs laid by the hen. Light schedules are usually 13-hr days, or lights on all night. Hens will be stimulated to start laying again as hours of daylight increase, not with continuous lighting. Supplemented lighting increases the risk of cannibalism in birds not individually caged. Chickens will lay eggs for -1 yr before going into a molt. As long as feather loss is not associated with insect infestation, reddened or abraded skin, poor nuttition, or open wounds, an "unusual molt" can be asswned for lengthy or bizarre-appearing feather loss. If desired, this is also the time hens can be culled from the flock. In general, even the best hens will approach only -70% of their former production level in their subsequent production petiod. All hens should molt at least once a year. If the hens do not naturally

BACKYARD POULTRY

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molt, molt can be induced by decreasing hours of light. Incubation and Hatching of Eggs:

Probably the largest deternlinant in deciding wheti1er to buy hatched chicks or hatch within the backyard flock is the desired size of the flock. For small flocks, inexpensive, eas y -to-operate incubators/hatchers are available at fam1 stores or through mail order catalogs. When first starting out, as many as 50"A, of tile eggs may not hatch, thus making egg space a concern if a large hatch is needed. Most home incubators have good temperature control but inadequate humidity control. Chicken eggs can withstand changes in humidity during incubation; however, other species such as turkeys are much more sensitive to poor humidity control. Witil home incubators, temperature should be regulated for at least 2-3 days before the eggs a.re placed. During incubation, the tempera­ ture should be checked twice daily (fluctuations between 98°F and 101 ° F are fine for chicken eggs; temperature require­ ments for other species should be researched before incubation) and the water pan kept full. Eggs (except dark shelled) should be candled at least once during incubation, typically after the first mortality peak at 7-10 days of embryonation. Candling consists of shining a light through the egg to detemline embryo viability by detecting movement of the embryo and presence of blood vessels. Fertile eggs will candle dark except for the air cell (air sac) with visible blood vessels and a live embryo. lnfertiles or "yolker" eggs will candle through with only a slight shadow for the yolk and have no internal structures and no embryonic development. Embryos tilat died with no positive development can also candle this way. Dead or nonviable embryos may have a blood ring around the embryo, caused by the movement of blood away from the embryo after death. Dead eggs can be removed before possibly exploding. Eggs need to be turned -4 ti.mes/day until the last few days before hatch (embryonation day 18 for chicken eggs). It helps to know approxinlate incubation periods of the poultry of interest to gauge when to provide adequate interference for a successful hatch. For example, the incubation period for chickens is 21 days, for Bobwhite quail 23-24 days, for guinea fowl 27-28 days, for ducks 28 days, and for geese 28---33 days. If eggs do not hatch, examination of the dead embryos can yield some clues as to the cause. Conm1on problems include early deaths (infertile eggs, too long or in1proper storage of eggs before incubation, extreme

1819

temperature fluctuation), late deaths but not pipped (extreme temperature fluctua­ tion, poor hwnidity), pipped but dried and stuck to the egg shell (generally poor humid­ ity in late incubation, hatching period, weakened embryos from temperature fluctuations), and pipped but drowned in egg fluids or malpositioned embryos (turning malfunction during incubation). Once the chicks are hatched, they should not be moved until dry and fluffed. Occasionally, chicks will hatch that have not completely absorbed their yolk sac and/or intestines. These chicks have a poor chance of survival, and euthanasia is warranted. If possible, all chicken chicks should be vaccinated for Marek's disease (seep 2849).

VACCINATION For tile small flock owner, vaccination is generally necessary only if U1e birds have had disease problems in tile past, may possibly be exposed to other birds (eg, at poultry shows, meat swaps, or wild bird access), or if new birds are introduced to the flock (open flock). Birds should not be vaccinated for a disease not present in their local area, because this will only introduce new organisms into the flock. Also, a sick bird's inunune system is compromised and tmable to withstand tile stress of vaccination. If certain diseases are a problem in a backyard flock, vaccination may be recommended after veterinary consultation. Ma.rek's disease is present in almost every flock, and vaccination of chickens is stnmgly reconunended in all cases; vaccination is key for control and is inexpensive. Backyard poultry owners may pw·chase chicks from hatcheries and request their chicks be vaccinated at hatch witil serotype 3, or they can vaccinate their own chicks if hatched onsite. Because the virus is ubiquitous and spreads through feather dander, vaccinating birds at hatch before they are most susceptible (2-7 mo) is critical to establish early inunWlity. There are three serotypes of Marek's disease: 1, 2, and 3. Because most backyard chickens are vaccinated only for serotype 3, they may not be fully protected. Vaccination does not prevent infection or shedding of the field virus.

COMMON MANAGEMENT­ RELATED DISEASES Birds are prey aninlals, so early signs of illness may be subtle and difficult to discern. Some early signs of illness include changes in eating and drinking habits; dull featl1ers; soiling of the feathers around nares, vent,

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BACKYARD POULTRY

shoulders, or eyes; swelling around or discharge around the eyes; discharge from the eyes or nares; abnormal feces; favoring or lameness in limbs; or decrease in activity. Cannibalism: Pecking or cannibalism (see p 2873) is one of the most frustrating and common problems to control in floor-reared birds. Certain species such as pheasants and quail are notorious for cannibalism, often leading to individual cages as the only housing option. Certain breeds can be more aggressive than others within specific species. Cannibalism usually does not begin in chicks 1-2 wk old. Clinical MD generally affects birds 4-14 wk old; however, it is not unconunon in older birds, and death loss 1s often sporadic ratl1er fuan explosive. If tumors are found m fue viscera of deceased birds, carcasses should be submitted to a diagnostic laboratmy for differential diagnosis between MD and avian leukosis (seep 2851), anofuer conunon lymphoid tumor disease. Avian leukosis is seen in birds >14 wk old, and tumors are sinular to those found witl1 MD. Avian leukosis has no treatment or vaccination. Infectious Bronchitis: Infectious bronchitis vims (IBV; seep 2909) causes a rapidly spreading respiratory disease in young chicks. Production is reduced and egg shell abnonnalities are seen in laying hens. Certain strains of IBV also clciuse kidney disease. Chicks infected early in life may have pennanent damage to the oviduct, so they do not produce eggs or become false layers (seep 2897). IBV is highly transnus­ sible but most birds recover with supportive treabnent. Antibiotics can be adn1inistered in fue water to prevent secondaJy infection. Vaccines are available; however, backyard chickens are usually not vaccinated unless they come in contact witl1 other chickens. Newcastle Disease: Newcastle disease vims (NDV; seep 2856) aifects numerous species of birds and is the reason for qu31·an­ tine regulations for birds entering the USA. Exotic NDV is highly fatal and is not present in the USA at this time. Past outbreaks have resulted in the slaughter of thousands of birds. Milder forms of NDV are present in the USA and are primaJily characterized

by respiratory disease and a drop in egg production. Mortality is variable aJ1d depends on the strain of the vims. As witl1 infectious bronchitis virus, vaccination is available but is generally givrn to backyard poultry only if exposed to oilier birds. Fowlpox: Fowlpoxvirns(seep 2824) causes crusty and nodular lesions prilnaJily on the unfeatl1ered pmtions of the bird. Occasionally, poxvirus caJ1 cause lesions in tl1e mouth and trachea, causing death clue to suffocation (wet fom1). If the bird recovers, inununity is generally lifelong. Not all pox outbreaks are caused by fowlpox vims but can be caused by related strains such as turkey pox, psittacine pox, quail pox, etc. Strains are usually species specific but can occasionally affect other species (eg, pigeon pox). One strain may not cross-protect witl1 another. Vaccination is available and should be given to flocks on premises with a previous history of pox or with presence of pox in nearby birds. Poxvirns is transmitted through contact of infected lesions with . open wounds and by insect bites (mosqw­ toes), 311d insect control is key to prevent spread. Avian Encephalomyelitis: Avian encephalomyelitis (AE; seep 2888) is seen in chickens, turkeys, pheasants, and quail. It prin1ari.Jy affects chicks 1-3 wk old. Nearly all conunercial flocks are infected, but clinical disease is low because of maternal antibodies. AE can be transmitted vertically in eggs laid between 5 and 13 days after infection and is an enteric infection under natural conditions. The spread is more rapid in floor-raised birds tl1an in cage-raised birds. There is no treatment, and vaccination of breeders (both chicken and turkey) for maternal antibodies to protect tl1e young during early life is critical to prevention. Because many specialty breeders, particu­ larly those that sell stock to an intern1ediate supplier, do not vaccinate, AE is a fairly conunon viral disease in backyaJ·cl poultry. Vaccination should be given after 8 wk of age but by at least 4 wk before production. Bacterial Infections Salmonellosis: In general, Salmonella Pullorw11 (see p 2865) and S Gallinarum (fowl typhoid; seep 2866) cause the greatesli problem for poultry, whereas STyphimu­ riun1 S Enteritidis, S Heidelberg, and S Ke�tucky are important in terms of public healtl1. S Pullorum is egg transmitted, causes a diaJTheal disease in young chicks and poults, and results in high mortality. Adult

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BACKYARD POULTRY

birds are asymptomatic carriers. Diagnosis is based on disease history and isolation of the bacteria. Prevention is achieved by pmchasing birds from a breeder flock that is NPIP certified (National Poultry Improve­ ment Plan) clean of S Pullorum and typhoid. Treatment is not recommended, because it can cause birds to become carriers. Fowl typhoid is seen in chickens, tmkeys, and many other game and wild birds. Fowl typhoid is similar in disease presentation and diagnosis to S Pullorum, although matme birds can show clinical signs of fowl typhoid. Clinical signs are infrequently observed in poultry infected with S Ente1itidis and S 'IyphimUiiUin, although most paratyphoid Salmonella infections are asymptomatic in most poultry. Flocks can be monitored by obtaining egg san1ples and environmental san1ples to cultme tl1e organism. Colibacillosis: Colibacillosis (see also p 2814) is caused by Escherichia coli and is usually secondary to other infections such as infectious bronchitis vims and mycoplas­ mosis. E coli is seen in most species and age groups. A wide variety of clinical signs affecting the respiratory, reproductive, and intestinal systems can be seen. Vigorous adherence to biosecUiity and sanitation progratns can effectively prevent the organism from causing disease. Many antibiotics can be used for treatment, and sensitivity to the antibiotic should be tested. Treatment is usually successful if the disease is in the early stages. Mycoplasmosis {Chronic Respiratory Disease): Chronic respiratory disease in

poultry (primruily chickens and tmkeys) is generally caused by Mycoplasma gallisepti­ cum infection (seep 2841). M gallisepticum is a repmtable disease in tmkeys in select states in the USA. Pathogenicity of M gallisepticum is enhanced by infection with other organisms. Clinical signs of respiratory disease develop slowly in a flock, and feed consumption drops. Infection of the sinuses with pmulent exudate (swollen face) is common in tmkeys. Serology and isolation and identification of the organism can be used for diagnosis. Prevention, as with the salmonellae, rests with establishment of a clean flock by eliminating the infected flock, completely sanitizing the premises, and obtaining cleru1 stock. Vaccination is available on a state-by-state basis. Treatment is expensive, and the disease often recurs after treatment is stopped. Other inlportant mycoplasmas in poultry include M synoviae

1823

(infectious synovitis) and M meleagridis (venereal infection ru1d airsacculitis). Fungal Diseases Aspergillosis: Aspergillosis (see also

p 2901), or brooder pneumonia, is seen in many poultry and other species of birds. Birds 0.9 mg/dL in ferrets. Ferrets require high levels of fat and protein in the diet and should be fed conunercial fen-et food or high-quality cat or kitten food. Most adult ferrets have a large spleen. this is usually caused by extramedullary hematopoiesis and is nonpathogenic; ultrasonography and aspiration can be used for a definitive diagnosis. Vaccination: Ferrets are vaccinated annually for rabies and canine distemper. There is one FDA-approved rabies vaccine for ferrets in the USA. It should be given to ferrets >16wk old and repeated annually. If this vaccine is w1available, a recombinant vaccine should be substituted. Canine distemper vaccines for ferrets should be of chick embryo or recombinant origin. Vaccines of mink or ferret culture (eg, most multivalent vaccines for dogs) should not be used, because they may cause seroconve1° sion and disease. There is currently one FDA-approved distemper vaccine in the USA for fen-ets. Ferrets should be

vaccinated at -8, 10, and 12 wk of age and then yearly. Vaccine reactions occur frequently in ferrets; vaccinated anin1als should be monitored for 20--30 min after vaccination, and only one vaccine (ie, rabies or distemper) should be given at a time. Fen-ets raised commercially are of� ten vaccinated for Clost1idium botulinum type C at 6--8 wk old.

INFECTIOUS DISEASES Bacterial Diseases: Helicobacter mustelae is found in the stomach and

duodenun1 of all ferrets after weaning. It is an oppo1tw1istic pathogen and can induce chronic, persistent gastritis and ulcer fom1ation similar to the disease in people. Gastric lymphoma may occw· in chronic cases. Clinical signs include inappetence, vomiting, bruxism, diarrhea, melena, and hypersalivation.Lethargy, weight loss, and dehydration can also occur. These animals may be painful on cranial abdominal palpation because of the ulcers induced or enhanced by tl1e presence of this bacteriwn. Definitive diagnosis requires examination of tissue from surgical or endoscopic biopsy but is not commonly pe1fonned because of the ubiquitous nature of this organism in the ferret GI tract. Silver stains and urease tests should be performed on the biopsy specimens when attempting to determine a definitive diagosis. A molec­ ular assay is available for fecal samples. Treatment is with multidrug regimens, including an10xicillin (2Q mg/kg, PO, bid), metronidazole (20 mg/kg, PO, bid), and bismuth subsalicylate (1 mL/kg, PO, bid). Clarithromycin (25 mg/kg/day, PO) and omeprazole (1 mg/kg/day, PO) can be used for refractory cases. Treatment is usually for 21 days. Because of the op­ portunistic nature of this pathogen, it is in1portant to look for underlying problems such as gastroenteritis, foreign bodies, or stress. Treatment for Helicobacter is com­ monly initiated when gastroenteritis or foreign bodies are diagnosed or when a gastrotomy is pefom1ed. Lawsonia intracellularis can cause a proliferative bowel disease, especially in younger ferrets. Signs include diarrhea,

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FERRETS weight Joss, and rectal prolapse. Treatment is with chloramphenicol (25 mg/kg, PO, bid) for 14-21 days. Salmonellosis in fen-ets is rare but associated with feeding raw or undercooked meat or unpasteurized milk. Signs include bloody diarrhea, cof\iunctivitis, and anemia. Salmonella Typhimurium, S Newport, and S Choleraesuis may be involved. 'freatment is with aggressive supportive care and antibiotics. Ferrets are susceptible to Mycobacterium avium,M bovis, and Mycobacterium tuberculosis. Intradermal testing is not reliable. Bacterial cystitis is rare in ferrets and is usually associated with urolithiasis and prostatomegaly. Escheri­ chia coli, Staphylococcus aureus, and Proteus spp are most commonly identified. Bacterial pneumonias in ferrets are caused by Streptococcus zooepidemicus, Mycobaclerium spp, and gram-negative bacteria such as E coli and Klebsiella pneumoniae. Other bacterial infections are similar to those seen in other carnivores.

Viral Diseases: Fen-ets are susceptible to canine distemper virus. Transmission is by aerosol or exposure to infected secretions. Clinical signs begin 7 1-0 days after infection and start as fever and dermatitis on the chin and inguinal area, progressing to anorexia, erythema of mucus membranes, and mucopurulent ocular and nasal discharge. Brown crusts on the face and eyelids and hyperkeratosis of the footpads also occur. Respiratory signs develop and progress rapidly. Diagnosis is by history, clinical signs, and positive immunofluorescent antibody testing or histopathology. Mortality is close to lO()OA, and typically occurs 12-14 days after infection. The human influenza virus causes fever, lethargy, anorexia, nasal discharge, sneezing, and depression in fen-ets. Treatment is supportive and includes antibiotics for secondary infections, antihistamines, and an1antadine (6 mg/kg, nasally, bid). Recovery is usually within 7 1-4 days. Two coronaviruses cause disease in feJTets. The fen-et enteric corona.virus causes epizootic catarrhal enteritis. This disease is highly transmissible and is often brought into a group of fen-ets by an asymptomatic juvenile animal. Clinical signs begin 2-14 days after introduction of the new feJTet or exposure through fomites and include anorexia, vomiting, green or mucoid diaJThea, melena, dehydration, lethargy, and weight loss. The disease is most severe in older fen-ets, which may take months to fully recover. The virus causes blunting of the intestinal villi and conse-

1825

quent maldigestion and malabsorption. Definitive diagnosis is difficult, although scanning electron microscopy of the feces may identify corona.virus. Increased ALT and alkaline phosphatase may occw· secondary to hepatic lipidosis. Treatment is suppo1tive and includes fluids, nutritional suppo1t, broad-spectrum antibiotics, and GI protectants. Prevention is by quarantine of new ferrets, thorough cleaning of new bedding and toys, and washing hands and changing clothes after hanclling other fen-ets. A second related corona.virus called ferret systemic coronavirus causes a systemic pyogranulomatous inflammato1y disease resembling the dry form of feline infectious peritonitis. This disease is seen in young ferrets (average age 11 mo) and is progressive throughout several weeks to months. Clinical signs include anorexia, weigh loss, diarrhea, and enlarged intra-abdominal and, Jess commonly, peripheral lymph nodes. Hypergammaglob­ ulinemia, anemia, and CNS signs can be seen as the disease progresses. This disease was initially called disseminated idiopathic myofasciitis because of the white nodules found in many tissues on necropsy. These nodules are pyogranulomatous inflanmia­ tion and involve many organs, including peritonewn, adipose tissue, viscera, and blood vessels. A pyogranulomatous pnewnonia has also recently been reported. Treatment is supportive with immunosup­ pressants such as prednisolone and anecdotal reports of use of polyprenyl il1m1w1ostin1ulants, which have resulted in some increase in swvival til11e. Average survival time is -2 mo. Aleutian disease is a parvovirus originally seen in mink, but at least two distinct ferret strail1s of the virus have been identified (seep 1872). The virus causes ilnmune complex deposition in organs, which results in a variety of nonspecific clinical signs such as progressive weight Joss, weakness, ataxia, hepatomegaly, and splenomegaly. A severe hyperganm1aglobu­ lil1emia is tl1e most consistent finding on blood work. A preswnptive diagnosis is based on clillical signs and hyperglobuline­ mia. The two most common tests for the virus antibody are counterinummoelectro­ phoresis and inmlunofluorescent antibody tests. Definitive diagnosis is difficult, because many apparently nom1al feITets have positive titers. The organism has been found in the urine, feces, and blood of symptomatic and asymptomatic anin1als. Treatment with anti-inflammatories and inmltmosuppresants such as prednisolone

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1826

FERRETS

and cyclophosphamide can be considered and may have clinical benefit. Treatment of infected mink kits with gamma globulin­ containing Aleutian disease virus antibody has decreased mortality rates, but this treatment has not been attempted in ferrets. There is currently no vaccine available for this disease in ferrets. Fungal Diseases: Ferrets are susceptible to Microsporurn canis and 1)'ichophyton mentagrophytes. Transmission is by direct contact or fomites and is often associated with overcrowding and exposure to cats. Infection is more conm1on in kits and young ferrets and is often seasonal and self-limit­ ing. A pyogranulomatous dermatitis and fungal pododermatitis has been associated with Microsporum nanum. Other fungal diseases in ferrets include cryptococcal meningitis and blastomycosis causing granulomatous meningoencephalitis. Fungal pnew11onia is uncommon in ferrets but can be caused by Blastomyces dermatitidis and Coccidioides immitis in endemic areas. Cryptococcosis from CryptococcitS bacillisporus and C neo­ j'(nmans var grubii has been diagnosed in ferrets. Signs include pneumonia, pleuritis, rhinitis, and regional lymph nude enlargement. Parasitic Diseases: Ear mites are the most conunon ectoparasite in ferrets and are caused by Otodectes cynotis. The same ear mite is found in dogs and cats, and it can be passed between species. Diagnosis and treatment are as for dogs and cats (see OTITIS EXTERNA, p 527). Fleas are also common in ferrets and can be transmitted between ferrets and other houscliold pets. Diagnosis is by visualization, and treatment is the same as for dogs and cats (see FLEAS AND FLEA ALLERGY DERMATITIS, p 880). Many of the long-acting topical treatments, such as fipronil, last longer in ferrets because of the increased sebwn in the coat. Mange in ferrets is caused by Sarcoptes scab'iei and can be seen as a generalized dermatitis or can be limited to the feet, toes, and pads in a pedal form unique to ferrets. Heartworm disease, caused by DirojUaria immitis, can be found in ferrets, especially if given outdoor access in endemic areas. Disease can be caused by even a single wonn. Clinical signs include lethargy, coughing, dyspnea, and ascites. Ferrets are typically infected with a very small nun1ber of worms (1-20), making diagnosis difficult. Echocardi­ ography is warranted, because the parasites often obstruct blood flow and cause right-side heart failure. Echocardiography may also be

helpful in identification of the worms in the right ventricle, pulmonary arteries, and vena cavae. Peripheral microfilaremiais uncom­ mon in ferrets; therefore, antigen testing is more beneficial. Treatment using Jongtem1 antithrombotic drugs and adulticides can be done but may cause problems. Low-dose ivennectin (0.05 mg/kg, SC, monthly until clinical signs and microfilaremia resolve) is the current reconunended treatment (see I-IEARTWORM DISEASE, p 127). Coccidiosis can cause disease in young ferrets including diarrhea, lethargy, and rectal prolapse. Diagnosis and treatment are similar to those in dogs. Rectal prolapse can also occur with coccidiosis and usually resolves after treating tl1e underlying disease. Topical hemorrhoidal creams may be helpful.

NEOPLASIA Cutaneous mast cell tumors are probably tl1e most conm1on nonendocrine tumor in ferrets. These twnors can appear anywhere on the body but typically affect the trunk and neck. The tun1or appears as a raised, in·egular, and often scabbed mass. Systemic signs are rare, but the tumors may bleed when scratched. Treatment is by excision. Local treatment with strontiun1 may also be beneficial. 4'ffiphoma is common in ferrets and can affect many organ systems, including the lymph nodes, spleen, liver, heart, thymus, and kidneys. Disease of the spine and CNS has also been seen. Lymphoma of young ferrets is often rapidly progressive, whereas it is often a chronic disease in adults. Clusters of lymphoma have been seen in related or cohabitating ferrets, and a viral agent is suspected in those cases. Diagnos­ tics should include a CBC, chemistry panel, radiographs, ultrasonography, and aspirates of any suspected tissues. Treatment protocols for ferrets have not been standardized but can include removal of the neoplastic tissue if possible, chemotherapy, and/or radiation therapy. Inununosuppres­ sion is a conunon problem witl1 chemother­ apy in ferrets, and frequent CBCs are inlperative with any treatment protocol. Chordomas and chondrosarcomas have been repo1ted in ferrets. Chordomas typically appear as firm masses on the tail. They may become ulcerated from dragging on the ground but otherwise cause few problems. These tumors have also been reported at the cervical region, causing paresis and ataxia. Surgical removal is suggested when possible. Chondrosarco­ mas can develop anywhere along the spine,

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FERRETS ribs, or sternum and tend to cause spinal cord compression and associated clinical signs. Treatment should include removal, if possible. Splenomegaly is common in adult ferrets and is usually caused by extran1edul­ lary hematopoiesis; however, lymphoma and hemangiosarcoma can occur. An irregular or firm spleen should be investi­ gated with ult:rasonography and aspiration.

ENDOCRINE DISORDERS Insulinomas are very common in ferrets >2-3 yr old. These functional trunors of the pancreatic (3 cells cause increased insulin levels, resulting in hypoglycemia and its associated clinical signs such as wealrness, lethargy, poste1ior paresis, hypersalivation, bruxism, and seizures. Diagnosis is based on demonstration of hypoglycemia and corresponding nom1al or increased insulin levels. Other blood tests are usually nom1al. Ultrasonography is only occasionally useful in demonstrating these pancreatic masses. Medical and surgical treatments are possible, but there is no cure, and owners should be made aware of the chronic and progressive nature of this disease. Surgical treatment involves removing discrete tumors via nodulectomies or partial pancreatectomy. Microscopic tumors within the entire pancreas are common; therefore, removal of the entire tumor is unlikely. A period of euglycemia occurs after surgery in some cases, but most cases require continued medical treatment. Major benefits of surgery are decreased severity of signs, ease of management, and moderately increased survival time. Medical management includes use of prednisone (0.&--2 mg/kg, PO, bid) and diazoxide (5-30 mg/kg, PO, bid) to counteract the effects of the tumor; however, this does not affect the tumor directly. Prednisone increases resting blood glucose levels and down-regulates peripheral insulin receptors, whereas diazoxide decreases insulin release from the (3 cells and competes at peripheral insulin receptors. These drugs can be used independently or synergistically. 'Iypically, prednisone is used first until the dosage approaches 2 mg/kg and then diazoxide is added. Medical treatment is lifelong, and glucose levels should be monitored &--7 days after changing doses and at least every 3 mo afterward. Hyperadrenocorticisrn in ferrets is caused by excessive secretion of the sex honnones progesterone, testosterone (in the fonn of androstenedione), and estrogen by the zona reticularis of the adrenal gland. It can be seen in ferrets as young as 1.5 yr

1827

old. The most common clinical sign is hair loss beginning on the tail and rump and progressing up the flank and head. In females, a swollen vulva and enlarged marnillae may also be seen, whereas males may develop aggression and stranguria secondary to prostatic enlargement. Bone marrow suppression may be seen in either sex, with severe hyperestrogenemia. A presw11ptive diagnosis is made after history and physical examination. The enlarged adrenal glands are often palpable cranial to either kidney. CBCs and chemistry panels are typically nonnal. Radiographs are not useful, because the masses do not calcify as commonly as in other species. Ultrasonog­ raphy can demonstrate enlargement of tl1e gland(s). Definitive diagnosis requires measurement of the three sex honnones, which can be perfonned in a panel (at University of Tennessee). Medical and surgical treatments exist. Sw·gical removal of the adrenal gland(s) is more likely to be curative than medical management, but there is still a recurrence rate of -4QOA, after surgery. The left gland is easier to remove, because the right gland is closely associated with the caudal vena cava. If both sides are affected, a subtotal adrenalectomy can be pe1ionned. Histology of these glands may reveal hyperplasia, adenoma, or adenoca.rcinoma. Functionally, all three grades are similar, and metastasis is unlikely. Hypoadrenocorticism may develop if both adrenal glands are completely or partially removed. This may be treated with rnineralocorticoid and glucocorticoid supplementation. Medical management of hyperadrenocorticism is ainled at reducing the clinical signs but does not affect the adrenal tw11or itself. Leuprolide acetate is the most common drug used. The mechanism is not completely understood but is probably related to down-regulation of peripheral honnone receptors. Leuprolide is a repositol fonnulation of a GnRH agonist that is fonnulated in 1-mo (100-400 mcg, IM) and 4-mo (2-4 mg, IM) preparations. Owners should be advised that this is a lifelong treatment to control the clinical signs of tlle disease. Recently, some clinicians have treated hyperadrenocorticism medically only during breeding montlls, typically November to March. Deslorelin acetate, a sinillar GnRH agonist, is also available. This is a longer­ acting inlplant that lasts 10---17 mo. This drug is well tolerated by ferrets. Melatonin can also be used at 1 mg per ferret per day, orally or in an injectable, repositol fonnulation, which is reported to last 4 mo. This drug cow1teracts tl1e alopecia and may help witll oilier signs as well, but, like leuprolide, is

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FERRETS

only symptomatic treatment. Drugs used to control sex hormone levels in people are beginning to be used in fenets and show promise in controlling clinical signs.

OTHER NONINFECTIOUS DISEASES Gastric foreign bodies are common in ferrets because of the animal's inquisitive nature. Foreign bodies are usually soft rubber or plastic items but can also be tlichobezoars. Clinical signs include anorexia, bruxism, hypersalivation, cranial abdominal pain, dianhea, and melena. Vomiting is more common with gastlitis than with foreign bodies. Diagnosis is with plain or contrast radiography. Treatlnent involves surgical or endoscopic removal. Gastlitis should be ti·eated after removal of the foreign body.

Dilated cardiomyopathy can occur in ferrets, usually those> 4 yr old. Clinical signs can be similar to those of insulinoma, so both should be excluded when examin­ ing a ferret with lethargy, wea.kpess, ascites, increased respiratory effort, or exercise intolerance. Diagnosis is by radiography and echocardiog:raphy. Treatlnent is based on echocardiographic abnormalities and includes furosemide, digoxin, enalapril, benazepril, and pimobendan. A fonnulary should be consulted for dosing instructions. Renal disease in ferrets is similar to that in other species. Renal cysts are common in adult ferrets and usually do not cause a problem unless present in large numbers. Uroliths can develop in ferrets fed diets high in plant proteins and are usually composed of struvite.

HEDGEHOGS Hedgehogs are in the family Erinaceidae, within the order lnsectivora. The centi·al African hedgehog (Atelerix albiventri.s), also known as the white-bellied, four-toed, or African pygmy hedgehog, is native to dry, open habitats in central and eastern Africa. They are nocturnal and very active, jogging for miles in search of inve1tebrate prey. In the USA, it is illegal to own a hedgehog as a pet in some states and municipalities; in other states, a permit is required. Addition­ ally, a USDA permit is required to breed, transport, sell, or exhibit hedgehogs.

Anatomy, Physiology, and ehavior:

The dorsum is covered in a dense coat of keratin spines; each spine has a basal bulb that firmly attaches it within the follicle, with a nanowed po1tion at the skin surface. Healthy spines are difficult to pull from the follicle without breakage. The spined skin has a thin and hairless epidern1is and a thick, fibrous dermis wilh much fat and few blood vessels. A wary hedgehog will raise the spines and crouch. If a hedgehog is frightened, contraction of the pa.nniculus muscle pulls the loose spiny skin over the entire body. The pa.nniculus is thickened at the rim to fonn the orbicularis, a purse­ string-like muscle that closes the spined skin over the animal. For selected physiologic data for Af1ica.n pygmy hedgehogs, see TABLE 10. Hedgehogs have brachydont teeth. The fast incisor in each quadrant is large

and projects forward, and there is a gap between the maxillary first incisors. The stomach is simple, and a vomiting reflex is present. The male has a conspicuous prepuce that opens mid-abdomen. There is no scrotal sac; the testes are located in a para-anal recess surrounded by fat and can be palpated in reproductively active males. The female urogenital opening is a few millimeters cranial to the a.nus. The uterus is bicornuate with a single cervix and no uterine body. Hedgehogs are polyestrous and breed throughout the year in captivity. Ovulation is believed to be induced, and sterile matings with pseudopregnancy may occur. Hedgehogs are born hairless, with closed eyes and ea.rs; at birth the spines are covered by a membrane that is removed within the fast few hours oflife. Hedgehogs are a.dept at climbing, digging, swimming, and jogging. While they have sensitive olfaction and heaiing, their sense of vision is not as well developed. Foraging hedgehogs norn1ally emit a variety of snuffling sounds; agitated hedgehogs make a loud hissing sound that may be punctu­ ated with various puffing and cough-like sounds. With intense disti·ess, a screain may be emitted. With patience, most hedgehogs lea.111 to accept handling. Hedgehogs demonsti·a.te a unique behavior called self-anointing, or anting. This behavior may be elicited by a variety of substances, paiticulai·ly those with a strong odor. The hedgehog takes the material into the mouth,

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HEDGEHOGS

•t#=iii•••

1829

PHYSIOLOGIC DATA FOR AFRICAN PYGMY HEDGEHOGS

Average body weight

Male : 400-600g Female: 300-400g

Life span

Average 4-6yr, may live to 8 yr

Body temperature

95.7° -98.6° F ( 35.4° -37.0°C)

Adult dental formula

2(I 3/2:C1/1:P 312:M 3/3) = 36(variations have been noted )

GI transit time

12-16hr

Heart rate

18 0-28 0bpm

Respiratory rate

25-50bpm

Age at sexual maturity

2-3mo

Reproductive life span

Male: throughout life Female: 2-3yr

Gestation

34-37days

Litter size

3-4 (range 1-9)

Birth weight

10-lSg

Eyes open

14-lSdays

Deciduous teeth eruption

Begins on day 18; all deciduous teeth erupted by 9wk

Permanent teeth eruption

Begins at 7-9wk

Age at weaning

5-6wk (start eating solids at 3wk )

mixes it with frothy saliva, and applies the mixture to its spines with the tongue.The purpose of this behavior is unknown.

MANAGEMENT

Housing: Wild hedgehogs are solitary; as pets they are usually maint.ained in individual cages. Some fanciers successfully house multiple animals together, but this can lead to disproportionate feeding and injUiies from fighting.Healthy hedgehogs are very active; 2 x 3ft are minimal floor dimensions.Hedgehogs are able to climb and can escape through small holes, so the cage must be secure and lidded.Glass tanks and plastic-bottomed cages with wire walls are suitable, provided that the wire spacing is sufficiently close. Widely spaced wires can lead to limb entrapment or death if the hedgehog's head becomes ensnared by its spines.A hiding place is essential.The cage substrate should be soft and absorbent. Recycled newspaper bedding is a good choice; aspen shavings, alfalfa pellets, and hay are other options.Wire, cedar, corncob, and dusty or scented substrates are not recommended, and cloth bedding poses a risk of limb entrapment. The substrate should be 3-4in.deep to allow for digging.

Ambient temperature should be 72° -90° F (22° -32°C); 75° -8 5° F ( 24° -29°C) is optimal. Hedgehogs may go into a torpid state if too cool or too wann; this is believed to be unhealthy for pet hedgehogs.A heating pad placed UI1demeath the enclosure or a ceramic reptile heater may be used.Low hUinidity ( SOOA, of the twnors were malignant. Prolifera­ tive uterine tun1ors or polyps ru·e common and ru·e associated with vaginal bleeding, hematuria, and weight loss. Ovariohys­ terectomy allows prolonged survival of hedgehogs with uterine twnors. Some sarcomas have been associated with retro­ viral infection. Signs depend on the location and severity of disease and may include palpable masses, weight loss, anorexia, lethru·gy, diarrhea, dyspnea, and ascites. Diagnosis is based on cytology or h.istopathology. Diagnostic imaging and blood testing may help detemline the extent of the disease and establish a prognosis. Treatment generally includes surgical excision and supportive cru·e, although other treatment modalities may be helpful. Not eve1y mass in pet hedgehogs is neoplastic; for exrunple, abscesses, bone cysts, papillomas, and ute1ine polyps are seen. Neurologic Diseases: New-ologic signs

(particularly ataxia) may be caused by torpor, hepatic encephalopathy, postprutwn eclrunpsia, malnutrition, traun1a, interve1te­ bral disc disease, toxins, infarcts, infectious causes (eg, parasitic migration, rabies), otitis media, demyelination, polioencephalomalacia, or neoplasia. Hedgehogs kept in cold (or sometimes excessively high) temperatures may enter a state of torpor or dormancy. In this state, the hedgehog has a greatly dinlinished response to stimulation, decreased heart and respiratory rates, and possibly increased susceptibility to infection. Do1n1ancy cru1 last for several weeks, during which the hedgehog may have periods of activity with ataxia. Hypocalcemia may result from post­ pattw11 eclrunpsia, malnutrition, or for unknown reasons, and usually responds to calciwn supplementation. Inte1vertebral disc disease has been repo1ted. Both cervical and lwnbar lesions have been identified; multiple discs were affected in each of these hedgehogs. Radiographic findings included spondylosis, disc-space natTowing, and disc mineraliza­ tion. Necropsy findings included degenera­ tion of the nucleus pulposus and armulus fibrosus, dorsal extrusion of disc material, and mineralization of the nucleus pulposus.

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HEDGEHOGS

One case had evidence of fibrocartilaginous embolism. Temporary improvement with corticosteroids has been described in two cases of intervertcbral disc disease. Vestibular signs may be caused by otitis media/internal or central neurologic disease. Demyelinating paralysis (wobbly hedgehog syndrome) occurs in as many as 100/o of pet hedgehogs. Onset can occur at any age but is more common in animals 18 mo old and weigh 40 kg (alpaca) or 90 kg (llama). When a female is truly receptive, she will usually assume a position of sternal reclllllbency (cushing) witllin seconds to a few minutes after introduction of a male and allow the male to breed. While mounting, the male will typically begin a vocalization described as "orgling." The voltune of tile ejaculate is relatively small (2-5 mL) and is mostly deposited directly into the body of the uterus after cervical dilation. Ejaculation occurs over an extended period of time. An ovulation induction factor in the semen stin1ulates reflex ovulation -24-30 hr after ma.ting. A functional corpus lutetun (CL) is present 2-3 days after ovulation. The fertilized oocyte is usually found in the uterus by day 7 after ma.ting, with in1pla.ntation occurring by -30 days of gestation. The type of placentation is diffuse epitheliochorial, developing in both horns. Altl1ough ovulation occurs from eitller ovary, uniquely, -95% or more of the pregnancies are carried in tl1e left horn. Live birtl1s of twins are extremely uncommon, with most twin pregnancies being resorbecl or aborted early in gestation. A female with a fw1ctional CL will aggressively refuse tile male's efforts to mount. An indication of pregnancy is the female's rejection of the male if he is reintroduced >15 days after tile initial

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LLAMAS AND ALPACAS

breeding. Progesterone concentrations of >1 ng/mL are typical in females with a functional CL and can be used for confirma­ tion of both ovulation at 6--9 days after mating and of pregnancy at >21 days after mating. Persistent CL are periodically seen and account for most false-positive results when using serum progesterone for pregnancy confinnation. Rectal palpation for pregnancy diagnosis is practical in llamas at >45 days of gestation. It is usually not possible to safely perform rectal palpation in alpacas, unless the palpator has small hands. Pregnancy can positively be diagnosed by transrectal ultrasound from -28 days of gestation, although it is possible to be suspicious as early as 10-12 days based on presence of fluid and to be reasonably sure by day 21 when a hyper­ echoic "embryo" is seen. Ultrasonographic transabdominal approach from 45-60 days can be expected to produce positive results. Nom1al gestation in camelids is -342 ± 10 days, with alpacas being somewhat shorter. Most normal birtl1s (>70%) occur in the morning. Dystocias due to excessively large c1ias are rare. There are few reliable indications of pending delivery. Stage I labor typically lasts 1-6 hr and may be accompa­ nied by increased frequency of urination, increased "hwnming," and separation from the herd. Stage II labor is rapid (typically l ng/mL) 7 days after copulation or hormonal

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LLAMAS AND ALPACAS

treatment is indicative of CL formation. Although persistent CL have been identified, they are relatively rare. Prostaglandin treatment will result in regression of a persistent CL and abortion throughout gestation. Induction of parturition with prostaglandins or glucocorticoids is not reconunended. Rapid death of llamas and alpacas has occurred after prostaglandin therapy, especially at high doses and when administered by other than SC route.

HERD HEALTH Neonatal Care: Crias should be on their feet and attempting to nurse within 2 hr after birth and every 1-2 hr thereafter for the first few days. While weight gain for the first 24 hr postpartum may be minimal, thereafter llamas should gain 250-500 g/day and alpacas 100-250 g/day. Healthy crias should approximately double their birth weight by 1 mo of age. Routine cria care should include weighing and single dipping the navel in 7% tincture of iodine or 0.5% chJorhexidine three times during the first 24 hr after birth. If appropriate for the area, supplemental seleniw11 could be provided by injection (0.5 mg for alpacas, 1 mg for llamas). At birth is an ideal time to take a blood sample if there is any concern of failure of passive transfer of colostral antibodies. Having a baseline sample to measure PCV and total proteins to compare with a subsequent sample at 24 hr will provide valuable infom1ation regarding failure of passive transfer and hydration. Parasite Control: Parasite control pro­ grams vary according to climatic condi­ tions, population density, and parasite load, and should be developed according to local conditions. No drugs have been approved for use in SACs. However, anthelmintics that are generally recognized as safe and effective include ivem1ectin, pyrantel pamoate, and fenbendazole. Parasite resistance has developed in all ruminant species, making it necessary to develop a strategic dewom1ing program, particularly in locations where the meningeal wom1 is present. Liver flukes can be a significant problem. Control with clorsulon or albendazole is usually effective, although repeated clorsulon treatment every 6-8 wk may be necessary. Vaccinations: Most vaccination protocols for SACs have been empirically derived. Most aninlals should receive Clostridium

pe1fringens type C and D vaccinations and

tetanus toxoid. In regions where liver fluke (Fasciola hepatica) infections or snake envenomations are a problem, use of polyvalent vaccines against C novyi, C septicum, C sordellii, and C chauvoei are warranted. One successful approach has been to give an initial vaccination at 3 mo of age, a booster 30 days later, and annual boosters thereafter. Llamas and al­ pacas are inununocompetent at birth, so neonatal vaccination can begin in the first week of life, followed by two boosters at 3-wk intervals. Abortions secondary to Leptospira spp infections are regionally a problem and can usually be prevented using an initial vaccination, followed by boosters twice a year. Killed rabies vaccines have been used with unknown efficacy in endemic areas. Any attempt to control other viral diseases (including West Nile virus infection) should only involve use of killed vaccines. Dental Development and Care: The dental pad of llamas and alpacas is similar to that of a cow. At birth, the first two pairs of lower incisors are nonnally through the gum line; lack of eruption is one indication of prematurity. The central, middle, and lateral mandibular deciduous incisors are replaced at -2-2Y2, 3-3Y2, and 4--6 yr, respectively, although determining age by the teeth is notoriously inaccurate in these species. A unique feature of SACs is the develop­ ment of the upper 13 and upper and lower canine teeth on both sides into "fighting" teeth that may grow to >3 cm long. The teeth can cause serious damage to other males during fights and usually need to be cut flush to the gum with obstetrical wire or a grinder beginning with eruption at 18-24 mo of age and repeated as needed in intact males. If castration is to be performed, eruption of the fighting teeth signals an ideal time to schedule both procedures. Growth of fighting teeth usually stops after castration. Fighting teeth in most females barely penetrate the gurnline and seldom, if ever, need to be cut. Tooth extraction to avoid periodic trimming is impractical because of very deep, curved roots. The incisors are open-rooted in alpacas and continue to grow throughout life. Poor occlusion of the incisors and dental pad necessitate periodic tooth trimming and appears to be more of a problem in alpacas than in llan1as. Cheek teeth are rooted, normally sharp, and do not require regular

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LLAMAS AND ALPACAS

floating. Premolar and molar occlusion should be checked and problems corrected in older animals exhibiting difficulty in chewing or weight loss. Abscessed lower second premolar and first and second molars are seen as a hard, well-developed swelling on the lateral surlace of the mandible over the affected teeth. A draining tract may or may not be present. The area is usually not painful on palpation, and most animals maintain body condition. No bacterial agent has been consistently isolated from the abscesses. Prolonged antibiotic therapy is palliative, although rarely curative. Tooth extraction usually requires making a lateral incision over the affected teeth, splitting the tooth because of the divergent roots and repelling the tooth into the oral cavity. Care should be taken during extraction to avoid mandibular fracture.

Nail Trimming: Some animals rarely need foot care, whereas others require nail trimming every 2--3 mo. Diet, genetics, and environment likely play a role. The nails should be trimmed flush with the bottom of the pad. Occasionally and especially with overgrown toes, "quicking" may occur but generally is inconsequential. DISEASES Congenital and Inherited Anomalies Although few congenital anomalies have conclusively been shown to be genetic in origin, it is assumed that defects inherited in other species are probably inherited in SACs as well. Accordingly, this should be considered in breeding decisions. Facial and cardiac defects are reported to be the most frequent inherited anomalies. A historically narrow gene pool is likely the reason that congenital defects are relatively common in SACs. Affected individuals commonly have more than one defect. Choanal atresia, a condition caused by failure of the inner nares (choanae) to open during embryologic development, is the most widespread congenital defect. It can be unilateral or bilateral and may result in complete or partial blockage. Accord­ ingly, the primary clinical presentation is a variable degree of respiratory distress in the neonate. Distress becomes more apparent during nursing, and crias com­ monly gasp as milk is inhaled. Surgical correction is not recommended. Wry face is characterized by a slight ( 60° ) lateral deviation of

1851

the maxilla The mandible may or may not have a similar deviation. When severe, occlusion of the nares and lack of apposi­ tion of the incisors and dental pad usually necessitate euthanasia of the cria. There appears to be a relationship of this defect to choanal atresia, in that they occasionally occur together. Ocular and ear conditions include juvenile cataracts (seen occasionally), blocked nasolacrimal ducts, and an association between blue eyes and deafness in some lines of white anin1als. Fused (tip or base) and short ("gopher") ears are recognized heritable defects, the latter appearing to be a dominant trait. Cardiac defects are relatively common, with ventricular septa! defects heading the list. Numerous musculoskeletal defects have been identified, including syndactyly and polydactyly. Arthrogryposis, rotated talus, angular lin1b deformities of the front limbs, and tendon laxity are also seen. Other congenital anomalies identified in llamas and alpacas include atresia ani, atresia coli, umbilical hernias, and several different types of tail defects, including a pronounced lateral deviation of the tail at the base. Urogenital defects are much more common in SACs than in other species. Significant defects in females include uterus unicornis, hypoplastic ovaries, double cervices, segmental aplasia of the vagina or uterus, and clitoral hypertrophy suggesting intersex conditions. Unilateral absence of a kidney is periodically seen, commonly in association with choanal atresia. Total absence of kidneys has also been seen. Congenital conditions in males include hypospadia, retained testicles, testicular hypoplasia, persistent frenulum, ectopic testicles, and corkscrew penis.

Bacterial Diseases Brucellosis, tuberculosis, and Johne's disease (paratuberculosis) have been identified in SACs, although the naturally occurring incidence of these infections is low. There are reported cases of both type C and D Clostridium perfringens, which has prompted the use of toxoid vaccination as a routine measure in most herds. Although SACs are not apparently highly susceptible to tetanus, most herd vaccinations using the CID toxoid include tetanus toxoid. C perfringens type A is a very important pathogen under stressful circumstances, especially in Soutl1 America, and results in a high death rate in crias 25 µmol/L) and enzyme concentrations (no1mal, alkaline phosphatase 15-121 nJ/L and AST 66-235 nJ/1) are also diagnosti­ cally useful. Hepatic lipidosis is a relatively conunon problem in SACs. Clinical signs associated witl1 liver failure in other species are frequently seen, altl10ugh acute death without prior indication of pending problems also has been reported. The cause is not clearly established, but stress and/or abrupt decrease or change in food consumption appear to play a role. Treatment is symptomatic. Mortality in untreated animals is frequently high.

Small- and Large-intestinal Diseases:

Diarrhea is relatively tmcommon in llamas and alpacas. Shortly after birth, SAC crias may experience a mild diarrhea due to abundant dam nillk production, essentially a substrate purge. The primary recognized infectious causes of diarrhea in neonates include rotavirus, coronavirus, crypto­ sporidia, and enteropathogenic strains of Escherichia coli. Some crias also have a transitory diarrhea 2-3 wk after birth, at about the time they experience new food matter. At this same time, some crias develop colic signs due to blockage in tl1e spiral colon. Diarrhea in older neonates is more likely associated withEimeria spp infection, especially associated with the stress of weaning. Identified causes of diarrhea in older animals include Yersinia pseudotuberculosis, Salmonella spp, Giardia spp, and Cryptosporidium parvum. Treatment options are the same as for other species (ie, fluid and electrolyte replacement and appropriate antibacteri­ als). Diarrhea in adult SACs is relatively rare but often accompanies a change of feed. Serious conditions characterized by diarrhea include eosinophilic enteritis, infection with Eimeria macusaniensis or Mycobacterium paratuberculosis, or severe nematode parasitism. Compared with that in cattle with Johne's disease, the clinical course in SACs tends to be short and fatal. When diagnosed by fecal examination,

1854

LLAMAS AND ALPACAS

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E macusaniensis must be promptly

treated, because infection can cause marked debilitation. Although variable, current therapy recommendations include oral ponazuril followed by parenteral sulfadimethoxine. Lymphosarcoma is the only neoplasia found with significant frequency in SACs. It can occur as either a juvenile lymphoma or a primitive malignant round cell tumor. Clinical signs and course vary depending on organ involvement.

Respiratory Diseases Auscultation of llamas and alpacas is difficult and frequently unrewarding. Little air movement is heard under nom1al conditions, and identification of areas of infection, congestion, or consolidation is typically difficult. Lateral radiographs may be required for diagnosis of pneumonia. Bacterial infections of the Iung are relatively rare, with Streptococcus and Corynebacte1ium spp being the most common isolates. Chronic obstructive pulmonary disease appears to be increasing in frequency. Animals allowed to live to their expected life span is a factor, but feeding practices can contribute to onset as well as exacerba­ tion of clinical signs---coughing, shortness of breath, and expiratory dyspnea. Therapy includes changing the feeding regimen to reduce dust, molds, and pollen. Bronchodi­ lators and steroids may be helpful but remain unproved.

Skin Diseases Unique features of normal can1elid skin histologically include a marked vascularity and significant presence of eosinophils. Several skin conditions are shared with sheep and goats, including ringwmm, contagious ecthyma, dem1atophilosis, and occasionally pizzle rot.

Shearing Injury and Sunburn:

Complications associated with shearing are common. Lacerations may occur where there are loose folds of skin, eg, near tl1e axilla. These often heal uneventfully with or without suturing. Hot shears may cause bums that lead to thick scabs, usually on the dorsum of the back, that may resemble "wool rot." A history of shearing by a novice often helps confinn the diagnosis. Antibiotic ointment is generally beneficial for these iatrogenic lesions. Sunburn also can occur after shearing, especially in light-skinned animals. If found in the acute stage, protection from further

exposure and applicatilpecies. The clinical signs may resemble t110ise of zinc deficiency. Deep skin scrapings or ibiopsies are ideal to make a definitive diagnosis. Although various options for tl1erapy exist, most mange cases will respond to routine J?arenteral doses of ivermectin repeated every l� 14 days. Oral therapy does not appeaf to be as effective. Chorioptes infestation t11ay require higher doses repeated every 14--21 days and local therapy. Refractory Sai-coptes cases involving the lower legs have benefited from the same topical treatment. With louse infestatio:n, it is in1portant to detennine whether pediculosis is due to biting (Damalinia breviceps) or sucking (Microthoraci11s cameli) lice. This can be accomplished with tl1e aid of a hand lens or microscope. Use of trai1sparent t.ape to retrieve lice for diagnosis from within the depths of wool can be :oittempted. Sucking lice can be treated witi1 injectable ivem1ec­ tin as per routine mange therapy. However, biting lice are not affected by parenteral ivermectin. Topical application of synthetic pyrethrin preparations has been effective, but ctitical doses for t11ese species have not been established. Preventive measures for lice and mange include toutine treatment of new herd additions .,swell as animals visiting and returning for breeding purposes or from shows. Ticks have caused tick paralysis as is seen in other species. In addition, ticks gaining :Lccess to ears have caused inner ear afflictions resulting in Homer syndrome as well as encephalitic death.

LLAMAS AND ALPACAS

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Copper Deficiency: Copper deficiency

is characterized by depigmentation of fiber with a wiry or steely teid;ure. Juveniles grow poorly and are predisposed to infections. Confirmation of deficiency is best based on comparison of liver copper levels with species nonnals. Therapy requires dietary supplementation. However, excessive supplementation will cause copper toxicity, which has been diagnosed more commonly than deficiency.

Dorsal Nasal Alopecia (Dark Nose Syndrome): The most common clinical

sign of dorsal nasal alopecia is usually alopecia over the bridge of the nose. The skin is nom1al or variably scaly, hyper­ pigmented, and thickened. Dark-haired animals are predisposed, presumably because insects prefer the warmer surface of a dark background. In some animals, the condition may be secondary to rubbing the nose; in others, it may be a fly bite exacerba-

1855

tion. Systemic or topical steroids produce some transient response, but steroids may cause abortion in can1elids. Tn northern climates, the condition tends to spontane­ ously improve during winter months. Alopecia of the ears has also been seen, particularly in black alpacas.

Idiopathic Hyperkeratosis (Zinc­ responsive Dermatosis): Onset of

idiopathic hyperkeratosis is possible at any age. The lesions appear as nonpruritic papules with a tightly adherent crust. Papules progress to plaques and then large areas of thickening and crusting. Lesions are most common in the less densely haired areas of the perineum, ventral abdomen, inguinal region, medial thighs, axilla, and medial foream1s, but the face may also be involved. The signs may wax and wane. Diagnosis is by skin biopsy. Treatment is 1 g zinc sulfate or 2-4 g zinc methionine per day. Calcium supplementation should be minimized and alfalfa hay discontinued. Affected animals may be zinc responsive but not deficient.

Idiopathic Nasal/Perioral Hyper­ keratotic Dermatosis (Munge): Most

Perinasal munge in a llama. Courtesy of Dr. LaRue

Johnson.

animals with munge are 6 mo to 2 yr old at onset. Variable degrees of hyperkeratosis (heavy, adherent crusts) in paranasal and perioral regions are seen. Less commonly, the bridge of the nose and periocular and periaural regions are affected. Inflamma­ tory lesions may wax and wane. Qifferen­ tial diagnoses include viral contagious pustular dermatitis, dermatophilosis, dermatophytosis, bacterial dermatitis, and autoimmune/immune-mediated disease. Treatment is directed at resolv­ ing secondary bacterial infections (ie, daily 10% povidone iodine scrubs plus application of 7% tincture of iodine). If lesions do not respond to antibiotics, adding topical glucocorticoid prepara­ tions or intralesional triamcinolone acetonide (2 mg/mL) may be beneficial. Some animals do not respond to any of the described therapies, including those with juvenile llama deficiency syndrome, which has been shown to affect both llamas and alpacas; in these cases, an evaluation of the immune response is indicated.

1856

MARINE MAMMALS

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MARINE MAMMALS Marine mammals are a diverse group of species that include cetaceans, pinnipeds, sirenians, sea otters, and polar bears. The cetaceans consist of two major groups with different physiology and anatomy: toothed whales (Odontocetes) and baleen whales (Mysticetes). The pinnipeds consist of three major groups: true seals (Phocidae), eared seals (Otariidae), and walrnses (Odobeni­ dae). Sirenians (Sirenidae) are of a single fanlily that includes manatees and dugongs. The sea otter (Enhydra lutris) is a marine member of the Mustelidae, and the polar bear (Ursus maritimus) is the only member of the U rsidae that is considered marine. Few pharmaceuticals or vaccines are approved for use in marine mammals. Many recommendations can be made based on personal experience or published reports, but clinicians should be cautious in their application.

MANAGEMENT The general rule in maintaining marine mammals in captivity is to duplicate their natural environment as closely as possible. Most live in marine habitats, although some species migrate into freshwater; Baikal seals (Phoca sibirica) and five species of river dolphins have adapted completely to freshwater habitats. Manatee subspecies vary in the time they spend in freshwater, but the dugong (Dugong dugong) is completely marine. Marine cetaceans sht>uld be kept in water with a salinity of 2&-35 g/L, preferably using balanced sea salts. Water for captive marine cetaceans should be maintained as close to the pH of mid-ocean waters (8-8.3) as possible. Freshwater cetaceans and seals require water sinlilar to that of their natural habitat. In the USA, the Marine Mammal Protection Act of 1972 specifies that colifonn bacte1ial counts of water for captive marine man1TI1als must be 51,000 MPN (most probable number/100 mL). Marine mammals kept in the extremes of their temperature tolerance range are more susceptible to environmental and infectious disease. In general, cetaceans and pinnipeds are better adapted to cold than to heat, but species-specific tolerances differ. Inappropri­ ately combining different species for display purposes can result in compromises that jeopardize the well-being of some species.

Good air quality, especially in indoor facilities (10-20 air changes/hr) is as important as good water quality. Photoperi­ ods, light spectral and intensity require­ ments, sound tolerances, and flight distance requirements are not well established for any cetacean. Extremes in any of these factors should be considered detrimental in the absence of specific data. Environmental requirements of pinnipeds are similar to those of cetaceans except that pinnipeds can "haul out" on land. Although captive pinnipeds can be kept in freshwater, saltwater pools that meet the specifications listed above for cetaceans are preferred. Most pinnipeds obtain their metabolic water requirements in food and do not require access to freshwater if provided fish with a high fat content. However, it is common practice to allow pinnipeds access to potable water. Pools for captive pinnipeds should provide shelter from wind and some shade. Haul out requirements are different for each species, and some pinnipeds ( eg, the N orthem fur seal [ Callorhinus ursinus]) require very specific timing of access to land (eg, only at the pupping season). Sirenians are warmwater species with water requirements sinlilar to those of cetaceans, although the most common sirenian in the USA, the Florida manatee (Trichechus manatus /,atirostris), migrates between marine and freshwater environ­ ments seasonally. Manatees do better in captivity if salinity is changed seasonally to match migration in the wild. In captivity, the sea otter thrives best in a cold marine water system. Because the fur of the sea otter is its major protection against hypothermia, the water must be kept free of oils and organic material that could mat or damage the coat. The polar bear naturally lives on arctic and subarctic ice. It has successfully adapted to subtropical climates in captivity but is more susceptible to dennatologic disease in warm climates. Polar bears traditionally have been provided with freshwater in captivity. Proper attention to filtration and water quality is beneficial.

Restraint: Marine mammals must be restrained for thorough examinations. Trained cetaceans and pinnipeds can be taught behaviors to facilitate examination

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MARINE MAMMALS and collection of diagnostic samples. For these animals, the presence of familiar at­ tendants is important. For complex procedures or tmtrained animals, the safest approach to restraining a cetacean is to remove it from the water. Captive enclosures should allow water drainage so that cetaceans can be stranded without the use of nets. As the animal begins to lose buoyancy in the draining water, it should be positioned over thick foam pads to minimize struggling and injury. Nets are an alternative for corralling small cetaceans kept in sea pens or encountered in the wild; however, experienced personnel are required to minimize the risk of drowning or iajury to the animal or staff. Netted cetaceans are placed on foam or specially designed stretchers or floats that can suspend the animal above water level. Small cetaceans (dolphins) can often be restrained by the weight of three or four attendants-one person controls the peduncle of the tail fluke and the others apply weight to the animal's body. The pectoral fins should be folded alongside the animal in a natural position to avoid permanent damage. In larger cetaceans (whales), the powerful tail fluke may be secured with mechanical restraints. Capturing pimlipeds is generally easier on dry ground, although small animals can be captured in the water with end-release hoop nets. Larger animals should not be netted in water but should be coaxed or driven from the water or have the water drained from their pool. On land, hoop nets can be used on larger animals. Cargo nets, baffle boards, and "come-along" poles also can be helpful. Once captured, small seals can be restrained for some procedures by an experienced handler sitting on the seal's back and holding the head. Larger pinnipeds or more complex procedures require an appropriately designed squeeze cage. Sirenians are relatively docile; problems in restraint are generally due to their bulk and weight, and caution is recommended because they tend to roll. They can be handled in much the same way as cetaceans. Sea otters can be restrained like most other large mustelids. Hoop nets can be used to remove them from pools. Once they are out of the water, restraint bags, squeeze boxes, or other restraint devices for small wild carnivores can be used. Polar bears are large and dangerous, and manual restraint is not advised.

Anesthesia: Physiologic adaptations to

diving and marine environn1ents make gen-

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eral anesthesia of cetaceans and pinnipeds difficult. Anesthetic drugs conunonly used in other animals often have narrow margins of safety or cause tmexpected reactions in marine mammals. Tranquilizers, sedatives, and anesthetics should be administered to marine mammals only by personnel experienced in their use. Specialized anes­ thetic machines and respirators (apneustic plateau) are required for cetaceans. Sire­ nians rarely require general anesthesia or tranquilization for treatment. Sea otters can be sedated with diazepan1 (0.2 mg/kg body wt) or tiletan1ine-zolazeparn (1 mg/kg). A combination of fentanyl (0.22 mg/kg) and diazepam (0.07 mg/kg) has been success­ ful for sample collection in wild sea otters. Narcotic recycling has been seen. Surgical anesthesia can be obtained with higher dos­ ages of fentanyl-diazepam (0.33 mg/kg/0.11 mg/kg); tiletan1ine-zolazepam (2 mg/kg); or halothane, isoflurane, or sevoflurane, with or without nitrous oxide. Polar bears are routinely immobilized with etorphine, tiletamine-zolazepam with or without medetomidine, ketamine with xylazi.ne, or a variety of other agents used IM. The required dose is highly dependent on the individual animal and environment.

ENVIRONMENTAL DISEASES Corneal Edema: Corneal opacity is

frequent in captive pinnipeds kept in either freshwater or saltwater; it is also seen in captive cetaceans but is rare in .wild animals. It can be due to various environ­ mental problems. Transient cases can be caused by sin1ply moving an animal to freshwater from saltwater or vice versa. Lack of shade and excessive bright light have been implicated. Poor water condi­ tions (eg, high bacterial loads or overuse of oxidative disinfectants in the water) also have been associated with the disease. Nutritional deficiencies have been suggested as causes, but response to supplementation with vitamin C or A has not been dramatic. Feeding other oral an­ tioxidants (leuti.n, grape seed extract) as a preventive measure is being evaluated. The condition is usually self-limiting if the underlying insult to the cornea is removed early enough in the pathogenesis.

Corneal Ulcers: Corneal ulcers are

conunon in captive pinnipeds and cetaceans. They can be the result of direct trauma or the sequelae of unresolved or tmtreated cases of corneal edema.

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MARINE MAMMALS

Diagnosis is by observation of epithelial defects on corneas stained with fluorescein. Culture of the lesion (bacterial, fungal) before therapy can help direct treatment of nomesponsive cases with associated infections. In trained animals, small lesions can be treated topically. In untrained animals, subcor\junctival ir\jections of antibiotics and steroid are required. Oral docycyline is being used in some pin.niped cases to stabilize the cornea, and topical cyclospo1ine or tacrolirnus is being used in tractable animals with some success in reducing recurrence. Extensive lesions benefit from protection by suturing tl1e eyelids. Deep ulcers or lacerations in danger of eroding Descemet membrane should be stabilized with a thin methylacrylate patch. As in corneal edema, successful resolution and prevention of recurrence depend on removal of the underlying cause.

Foreign Bodies: Many captive marine mammals develop tl1e habit of swallowing objects dropped into tl1eir pools. In cetaceans, the opening to the second compartment of the stomach is small, and foreign objects remain in the first compart­ ment. In pinnipeds, the small pylorus prevents passage of most foreign bodies. Frequently, no clinical signs are evident. On occasion, anorexia, regurgitation, or lethargy may be seen. Diagnosis is often made by having witnessed tl1e anin1al swallow an object. Smaller anin1als can be radiographed; in small cetaceans, the esophagus can be palpated to establish the presence of foreign bodies. Animals occasionally regurgitate foreign bodies; however, assisted removal is usually indicated. Removal is usually best performed by gastroscopy, whlch is also used as a method of diagnostic confim1ation. All efforts should be made to prevent ingestion of foreign bodies. Training anin1als to retrieve for reward as a displacement to swallowing foreign objects is thought to be beneficial. Gastrointestinal Ulcers: GI ulcers are

a significant problem in captive marine mammals and are also found in free-ranging marine mammals. Ulcers of the first compartn1ent of the cetacean stomach are a common necropsy finding and pose less severe clinical problems than do ulcers of the pyloric region or proximal duodenwn. Gastric ulcers in pinnipeds frequently progress to perforation, whlch results in peritonitis and subsequent deatl1. Gastric ulcers also are found in sirenia.ns. Altl10ugh ulcers in cetaceans perforate less frequently than in pinnipeds, they should be treated as a serious problem. Various causes, including

parasitic damage and increased histamine content of spoiled fish, may be involved in the cause of a GI ulcer, but the disease in captive animals should be considered associated with environmental or stress­ related conditions. Dramatic environmental changes, including changes of personnel or companion animals, can precipitate se1ious GI ulceration in cetaceans or pinnipeds. Clinical signs include lethargy, partial anorexia, abdominal splinting, pallor, and occasionally regurgitation. Animals with bleeding ulcers show anemia and possibly leukocytosis. Diagnosis generally is based on identification of man1.111alian RBCs in gastric washes; confirmation is by endo­ scopic visualization of the lesions. Palliative treatment of nonpe1forating ulcers usually consists of administration of histamine blockers and alW11ina gel-based antacids with or without sin1ethicone, along with frequent small meals. The w1derlying cause must be identified and corrected for success­ ful resolution. Management of perforating ulcers with resulting peritonitis includes intensive broad-spectrU.111 antibiotic and fluid therapy. As in people, stress-induced GI ulcers are more likely to develop in marine mammals that have previously had an ulcer.

Trauma: Traumatic lesions (eg, cuts,

wounds from gunshots or propeller blades) are common in marine mammals. Propeller ir\juries are a major problem in manatees, which commonly enter heavily navigated recreational waters in Florida. Traumatic wounds should be cleaned, debrided, and generally allowed to heal as open wounds unless body cavities are breached. Antibiotics should be administered during convalescence to prevent gross infection. Maintenance of good water quality and a high plane of nutrition is beneficial to the healing process. Large wounds frequently heal uneventfully.

Oil Exposure: Exposure of marine mammals to spills of petroleum hydrocar­ bons is a major concern. Sea otters are paiticularly susceptible to such exposure because of their natural grooming habits and their lack of an insulating blubber layer. Hepatotoxicity, renal toxicity, GI damage, and loss of horneothermic ability are irnportai1t effects of exposure to petroleum hydrocarbons; however, the most devastating effects are due to direct pulmonary danrnge from inhalation of volatile hydrocarbons. Experimental evidence suggests cetaceans and pinnipeds will avoid petroleum spills if possible (unlike sea otters) and are relatively

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MARINE MAMMALS resistant to toxicities from direct skin contact. Ingestion of large quantities of oil by these species is unlikely, and although baleen fouling occurs in mysticete whales, it usually resolves within 24-36 hr. Pinnipeds and cetaceans are susceptible to severe puhnonary dan1age due to inhalation of volatile hydrocarbons as are other mammals, including people. Efforts to reduce human exposure to hydrocarbons when dealing with oil-contan1inated anin1als is a top priority. Treatment of exposed anin1als includes removal of oil from both the skin (using mild detergents, eg, 2% New Dawn) and the GI system (activated carbon gavage), along with physiologic supportive therapy. For sea otters, use of warm wash water and provision of soft freshwater reduces recovery time. It is critical to recognize that capture, transport, and holding stresses appear to lower the threshold of hydrocarbon toxicity in these animals.

NUTRITION AND NUTRITIONAL DISEASES Generally, captive anin1als fed a diet that is solely or primarily fish are provided dead fish that have been frozen. The logistics and difficulty in providing this diet can lead to some special nutritional concerns. All fish are not of equal nutritional value; diets consisting of a single species of fish are unlikely to provide balanced nutrition for any animal. Sinularly, one diet will not serve all piscivores equally. Only fish suitable for human consumption should be fed. (See ai,so NUTRITION: EXOTIC AND ZOO ANIMALS, p 2297.) Storage and thawing of frozen fish must be monitored carefully. Feed fish should be held at or below - l 9°F ( 2-8°C) to slow deterioration of their nutiitional value through oxidation of an1ino acids and unsaturated lipids. Dehydration of frozen fish can also be a problem for animals that obtain their water from food. Fatty fish should not be stored >6 mo. Few fish, with the possible exception of capelin, should be stored > 1 yr. To retain optimal vitamin content and reduce moisture loss, frozen fish should be thawed in air under refrigeration. Thawing in water leaches away water-soluble vitamins. Thawing at room temperature encourages bacte1ial growth and spoilage. The energy requirements of marine mammals vary with age, environmental temperatures, and condition. Young, growing bottlenosed dolphins and smaller pinnipecls generally require 9o/ 150 g), it is riskier in smaller birds. Microchipping small birds (700Ai. lt has been reported in birds with chronic respiratory diseases and in macaws with pulmonary hypersensi­ tivity syndrome, a condition that occurs in macaws housed in poorly ventilated areas with birds that produce large amounts of powder clown such as cockatoos, cocka­ tiels, and Af1ican grey parrots. Avian RBCs are nucleated, so traditional mammalian methods of WBC determination are not adequate. Various diluents (eg, Eosinophil Unopette®, Natt-Herricks® solution) are available to enable accurate WBC detenninations. Estimated WBC counts are less accurate but can be useful when the individual perfom1ing the estin1ate produces blood smears of consistent quality and thickness. Normal total WBC counts vary with species and age (see TABLE 15). Adult cockatiels often have total WBC counts of 4,000-7,000 x 103/µL. Adult macaws are usually at the high end of the normal avian range (12,000-15,000 x 103/µL). For many avian species, reference values for WBC counts are still being determined. A leukocytosis, and the differential or type(s) of WBCs that are increased, can identify underlying disease and give an indication of the most likely ca.uses. The differential count in birds can be affected by bacterial, fungal, and viral diseases, as well as toxins. The types of avian WBCs are the heterophil, eosinophil, monocyte, and basophil. Heterophils are equivalent to manunalian neutrophils, with much the same function. Avian heteropl1ils contain lysosomal enzymes and are bactericidal and phagocytic. They are the first cells Lo respond to any infectious or inflammatory disease process. Instead offomung a Ii.quid pwulent material, avian heterophils form an inspissated, caseous mate1ial. This caseous material is

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1890

PET BIRDS

then walled off by macrophages and fibrous tissue to fonn a granuloma Heterophilia can occur during infection or from stress. Heteropenia is often associated with an overwhelming infection or viral disease. Lymphocytes function in antibody and antigen production and cellular and hurnoral immune reactions. Lymphocytosis may occur in chronic infections (chlamydia!, fungal, mycobacterial) or with lymphoid neoplasia. In some species (eg, canaries and Amazon parrots), up to 70%of the WBCs are normally lymphocytes. Lyrnphopenia is often associated with viral diseases (eg, circovirus or polyomavirus) or sepsis. Monocytosis is often associated with chronic granulomatous diseases such as chlamydia!, fungal, or mycobacterial infection. Eosinophilia has been reported with parasitic diseases and has also been associated with delayed hypersensitivity reactions. Basophilia can occur during inflam­ matory conditions and chronic infection. Physiologic differences in birds create variations from accepted mammalian nom1al values for many biochemical measure­ ments. Because of the excretion of uric acid rather than urea as the primary product of protein metabolism, uric acid levels are significantly higher in birds than in mammals, whereas BUN is significantly lower. Uric acid may be increased in severe renal disease or with articular gout (seep 1926). Severe dehydration may increase uric acid levels, but levels return to normal with rehydration.

lftNll�I

No reliable biochemical indicator is currently available to detect early renal inlpairment. Serum or plasma glucose is higher in birds than in mammals, with levels of 250-400 g/dL common, depending on species. Levels that indicate diabetes also vary with species and individuals but often are >700-800 g/dL (seep 1925). Hepatic enzymes measured commonly include AST and LOH, which have normal values several times those of mammals (AST, 10-400 U/L; LOH, 75-450 U/L). Measurement of CK is often performed concurrently to differentiate increased values of AST due to muscle necrosis from those due to hepatic damage. LOH is a short-lived enzyme of limited usefulness in detection of hepatic necrosis. ALT levels are very low compared with those in man1mals (5-15 U/L); however, increased levels can indicate hepatocellular necrosis. Birds have low bilirubin reductase levels; therefore, total bilirubin is normally also very low, and increases with hepatic disease are not consistent (total bilirubin range 0-0. l rng/dL). Birds also do not become icteric with hepatic disease as do mammals; they excrete biliverdin through their kidneys, resulting in yellow or lime­ green urates. Bile acid measurements are useful indicators of hepatic function, with levels 10 mg/dL), usually with a relatively normal ratio of these miner­ als. Total solids as measured via refractom­ eter are significantly lower in birds than in mammals, with levels of 3--5.5 g/dL normal for most species. Total solids can also increase in reproductively active hens. Cholesterol and triglyceride reference ranges are still being evaluated, but reference values are -180-250 mg/dL for cholesterol and 51-200 mg/dL for triglycer­ ides. Increased levels of both triglycerides and cholesterol have been reported in birds fed a high-fat diet. High levels can also be seen in reproductively active females and may be a risk factor in birds that develop atherosclerosis. Omega-3 fatty acids added to the diet as well as dietary restriction and conversion to a pelleted diet have been shown to reduce hypertriglyceridemia and hypercholesterolemia. Hematology and Plasma Biochemistry of the Neonate: Neonates have some in1portant differences from mature birds in their hematologic and biochemical parameters. Neonates have a lower PCV (20%-300Ai). The normal adult range is present beginning at 10-12 wk in most species. Neonates have a lower total protein (1-3 mg/dL) and concomitant lower plasma albumin concentrations than adults. A high WBC count (20,000-40,000 cells/uL) is common in neonates; the nom1al adult range is present at 9-11 wk of age. Neonates also have lower uric acid values and higher alkaline phosphatase and CK concentra­ tions than adults. Routine Medical Procedures: Injec­ tions can be given by several routes. SC injections are used for fluid administration, some vaccinations, and many routine medications such as antibiotics. Preliminary studies show that the SC route may be as effective as IM injections for most medica­ tions, without the associated muscle necrosis. To ensure that the medication or fluid being injected is actually deposited subcutaneously, the skin must be clearly visualized; use of alcohol to wet the skin and feathers is recommended to aid in visualization. Insulin syringes (50 U or 0.5 mL) with 27-gauge needles are invaluable for accurate dosing when small quantities must be administered. SC fluids are often used in birds. To maximize their absorption and minimize discomfort, fluids should be

1891

warmed to 102°-106° F Sites of administra ­ tion are the lateral flank, the inguinal web, and the back. Maintenance fluids are estimated at 50 ml/kg divided bid-tid. In dehydrated birds, 500Ai of the total daily maintenance can be administered SC (25 mllkg) and repeated every 6-8 hr until hydration is reestablished. IM injections are given into the pectoral muscles in most pet birds; leg muscles are also used in some species, particularly raptors. The muscle fibers of birds are more vascular and tightly packed than those of man1rnals, making both muscle necrosis and inadvertent IV ir\jection more likely. IV ir\jections are occasionally indicated in birds. Con1rnon medications administered IV are some antibiotics, amphotericin B, chemotherapeutic drugs, contrast media, and fluids. Indwelling catheters can be placed in the jugular, basilic, or medial metatarsal veins for constant-rate infusions or intem1ittent fluid administration. Intraosse­ ous (IO) catheters can also be inserted, generally in the proximal tibiotarsal bone or distal ulna. A standard hypodermic needle may be used (usually 25-gauge for initial entry, followed by a second 22-gauge needle sutured in place), or a spinal needle with stylet may be used for large birds. Without a stylet or second needle, a bone plug may obstruct the needle. The IO or IV catheter is intermittently flushed with wann saline whenever fluids are not being infused. Maintaining an IV catheter in an avian patient can be challenging, and IO catheters are often preferable for longte1m fluid therapy. However, fluid tllerapy via IO catheters can be painful to the bird, especially after 1-2 days. Crop (gavage) feeding may be used to meet caloric needs in anorectic birds. Con1rnercial formulas are available and convenient to use. Adequate hydration and normal body temperature (103 °- l 06° F [39°-41°Cl) must be established before initiating crop feeding to prevent desicca­ tion of the crop food and GI stasis. In adult birds, generally 30 mVkg can be adminis­ tered tid-qid. Baby birds have a much more distensible crop and will hold -lOOAi of their body weight per feeding (100 mllkg). Oral medications may be added to the crop feeding or given directly by mouth. The technique of holding tile bird so that the medication is administered into tile con1rnissure of tile mouth and rolls onto tile tongue will minimize stress, loss of medication, and tile danger of aspiration. Medicating birds can be quite difficult for owners; wrapping the bird in a towel for

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1892

PET BIRDS

administration of medication can be stressful for both the bird and the owner and, in some cases, adversely affect the human-bird bond. Compounding medica­ tions to make them more palatable and in a smaller volume can be very helpful in using oral medications. Mixing the flavored medication with favorite foods, juice, or baby food can also help ensure compliance. Medications administered in the water are indicated only in special circumstances such as small flocks of birds or aviary birds not used to handling and would require daily netting and restraint, or in special cases in which an owner cannot handle a bird. Enrofloxacin and doxycycline in drinking water generally provide adequate blood levels for efficacy. However, lack of accurate dosing, stability of the medication, and palatability make this route undesirable in most cases. Sedation is sometimes desirable for diagnostic or treatment procedures to reduce stress and minimize fear. Midazolam admin­ istered at 0.5--1 mg/kg, IM, or 1-2 mg/kg intranasally (IN) is a safe and effective sedation protocol in most pet birds; flumazenil (0.02-0.1 mg/kg, IM or IN) may be given to reverse the effects. If the bird is thought to be in pain or discomfort, butorphanol (0.5--3 mg/kg, IM or IN, depending on species) may be given alone or with midazolan1. Amazon parrots often require the higher dosage (2--3 mg/kg) of butorphanol, whereas raptors require the lower dosage (0.5 mg/kg). lsoflurane or sevoflurane anesthesia delivered by face mask can also be used alone or in conjunc­ tion with sedation for more prolonged procedures or painful treatments. Intubation in birds is relatively easy, because the absence of an epiglottis facilitates visibility of the tracheal opening and arytenoids. Fasting before anesthesia should be of minimal duration; fasts of 4-6 hr are typical. Regardless of the duration of the fast, the crop should be palpated for the presence of food or fluid before anesthesia. Delayed crop emptying is cmm11on in clinically ill birds. If anesthesia must be administered to a bird with food or water still in the crop, fluid should be removed by a feeding tube if possible, and the head should be elevated for the duration of anesthesia, regardless of whether the bird is intubated. Endotracheal tubes should be uncuffed, because the absence of a tracheal ligament increases the risk of tracheal necrosis if a cuff is overinflated. Even an uncuffed tube can cause tracheal damage or necrosis; therefore, after the bird is intubated, head movement should be

minimized. A small animal ventilator can be used for most birds as small as 100 g and can greatly improve ventilation during anesthesia. If a mechanical ventilator is not available, manual intermittent positive­ pressure ventilation will increase oxygena­ tion in anesthetized birds. A capnograph, pulse oximeter, and Doppler are also useful for anesthetic monitoring. The normal body temperature of most psittacines is 103°-l06° F (39 °-41 °C). Birds tend to lose body heat rapidly when anesthetized, and maintaining body temperature drning prolonged anesthesia or surgery is crucial for recovery. Birds with feather loss ru·e more at risk of hypothennia. Water warming blankets under the bird or Bair HuggersTM can be used effectively to maintain body temperature. An emergency drug sheet and emergency drugs should be readily available whenever a bird is anesthetized. Environmental management is very in1portant; severely ill birds benefit greatly from increased environmental temperature and hun1idity (eg, use of commercial incubators with temperature ru1d hrnnidity controls). For at-home emergencies, a warm environment cru1 be created by wrapping clear plastic wrap ru·ound three sides of the cage and placing an electric heating pad on the remaining side, being sure the bird cannot reach the pad. Digital thennometers with remote probes can provide accurate monitoring of environ­ mental temperatures. A quiet location, away from the sound of barking dogs and other excessive activity, will decrease stress. The cage arrangement cru1 be critical for ill birds. If a perch is supplied, tl1e food and water must be elevated so that the bird has ready access without having to climb down from the perch. Often, it is best to remove perches entirely from the cage of an ill bird and place the food and water container on the cage floor so that the bird has easy access and does not expend energy simply trying to maintain a perched position.

PEDIATRIC DISEASES Birds are classified by their maturity level at hatching. Parrots, doves, and fmches ru·e altricial, hatched without feathers, with eyes closed, and helpless. Poultry, ratites, and waterfowl are born precocial, with down feathers, open eyes, and the ability to walk and feed themselves at hatching. Psittacine .neonates are completely dependent on tl1e pru·ent birds for wam1tl1 and food; they also lack a functional inunrn1e system and are more susceptible to disease. Because of these characteristics,

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PET BIRDS

proper husbandry and nutrition of the chick and parents is critical for their health and survival. Today, chicks are either parent raised (most small parrots such as budgerigars and lovebirds) or hand raised (large parrots). There are advantages and disadvantages with both methods. Most aviculturists believe that hand-raised parrots make better pets and that incubator hatching and hand raising reduces the incidence of some infectious diseases. Disadvantages of hand raising can include stunting and an increase in husbandry-related diseases such as crop stasis or aspiration pnewnonia Many avian veterinarians and behaviorists also believe that hand raising may lead to behavioral issues because chicks cannot learn species­ speci.fic behaviors from parent birds and become in1p1inted on people. The health of a chick depends on many factors, such as the health of the parents, genetics, the incubation process, nutrition (type of food, temperature, and consis­ tency), environment (hwnidity, warmth, and cleanliness), and exposure to infectious diseases. When an ill neonate is presented, the history of not only the chick, but also of its parents, the avia1y, and the nursery a.re in1portant. Is the chick being hand fed or parent fed? Is the chick incubator hatched? How old is the chick? Is the nursery closed, or are chicks taken in from other facilities? What is the temperature and hwnidity of the nursery? What is the type of food fed, its consistency, temperature, amount fed, and frequency of feedings? What are the cleaning practices? General environmental temperature guidelines are for newly hatched psitta.cine chicks, 92°-94° F; Wlfeathered chicks, 90 °-92° F; pin-feathered chicks, 85°-90 ° F; and fully-feathered and weaned chicks, 75 °---80 ° F. A diet of25o/e>-30% solids should be fed to chicks >2 days old (more dilute fonnula for newly hatched), with the environmental temperature between 102°-l06° F Most medical issues aiise in young birds in the first week of life, at fledging, or at weaning. Physical exainination of the chick can typically be done with minimal restraint, and the chick should be kept warm throughout the exainination. The crop should be palpated at the beginning of the exan1ination. Birds with food in their crop should be handled carefully to reduce the risk of regurgitation and/or aspiration. Menta.tion and body weight (a growth cha.rt should be requested from the breeder if possible) should be noted. Before they fledge, chicks have little musculature over

1893

their keel bone; therefore, the muscle and subcutaneous fat over the hips, elbows, and toes should be evaluated. It should be detennined whether the ea.rs and eyes are open, or when they opened, if known. The skin, feather quality, and distribution of the feathers should be exainined. Healthy chicks have yellowish pink skin, and feathers first appear on the head, wing, and tail. Abnormal feather growth or delayed or abnom1al opening of eyes can be a sign of stunting. Stress bars (lucent areas a.cross the vane of the feathers) indicate a period of stress when that portion of the feather was fonning. These are common during weaning, so a few stress bars are not uncommon. A large nwnber of stress bars may indicate an underlying illness or condition. The oral cavity should be moist with no plaques or lesions, and the choana should be exaniined for blunting of the choanal papilla, which can indicate hypovitanlinosis A or chronic respiratory disease. The crop may be quite full in a neonate. The veterinarian should observe for crop contractions and ask when the chick was last fed and how much was fed, to detemline whether the crop is emptying nonnally. Nestlings have a nom1ally distended abdomen because of an enlarged proventriculus and ventriculus from being fed lai·ge ainounts of fom1ula. Chicks should be handled carefully to avoid placing excess pressure over their abdomen. The spine, neck, wings, legs, and feet should be exanlined for abnonnal curvature or weakness and evaluated for npm1al posture. The vent should be clean of debris. Aspiration Pneumonia: Aspiration pnewnonia is one of the most common causes of respiratory disease in hand-fed psittacine birds. Chicks can aspirate while being fed large quantities of liquid formula, especially when being fed by ai1 inexperi­ enced person. Aspiration often occurs as birds begin to wean. Clinical signs include increased respira­ tion, respiratory distress, poor feeding response, and depression. Depending on the age and size of the chick, a CBC and radiographs may aid in the diagnosis; however, diagnosis is often based on history and physical exainination findings. Treatment consists of oxygen therapy, nebulization, antibiotics, antifungals, wa.nnth, supplemental fluids, ai1d anti­ inflanll1latory drugs. Prognosis is guarded. Bacterial Disease: The nonnal gut micro­ flora in chicks is primarily grain-positive

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PET BIRDS

bacteria. The presence of large nwnbers of gram-negative bacteria or budding yeast indicates infection. Bacterial infections can occur from multiple sow·ces: an unsanitary envirorunent, inappropriate storage of formula, and use of unclean feeding utensils. Clinical signs can include crop stasis, poor feeding response, regurgitation, depression, and dehydration. Diagnosis is based on clinical signs and results of a fecal or crop Gram stain, CBC (leukocytosis, monocyto­ sis), and culture and sensitivity testing. Treatment is with antibiotics, based on cultme and sensitivity results if available, and supportive care. Neonates on antibiot­ ics often develop secondary yeast infec­ tions; therefore, prophylactic treatment with an antifungal drug such as nystatin or fluconazole may be warranted (see TABLE 18, p 1901).

Yeast Infection: Candida albicans can be present in low nun1bers in a healthy chick but may proliferate in the presence of antibiotic treatment, malnutrition, stress, or immunosuppression. It is the most common fungal infection in young birds and can result in thickening of the crop mucosa, which may be palpable externally and has been described as "Turkish towel in appearance." Clinical signs are crop stasis, poor feeding response, and depression. There may be lesions or plaques in the oral cavity. intestinal or gasbic candidiasis can result in malabsorption. Diagnosis is with fecal or crop cytology revealing large numbers of budding yeasts. Treabnent is with antifungal medications. Antifungals should be given to baby birds prophylactically when on antibiotic therapy to prevent yeast overgrowtl,1 (seep 1899). Viral Disease: The most common viral

diseases in psittacine chicks are polyoma virus, avian bomavirus, proventricular dilatation disease and circovirus, and psittacine beak and feather disease (see p 1908).

Foreign Bodies: Foreign bodies can be found in young birds, including ingestion of substrate, toys, or feeding tubes. Diagnosis is based on clinical signs, history, and radiographs or CAT scan results. Treabnent may require an ingluviotomy to gain access to the mucosa! swface and lumen of the crop, provenbiculus, or ventriculus. Removal of a foreign body, such as a feeding tube, is the most common indication for this procedure in pediatric birds. In larger or

older birds, a rigid endoscope may be necessary to visualize and extract upper GI foreign bodies. The endoscope may be used either orally or through an ingluviotomy incision, depending on the accessibility of the foreign body.

Crop Stasis: Crop stasis, defined as the inability of the crop to empty in a normal time frame, is a common condition in hand-fed chicks. Crop stasis can occur due to poor husbandry and nutritional practices or p1imary disease. Envirorunental temperatures that are too cold or inad­ equate humidity can lead to crop stasis, as can feeding formula that is too cold or thick. All aspects of the nursery and feeding practices should be evaluated. Clinical signs include a distended crop, dehydration, poor feeding response, regw·gitation, and depression. Diagnosis is based on physical examination findings, palpation of the crop, and cytology and/or culture of the crop contents. Treat111ent may include physically emptying the crop, fluid therapy, antibiotics and /or antifungals, and providing smaller, more dilute, and more frequent feedings once the crop is emptying. Crop Burns: Crop bwns result from feeding baby bird formula that is too hot. This can occur when a microwave oven is used to heat the forn1ula (not recommended because of the formation of hot spots within the fom1ula). Mild cases may result in red and inflamed skin in the area of the crop. Second- and third-degree bwns will be acutely inflamed and blistered and may lead to tissue necrosis and fistula forn1ation. In subacute cases, birds may be presented with food draining from a fistula tlu·ough the crop wall and skin. Diagnosis is based on history, clinical signs, and physical examination findings. Treab11ent includes antibiotics, supplemental fluids, anti-inflanu11atory cl.tugs, and nutritional suppmt. Surgical repair is often required but should be postponed until the burned area is well demarcated (usually several days); repair involves debriding devitalized tissues, separating the crop wall from overlying skin, and closing the two layers separately. Prognosis is good if tl1e remaining crop wall is sufficient for closure and the esophagus is intact. Esophageal and Pharyngeal Trauma:

Esophageal and pharyngeal traun1a occurs from improper hand-feeding teclmique, either with the syringe tip or a rigid feeding

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PET BIRDS tube. This leads to tissue trauma, cellulitis, and distribution of food into subcutaneous tissues. Birds may present depressed, anorexic, cold, and dehydrated, with poor feeding response. Swelling may be palpable in the neck area. Diagnosis is based on the history of hand feeding and oral or endoscopic examination to identify the puncture site. Surgically opening the pockets, flushing the wounds, and allowing for drainage is important in treatment, along with antibiotics, analgesics, anti-inflammatory drugs, and supportive care. Prognosis depends on severity of the lesion, an1ount of food deposited in the tissues, and how quickly the lesion is detected and treated. In severely trawnatized cases, prognosis is guarded to poor. Hepatic Lipidosis: The liver relative to total body weight is typically larger in neonates than in adult birds, so some degree of hepatomegaly is nmmal in chicks. However, neonates with hepatic lipidosis typically have the following characteristics: 1) they are usually still being hand fed, often with a commercial formula to which the owners have added peanut butter, oil, or some other high-fat food, and 2) they are usually heavy for their age and exhibit severe respiratory distress. These birds must be handled gently and minimally. Cool oxygenation is the best first step. They have virtually no air sac capacity, and tl1e stress of feeding and breatlli..ng at the same tin1e may exceed their oxygen reserves. Drastically reducing the quantity of crop food per feeding, adjusting the content of the formula, and adding lactulose to the fo1mula are the general nutritional changes required. Parenteral fluid supplementation will help keep the initially hyperthennic bird hydrated. When possible, blood san1ples should be submitted to check for concurrent infection or other diseases. Failure to Thrive: Hereditary, congenital, and husbandry issues may affect the growth of young birds. Stunted chicks are thin, and the head is dispropo1tionately large. Toes, wings, and hips are thin; eye and ear openings may be delayed. The skin may be dry and without adequate subcutaneous fat. Abnonnal feather patterns (swirls) may develop on the head of a stm1ted chick. Stunting can develop early, in the frrst 30 days, or shortly after purchase from the breeder. Usually stunting is caused by husbandry and nutritional issues, often

1895

because of handlers inexpe1ienced at hand feeding. Inappropriate quantities of han d f- eeding fonnula, incorrect tempera­ ture, and incorrect consistency of the fonnula cause reduced feeding response and/or GI stasis. Birds purchased soon after arriving at the pet store are often mistakenly labeled as "weaned." In nature, these birds would be eating paitially on their own but still receiving supplementation from their parents. When such a bird is sold to an uninforn1ed owner, it usually takes a few days to a few weeks for the bird's insuffi­ cient food intake to create noticeable debilitation and weakness. These birds may also have underlying problems, eg, decreased hepatic function or inm1unosup­ pression. Diagnosis is based on the history and physical exai1li..nation findings. Treatment is supportive (fluids, nutritional support, and wanntl1). Antibiotics or antifungal drugs may or may not be needed, based on diagnostic test results. Some of these birds will survive, but many will not. Splayleg or Rotational Leg Deformity: The term splayleg is a catchall for deformi­ ties of the legs in young birds. Often, there are laxities of the ligai11ents of the stifle and/or angular deforn1ities of the femur, tibiotarsus, and tai'Sometatarsus. Causes are poorly documented, but risk factors include nutritional deficiencies (consistent with those of metabolic bone disease, see p 1917) and insufficient support or substrate in the enclosure. Various methods of external coaptation have been devised ai1d are most successful when the bird is young. Placing tl1e chick in a deep enclosure with a suspensory device or cloth that allows the leg to be directed vertically or taping the legs together in a "hobble" may be cmTective if implemented early. Stifle subluxation can develop because of disruption of the cruciate and /or collateral ligainents. Surgery (osteotomy and external skeletal fixator) may be used for rotational deformities. Beak Deformities: Mandibular prognathism commonly occurs in several birds from the san1e clutch and is seen most commonly in cockatoos. If detected early, tl1e hand feeder may be able to correct prognathism by pulling the beak upward and out for several minutes, several tin1es a day. In older chicks, the condition may require a prosthetic that pulls the upper beak out and over the lower beak. This can

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be cumbersome and painful, and the prosthetic often needs to be reapplied. Trans-sinus pinning is a more recent and more reliable method of correction but carries some risk. Scissor beak is a lateral deviation of the upper or lower beak. This may be caused by improper incubation temperature or possibly genetic factors in some chicks. If detected early, mild scissor beak can be corrected by manually placing a counter force on the beak for several minutes 2-3 times daily. More severe defects may require placing a beak prosthetic.

Constricted Toe Syndrome: Con­

stricted toe syndrome is fairly common in neonates, often affecting more than one digit. An annular band of fibrous tissue forms at a joint of the digit, impeding circulation. The cause is unknown, although either excessively low or high htunidity and septicemia have been proposed. This syndrome is most common in Eclectus pa.tTOts a.i1d macaws, usually in chicks housed in environments with inadequate humidity. When detected early, debriding the annular ba.i1d and applying a moist dressing is often effective. In more severe cases, small longitudinal incisions can be made on the medial and lateral surfaces of the affected toe to allow for swelling and to promote circulation. If circulation Joss is severe and necrosis is appa.i·ent, a.inputation may be necessary. NSAIDs can be used to reduce inflan1mation and pain. A bandage will protect the site from contan1ination a.i1d secondary infection. Early detection a.i1d intervention is c1itical in successful treatment.

Toe Mal position: Toe malposition

usually involves the lateral or fourth toe, which points forwa.i·d instead of backwa.i·d. If discovered early, malposition is easily corrected by taping the toe in a normal position. In young birds, the foot can be bandaged with the toe pointing backwa.i·d in the nom1al position for several days. Older chicks may need prolonged bandaging.

Cryptophthalmia (Eyelid Atresia):

Cryptophthalmia is most commonly seen in cockatiels and is often observed in clutch mates. The condition is usually bilateral. The eyelids, if present, are generally normal in conformation but greatly reduced in length, leading to small to nonexistent palpebral fissures. If the palpebral fissure is sufficient to allow functional vision, no

correction is needed or recommended. Extending the palpebral fissure by cortjunctival eversion can be performed with modest success when the palpebral ape1ture is absent or reduced and functional vision is compromised. '

"Lockjaw": Bordetella avium is the causative agent of a syndrome that can appear in clutch mates, most commonly in cockatiels. Bacterial invasion from the sinuses progresses to the skeletal muscle of the mandible, resulting in a myositis and "locltjaw." Treatment is antibiotics and supportive care. Manually opening the beak can be difficult, so feeding and medicating the bird can be challenging. Prognosis is guarded to grave. Choanal Atresia: Choa.i1al atresia is seen

most commonly in African grey parrots but has also been documented in other species. With choanal atresia, the conununication between the nares, infraorbital sinus, a.i1d the choana is incomplete or absent. Clinical signs are increased mucus accumulation a.i1d possible infection in the nares and sinuses. Blunted choa.i1al papilla may be detected on oral exa.inination. Diagnosis is by endoscopic exa.inination of the choana. Atresia can be treated by creating an opening in the choana through the na.i·es with an intra.inedullary pin. A red rubber feeding tube is then threaded through the nares, out the choana, and back behind the head of the bird and is left in place for 2-3 wk This procedure is usually performed in stages, beginning with a small tube first and following with a larger tube.

BACTERIAL DISEASES Bacterial diseases a.i·e common in pet birds and should be considered j.n the differential list of any sick bird. Inappropriate husban­ dry and nutiition are often contributing factors. Neonates and young birds a.i·e especially susceptible. GI and respiratory infections are most common a.i1d can lead to systemic disease. Normal bacterial flora of companion birds include Lactobacillus, Corynebacte­ rium, nonhemolytic Streptococcus, Micrococcus spp, and Staphylococcus

epidermidis.

The most commonly repmted pathogens are grain-negative bacteria (Klebsiella,

Pseudomonas, Aeromonas, Enterobacter, Proteus, and Citrobacter spp, Escherichia coli, and Serratia marcescens). Pasteurella

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PET BIRDS spp have been repo1ted as possible septicemic agents in birds attacked by pet cats or rats. Mycobacterium and Chla­ mydia are common intracellular bacterial pathogens. Infections with Salmonella spp are occasionally seen. The most common gram-positive bacterial pathogens are Staphylococcus

aureus, S intermedius, Clostridium, Enterococcus, Streptococcus, and other Staphylococcus spp. Methicillin-resistant S aureus (MRSA) is rare but has been documented. Mycoplasma spp have been

in1plicated in chronic sinusitis, often found in cockatiels. This organism is difficult to culture, and the true incidence is unknown. Staphylococci and streptococci (especially hemolytic strains) and Bacillus spp are thought to be responsible for several dem1atologic conditions in psittacine birds. Staphylococci are often isolated from lesions of pododermatitis (bumblefoot) in many avian species. Clostridial organisms are conunon secondaiy invaders of dainaged cloacal tissue in birds with cloacal prolapse or papillomatosis. Several specific syndromes of birds cai1 aiise from various species of clostridia. A Grain stain or anaerobic culture is necessaiy to identify these organisms.

•M:iifrj

Diagnosis is based on clinical signs and results of cytologic examination and culture of tissue or swab san1ples. A Gram stain is used to identify normal flora, yeast, and spore-forming bacteria. Culture is needed to identify specific organisms and their sensitivity to antibiotics. Sainples can be obtained from the respiratory, GI, urinary, and reproductive tracts. Sample sites for culture and cytology include the choanal slit, sinus, cloaca, wounds, conjw1ctiva, internal organs (via ultrasound-guided fine-needle aspirates, endoscopic exan1ina­ tion, or surge1y), and blood. Treatment is based on location of infection and results of culture and sensitivity testing. See TABLE 16 for a paitial list of frequently reconunencled antimicrobials.

Chlamydiosis (Psittacosis, Ornithosis)

Chlamydia psittaci is an obligate intracellular bacterium tl1at can infect all companion birds but is especially common in cockatiels, budgerigars, and parrots. Cu1Tent state and federal regulations governing the testing, reporting, treatment, and quarantine for Chlamydia should be followed.

ANTIMICROBIALS USED IN PET BIRDS

Antimicrobiala

Dose, Route, and Frequencyb

Amikacin sulfate

15 mg/kg, IM, bid

Amoxicillin/clavulanate

125 mg/kg, PO, tid

Azithromycin

50 mg/kg/clay, PO

Ceftazidime sodium

75 mg/kg, IM, tid

Ciprofloxacin

25 mg/kg, PO, bid

Clindan1ycin

100 mg/kg, PO, bid for 5 days to treat Clostridium

Doxycycline

25 mg/kg, PO, bid for 45 daysc

Doxycycline injectable, 20 mg/mL

75-100 mg/kg, IM or SC, every 5 days, then weekly for six treatments0

Enrofloxacin

15-20 mg/kg, PO or IM, bid

Metronidazole

25 mg/kg, PO, bid for 14 days for Giardia,

Marbofloxacin

2.5 mg/kg/day, PO

Trimethoprim/sulfamethoxazole

50-100 mg/kg, PO, bid

Clostridium

a Most are unapproved for use in birds, and caution is indicated. b

1897

May vary with etiology and species treated

c Duration and dosage for treatment of Chlamydia

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The incubation period of C psittaci is from 3 days to several weeks. The organism is excreted in the feces and in nasal and ocular discharge of infected birds. Although labile in the environment, the organism can remain infectious in organic debris for > 1 mo. Clinical signs range from asymptomatic carriers to severe disease and may include ocular, nasal, or cor\junctival irritation and discharge; anorexia; dyspnea; depression; dehydration; polyuria; biliverdi.nuria; and diarrhea. Clinically ill birds may have a leukocytosis, monocytosis, and increased AST and bile acid concentrations. Radio­ graphs may reveal hepatomegaly, spleno­ megaly, or airsacculitis. Diagnosis of C psiltaci can be challeng­ ing, especially in the absence of clinical signs. Few laboratories will culture the organism. Various antibody and antigen tests are available, but these have limita­ tions. Serologic tests available include indirect fluorescent antibody, complement fixation, ELISA, and fluorescent antibody. A positive serologic test result is evidence that a bird has been infected but might not indicate active infection. Exposed but clinically normal birds may produce appreciable antibody titers. Acutely ill birds may not mount an antibody response, also yielding false-nPgative results. These factors make an antibody test an insufficient screening tool for chlamydiosis in birds when used alone. Because of the intracel­ lular nature of Chlamydia and the reduction in numbers of organisms that accompanies antibiotic use, false-negative results of antigen tests are conm1on. With the advent of PCR testing, diagnosis of Chla.mydia is more readily accomplished, and attempts to culture the organism or identify elementary bodie·s in tissue specimens are rarely done. Laboratories should be consulted before shipment to identify appropriate samples and shipping methods. Because of the difficulty in diagnosing Chlamydia, a single test method may not be adequate, and a PCR assay of a combined cor\junctival, choanal, and cloacal swab sample, in cor\junction with a serologic test, is recommended. Doxycycline is commonly used for treatment of Chlamydia infection. Because the treatment pe1iod required to eliminate the organism is uncertain, treatment for 45 days is reconm1ended. Dietary calcium sources should be reduced if doxycycli.ne is administered orally. Clinically ill birds should be treated with oral or injectable doxycycli.ne initially to establish therapeu­ tic drug levels quickly. Fonnulations of doxycycline in the food or water and

chl01tetracycline-in1pregnated seeds or other foods are available or can be manufactured to treat infected flocks. A doxycycline-medicated feed for budgerigars can be created by combining 300 mg of doxycycline hyclate (froni capsules) with 1 kg of a mixture of oats, millet, and sunflower oil ( 1 part cracked steel oats is mixed with 3 parts hulled millet; add 5-6 mL of sunflower oil per kg of the oat/seed mixture). Fresh medicated mix should be made daily and feel as the sole diet for 30 days. Doxycycli.ne may also be added to the water for cockatiels (200-400 mg doxycy­ cline hyclate/L of water), Goffin's cockatoos (400-600 mg/L), and African grey paiTots (800 mg/L). A doxycycli.ne syrup, using a monohydrate- or calcitm1-syrup formula­ tion, can be given at 40-50 mg/kg/day, PO, to cockatiels, Senegal paiTots, and blue­ fronted and orange-winged Amazon paITots; in African grey paITots, Goffin's cockatoos, blue and gold macaws, and green-winged macaws, the recommended dosage is 25 mg/kg/day, PO. These indirect modes of antibiotic administration depend on ingesting sufficient quantities of antibiotics to maintain effective blood levels, which may not always occur. Only certain forrnulations of doxycycline can be given IM or SC. Doxycycli.ne i.rtjectable has been successful at 75-100 mg/kg every 5-7 days for 6 wk. Because C psillaci is transmissible to people, the zoonotic risk must be considered when designing the diagnostic and thera­ peutic plan. Current state and federal regulations governing the testing, reporting, treatment, and quarantine for birds infected with Chlamydia should be followed. A compendiw11 of control measures is available at www.nasphv.org/docurnentsCompendia ­ Psittacosis.html. Avian Mycobacterioi:is Avian mycobacteriosis infections are usually caused by Mycobaclerium aviiim and M genavense. Mycobacterium inlrncel­ lulare, M bovis, and M tuberculosis are less commonly reported. Psittacine birds most commonly infected are brotogeris parakeets and Amazon paJTots. Avian mycobacteriosis is a chronic progressive disease affecting the liver and GI tract. Clinical signs include anorexia, weight loss, depression, and diaiThea. Birds with eai·ly infections may show few clinical signs. Diagnosis of mycobacterial infection can be challenging and is most reliably done by acid-fast staining, culture, and/or DNA probe of a biopsy specin1en. Biopsy of the

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PET Bl RDS liver, intestines, spleen, or a suspected mass is recommended; however, PCR testing of ultrasound-guided fine-needle aspirates of the liver may be diagnostic. Avian mycobac­ teria are difficult to culture, so a negative culture result does not exclude infection. A fecal acid-fast stain has poor sensitivity but may identify birds shedding large numbers of organisms; PCR testing of a fecal sample is a more sensitive test method. Most birds will have a significant leukocytosis with a monocytosis. Radiographs may reveal hepatomegaly and splenomegaly. Granulo­ mas may occur that may be confused with tun10rs. If infected birds are in a multiple bird collection, determining whether other birds are infected can be difficult. Husbandry and sanitation should be assessed. High-risk birds should be isolated and monitored by serial examinations (weights), CBCs, and fecal acid-fast stains or PCR testing. Treatment involves combination antibiotic therapy for 6-12 mo or longer. Owner compliance is critical and should be discussed at length before beginning treatment. Use of multiple antibiotics (typically three) is recommended, because mycobacterial organisms are prone to developing antibiotic resistance. Antibiotics in differing combinations that have been used successfully are rifabutin (45 mg/kg), clarithromycin (60---85 mg/kg), ethambutol (30 mg/kg), and enrofloxacin (20-30 mg/kg). All combinations are used daily. Birds with advanced disease and granuloma formation have a poor progno­ sis. Although human infection has not been associated with exposure to birds, precautions should be taken for zoonotic risk, especially in immunocompromised people.

MYCOTIC DISEASES Fungal diseases are conunon in companion birds. Often, they are a secondary infection in an already ill or immunocompromised bird. The most common fungal diseases are respiratory tract infections caused by Aspergillus spp and GI tract infections caused by Candida spp. Macrorhabdus is an unusual fungus that affects the GI tract and occurs most commonly in small pet birds (budgerigars, lovebirds, finches, parrotlets, and cockatiels).

Candidiasis Candidiasis is a common fungal disease seen in pet birds. The etiologic agent is the opportunistic yeast Candida albicans,

1899

which commonly affects the GI tract. Although C albicans is the most common isolate, others including C tropicalis, C parapsilosis, C glabrata, and Ha,nse­ nula spp may also be found and may be refractory to treatment. C albicans is not generally considered a primary pathogen. Small nun1bers of Candida are commonly found in the GI tract of birds and may become pathologic when normal digestive flora are disrupted by in1munosuppression. (See also CANDIDI­ ASIS, p 2791.) Candidiasis most conunonly affects unweaned chicks. Those on broad-spec­ trum antibiotics are most at risk. Neonatal cockatiels are considered most susceptible. Infection may be endogenous, because of yeast overgrowth, or caused by oral inoculation of large numbers of Candida, either by parental feeding or by hand feeding with utensils that are inadequately cleaned. Clinical signs in adult birds are typically mild and may include mild weight loss, lethargy, and dull plumage. Young birds may have more severe disease, especially if they are immunocompromised. Clinical signs in juvenile birds include anorexia, crop stasis, white plaques in the oral cavity, regurgita­ tion, and weight loss. Localized infections in the oral cavity can lead to difficulty swallowing or halitosis. With severe infections, there may be complete crop and GI stasis. Thickening of the crop may develop (Turkish-towel appearance). Infection of the proventriculus and ventricu­ lus can also occur and may lead to more severe clinical signs such as weight loss, regurgitation, diarrhea, and depression. See TABLE 17 for differential diagnoses for regurgitation in birds. Diagnosis of candidiasis is by identifying Candida spp on a Gram, Romanowsky-type, or new methylene blue stain of the feces, crop contents, or regurgitated material. Scrapings or impression smears may also be performed to diagnose suspected yeast infections of the skin. In severe cases, when tissue invasion has occurred, the budding yeast will produce hyphae that can be seen in scrapings obtained from the crop or pharynx, or from the feces. Often candidiasis is secondary to poor husbandry and an unclean environment. If a reservoir of exogenous Candida is present (eg, poor nest box or feeding tube hygiene), then eliminating the source of the Candida is critical. In neonates with crop stasis, the crop must be emptied and smaller amounts fed until the crop stasis has resolved. Metoclopramide may help

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lffl:11111

DIFFERENTIAL DIAGNOSES FOR REGURGITATION IN PET BIRDS

Problem

Species Commonly Affected

Toxicosis

Common Agents (if known)

Typical Signs

Various

Lead, zinc, pesticides, medications

Vomiting, abnormal droppings, lethargy, possible CNS signs

Oral upper GI irritation

Cockatiels, various

Plants (Pathos, Philodendron),

Lethargy, ptyalism, passive regurgitation of water, erythema of tongue and pharynx

Proventricular dilatation syndrome

Macaws, miniature macaws, African grey parrots, cockatoos, others

Avian bornavirus

Weight loss, vomiting, seeds in feces, possible CNS signs

Bacterial GI infections

Various

Gram-negative bacteria

Vomiting, watery droppings, lethargy

Candidiasis

Cockatiels, lovebirds, others

Ca.ndida, spp

Regurgitation, crop distention, oropharyngeal and crop lesions

Trichomoniasis

Budgerigars, cockatiels, doves, others

Trichomonas spp

Regurgitation, mouth and crop lesions (white matter), mucus in crop

Ventricular, proventricular, or crop obstruction

Cockatoos, macaws, Eclectus parrots, cockatiels, others

Wood shavings, corncob bedding, other bedding, fibers, foreign bodies, ascarids

Vomiting, depression, weight loss

Proventricular adenocarcinoma

Various

Neoplasm

Vomiting, weight loss, lethargy, severe pain, sudden death

Internal papillomatosis

Amazons, macaws

Psittacine herpesvirus 1

Vomiting, straining to defecate, secondary cloaca! and choanal infections

Abdominal mass

Budgerigars

Renal or gonadal mass-usually neoplasia

Weight loss, lameness, vomiting

Behavioral

Various

Courtship behavior Regurgitation on mirror, owner, toy, or cagemate

various medications, other caustic materials

crop motility and prevent regurgitation. After identifying and resolving any predisposing factors, treatment with nystatin or fluconazole should be initiated. Nystatin (300,000 IU/kg, PO, bid) is commonly used for treatment because of its low cost and low toxicity. Disadvantages are poor taste and large volume required. Because it is fungistatic and not absorbed

from the GI tract, it is only effective when in direct contact with infected tissue, so it is often administered tid before feeding. If the yeast is resistant to nystatin or the bird is difficult to medicate, then fluconazole (20 mg/kg, PO, every 48 hr) is available for systemic treatment Flock treatment has historically been accomplished with use of chlorhexidine at

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PET BIRDS

10 mlJgal. of drinking water for 1-3 wk. Because chlorhexidine is a disinfectant,its use will also deplete the normal digestive flora. Acidification of the upper GI tract by use of apple cider vinegar has also been reported to resolve Candida overgrowth. See TABLE 18 for some antifungal drngs used in pet birds.

Aspergillosis Aspergillosis is an opportunistic infection that typically occurs in inm1unocompro­ misecl hosts (malnutrition,especially vitamin A deficiency) or when birds are

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exposed to large numbers of aerosolized spores. It is not transmitted bird-to-bird. Aspergillusfumigatus is the most common species isolated; A.flavus and A niger are also found. Rhizopus, Penicillium, Miicor, and Scedosporium apiosper-mimi can cause similar signs and are more difficult to diagnose and treat. Predisposing factors for developing infection include species predilection (African grey parrots,Amazon parrots,cockatiels,and macaws),aspiration of food or medications,immm1osuppres­ sion (underlying disease), moldy bedding or feed, and use of corticosteroids. Poor hygiene and inadequate ventilation,

ANTIFUNGALS USED IN PET BIRDS

Antifungala

Dosage

Route, Frequency

Amphotericin B

1 mg/kg intratrachcal; 0.25-1 mg/mL sterile water for nebulization

Given intratracheally once daily; nebulizecl 10-20 min,bid

1.5 mg/kg

IV,tic!

lOO mg/kg

PO,bid x 30 clays

2 mg/kg

Given intratracheally,once daily x 5 days

10 mg/mL (1%)

Nasal flush; nebulized for 30 min bid

1 mg (0.05 mIJkg of a 1:10 dilution)

Given intratracheally,once daily x 7-14 clays

0.1 mIJkg in 5 mL sterile water

Nebulize for 30 min, 5 days on,2 days off

Arnphotericin B suspension Clotrimazole

Enilconazole

5-15 mg/kg

PO,bid

20 mg/kg

PO,every 48 hr x 3 treatments

10 mg/kg

PO,bid

5-Flucytosine

20-75 mg/kg

PO,bid

F- lO b (quaternary ammoniun1 disinfectant)

1.5/400 mL distilled water

Nebulization for cutaneous and possibly respiratory fungus

Itraconazole

5-10 mg/kg

PO,once to twice daily Oower dosage, and use cautiously in African grey parrots)

Fluconazole Griseofulvin

Ketoconazole

10-30 mg/kg

PO,bicl

Terbinafine

10-15 mg/kg 1 mg/mL solution

PO,bid Nebulization for 30 min

Nystatin oral suspension (100,000 U/mL)

300,000-600,000 U/kg

PO,bid

Voriconazole

12-18 mg/kg

PO,bid

a Most are w1approved for use in birds, and caution is indicated. b

1901

Quaternary ammonium and biguanidine compound; nontoxic, an1pholytic swfactant

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PET BIRDS

especially in warm, hw11id climates, can also increase the incidence of disease.

Clinical Findings: Clinical signs depend

on the site of infection. Most infections occur in the upper respiratory tract, air sacs, lungs, trachea, and syrinx. Systemic infections occur when the infection spreads to internal organs, including bone, liver, kidneys, or brain. Eye and ski11 infections can also occur. Anorexia and weight loss are often present. Respiratory signs may include dyspnea, tail bobbing, exercise intolerance, and voice change. Rhinitis caused by Aspergillus appears similar to bacte1ial rhinitis or sinusitis. A Gran1 stain or modified Wright's stain of lesions or deb1is often demonstrates fungal hyphae. Infraorbital sinusitis caused by aspergillosis often must be surgically debrided before therapy is effective. Extensive or chronic fimgal sinusitis may lead to osseous changes and pem1anent malformation of the upper respiratory architecture. Extension of infection to the brain can cause CNS signs. Tracheitis due to aspergillosis can occur in immunocompromised birds. Aspergillus granulomas often fom1 in the syrinx of psittacine birds and raptors and are particularly challenging to treat. Changes in vocalization may occur before dyspnea is observed, and often these birds will stretch out their necks while breathing. Lower respiratory disease, including airsacculitis, often involves invasion by Aspergillus spp. Granulomas of the air sacs or the coelom.ic cavity are also common, usually in the caudal thoracic or abdominal air sacs. These lesions may require surgical resection.

Diagnosis: Diagnosis can be challenging but should be pursued because treatment is longtem1 and costly. Aspergillosis should be considered in any pet bird presenting with signs of upper or lower respiratory disease, wasting disease, or marked leukocytosis/ monocytosis. A leukocytosis/monocytosis combined with clinical signs and radio­ graphic findings can provide a strong presw11ptive diagnosis in suspect cases. Often birds with chronic disease will be anemic. A radiograph may reveal airsacculi­ tis, granulomas, or severe pulmonary disease. A CT scan or MRI is more likely to reveal more subtle or diffuse disease. Serologic testing is of limited use; antibody and antigen titers, including galactoma.nnan antigen testing, often result in false-negative or false-positive results. A false-negative often occurs because of immunosuppres-

sion, so consultation with the laboratory regarding interpretation is important. PCR testing to detect specific Aspergillus DNA is a much more sensitive method to confirm infection and is more suitable for immuno­ compromised birds because detection of antibodies is not involved. Plasma protein electrophoresis showing increased 13-globulin levels is consistent with aspergillosis. Definitive diagnosis may require direct visualization of lesions either by surgery or endoscopy and confirmation by biopsy, cytology, and/or fimgal culture of lesions. Low fimgal viability may yield a negative culture despite confinnation by cytologic results.

Treatment: Treatment vaiies depending on the site of infection. An acute tracheal infection with obstruction by an aspergil­ loma is an emergency that may require placing an air sac tube. After tube place­ ment, syiingeal or tracheal plaques ai·e removed with a rigid endoscope. Arnpho­ tericin B can then be instilled intratrache­ ally at 1 mg/kg through the glottis, and treatment with systemic antifimgals and nebulization should be started. Ampho­ tericin B is the only fimgicidal agent available and can be used in nebulization, as a nasal flush, intratracheally, ai1d in IV administration. For nebulization, a concentration of 0.25-1 mg/mL of sterile water can be used. Nasal and sinus flushes are generally more dilute at 0.05 mg/mL of ste1ile water. Arnphotericin should not be diluted with saline, because th.is decreases its potency. Flushing the nares and sinus with Wl11ledicated sterile water or saline before medicating may allow saniples to be obtained for cytologic exanlination and culture. Several flushes ofunmedicated warm isotonic saline or sterile water should be done before a final infusion of the medicated mixture. Care must be exercised to maintain the bird's head in a downward position to avoid the potential for aspiration of the infected debris into the lower respiratory tract. Itraconazole (5-10 mg/kg, PO, once to twice daily) is the most commonly used azole for systemic infection. African grey parrots are more sensitive to adverse effects of itraconazole, especially regurgitation and anorexia, and should be dosed at 5 mg/kg/day, PO. Terbinafine (10-15 mg/kg, PO, bid) can be used in lieu of or in conjunction with itraconazole. Clotrimazole can be used for nebulization in conjunction with systemic therapy (10 mg/mL, nebulized 15-30 min

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PET BIRDS 2-4 times/day). Voriconazole (12-18 mg/kg, PO, bid) is being used for resistant strains of Aspergillus. If fungal granulomas are identified and the lesions are accessible, debulking endosurgically or treating the lesions topically with amphotericin B may in1prove the outcome. Birds undergoing treatment should be monitored closely for adverse effects of many antifungal drugs, which can include depression, anorexia, and liver dysfunction. Hepatic enzyme, bile acids, and uric acid concentrations should be monitored every 4 wk druing treatment. Treatment success may be difficult to detennine, but serial CBCs and radiographs may be helpful. Treatment with oral drugs should be continued for 2-4 wk after clinical signs have resolved. Birds with aspergillosis often have underlying disease problems and may be inlmunocompro­ mised, which may affect treatment and recovery. Thickened and scarred air sacs that develop during and persist after infection can provide an ideal environment for disease recurrence.

Macrorhabdus ornithogaster

Infection (Macrorhabdosis, Megabacteria, Avian gastric yeast)

Macrorhabdus ornithogaster most often

affects the proventriculus and ventriculus of smaller companion birds (eg, budgerigars, parrotlets, lovebirds, cockatiels, and finches). Previously described as a bacteriUlll, this organism has a worldwide distribution and varies widely in pathogenicity.

Clinical Findings and Diagnosis: Clinical signs of infection are weight loss, regurgitation, lethargy, passage of undigested food, and diarrhea. These clinical signs may minlic proventricular dilatation disease. Mortality may be high, but birds may recover. In birds that recov­ er, relapses and potential shedding of the organism in the feces are likely. This dis­ ease is often seen in conjunction with im­ munosuppression (eg, polyomavirus and ci.rcovirus infection, or associated with poor husbandry). Asymptomatic infection is common. Diagnosis is made by examining a wet mount of a fresh dropping at 10-50 x magnification with the stage condenser mostly closed to increase contrast. The large, rod-shaped organisms are approxi­ mately 2-4 µm wide and 60-90 µm long. Many birds are asymptomatic and shed low

1903

n\llllbers of organisms, whereas sick birds tend to shed large nun1bers. Birds may shed the organism intennittently, so a negative fecal examination does not exclude infection. Wet mount, modified Wright's, or Gram stain of a fecal sample often reveal organisms. M ornithogaster appears as a large, gram-positive rod, with mottling or stippling throughout its length. Although the size and length may vary, organisms recovered from the droppings are generally several magnitudes larger than the normal digestive bacilli found in birds. Selected veterinary laboratories offer both visual identification and PCR testing. M orni­ lhogaster does not grow on conventional fungal media. Radiographs may reveal a dilated proventriculus. Necropsy lesions may include thinning of the isthmus, proventricular dilation and ulceration, thickening of the proventricular wall, mucus production, and softening of the koilin layer of the ventriculus. Treatment and Control: The goals of treatment are to reduce the mm1ber of organisms and improve the general health and inlmunocompetence of the bird. Ampho­ tericin (100 mg/kg, PO, bid for 30 days) has had the highest treatment success rate, but failures are common, especially with a shorter duration of treatment. Acidification of the proventriculus (apple cider vinegar, vitamin C) has been reported to create an environment less conducive to proliferation ofMacrorhabdus. Voriconazole has been successful (anecdotal) at 10 mg/kg, PO,,bid. Treatment with sodiUlll benzoate in the drinking water has been anecdotally reported to be successful but still experi­ mental. SodiUlll benzoate at 1 tsp/L water for 5 wk cleared the infection in nonbreed­ ing budgerigars, but in budgerigars that were rearing chicks in high environmental temperatures >90°F, treatment with Y2 tsp/L water resulted in neurologic signs and death of the adult budgerigars because of their increased water intake. The current reconunendation for treatment of Mac­ rorhabdus with sodiUlll benzoate is Y2 tsp (2.5 g) of sodiun1 benzoate powder/L of water (used as only water source and made fresh daily). If the birds are not d1inking the medicated water, the dose should be decreased to 1/.1 tsp (1.25 g)/1 of water, and slowly increased back to Y2 tsp over the next few days. Feces should be rechecked at 14 days; if Macrorhabdus organisms are still present, the dose should be increased over several days to 1 tsp (5 g)/1. Feces should be rechecked at 30 days. The lower dose of 1/.1 to Y2 tsp powder/L of water should be used

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1904

PETBIRDS

in birds housed outdoors in summer (temperatures >90 °F [32.2° C]) and in birds feeding chicks. Gloves should be worn when handling medication. Asymptomatic carriers are common. Artificial incubation of eggs and hand feeding nestlings can help establish a pathogen-free flock.

Malassezia spp Mala.ssezia spp have been reported in birds with feather picking and dermatologic conditions. In suspect cases, biopsy or cytology should be performed. Culture is often unrewarding. The recommended treatment is fluconazole at 5-10 mg/kg, PO, once to twice daily. Topical therapy with either dilute chlorhexidine 0. 1% spray or clotrimazole may be used alone or in conjunction with systemic treatment. Cryptococcus neoformans Cryptococcosis is worldwide in occurrence and caused by a saprophytic fungus, C1yptococcus neofonnans. This fungus is tmcommon in avian species, but it has been isolated from the fecal droppings of wild birds, particularly pigeons, and from feces of canaries and psittacine birds. C neo­ fonnans infection has been reported in Columbiformes, a Moluccan cockatoo, a thick-billed parrot, a green-wing macaw, and an African grey parrot. Veterinarians should be aware that not only can birds be carriers of the disease and become ill but also that C neoformans is zoonotic. Most hun1an irLfections with C neoformans occur in irnrnunocompromised individuals and are associated with environmental exposure, although cases have been reportecLin which contact with a pet bird appeared to be the source of irLfection. Clinical signs of Cryptococcus irLfection include weakness, lethargy, anorexia, diarrhea, and dyspnea. With CNS involve­ ment, neurologic signs such as blindness and paralysis may occur. Clinical diagnosis can be difficult. A definitive diagnosis requires demonstrating the organism on cytologic or histologic examination or culture. The organism is a round to oval yeast with a mucopolysaccharide capsule. A mucoid gelatinous exudate may be noted within the respiratory tract, coelomic cavity, sinuses, brain, or within the Jong bones. Treatment recommendations for birds include amphotericin B, itraconazole, ketoconazole, fluconazole, or voriconazole. Fluconazole or voriconazole are the drugs of choice for CNS or ocular irLfections.

Rhodotorula mucilaginosis Rhodotorula nwcilaginosis is a yeast occasionally seen in skin infection in raptors (falcons). It causes yellowish brown ctusty areas of the skin in the axillary or inguinal areas. Untreated lesions may develop into hyperkeratotic proliferative growtl1s. Diagno­ sis is based on physical exan1ination findings and results of cytologic or histopathologic examination and culture of infected tissues. Treatment involves excision of prolifera­ tive lesions and topical antifimgal tl1erapy. Antibiotics may be necessary to prevent secondary irlfections, and analgesics or anti-inflammatory drugs may be warranted for pain. Miscellaneous Mycoses Dermatophytosis, including Trichophyton and Microsporum spp is occasionally reported in pet birds. Treatment protocols for dogs and cats are used (seep 874). Histoplasmosis and mucormycosis are also occasionally reported in pet birds. PARASITIC DISEASES See also roui:rnv, p 2780 et seq. Parasitic disease has become less conm1on in captive parrots throughout the past20 yr with the restrictions against in1portation of wild-caught birds; many pet birds now are incubator hatched, hand raised, and have little to no access to the outdoors or to other birds. Commonly reported parasitic diseases include protozoa.I irLfections such as giardia­ sis in cockatiels, sarcocystis in larger parrots, and mites in budgerigars and passerines. Parasites of the Circulatory System See also BLOODBORNE ORGANISMS, POUl:rRY, p2780. Protozoa: Haemoproteus was previously documented with great frequency in imp01ted Cacatua spp. Leucocytozoon, P/.asmodium, and Atoxoplasma spp are all seen occasionally in various species, most commonly in raptors, canaries, and Columbifonnes, and are currently not of major significance in psittacines. Atoxo­ plasmosis is still diagnosed in canaries. Parasites of the Gastrointestinal System Giardiasis: Giardiasis has been reported in many species of birds but is most commonly seen in cockatiels. Adult birds may be latent

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PETBIRDS carriers. Transmission is presumably direct (ingestion of infective cysts). Affected cockatiels occasionally exhibit feather pulling in the axillary and inner thigh regions, along with vocalization. A true causal relationship between giardiasis and these clinical signs has not been proved. Droppings of affected cockatiels may be voluminous and aerated (a "popcorn" appearance). There are several ways to diagnose Giardia spp infection: the zinc sulfate flotation test of feces to detect cysts, the direct saline smear of fresh feces to detect motile trophozoites, and an ELISA test for Giardia spp antigen in feces. Because the presence of cysts is variable, serial tests may be needed. The accuracy of the Giardia. spp SNAP test designed for people is unknown. Metronidazole (50 mg/kg/day, for 5--7 days) or carnidazole (20 mg/kg/day, PO, for 1-2 days) is the recommended treatment. In cockatiels, treatment of giardiasis with fenbendazole at dosages extrapolated from dogs has been anecdotally reported to cause death. Trichomoniasis: Trichomoniasis has been

reported in many orders of birds, including Colurnbifom1es, Galliformes, Falconi­ formes, Psittacifom1es, and Passe1ifom1es. Trichomonas gallinae (called frounce in birds of prey and canker in Columbifom1es) is occasionally seen in pet birds, notably budgerigars. Clinical signs may include anorexia, dysphagia, weight loss, and dyspnea. Whitish yellow, caseous lesions adherent to the mucosa of the oropharynx, crop, and esophagus may be seen in raptors and Colurnbifom1es. Budgerigars generally do not have grossly visible oral lesions but do have increased salivation and regurgita­ tion. Transmission is by direct (parents feeding young) or indirect (ingestion of contaminated food and water) contact; raptors may become infected by ingesting infected pigeons or doves. Microscopic examination of a warm saline mount of material from the oral cavity may reveal the flagellated organism. Treatment protocols include carnidazole (20 mg/kg, PO, once), ronidazole (&--10 mg/kg/day, PO, for 14 days), or metronida­ zole (50 mg/kg/day, PO, for 5 days). Other Protozoa! Diseases: Other protozoan parasites such as coccidia are much more common in gallinaceous or Colurnbifonne birds, although coccidial oocysts are seen occasionally in psittacine and passerine birds.

1905

Cryptosporidiosis has been seen in a variety of avian species but is thought to be a secondary rather than a primary pathogen. Transmission of Cryptosporidium spp is through ingestion or inhalation of sporu­ lated oocysts. Because of the small size and low shedding rate of Cryptosporidium spp, diagnosis can be difficult, but a Sheather's sugar flotation test is best. An acid-fast stain can also be used to detect the organism. Clinical signs may involve the GI, respira­ tory, or urinary tract, especially in immunosuppressed birds. Treatment for cryptosporidiosis in birds is not described. Plasmodium spp infection (malaria) is highly pathogenic in gyrfalcons, canaries, and penguins. Plasmodium is spread by mosquitoes. Clinical signs may be none to weakness and death. Treatment for malaria, if needed, is with chloroquine. Atoxoplasmosis is a highly pathogenic protozoa! disease that causes hepatomegaly and splenomegaly in canaries, with coccidia­ like oocysts shed in the feces. The host becomes infected by ingesting the oocysts. Infected birds may be asymptomatic or exhibit anorexia, weight loss, diarrhea, and depression. Clinical disease is typically more severe in fledgling birds, whereas adults are often asymptomatic. Diagnosis is made by fecal flotation (best in adults), buffy coat smear with Romanowsky stain, liver impression smear, or PCR testing of feces. Treatment options are toltrazuril (12.5 mg/kg/day, PO, x 14 days) or sulfa­ chlorpyridazine (150-300 mg/L drinking water, 5 days/wk x 2-3 wk). Other protozoan parasites such as coccidia are much more common in gallinaceous or Co!umbiforme birds, although coccidial oocysts are seen occasionally in psittacine and passerine birds. Roundworms: Various genera and species of roundworms infect pet birds, and wild birds may transmit nematodes to captive parrots housed outdoors. Transmis­ sion is direct by ingestion of embryonated ova. Clinical findings include loss of condition, weakness, emaciation, and death; intestinal obstruction is common in heavy infections. Diagnosis of intestinal nematode infection is by fecal flotation, although shedding of ova may be intermit­ tent. Ivermectin (0.2 mg/kg, PO, SC, or IM, repeated in 10-14 days), pyrantel pamoate (4.5 mg/kg, PO, repeated in 10-14 days), or fenbendazole (20-50 mg/kg, PO, repeated in 14 days) are generally effective. In warm climates where exposure via outdoor aviruies is likely, routine deworming

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PET BIRDS

(every 6 mo) with one of these anthelrnin­ tics is often practiced.

Cestodes: Cestodes are uncommon in

domestically bred birds. The most common pet birds infected with tapewom1s are cockatoos, African grey parrots, and finches. Intennediate hosts are most likely insects and arachnids of various types, earthwom1s, and slugs. Infected birds are asymptomatic or are unthrifty, with or without diarrhea. Diagnosis is based on visualization of eggs on a fecal flotation. Praziquantel (5--10 mg/kg, PO or IM, once) is the recommended treatment. Recurrence is rare in cases in which the intermediate host is not indigenous to the area where the bird is housed.

Parasites of the lntegumentary System Scaly Face (Leg) Mite: Knemidocoptes pila.e (also Cnemidocoptes pila.e) is common in budgerigars and rare in all other psittacine species. In budgerigars, white, porous, proliferative encrustations involving the comers of the mouth, cere, beak, and occasionally the periorbital area, legs, or vent are typical. In passerine birds (particu­ larly canaries and European goldfinches), crusts fom1 on the legs and surfaces of the digits ("tassel foot"). The mites can be recovered from facial scrapings of budgeri­ gars, although the clinical appearance is generally pathognomonic. In passerines affected with Knemidocoptes, skin scrapings of tl1e legs often result in hemorrhage and are generally not recommended. Ivennectin (0.2 mg/kg, PO or IM) or moxidectin (0.2 mg/kg, PO or topically) is generally effective. The treatment is repeated in 2 wk. Feather Mites: Psittacine birds are seldom affected by feather mites. Occasion­ ally, infestation with the red mite (Derma.n­ yssus ga.llina.e) may be found in outdoor aviaries, especially in nest boxes. A causative relationship between mites and feather picking is often assumed by owners of feather-picking birds, although this is rarely the case. More commonly, behavioral, husbandry, and/or systemic factors are linked to feather loss (see p 1927). Mite-infested birds may be treated with pyrethrin sprays, 5% carbaryl powder, or ivermectin (0.2 mg/kg, PO or IM) repeated in 2 wk. Nest box treatment includes mixing 5% carbaryl powder into the nest box substrate. Cages should be cleaned thoroughly, and wooden nest boxes should be discarded and replaced.

Parasites of the Respiratory System Air Sac Mites: Ste1'nostoma. tra.chea.­

colum parasitizes the entire respiratory tract, most frequently of canaries and gouldian finches. The mites aie found in the trachea, syrinx, lungs, and air sacs. All stages of the mite are found within the respiratory tissues. The life cycle is poorly understood. In mild infections, birds are usually asymp­ tomatic; in heavy infections, audible dyspnea (high-pitched noises and clicking), sneezing, tail bobbing, and open-mouthed breatlling are noted. Copious amounts of saliva are seen in the oropharynx, and ptyalism may be present. Signs are exacerbated by handling, exercise, and other stresses. Mortality can be high. Transillumination oftl1e trachea in a darkened room occasionally reveals the mite. Response to treatment can help reach a diagnosis. When the recovery of an individual bird is paran10unt, treatment should be adminis­ tered quickly and with minimal handling. Ivermectin (0.2-0.4 mg/kg, PO or IM) repeated in 2 wk or moxidectin (0.2 mg/kg, PO or topically) repeated in 2 wk may be administered.

Sarcocystosis: Sarcocystosis is a major cause of mortality in parrots housed outdoors in the southern USA. In severely affected areas, even indoor birds can be infected via contaminated food. The oocysts of this protozoan parasite are passed from infected opossum feces by insects (eg, flies, cockroaches) or mice and rats into the feed cups or enclosure of the birds. The feces of these transport hosts are then consumed by the birds, and a rapidly fatal disease can develop. Old World species are immunologically naive to this disease, and a high mortality rate is observed in untreated birds such as cocka\ toos, African grey parrots, and Eclectus parrots. Cockatiels are also susceptible, and renal as well as pneumonic lesions are often noted at necropsy in this species. Although not contagious, cases tend to occur in clusters because the infected opossum feces are spread via insects around the aviary grounds. Large die-offs have been documented. Clinical signs are lethargy, passive regurgitation of water, respiratory distress, weakness, ataxia, and anemia. In Old World paiTots (eg, cockatoos, Afric3.11 grey parrots), disease occurs in the early stages of infection as the parasite is undergoing schizogony or merogony (asexual reproduction) in the lung. This causes lung dainage, 3.lld the birds die

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acutely with or without signs of respiratory distress. In New World parrots (eg, macaws, conmes), the organism encysts in the muscle or CNS, causing weakness, ataxia, or nemo­ logic signs. The disease can manifest as an asymptomatic or clinically apparent muscular disease, cardiac disease, acute pulmonary disease, or encephalitis. Encephalitis (paresis, intention tremors, and head tilt) has been seen in psittacines and raptors. No specific diagnostic test is available, although results of plasma protein electrophoresis may indicate infection (marked increase in 13-globulin concentra­ tions with or without a marked increase in gamma globulin concentrations). An indirect immunofluorescence antibody (IFA) test has been developed that may aid in antemortem diagnosis of the nonperacute form of sarcocystosis in psittacine birds. The sensitivity and specificity of the IFA test ranges from 83%-86%. Results of muscle biopsy may be conclusive for the encysted stages but is not commonly perfom1ed. When a muscle biopsy is done, the quadriceps muscle has been reported to be a better biopsy site than the pectoral muscle. Increases in enzyme activities of LDH, AST, and CK have been reported. Protracted treatment with trimethoprim/ sulfa (30 mg/kg, bid) and pyrimethamine (0.5 mg/kg, PO, bid) has had linlited suc­ cess. Response to treatment is generally monitored by serial PCV san1pling. Newer drngs used to treat infection by the related protozoa, Sarcocystis neurona, that affects horses have not yet been evaluated for treatment in birds. Gross necropsy findings include increased lung density, hemorrhage, and renal lesions. Clinical signs may also reflect CNS involvement. Histopathologic san1ples should include lung, kidney, muscle, and CNS tissue if neurologic signs are apparent.

VIRAL DISEASES Avian Polyomavirus (Papovavirus, Budgerigar fledgling disease, Psittacine polyomavirus)

Avian polyomavirus (APV) primarily affects young birds. There are two primary fonns of the disease based on species affected: budgerigar fledgling disease and a nonbudg­ erigar polyoma infection. Both are character­ ized by peracute to acute death of preweaned neonates. Adult birds typically are resistant to infection; they will seroconvert and shed the virus for up to 90 days, then clear the infection. The incubationpe1iod is 7-10 clays.

1907

The typical presentation of budgerigar fledging disease is a well-fleshed juvenile, just before fledgling age, with acute onset of lethargy, crop stasis, and death within 24-48 hr. Other clinical signs are cutaneous hemorrhage, abdominal distention, and feather abnormalities. Surviving budgeri­ gars >3 wk old often exhibit feather dystrophy (French molt or feather dusters). In other species of psittacines 35 days old, with a booster vaccination in 2-3 wk. Psittacine Beak and Feather Disease

Psittacine beak and feather disease (PBFD) is caused by a psittacine circovirus. The virus was first recognized in the 1970s in cockatoos with beak and feather lesions. Since then, it has been recognized in most species of parrots and also in Passeri.f01mes and Columbi.fom1es. Infected birds shed virus in their feathers, feather dander, feces, and oral secretions. Transmission occurs by inhalation and/or ingestion of the virus and can occur vertically. The virus is very stable in the environment, so fomites can be a signillcant source of infection. The nan1e is not as representative of the current typical clinical presentation, which often does not include beak abnom1alities and is less likely to have the severe, classic feather abnor­ malities seen in cockatoos when the disease was first documented. Use of screening PCR tests has greatly decreased the prevalence of the virus in captive bred Cacatua spp. However, disease is still seen in African grey parrots, Eclectus parrots, lovebirds (Agapornis), lorikeets, and other species, but is rare. The natural infection appears to occur primarily in juvenile birds, with few instances of clinical infection seen in birds >3 yr old. In the classic PBFD infection, the first indication of the presence of disease is a lack of powder down on the beak. The virus causes abnormal formation of growing feathers and inlmunosuppression. Feathers are pinched or clubbed at tl1eir base and may have hemon-hage within the developing shaft. The feathers fall out easily and grow back slowly or not at all. The distribution of affected feathers depends on the age of the bird and the stage of the molt when infected. Pigment loss may occur in colored feathers. The bi.rd may live with these lesions for months to years. As the disease progresses, the inlmune system is affected, and most birds die of secondary infections. A peracute f01m of the disease occurs in young birds, which develop enteritis and pneumonia, lose weight, and die. African grey pan-ots may develop a pancytopenia, because the virus attacks the bone marrow. These birds die suddenly with viral inclusions in the thymus, bursa, and bone marrow.

Diagnosis is based on clinical appear­ ance; results of PCR testing of feces, feather dander, or blood; and biopsy of affected featl1er follicles showing basophilic intracy­ toplasmic inclusions.,Testing by PCR may detect infection in birds tl1at still appear healthy. These birds may subsequently become ill or may mount an effective response to the virus. Because of tl1e stability of the virus, PCR analysis can also be used for environmental testing. Quarantine and retesting are recommended for PCR-posi­ tive, asymptomatic birds. At necropsy, affected birds often have no gross lesions internally, but intranuclear or intra.cytoplas­ mic inclusions may be seen histologically in the feathers, bursa, thymus, liver, or other organs. There is no specific treatment for PBFD, and treatment of infected birds is support­ ive. The contagious nature of PBFD and its generally tem1inal outcome in clinically affected birds warrant isolation and eventual euthanasia in most clinical cases. Strict hygiene with attention to dust control, screening protocols including PCR testing of both birds and tile environment, and lengthy quarantines are highly recom­ mended in breeding facilities with susceptible species. All new susceptible birds should be tested before introduction to the aviary. In infected breeding colonies, removing all eggs for cleaning and artificial incubation may also be required. Since the development of a PCR-based assay, prevalence of the disease has decreased. Pacheco's Disease

(Pacheco's herpesvirus) Psittacine herpesvirus is an alpha herpesvi­ rus that is the causative agent of Pacheco's disease and internal papiUomatosis in parrots. Pacheco's disease causes a viral hepatitis seen predoh1inantly in N�w World species (Amazon parrots, macaws, and conures). Internal papillomatosis occurs in parrots that have survived Pacheco's disease. Papillomatosis is most commonly observed in macaws, Amazon parrots, conures, and hawk-headed parrots. Disease is associated with stress, which can cause clinically healthy carriers to shed virus and initiate infection in susceptible birds, as often occurs during introduction of new birds, relocation, or in those with underly­ ing illness or during breeding. It is spread by direct contact, aerosol, or fecal contamina­ tion of food or water, with an incubation period of3-14 days. The outcome of tl1e infection depends on the genotype of the

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PETBIRDS vims, the species of bird infected, and the bird's overall health. Wected birds become chronic carriers and will remain persistently infected and intem1ittently shed tl1e virus tlu·oughout their lives. Old World species a.re Jess likely to be either ina.ppa.rent carriers or clinically susceptible. Patago­ nian species and some Aratinga spp may be natural hosts in the wild, and some individuals of these species may a.sympto­ matically shed vims when stressed. Other species can also a.ct as carriers. Ten11inal signs include a.cute death in well-fleshed birds and bright yellow ura.tes �itl1 scant feces. Other clinical signs a.re dia.ffhea., green ura.tes, lethargy, regurgita­ tion, weakness, and depression. Diagnosis in the live bird can be done by DNA probes of combined oral and cloaca! swabs or blood samples. Increases in plasma.AST activity and marked Jeukopenia. have been reported. Because of the a.cute nature of the disease, gross histologic lesions may not be evident. However, most affected birds will have hepa.tomegaly, splenomegaly, and renomeg­ aly. The liver may be mottled or grossly discolored. Ecchymotic and petech.ial hemoffha.ges may be present on the pe1ica.rdium and within the mesente1ic fat. Intra.nuclear inclusions a.re seen histologi­ ca.Jly in tl1e liver, spleen, intestinal epithe­ lium, and pancreas. Primary differential diagnoses for Pacheco's disease include a.cute salmonellosis, polyoma.virus, and psitta.cine reovitus. Acyclovir (80 mg/kg, tid, or 400 mg/kg in feed) can be used dilling an outbreak; however, the risk of increased transmission because of hanclling is great. Autogenous vaccines have been developed during outbreaks and have effectively decreased morbidity and mortality. An inactivated vaccine is available.

Cloacal papilloma, gross lesion, in a blue· fronted Amazon parrot. A red proliferative mass commonly originates from just inside the rim of the cloacaI opening. Courtesy of Dr. Louise Bauck.

1909

The lesions of pa.pilloma.tosis are predominantly present in the oral and cloaca! mucosa but may also be folllld internally in the intestinal tract, or less commonly, in the conjunctiva or bursa. Owners usually first notice blood from a papilloma. in the droppings, ancVor the pa.pilloma prolapses tlirough tl1e cloaca. Lesions may be mild or severe ( ulcerated and bleeding) and often wax and wane. Ulcerated lesions may need to be cauterized or surgically removed, although they typically recur. Treatment is supportive, such as analgesics, cautery, and antibiotics to prevent secondary infection. Antiherpes­ vit·al drugs a.re not curative and do not appear to in1pa.ct tl1e course of disease. Other Herpesvirus Infections:

Amazon tracheitis is also caused by a herpesvirus, although the incidence of this infection is low. Other clinically significant herpesvimses include the strain responsible for papillomatous foot lesions in Cacatua spp and the depigmentation lesions noted on tl1e feet of macaws. Avian Bornavirus/Proventricular Dilatation Disease (Macaw wasting disease)

Proventricula.r dilatation disease (PDD), also known as macaw wasting disease, neuropathic ganglioneuritis, lympho­ pla.smacytic ganglioneuritis, psitta.cine encephalomyelitis, and most recently avian bomavirus (ABV), was first recognized in the late 1970s in ma.caws imported into the USA and Gem1any. The disease p1ima.rily affects ma.caws, conures, and African grey parrots, although all pa.iTots a.re probably susceptible. The causative agent of this disease is avian boma.virus. The common presentation of affected birds is chronic weight loss (often following an initial increase in appetite), passage of tmdigested food (most easily recognized when whole seeds are found in the droppings), and regurgitation. A dilated proventriculus may be seen ra.diographi­ cally. Neurologic signs (convulsions, tremors, weakness, ataxia, blindness) may occur in some species, with or without concuffent GI signs. Clinical signs may be slowly progressive or develop a.cutely. Outbreaks a.re sporadic, with a low morbidity a.i1d a high mortality. Before the discovery of ABV as the causative a.gent of PDD, the only ante­ mortem diagnosis was identification of lymphopla.sma.cytic infiltrates in the tissues

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PET BIRDS

of affected birds, most commonly with a crop biopsy. Histopathologic lesions can be present in the brain, spinal cord, pelipheral nerves, nerves of the GI tract, heart, adrenal gland, lungs, and kidneys. Transmission is fecal/oral, and positive results of PCR testing of choanal, cloaca!, or fecal swabs confirms the presence of ABV. Serologic assays such as ELISA can also confirm exposure. Although the presence of ABV in the droppings indicates shedding, many birds are positive for ABV with no clinical signs of PDD. If or when these birds may develop disease is unknown. Because shedding of the virus is intennittent, one negative result of fecal or cloaca! PCR testing does not exclude disease. Testing at least three times at weekly intervals, with all three tests being negative, is best before declaling a bird negative for ABV. Differential diagnoses are heavy metal toxicosis, foreign body intestinal obstruction, internal papillomato­ sis, internal neoplasia, and GI infections (including bactelial and fungal proventlicu­ lar infections). Clinicopathologic findings vaiy, but increased plasma CK activity and mild lyrnphocytosis, monocytosis, or hetero­ philia may be seen. Proventiicular biopsies in affected birds are prone to dehiscence and are not done routinely. Crop biopsy is a less invasive diagnostic tool and may be useful if the collected sainple contains sufficient innervation to be diagnostic; however, a negative crop biopsy does not exclude the presence of PDD. Treatment for PDD includes providing easily digestible foods and may be aided by adn1inistration of an NSAID (eg, meloxicain, celecoxib). Isolation of positive"birds is in1portant in disease prevention. Testing by PCR (a minimun1 of three tests) and separating positive birds from negative birds is a recommended control measure, although the number of false-negative tests (due to intemtittent shedding) makes this a long and potentially difficult task. ABV is not a long-lived virus in the environment; therefore, good hygiene and ultraviolet light can help to linut spread of disease in a home or aviary setting.

birds are rarely exposed to a susceptible strain. Because of import restlictions, poxvirus in blue-fronted Amazon parrots is no longer commonly seen. In pet bird practice, vetelinalians will generally encotmter only canary, lovebird, and pigeon poxviruses and fowlpox (seep 2824), which have specific host ranges. Poxviruses are environmentally stable, increasing the likelihood that a viable orgaiusm will come into contact with a susceptible host. Poxviruses cairnot penetrate intact skin, and a break in the skin or mucous mem­ brane must be present for infection to occur. Poxvirus infection may cause cutaneous, diphthelitic, or systemic infections based on the strain of virus, route of exposure, affected species, and age and health of the bird. The cutaneous fonn appears as nodular proliferations or wartlike lesions on the unfeathered skin around the eyes, beak, nares, and legs. The diphthelitic forn1 is characterized by lesions on the mucosa, tongue, pharynx, and larynx. The septicenuc fo1m is characterized by a ruffled appear­ ance, depression, cyanosis, anorexia, and wartlike tumors of the skin. The cutaneous fonn is most commonly seen in psittacines and raptors. Clinical signs depend on the fonn of disease, location of the lesions (eye, oral, ear), and overall health of the bird and may include lethargy, respiratory distress, partial blindness, difficulty eating, weight loss, emaciation, and skin lesions. Diagnosis of poxvirus infection is typically confim1ed through history, physical exainination findings, and histologic findings of Bollinger bodies in affected tissues. Treatinent is usually nonspecific and may include supportive care, fluids, parenteral vitanun A, ophthalmic ointinents for eye infections, assisted feedings, and antibiotics to prevent or treat secondary ir)fections. Lesions on the skin may need daily cleaiung. Transntission is via insect vectors (mosquito bites) or other entry through breaks in the skin. Therefore, mosquito conti·ol and indoor housing are vital to prevent outbreaks. Vaccines for canarypox, fowlpox, and pigeonpox are available but are specific for their host species.

Poxvirus Infections

Viscerotropic Velogenic Newcastle Disease

Poxviruses are large DNA viruses that induce intracytoplasmic, lipoplulic inclusion bodies (Bollinger bodies) in the epithelial cells of the integument, respira­ tory tract, and oral cavity. All birds are considered susceptible to poxvirus infection, but many compaiuon and aviary

(Exotic Newcastle disease)

Viscerotropic velogenic Newcastle disease (VVND, seep 2856), caused by a parainyxo­ virus group 1, affects most avian species and is a significant threat to the poultry

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PET BIRDS industry. Transmission is by respiratory aerosols, fecal contamination of food or water, direct contact with infected birds, and fomites. Birds may be asymptomatic or die acutely. Clinical signs include depression, anorexia, weight loss, sneezing, nasal discharge, dyspnea, coajunctivitis, bright yellow-green diarrhea, ataxia, head bobbing, and opisthotonos. In prolonged cases, unilateral or bilateral wing and leg paralysis, chorea, torticollis, and dilated pupils also may be seen. Primary differential diagnoses include other paran1yxoviruses (non-Newcastle), psittacine proventricular dilatation syndrome, and heavy metal toxicosis. Lesions include hepatomegaly, splenomegaly, petechial or ecchyrnotic hemorrhages on serosal surfaces of all viscera and air sacs, airsacculitis, and excess straw-colored peritoneal fluid. Diagnosis is traditionally via viral isolation, but agar gel inununodiffusion tests that can be performed on whole blood or serum are available. Only symptomatic treatment is possible and thus not advised. If suspected, VVND must be reported to appropriate federal and state authorities. Vaccination is prohibited in birds entering the USA, because it does not eliminate the carrier state and hampers viral detection during quarantine.

Other Paramyxovirus Infections:

There are several less pathogenic strains of paramyxovirus. Paramyxovirus groups 2 and 3 are endemic in aviculture. Para­ myxovirus group 2 causes mild illness in passerines and a more serious disease in psittacines. Clinical signs in psittacines include tracheitis, pnewnonia, and enteritis. Paramyxovirus group 3 is reported most frequently in Neophema spp, lovebirds, and gouldian finches and typically causes mild disease. Clinical signs may be absent, and disease results in acute death. In disease of longer duration, respiratory signs, pancreatitis, and torticollis may occur. Diagnosis is the san1e as for para.myxovi­ rus group 1. Treatment for paramyxovirus groups 2 and 3 infections is supportive care. The vaccine for paramyxovirus group 1 should not be used in psittacines, because it can cause fatal reactions.

West Nile Virus West Nile virus (WNV) infection is an arthro­ podbome virus in the genus Flavivirus (fanilly Flaviviridae). WNV was first reported in birds in the USA in August 1999. Many species of birds can be infected, and it

1911

has been reported in >320 species of birds. The American crow (Corvus brachy1un­ chus) and other corvids have suffered particularly high morbidity and mortality. Other affected species include canaries, psittacines, and raptors. Although psittacines appear to be somewhat resistant, the disease has been reported in parakeets, cockatoos, conures, rosellas, caiques, lorikeets, and a King pan·ot. Affected parrots have been adults housed outdoors with docwnentation of mosquito populations present. Mosquitoes (Culex spp) are the p1incipal vectors of disease. Clinical signs include depression, anorexia, weight loss, head tremors, ataxia, blindness, seizures, and death. Juvenile birds are the most commonly affected. Ophthalmologic findings in raptors are anterior uveitis, exudative chorioretinal lesions, and chorioretinal scarring. Antemortwn diagnosis can be difficult. Initial diagnosis may be based on clinical signs, species, and age; however, many diseases may cause similar clinical signs. Serologic tests (serum neutralization) may indicate antibody response to infection. Paired samples submitted 2 wk apart may reveal a rise in antibody levels and give a more definitive diagnosis. Adult birds may have high circulating antibody levels in endemic areas. Diagnosis is often deter­ mined at necropsy. The brain and kidney are the preferred tissues to submit for histopathologic exan1ination. There is no specific treatment for WNV in birds. Some birds may improve witl1 supportive care (fluids, feeding, antibiotics/ antifungals as needed) and time. A vac­ cination protocol using a recombinant vaccine has been successful in some birds. The recommendation is vaccination of captive birds 2-4 wk before mosquito season, with a booster 3 wk after the initial dose. During the mosquito season, birds should be housed indoors or in completely covered outdoor facilities. Mosquito netting and mosquito traps should be used, and any standing or stagnant water sources eliminated.

Avian Influenza Avian influenza is caused by an orthomyxo­ virus. Because of the zoonotic potential of some strains and the recent discovery of new mutations, this virus may become a more significant pathogen. Both the zoonotic potential and the economic effects on the poultry industry are causes for concern. (See also AVIAN INF'LUENZA, p 2902.)

1912

PET BIRDS

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GERIATRIC DISEASES Until recently, geriatric medicine has been a neglected area of avian medicine. Infectious diseases, inadequate diets, and poor husbandry meant that most pet birds did not live long enough to develop geriatric conclitions. As the knowledge base of avian medicine, nutrition, and proper husbandry has grown, so has the life span of pet birds increased. Most pet birds have tl1e potential to live 20-80 yT, depending on tlleir size (with smaller birds having a sho1ter life span and larger birds a longer life span). Witl1 pet birds living longer, tile incidence of ge1iat:tic-onset diseases, including cataracts, neoplasia, arthritis, and cardiovascular disease, has increased. Cataracts Cataracts occur in many species of psittacine birds as they age, notably macaws, Amazon parrots, and cockatiels. These species may be prone to cataracts or may be overrepresented in t11e older pet bird population. If tile onset of cataracts is gradual, adaptation to decreased vision usually occurs; if not, clinical signs can be depression, inactivity, and reluctance to come out of or move around in t11e cage. The eyes of older birds should be examined annually to detect early changes in lens opacity. Because of tile small size of the exposed cornea and pupil in psittacines, and tl1e nun1erous acquired diseases that can occur, screening by an ophtllalmologist is rec01runended. Cataracts often develop secondary to infection or trauma or may be age related. Uveitis may also be present. Additional ophthalmic 700-800 mg/dL) and glucosuria, along with clinical signs of disease. Treatment includes converting the bird to a healthier (pelleted) diet and limiting treats. Response of birds to mammalian insulin is variable, and insulin treatment is generally less effective in birds than in mammals. Regular insulin at 0.1--0.2 U/kg has been used successfully to stabilize birds. Longer-acting insulins (NPH or ultra-Lente) at 0.067-3.3 U/kg, once to twice daily, have been used for longtem1 control. Bird owners are often reluctant to give injections to their birds, so often oral antidiabetic medications are used. Glipizide (0.5 mg/kg, PO, bid, or 1.25 mg/kg/day, PO) and metfonnin ( 100-500 mg/L of drinking water) have been used anecdotally. Water intake, urine output, weight, and glucosuria should be monitored to deteffi1ine whether the treatment protocol is effective. Il} some cases, dietary conversion and weight loss can result in resolution of the clinical signs, reducing or eliminating the need for oral medications or insulin. Gout: Gout is the abnom1al deposition of uric acid in the body. Uric acid is the major end product of protein breakdown in birds. It is produced and secreted primarily in the kidneys and liver and eliminated by tubular secretion. Elimination is independent of glomerular filtration rate. Hydration has only a minimal effect on plasma uric acid levels; therefore, hyperuricemia can be an indicator of renal disease in birds. Gout typically occurs secondarily from increased plasma uric acid levels. Articular gout occurs in the joints (most often the metatarsal and phalangealjoints) of birds, and visceral gout occurs on the serosa of various organs and is commonly found on the pericardium, liver, and spleen. Clinical signs of articular gout are pain, lameness, swelling in the joints, depression, anorexia, and dehydration. Visceral gout is

rarely diagnosed antemortem and is typically found at necropsy. Acute death is often the only clinical sign. The serosal surface of various organs and the renal tubules are the locations of uric acid deposition.Diagnosis of articular gout is by identifying gout tophi-whitish yellow, subcutaneous, and intra-articular deposits that demonstrate uric acid crystals on staining. Uric acid levels commonly are increased. Treatment includes fluid therapy to reduce uric acid levels and analgesics for pain. Articular gout tends to be severely painful. lf effective pain control cannot be accom­ plished, euthanasia should be considered. Surgical removal of these tophi is not practical in most cases, because they are extremely vascular and the risk of fatal hemorrhage is high. Additionally, unless the underlying condition can be identified and corrected or controlled, new tophi will appear very rapidly. Allopurinol (10-30 mg/kg/day, PO) and colchicine (0.04 mg/kg, PO, once to twice daily) may be useful in control of articular gout. The genetic, nutritional, or environmental factors that predispose a bird to gout are not fully understood. However, current treatment of birds with increased uric acid levels include conversion to an appropriate diet (this may be a pelleted diet in some species) or a diet change to whole grains, seeds, fruits, and vegetables for some smaller birds such as cockatiels and budgerigars (for whom a pelleted diet may be a factor in renal disease). Essential fatty acids (omega 3) at 0.1--0.22 mllkg/day, PO, have been used anecdotally to manage renal disease in birds.

This macaw has a single, large ingrown feather or feather cyst. Canaries are commonly affected with multiple feather cysts. Courtesy of Dr. Louise Bauck.

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PET Bl RDS Feather Cysts: Feather cysts are ingrown feathers that result in a granulomatous mass. Recurrence is common unless the extensive dissection of the feather follicle is accom­ plished. In birds witl1 multiple affected feathers, such as the genetically predisposed Norwich canary, this is not practical. Feather Destructive Behavior: The phrase "feather plucking" is commonly used to describe behavior that ranges from mildly excessive preening to self­ mutilation. Management of this condition is frequently challenging. Feather plucking seldom has a single etiology, and it is prudent to thoroughly explore all possible contributing factors, including underlying medical problems. Good communication concerning feather plucking in birds at the onset will help owners realize that this is a complicated behavior that is difficult to stop. The goal should be to improve tl1e health of the bird and to reduce (or elimi­ nate) the plucking behavior if possible. Possible medical causes for feather plucking include: 1) Endoparasites (espe­ cially giardiasis in cockatiels) and, rarely, tapeworms or roundwom1S. 2) Ectoparasites (rarely). 3) Hepatic disease, with associated pruritus. 4) Coelomic cavity granuloma or mass. 5) Neoplasia, which typically causes localized plucking of the area associated with an underlying mass. 6) Folliculitis or dennatitis that is primary, or secondary to excessive plucking and/or mutilation. Bacteria, viruses, fungi, or yeasts may be involved. 7) Allergies. Although difficult to confirm, a change in environment or diet when allergens are suspected may lead to a decrease in plucking and a tentative diagnosis by elimination. 8) Endocrine abnormalities, the most likely being hypothyroidism. However, hypothyrnidism is overdiagnosed in part because of the lack of established normal values for avian thyroid levels, the low range for baseline T4 noted in birds, and difficulty in obtaining a reliable thyroid­ stimulating hormone (TSH) response test. Nevertheless, some obese birds that demo­ nstrate a lack of weight loss after aligid diet, accompanied by poor quality featl1ers and infrequent molts, may be thyroid deficient. The plucking exhibited by these birds is often an attempt to rid themselves of old, damaged feathers. 9) Heavy metal toxicosis, notably zinc. Barbering and feather plucking from zinc ingestion have been hypothesized. Many of these cases lack radiographic evidence of heavy metal and require a blood zinc analysis for diagnosis.

1927

Malnutrition is likely a more common contributing factor to feather plucking than the medical conditions listed above. Basic seed and table food diets often create multiple nutritional deficiencies. These deficiencies cause abnormal skin and feather development resulting in plucking behavior, as well as myriad other medical problems that may occur. The dyes and preservatives added to seeds and most pelleted diets may be a factor for some birds. The relatively low humidity in most households also has a drying effect on the skin. Being deprived of natural sunlight, fresh air, humidity, and the nom1al light/ dark cycle has negative physiologic and psychologic effects on birds. A diagnostic evaluation for a bird with feather destructive behavior may include a CBC, biochemical profile, viral testing, skin biopsy, radiographs, and/or endoscopic examination. Behavioral feather picking should be detem1ined only after a complete evaluation that excludes as many medical causes as possible. Treatment is based on the findings of the diagnostic evaluation. A hom10nal bird may need an injection of leupolide acetate, a GnRH agonist, to reduce reproductive behavior, along with environmental changes (seep 1920). Altl10ugh treatment of medical and environmental factors may reduce tl1e severity of feather plucking, a strong behavioral component is often involved. Treatment of some of the above-mentioned problems may lead to initial improvement, followed by a relapse. Psychologic stressors can lead to feather plucking as a displace­ ment behavior. Unfortunately, once the stress has been relieved, the habit may still remain. Feather plucking does not occur in the wild, where birds are occupied with finding food, maintaining their social status in the flock, seeking a mate, avoiding predators, and breeding and raising young. Therefore, often the best-kept birds, which have all tl1eir apparent needs met, will pluck feathers for behavioral reasons. Psychologic conditions that may cause featl1er plucking in birds vary. Overstirnulation may cause plucking in a nervous bird. Another bird that plucks from boredom may feel both stimulated and slightly threatened by increased activity in the home and stop plucking to pay attention to the environment and guard itself against potential predators. Birds that reach sexual maturity may begin to pluck as an outlet for their increased energy and agitation. Owners of these birds often report that tl1eir birds show more cage territoriality, more

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PET BIRDS

aggression toward family members, and potentially, sexual behavior toward a perceived human mate or inanimate objects. All feather destructive behavioral issues require a multimodal treatment approach that involves proper nutrition, eruichment, providing foraging opportunities and, in some cases, psychotropic medications (see TABLE 20). Neither of these catego1ies of drugs tends to produce longtenn positive results, and adverse effects may be seen. As is true of most medications administered to pet birds, these drugs are not approved by the FDA Psychotropic drugs should not be used alone but only in conjunction with dietary modifications, enrichment, and foraging opportunities. In addition, changes may need to be made in the owner/bird interactions. Dietary modifications include both conversion to a healthier fomrnlated diet and providing foraging opportunities for the bird. Owners can place food in

multiple food dishes throughout the cage or hide food inside foraging toys to stimulate normal foraging behavior. Enrichment can be provided in the form of natural branches, toys, wood to chew on, multiple play gyms throughout the house, natural sunlight, and ideally a flight cage to encourage activity. Exercise should be encouraged, either through flight or walking and climbing activities. Rope and boing perches stimulate activity and balance. Teaching birds tricks such as waving, dancing, and recall can provide intellectual stimulation and positive interaction between the owner and bird. In addition to traditional medical therapies, acupuncture has been reported to be helpful in some cases. Dietary supple­ mentation with omega fatty acids has been repmted to be helpful. Whether this is due to the antiprostaglandin effect or a true fatty acid deficiency is not certain.

PSYCHOTROPIC MEDICATIONS USED FOR FEATHER PLUCKING IN PET BIRDS Medicationa

Dosage

Comments PSYCHOTROPIC MEDICATIONS

Arnitriptyline

1-2 mg/kg, PO, once to twice daily

Maximal effects may require treatment for several weeks.

Clomipramine

l mg/kg/day, PO

Effects similar to those of amitriptyline but may be effective in some cases in which amitriptyline is not.

Diazepan1

2.5-4 mg/kg, PO, as needed

Limited usefulness; most birds require a close that causes sedation to inhibit plucking.

Haloperidol

0.15 mg/kg, PO, once to twice daily for larger birds; 0.2 mg/kg, PO, bid for smaller species

Serious adverse effects, including anorexia, hepatic dysfunction, and CNS signs have been reported; most often used in cockatoos.

Fluoxetine

2 mg/kg/day, PO, once to twice daily

Effectiveness reported to vary; maximal effects may require treatment for several weeks.

HORMONES Medroxypro­ gesterone acetate GnRH agonist, eg, leuprolide acetate

Decreases sexual behavior; not recom­ mended because of serious adverse effects, including weight gain, polyuria, polydipsia, lethargy, hepatopathy, diabetes mellitus, and death. 300-800 mcg/kg, IM

a All are extra-label usages.

Decreases sexual behavior by negative feedback, reducing production of sex hormones.

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POTBELLIED PIGS An ideal medical treatment is not likely to be found for feather plucking in captive birds. Environmental manipulation, ensuring quality nutrition, and psychologic adaptations suited to the species and temperament of the bird offer the best hope to reduce this syndrome. Consultation with a board-certified behaviorist fan1iliar with psittacines may be indicated.

Hypersensitivity Pneumonitis:

A respiratory condition sinlilar to chronic obstructive pulmonary disease (COPD) has been reported in macaws (prinlarily Blue and Gold macaws). These birds often have a history of being housed with birds that produce large amounts of powder down, such as cockatiels and cockatoos in poorly ventilated environments. The birds may also have secondary bacterial or fungal infections. Clinical signs include increased respi­ rations, exercise intolerance, dyspnea,

1929

respiratory distress, and cyanosis of the facial skin. Diagnosis is based on a history of being housed with feather down-producing birds in poor ventilation with respiratory disease and often polycythemia (>600/-700A,). Pulmo­ nary biopsy is diagnostic. Histopathologic lesions are confined to the lower respiratory tract. The most prominent lesion is atrial smooth muscle hypertrophy and some atrial loss due to fusion and epithelial bridging. Treatment is supportive care and removal of the bird from the offending environment. Improved ventilation and separation from birds that produce powder down is critical. NSAIDs such as meloxi­ cam (0.5--1 mg/kg, PO, once to twice daily) may help reduce inflan1mation. AJbuterol (0.05 mg/kg, PO, bid) has been used anecdo­ tally. Birds should be housed to reduce stress and minimize exertion. Often, birds with confirmed pulmonary hypersensitivity will not have a normal life expectancy.

POTBELLIED PIGS Potbellied pigs (PBPs) have a short to meclium wrinkled snout, small erect ears, large jowls in proportion to the head, short neck, pronounced potbelly, swayed back, and straight tail with a switch at the end. The CON and LEA lines of PBPs at l yr of age should not be>18 in. at the withers (ideal height �14 in.) or weigh> 95 lb (ideal weight � 50 lb). The life span of PBPs is probablyS--20 yTwith -10-15 yr typical. Very small or obese PBPs may have a shortened life span. For hematologic and senun biochemical reference ranges, see TABLES 6 and 7, pp 3176 and 3178. The term "teacup" pigs has no strict definition, and it is difficult to make an educated guess of mature size without seeing the parents and grandparents, which is rarely possible. Mature size is also heavily influenced by adequate nutrition. ln general, when pigs are "selected for smaller size," in addition to nutritional stunting, many other possible problems of miniature pigs may be magnified. These include hypoglycemia, idiopathic seizures, musculoskeletal defom1ities, heart disease, cleft palate, atresia ani, and reproductive problems such as dystocia and agalactia.

MANAGEMENT Environment: PBPs are sensitive to extremes of heat and cold and should be provided a clean, dry, draft-free environ­ ment. Adults are usually comfortable in a temperature range of 65-75°F (18.3-23.9°C). Because pigs do not sweat, temperatures �85° F (29.4°C) are stressful to adults. Extended exposure to high temperatures combined with high hwnidity may be fatal to PBPs not acclimated to such an environment. Cooling methods for adult PBPs include moving air across the body, wetting the skin for evaporative cooling (more efficient as hwnidity decreases), providing shade, and resting on cool surfaces. Newborn pigs are very susceptible to drafts and chilling and require an environ­ mental temperature of -90° F (32 °C). Chilled pigs will pile on each other and shiver, and their hair will stand on end. A poor environ­ ment may cause neonates to become moribw1d and hypoglycemic (see MANAGEMENT OF'THE NEONATE IN LARGE ANIMALS, p 2088) within 24--36 hr. Heat lamps or pads can be used to provide supplemental wam1th, but their use

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POTBELLIED PIGS

should be monitored closely because of the electrocution risk from chewed cords; pigs tl1at become too hot will spread out and pant. Housing: PBPs may be housed outdoors or indoors (or both) but must be appropri­ ately acclimated to the specific environmen­ tal situation. PBPs housed outdoors should have a large pen (�50 sq ft/pig) with a structure within to provide sleeping, feeding, and watering areas. Pigs will use dirt for elimination, and daily removal of feces and addition of fresh dirt to cover and absorb urine is required. Hay or straw may be added to prutially satisfy the need to root. However, "rooted-up" pen ground should be filled in with fresh dirt from time to time. Fencing should be well secured in the ground to prevent it from being rooted up, but it should also be portable so that the entire pen can be moved periodically, giving access to fresh, clean dirt. The old pen dirt should then be smoothed out and left wmsed for several montl1s before being used again. If pens are maintained on solid surfaces (eg, concrete pads), feces and urine should be removed daily, and fresh hay or straw provided as needed. Water dispensers must be secured to keep pigs from spilling the water by rooting or dru11aging the device by chewing. PBPs housed indoors should have a particular area (eg, a laundry room), with an elimination area in one comer and a sleeping and eating area in another corner. A litter box with the side cut down to accommo­ date easy entry and exit may be used for elimination. Nontoxic material should be used for litter because pigs are curious and tend to chew on everything. A blanket may be provided to allow the pig to burrow under and partially satisfy the need to root while indoors; a box of dirt is another alternative. Exercise: PBPs should be exercised whether kept outside or indoors. They may be trained to walk on a leash or released into exercise areas. Daily exercise is important not only for physical health but also to relieve boredom that may otherwise manifest as destructive chewing or rooting or as aggression. Even if the PBP does not exercise much when given the oppo1tunity, the various stinmli from an outside environment appear to be beneficial to overall temperan1ent. Many household and garden plants are toxic to PBPs, which are adventw·ous eaters (seep 3103). Temperament: As healthy, neutered PBPs mature, they may become more aggressive

and challenge other PBPs or people for status. Such challenges need to be addressed, or the pet may leru11 to use aggression to get what it wants. A combination of aversive techniques (eg, hand clapping, grnff vocalizations, stomping) and rewarding the PBP for positive behavior may help manage the problem. Failure to deter this unwanted behavior is a common reason why PBPs are placed in rescue operations or abandoned. Vaccinations: Neutered PBPs should be vaccinated against erysipelas and tetanus. Tetanus toxoid is especially important in PBPs housed outside in contact with other species (eg, petting zoos). Leptospirosis vaccine (6-way) may also be considered, but there is a substantial risk of high fever after use. Vaccines are not specifically approved for PBPs, so those commercially available for domestic swine are substituted. Two initial vaccinations 3---4 wk apart ru·e followed by boosters every 6 mo for erysipelas and every year for tetanus, or both boostered yeru·ly at the time of armual physical exan1ination. Breeding PBPs should be minimally vaccinated against erysipelas, leptospirosis (6-way), and pruvovirus; tl1ey should be vaccinated twice, 3---4 wk apart, before breeding and before rebreeding or every 6--12 mo. Other vaccines should be used as exposure risk indicates. Routine vaccination against various pathogens not only minimizes sickness but helps prevent zoonotic disease and may satisfy require­ ments for pet licensure. Safety and efficacy are concerns when using conunercial domestic swine vaccines in PBPs. Consid­ eration should always be given to the an1ount of antigen per body weight that is injected, especially in small pigs. Excessive antigen administration may cause adverse reactions. No rabies vaccine is approved for use in PBPs because of tl1e extremely low incidence of rabies in swine in the USA. Parasite Control: External and internal parasites are possible health problems in PBPs, and the zoonotic potential of sarcoptic mange and roundwonns should be considered when counseling owners. Fecal san1ples via fecal flotation may be evaluated in PBPs as early as 6 and 10 wk old for whipwonns and roundworms, respectively. Dewonners, such as oral fenbendazole at 3 mg/kg/day for 3 days; ivennectin at 300 mcg/kg, SC; or doran1ectin at 300 mcg/kg, IM, should be used as indicated. Iajectable ivennectin and dorrunectin are highly effective against sarcoptic mange, the most conunon external parasite in PBPs.

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POTBELLIED PIGS

Dental Care: The eight needle teeth (four deciduous lateral incisors and four deciduous canines) of newborn PBPs should be trimmed to prevent injury to littermates and laceration of the sow's underline. Four pennanent canine teeth erupt at -5-7 mo of age and are first trimmed at or after l yr of age. Elongated permanent canine teeth may cause discom­ fort, malocclusion, and persistent chewing motion and salivation. In PBPs, the canine teeth grow continually and should be cut about once a year using obstetrical wire, mechanical saws, or other instruments. Sedation or anesthesia is required. Teeth should be cut as close as possible to the gum line without cutting the oral mucosa or lips; there should be no exposed root canal after cutting the canine teeth of any type of swine. Tetanus antitoxin (500-1,500 U, depending on PBP size) and antibacteri­ als are usually administered. In PBPs properly vaccinated with tetanus toxoid, a tetanus antitoxin injection is unnecessary. Tartar buildup can be removed manually by instmment scraping at the same time the canine teeth are cut. Dental cleaners for small animals may be used with care, positioning the head of the PBP downward during use to prevent water aspiration. Geriatric PBPs may have abscessed and/ or exposed tooth roots; sedation (tiletamine­ zolazepam 2.2 mg/kg, IM, in ham) and exami­ nation of the oral cavity with or without endoscopy is indicated if anorexia and/or bruxism are reported. Radiographs may be necessary to diagnose tooth root abscessa­ tion. Swelling followed by a draining tract at the angle of the mandible, especially in geriatric PBPs, indicates canine tooth abscessation. Removal is challenging even for skilled surgeons and may result in mandibular fractures. However, PBPs seem to recover well after tooth extraction followed by antibiotics and tetanus prophylaxis. REPRODUCTION Females: First estrus occurs as early as 3 mo of age in gilt piglets. The lack of estrus or a distended abdomen in a young gilt may be due to pregnancy if she has been exposed to littermate boars. If the female does not cycle, the abo1tifacient prostaglandin F2o:, given as two injections (8 mg and 5 mg in a 25-kg pig) 12 hr apart, can be administered when corpora lutea have become suscepti­ ble to luteolysis after day 13 after estrus. Estrus should occur 3-7 days later.

1931

Dystocia is of special concern in PBPs. Because the birth canal is too small to inspect for unborn pigs via palpation, radiography or ultrasonography may be indicated to reveal undelivered piglets. Oxytocin (5-10 U) may be used to aid delivery if the vaginal canal is patent. The decision to perform a cesarean section, if indicated, should be made promptly, before the sow becomes toxic and has friable uterine tissue and vessels. Cesarean section may be performed by several approaches, but the right flank approach has two advantages: the piglets nurse away from tl1e incision, and gravity pulls the incision shut, minimizing the chance of dehiscence. Regardless of surgical approach, surviving piglets will probably require hand-raising. Ovariohysterectomy in PBPs at 4-6 mo of age is ideal. Older female PBPs generally display irritable behavior for 2-3 days of estrus out of every 21 days of the estrous cycle. Perforn1ing an ovariohysterectomy during estrus in older PBPs is a formidable task because of the tremendous vasculature in the broad ligan1ents of the horns of the uterus; surgery should be delayed until -7-10 days after estrus. A distal midJine approach, as if perforn1ing a cystolomy, is routinely used for ovariohysterectomy. The uterine horns fold back and are located beside the body of the uterus witll the ovaries. No ovarian ligament teruing is necessary as in dogs and cats. Penetration of the cervix by sutures should be avoided when ligating the uterine stump to prevent intermittent postsurgical hemorrhage from the vulva. A right flank approach may be used in extremely obese PBPs, in which wound dehiscence could be a complication. Isoflw·ane or sevoflurane anestllesia provides excellent muscle relaxation. (Malignant hyperthennia [seep 1027] has been reported only once in a PBP under isoflurane gas anesthesia, so it is thought to be rare in PBPs.) Hypothermia during and after surgery is an important concern. A baseline rectal temperature should be recorded at anesthesia induction, and normal body temperature should be maintained until recovery is complete. Injectable anestlletics such as xylazine plus tiletanline-zolazepam can delay normal tl1ermoregulation for 5-6 hr after anestlle­ sia. Because some PBPs may become apneic when placed in prolonged dorsal recwnbency, intubation is preferred to masking; however, PBPs may be difficult lo intubate, and prolonged efforts at intuba­ tion may cause laryngeal edema and postsurgical complications.

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1932

POTBELLIED PIGS

Early spaying also reduces the risk of ovarian cysts, uterine tumors, and cystic endometrial hyperplasia. An obviously distended abdomen is seen with large ovaiian or uterine masses (;:,,20-30 lb). Vulvar hemorrhage may be a sign of uterine tumor and can be life-threatening. Although most ovarian or uterine masses can be surgically removed, some are so extensive and invasive that euthanasia is required. Males: PBP boars retained for breeding should be kept in secure pens; they should not be kept as pets because of the unpre­ dictable behavior of boars around other animals or people. Neutering is usually performed at 8-12 wk of age, using it\jectable or gas anesthesia. One protocol for it\jectable anesthesia is xylazine at 2.2 mg/kg, IM, followed by tiletamine-zolaze­ pan1 at 6.6 mg/kg, IM, both injections in the ha.ins. Detennining whether both testicles ai·e descended before surgery is itnportant because cryptorchidism is seen in PBPs. An inguinal hernia is another possible complicating factor. The midline skin incision is made craiual to the scrotum, and structures such as the vas deferens and blood vessels ai·e ligated a.11d excised similar to the procedure in dogs. Both inguinal ring areas should be closed to prevent hernia­ tion. Removal of tunic, cremaster muscle, a.11d extraneous subcutaneous tissue, followed by closure to obliterate empty space, help prevent seroma fom1ation. At the titne of castration, the preputial diverticulum or "scent gland" may be removed by eversion and excision to minimize the pooling and discharge of foul-smelling preputial fluid. Umbilical hernia may complicate removal. Early castration may interfere with the develop­ ment of the preputial diverticulun1, making its removal urmecessary, especially in PBPs kept outside. Tetanus antitoxin (if no current tetanus toxoid vaccination) and antibacterial injection are given after surgery of the reproductive tract.

FEEDING AND NUTRITION Fresh water should be available at all titnes to prevent dehydration and salt toxicity (water deprivation). Balanced diets are essential to provide proper daily nutrients and prevent obesity. Starter, grower, and maintenance rations for PBPs are commer­ cially available as crumbles or pellets. The recommended an1ount per body weight should be fed divided into at least two meals/ day. Rations for commercial domestic swine,

available in meal, crumble, or pellets, may also be used with professional veterinary guidance. Green leafy vegetables, alfalfa, and green grasses (but not weeds, because some are toxic) can be added to the ration to satisfy appetite. Fruits such as apples and grapes may be given in litnited an10unts. High-energy treats should be avoided because PBPs tend to become overweight. Even when calorie intake is restricted, weight loss is difficult because the minitnal ainount of exercise possible in obese PBPs burns few calories. Laineness is another conunon factor litniting exercise capacity. Maintaining nonnal hoof length via tritnming is itnportant for mobility. Swimming is an alternative form of exercise for obese, lame PBPs, but acclitnation and supervision is necessary. Young weaned PBPs thrive best if adequate colostrum was conswned within the first 24 lu· of life. PBPs deprived of colostrum easily succumb to diarrheal and septicemic disease. For early nutrition, commercial milk replacers are available, but 2%-3% pasteurized milk or powdered milk also can be used successfully. Approxi­ mately 1 oz every 4--6 hr should be fed from a bottle with a nipple until the pig is trained to drink the milk from a shallow bowl or pan; usually, this can be done in 3 kg), the ear veins can also be used. The auricular or marginal ear vein provides a site for venous administration or catheterization. Drugs should not be if\iected through the ear veins, because this can lead to phlebitis and subsequent ear sloughing. Only physiologic crystalloid fluids should be administered via the ear vein. The centi·al aitery can be accessed for direct blood pressure monitoring during anesthesia; no drugs should be injected into the central aitery. The auricular vasculature is sensitive to temperature; having the rabbit wann (or

at least having the eai· wann) and applying a topical anesthetic cream greatly facilitate tl1ese procedures. Clinical Pathology: Clinical pathology in

rabbits vaiies from that in other domestic animals. The n01mal neutrophil:lymphocyte ratio is 1: 1. The rabbit neutrophil is called a "pseudoeosinophil" or heterophil because of its red-staining cytoplasmic granules. Both the heterophil and the granules are smaller tl1an the eosinophil and eosinophil red granules. Rabbits do not usually respond with a leukocytosis to an active infection. In case of stress, tl1e ratio of the heterophils and lymphocytes changes toward a relative heterophilia without increasing the total WBC count. Many sick rabbits have hemoglobin and PCV values much lower than nonnal; this makes the PCV one of the best indicators of healthy or sick animals. Calcium metabolism in rabbits results in higher norn1al blood calcium levels (up to 16 mg/dL) and a wider range than in other animals, which can lead to an e1Toneous diagnosis of hypercalcemia. Rabbit urine ranges from yellow to brown or reddish. A dipstick can quickly differenti­ ate norn1al rabbit urinary pigments from hematuria. Traces of glucose and protein are normal in rabbit U1ine. Therapeutics: Very few products are licensed for use in rabbits, leading to exti·a-label use of drug therapies approved for use in other species. Paiticulai· caution must be exercised in use of antibiotics that suppress norn1al GI microflora and result in enteric dysbiosis and/or enterotoxemia. This has been called "antibiotic toxicity." Antibiotics contraindicated in rabbits include clindan1ycin, lincomycin, erythro­ mycin, arnpicillin, arnoxicillin/clavulanic acid, and cephalosporins. The flea treat111ent fipronil is contraindicated in rabbits because of severe toxic reactions in some individuals. Supportive care for rabbits often includes aggressive IV fluid support. The maintenance fluid rate for rabbits ( 120 mUkglday) is much higher that1 that for dogs and cats. Hospitalized rabbits often require doubling of maintenat1ce rates, or 10 mllkglhr. In addition to fluid support, pain control is also commonly needed. NSAIDs and opioids are often used in synergy. The dosage of meloxicain in rabbits is 1 mg/kg/ day, which is also signi.ficat1tly higher that1 tl1at in dogs at1d cats. Opioids such as oxyrnorphone or hydromorphine cat1 readily be used at1d have not been shown

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to cause GI stasis. In most cases, additional force feeding is not required, and the rabbit should be offered food after fluid and pain management has been initiated. Syringe­ assisted feeding can be offered to see whether the rabbit is interested in food intake. In rare cases in which the rabbit refuses to eat, eg, cases of severe hepatic lipidosis, active feeding is necessary; treatment may require aggressive nutritional suppmt via syringe feeding, nasogastric tube (3-5 French), or pharyngostomy tube (soft esophagostomy tube designed for cats). The least invasive method is often the most successful approach. Vaiious commercial products for assisted feeding of rabbits are available. Products are available for immediate c1itical care (eg, Emeraid®) as well as for longterm assisted feeding and to meet the needs of the recovering rabbit (eg, Recovery®, Recovery Plus®, Critical Care®).

Reproduction: Rabbit breeds of medium size are sexually mature at 4-4.5 mo, giant breeds at 6-9 mo, and small breeds (eg, the Polish Dwarf and Dutch) at 3.5-4 mo of age. The rabbit is an induced ovulator and, contrary to popular belief, has a cycle of mating receptivity; rabbits are receptive to mating -14 of every 16 days. The degree of mating receptivity is indicated by the color of the vaginal orifice and by the an10unt of moisture on the labia. A doe is most receptive when the vagina is red and moist. Does that are not receptive have a whitish pink vaginal color with little or no moisture. Many breeders test mate the doe 10-16 days after breeding as a way to detect preg­ nancy, but this is unreliable. Palpation of the doe's abdomen for "grape-sized" embryos in the uterus is a much better technique to detect pregnancy. The best time to palpate is 12 days after breeding. Pseudopregnancy is common in rabbits and can follow any induced ovulation, the introduction of a male rabbit in the environment, or other stimuli. A ratio of l buck to 10 does is common practice, but many commercial growers find that l buck to 20-25 does is more economi­ cal. Bucks can be used daily without decreasing fertility; more frequent use requires periods of rest. The doe should always be taken to the buck's cage for breeding. The breeding program should continue year round. Does that experience long periods of rest between litters tend to become obese and difficult to breed. Docs constantly in gestation and lactation may become underweight, and their receptivity to the buck and fertility decrease dramati-

1939

cally. If breeding is delayed several weeks and the doe is given full feed, weight is quickly regained. The gestation period is -31-33 days. Does with a small litter (usually S4) seem to have a longer gestation period than does that produce larger litters. If a doe has not kindled by day 32 of gestation, oxytocin (1-2 IlJ) should be given to induce parturi­ tion; otherwise, a dead litter is almost always delivered sometime after day 34. Occasion­ ally, pregnant does abmt or resorb the fetuses because of nutritional deficiencies or disease. Nest boxes should be added to the cages 28-29 days after breeding. If boxes are added too soon, the does foul the nests with urine and feces. A day or two before kindling, the doe pulls fur from her body and builds a nest in the nest box. The young are born naked, blind, and deaf. They begin to show hair on day 2-3 after bi.Jth, and their eyes and ears are open by day 10. Neonatal rabbits are unable to them1oregulate until about day 7. Rebreeding can occur any time after parturition, because the doe can conceive 24 hr after kindling. Some commercial growers use accelerated breeding schedules and rebreed 7-21 days after parturition, whereas most people raising rabbits for show or home use rebreed 35-42 days after parturition. Most mediun1-sized female rabbits have 8-10 nipples, and many kinclle 12-15 yOLmg. lf a doe is unable to nurse all the kits effectively, kits may be fostered by removi.J1g them from the nest box during the first 3 days and giving them to a doe of approxinlately the same age with a smaller litter. lf the fostered kits are mixed witl1 the doe's own kits and covered with hair of the doe, they are generally accepted. Moving the larger kits to the new litter instead of the smaller kits increases the chance of success. Does nurse only once or twice daily. Kits nurse 5,000 IU/kg and 4% fat. This is manifest as Jipemia and is more pronounced in males. Gerbils excrete little urine, and fecal pellets are hard and dry. Their cages require less frequent cleaning than other pet and laboratory rodents. Gerbils adapt to a wide range of an1bient temperatures. Because they have a propensity to develop nasal dermatitis at relative hwnidities >500A,, a low hun1idity is advisable. Gerbils require sandbathing to keep their coats from becoming oily. The lipids have two sources: Harderian gland nasal excretions spread by autogrooming and sebaceous exudates from the skin. The consequences of lipid removal by sandbath­ ing a.re multiple; it not only cleans and grooms the pelage but also deposits lipids on the substrate that a.ct as olfactoty signals. Sandbathing is usually completed within 5 min. Additionally, it has homeo­ static consequences. Hair color lightens in Mongolian gerbils allowed to sand bathe. When sandba.thing is prevented, accumulat­ ing hair lipids mat the pelage;and behavior changes. Sandbath-deprived gerbils increase their frequency of "sand rolls" (rolling onto their side or back and returning to their feet within 1 second), decrease grooming, and increase territorial marking (especially males). Gerbils often stand erect on their hindlin1bs, so it is irnpmtant that cages have a solid bottom and that the floor-to-lid height is tall enough to allow for this behavior. Pet gerbils kept in inferior cages painted with lead pa.int or that use alloys containing lead have a high potential to develop chronic lead toxicosis because of their gnawing behavior and the urine-concentrat­ ing ability of their kidneys. Chronically, gerbils become emaciated, livers are small and pigmented, and kidneys are small and pitted. Microscopically, acid-fast inclusions

a.re noted in the proximal collecting tubules and hepatocytes.

Physical Examination The gerbil's overall appearance and behavior, pa.iticularly in relation to its cagemates, should be noted. Sick animals are often isolated from others a.i1d may demonstrate weight loss, hw1ched posture, letha.i·gy, rough fur, labored breathing, and a loss of exploratory behavior. Early signs of illness involve changes in the color, consistency, odor, and a.inount of urine and feces. The perinea! area should be checked for fecal or urine stains or discharges from the vulva in females. Fecal sa.inples may be taken for parasite detection and bacterial culture. The fw· and skin should be exa.inined for alopecia, fight wounds or other trauma, ectopa.i·asites, and elasticity for evidence of dehydration. The oral cavity should be checked for overgrown teetl1. Ea.is and eyes should be exa.inined for discha.i·ges or inflammation. Feet should be exa.inined for sores and overgrown or broken nails. The abdomen should be palpated for masses. Normal body temperature is 98 °-102° F (37°-39° C). Respiratory rate or signs of labored breath.ing should be noted. The thorax can be auscultated with a pediatric stethoscope. Gerbil tails are fragile, and only the base of the tail should be grasped during handling to avoid injury. Infectious Diseases Bacterial, Mycoplasmal, and Rickett­ sial Infections: "Facial eczema," "sore

nose," and nasal dermatitis all describe a common skin condition seen in gerbils. Clinical lesions next to the external nares appear e1ythematous initially, progress to localized alopecia, and develop into an extensive moist dem1atitis. The cause is believed to be increased Harderian gland secretion of porphyrins (simila.i· to chromodacryoIThea in rats), which act as a primary skin irritant. Experimental Ha.i·deria.i1 gland-adenectornized gerbils do not develop nasal or facial lesions. Various staphylococcal species (St,aphylococC'us aureus and S xylosus) may act synergisti ­ ca!Iy to produce the dermatitis. Stress factors such as environmental humiclity >50% or overcrowding cause excessive Harderian gland secretion. Nasal dennatitis infection may extend to tl1e maxilla.i-y sinuses. Affected gerbils develop anorexia, stop drinking water, lose weight, and die. The distribution and nature of the lesions

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RODENTS

are useful in diagnosis. Accwnulated porphyrins will fluoresce W1der ultraviolet light (Wood's lamp). Routine bacte1iology yields isolation of pathogenic staphylococci. Treatment includes carefully cleaning the skin lesions and use of topical (chloram­ phenicol l % ophthalmic ointment, tid) or parenteral antibiotics (except streptomycin, which is fatal in gerbils). Prevention requires reduction of environmental hwnidity below 400,6, reduction of sources of stress such as overcrowding, or sandbath deprivation. Naturally occurring Tyzzer disease, an enterohepatic disease caused by the obligately intracellular bacteriwn Clost1id­ ium piliforme, is the most frequently described fatal infectious disease of gerbils. Conunon clinical and pathologic findings are sudden death or death after a short period of disease, and the presence of multiple foci of hepatic necrosis. Diarrhea and necrotic lesions in the intestinal tracts are variably present. The probable route of infection in naturally occurring infection is by mouth, because gerbils exposed to infected bedding will contract Tyzzer disease. Supportive fluids and prophylactic treatment with doxycycline (5 mg/kg, PO, bid for 7 1-0 days) or metronidazole (20 mg/kg, PO, bid for 7-10 days) are recom­ mended to reduce mortality in cagemates. Because the bacteria form spores, the housing environment should be thoroughly sanitized and disinfected. The Mongolian gerbil is susceptible to infection by Helicobacter pylori, which causes severe gastritis, gastiic ulceration, and intestinal metaplasia. Gastric adenocar­ cinoma develops in approxin1ately one-third of infected gerbils>15 mo old. Clostridium dilficile-associated fatal enterotoxemia has been associated with treatrnent using nutritionally balanced triple-antibiotic wafers (containing amoxicillin, metronida­ zole, and bismuth) to eliminate naturally occurring Helicobacter infections. Affected animals are repo1ted to die within 7 days of antibiotic treatment. Viral Infections: Naturally occmring viral infections of gerbils are not reported. Parasitic Infections: Syphacia obvelata,

the mouse pinwonn, and Dentostomella translucida, an oxyurid, are found in Mongolian gerbils. Pet store gerbils often are infected with mouse pinworms. D translucida is commonly foW1d in the small intestine of both research and pet gerbils. There is an average of four parasites per animal, but no clinical manifestations of disease are associated with tl1e infection.

2013

Infections with dwa.rftapewonns,

Hymenolepis diminuta and Rodentolepis (fom1erly Hymenolepis) nana, are

reported in pet gerbils. Dehydration and mucoid diarrhea are often presenting signs. R nana has a direct life cycle and may potentially infect people if ingested. Recommended tream1ent is niclosarnide fed at 10 mg feed/100 g body wt for two 7-day periods separated by 1 wk Also effective are thiabendazole (0.33% mixed in the feed for 7-14 days) or praziquantel (5-10 mg/kg, IM, SC, or PO, repeated in 10 days). Historically, reports exist of pet gerbils infected with the tropical rat mite Ornitho­ nyssus bacoti (seep 2030). Fungal Infections: There have been no reports of naturally occuning or experi­ mental dermatophyte infections in the Mongolian gerbil. Other fW1gal infections in Meriones spp are exceedingly rare. Metabolic and Nutritional Disorders

Gerbils develop spontaneous, insidious periodontal disease after 6 mo on standard laboratory rodent diets. On the same diets, -lO"Aiof the animals will become obese, and some will show decreased glucose tolerance, increased sefillll immwioreactive insulin, and diabetic changes in the pancreas and other organs. Traumatic Injuries

Thin skin covers the tail of the gerbil. Unlike rats or mice, if a gerbil is picked up by the tip of its tail, the skin will often slip off, leaving a raw, exposed tail that eventually becomes necrotic and will shed. If the tail skin is lost, the bare tail must be surgically amputated where the skin ends. Iatrogenic Conditions

A fatal syndrome of acute toxicity is produced in Mongolian gerbils after injection of penicillin-dillydrostreptomycin­ proca.ine combination. The toxicity is due to the dillydrostreptomycin, and 50 mg will produce almost l OO"Aimortality in adult gerbils. Approximately 20"/o-400,6 of gerbils develop reflex, stereotypic, epileptiform (clonic-tonic) seizures from -2 mo of age. Animals seize in response to sensory stimulation and forced exploratory behavior, but t11e incidence and severity of their seizures are variable; the seizures generally pass in a few minutes, may be mild or severe, and have no lasting effects. Although tile incidence and severity of seizures often decrease with age, certain

VetBooks.ir

2014

RODENTS

subsets of adult gerbils do not improve with age but progressively become more severe. The susceptibility is seen in selectively bred lines but may occur in pet gerbils. Seizures can be suppressed in genetically predis­ posed gerbils if they are frequently stimulated by handling during the first 3 wk of life. Anticonvulsant therapy is unneces­ sa.iy. Cystic ovaries occur frequently in Mongolian gerbils. Cysts range in size from 1-50 nun in dia.i11eter. Removal of affected ovaries does not sigruficantly affect reproductive perfom1ance. Females with one ova.iy are slightly inferior in fertility compared with normal females; a general decline in fertility may be evident in older females. Neoplasia Ma,jor surveys of spontaneous neoplasia in laboratory colonies of Mongolian gerbils have been reported. A 25%---4()0A, incidence of neoplasia in gerbils usually occurs after 2-3 yr of age. Squa.i11ous cell ca.i·cinoma of the sebaceous ventral marking gland in males and ova.i·ian granulosa cell tumor in females account for SQOA, of tun1ors seen in animals >3 yr old. The ventral marking gland tumors invade locally a.iid can metastasize to lymph nodes and lung. Adrenoco1tical tumors, cutaneous squa.i11ous cell carcinoma, maligna.iit mela.iioma, and renal a.iid splenic hema.iigiomas were the next most com­ monly repmted tumors. Numerous other tumors, including duodenal and cecal adenocarcinoma, hepatic lympha.iigioma, hema.iigioma a.iid cholangiocarcinoma, splenic and renal hema.iigioma, uterine leiomyoma mid hema.iigiopericytoma, ovarian teratoma, testicular teratoma, and maligna.iit mela.iioma, were also reported. However, the total incidence of these tumors was 2 yr old. Cholesteatomas in the ear canal displace the tympanum into the middle ear. Compression and seconda.iy infection result in bone necrosis and inner ear destruction. Clinical signs include head tilt. Zoonotic Risk There are no specific reports of zoonotic disease transmitted by pet Mongolia.ii gerbils, although pet gerbils infested with Ornithonyssus sylvimum (tl1e nmthem fowl mite) and Derma.nyssus gallinae (the chicken mite) have been the source of avian mite den11atitis in children. Avian mite infestation is a rare cause of pmritic dem1atoses in people. The mites spend most of their life cycle on the avia.i1 host but may be transmitted to people by direct or indirect contact. The scarcity of reports may be a true reflection of the absence of zoonotic disease in gerbils or may reflect their low popularity as a pet rodent.

GUINEA PIGS Guinea pigs, like chinchillas, are hystJ.icog­ nath rodents. They belong to tl1e fa.i11ily Cavidae, which contains 14 species of animals commonly known as cavies and Patagonian hares (or ma.i·as). Four digits on the forepaw and three on the hindfoot characterize Cavidae. A stocky build, large head, short legs, and unfU1Ted, short ears characte1ize guinea pigs. Head and body length is 200-400 rru11, there is 110 external tail, and weight is 500-1,500 g. In South America, wild cavies inllabit rocky areas, sava.imas, forest edges, and swan1ps from Colun1bia and Venezuela southward to Brazil and northern Argentina. They live in groups of up to 10 individuals and inllabit burrows that they or other animals dig. They are most active at night, when they forage for a variety of plant materials. Domestication of the guinea pig began at least by 900 BCE and may have begun as early as 5,000 BCE. Biology The An1erican Cavy Breeders Association recognizes 13 breeds that it divides into groups or varieties. The most conu11on breed is the American cavy and was known 01iginally as the English cavy. Self cavies are

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RODENTS a group of solid-colored animals (eg, black, cream, red, lilac, beige, saffron, and chocolate). Nonselfs are a group made up of the coated breeds, the marked breeds, and the ticked or agouti breeds. The coated cavies include the Abyssinian, Rex, Longhaired varieties (Peruvians, Silkies, Shelties, Coronets, and Texels), Crested, Teddy, and Satins. The short, wire-haired_ Abyssinian may look unhealthy because its coat is arranged in whorls or rosettes, giving it a rufl1ed, untidy appearance. An tmdercoat and projecting guard hairs make up the normal fur coat of a cavy. The Rex has short guard hairs that do not appear above the level of the undercoat, the Satin breeds have an abnormal hair fiber that produces a sheen, and the Teddy breeds have a kinked or bent hair shaft that causes the coat to stand erect over the entire body. The marked group contains Dalmatian, tortoise shell, and Himalayan varieties. The tern1 "variety" describes a color (eg, steel grey, tortoiseshell) that is not yet a recognized breed. Several researchers have analyzed guinea pig calls and distinguish between 7 and 11 distinct sound patterns. Although different authors have given different nan1es to each unique sound, there is general agreement on at least 7 sounds. Lymphocytes are the predominant WBC in guinea pigs and range from 45%-809u of the WBC count. Many small lymphocytes are sinlilar in size to erythrocytes. Large lymphocytes contain Kurloff bodies, large intracytoplasmic mucopolysaccharide inclusion bodies. Kurloff bodies are seen under normal conditions in guinea pigs and are estrogen dependent. Pregnant females may have 2%---5% lymphocytes with Kurloff bodies in their peripheral blood; they are present in large numbers in adult females, and numbers fluctuate with the stage of estrous cycle. There are few Kurloff bodies in adult males, and they are rarely seen in newborns. Like chinchillas, guinea pigs share unusual reproductive physiologic charac­ teristics of hystricomorph rodents. Female guinea pigs (or sows) have a pregnancy of 68 days (range 59---72 days) and an average estrous cycle length of 17 days (range 13-25 days). They have a vaginal closure membrane that is open at estrus and parturition but sealed during anestrus and pregnancy. Guinea pigs have an average of 4 young per litter, with a range of 1---13. The young (of both species) are born fully furred and well developed. Young guinea pigs usually nurse for 21 days, although they can smvive on solid food alone after 5

2015

days. Guinea pigs have only a single pair of inguinal nipples. Male guinea pigs have pronounced penile styles or spicules on the glans penis. Yotmg male guinea pigs reach puberty at -3 mo of age and females at 2 mo. Guinea pigs live 6---8 yr. Husbandry As a species, guinea pigs are extremely adaptable to a great range of climates, although as individuals they are highly susceptible to vaiiations in local tempera­ ture and hmnidity. Guinea pigs are nervous animals and may refuse to drink or eat for a period after any significant change in their location, feed, or husbandry. The effect of environmental changes on guinea pigs is minimal or nonexistent when two ailimals are kept together. If a sick guinea pig must be kept in hospital, housing a cagemate with the sick animal reduces stress. Guinea pigs live in fainily units centered on an alpha male. Mature males, and especially strangers, will fight. However, two males raised together from a young age or a group of nonbreeding females will not enc0tmter dominance problems. Social problems are diminished with castration and ovariohysterectomy, but lea.111ed behavior in adult males after castration may still make them antisocial. Guinea pigs require a constant source of water that must be changed daily. They dirty their water bowls or sipper tubes with food when they drink They do not lick sipper tubes without training, defecate· indiscriminately, and are prone to sit in and soil their food bowls and sleeping areas. However, they are generally good eaters and not as fussy as rabbits. Guinea pigs produce two types of fecal pellets: one nitrogen-rich intended for cecotrophy, and one nitrogen-poor delivered as fecal pellets. When food is continually available, -400/o of the feces are reingested, and 900/o of this coprophagy occurs at night. However, when food is limited, guinea pigs ingest feces during parts of the day when food is unavailable. Physical Examination Guinea pigs are easy to hold and restrain. Although they do not bite, very young guinea pigs may nip. Healthy guinea pigs feel "dense" and are alert. Fatigue, lack of interest in surroundings, and light body weight are often general signs of illness. Sick guinea pigs may show evidence of weight loss, hunched posture, abnormal gait, drawn in abdomen, scruffy fur, or

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2016

RODENTS

labored breathing. They may be lethargic or unresponsive to stimulation. Respiratory and GI conditions are most commonly encountered; thus, ocular or nasal dis­ charges or diarrhea may be present. Feet should be examined for sores or broken nails. Teeth may sometimes overgrow and should be checked. However, the mouth is small, and examination of the oral cavity is difficult. Ears and eyes should be examined for discharges or inflammation, and the submandibular area should be examined for swellings. Venipuncture can be difficult in guinea pigs because of the lack of obviously accessible peripheral veins. The lateral saphenous vein and the cephalic vein are useful to draw small amounts of blood. For large an1ounts of blood, the anterior vena cava can be used, with the guinea pig under anesthesia. This technique requires practice. If performed incorrectly, there is a risk of death associated with intrathoracic, pericardia!, or pulmonary hemorrhage. Infectious Diseases Bacterial Infections: Streptococcus equi subsp zooep·idemicus (previously S zooepidemicus) may be carried in

the nasopharynx as a latent infection. Abrasions of the oral cavity (eg, molar malocclusion) allow bacteria to be transported to draining lymph nodes of the head and neck, causing suppurative lymphadenitis. Clinically, guinea pigs present witl1 large, unilateral s�ellings in the neck. The affected aninlal is often in good flesh and shows no other signs of disease. The differential diagnosis should always include cavian leukemia. Treatment is surgical excision of the affected lyii1ph nodes and systemic antibiotic treatment. Bacterial culture and antibiotic sensitivity should always be recommended. Strepto­ cocci are generally sensitive to chloran1phenicol (50 mg/kg, PO, bid), and this antibiotic is "safe" to give systemically to guinea pigs. Alternative "safe" antibiotics are azithromycin (15-30 mg/kg/day, PO; discontinue if soft feces) and fluoroquino­ lones; however, bacterial resistance to these antibiotics is now frequently seen. StreptococC'Us pneumoniae may be carried in nares as an inapparent infection. Predisposing factors for development of bacterial pneumonia are changes in environmental temperature, humidity, or ventilation. This always occurs in winter in guinea pigs kept outside. The young, old, and pregnant are the most susceptible. Clin­ ical signs of pneumonia are dyspnea,

wheezy breathing, sneezing, nasal discharge, and coughing. The affected guinea pig becomes depressed and anorectic. S pneumoniae infections are nearly always associated with middle ear infection and head tilt. Increased rndioden­ sity of the affected tympanic bulla may be seen on radiographs. Because of limited antimicrobial sensitivity, chloramphenicol (50 mg/kg, PO, bid) is the recommended treatment. A major differential diagnosis for pneumonia is Borclete/J.a bronchiseptica infection. Rabbits may harbor B bronchiseptica in their respiratory tracts without developing disease. However, this organism is an aggressive pathogen in guinea pigs, causing pneumonia, conjunctivitis, otitis media, abortions, and stillbirths. The clinical signs include anorexia, inappetence, nasal and ocular discharge, dyspnea, and often sudden death (this could also include S pneumoniae and S equi zooepidemicus). Rabbits and guinea pigs should not be housed together as pets. Treatment is ciprofloxacin (10-20 mg/kg, PO, bid). B bronchiseptica possesses a �-lactamase and is resistant to many penicillins and cephalosporins and mostly resistant to trimethoprim-sulfarnethoxazole. Most isolates are sensitive to doxycycline (2.5--5 mg/kg, PO, bid) and fluoroquinolones (marbofloxacin, 4 mg/kg/day, PO; cipro­ floxacin, 10-20 mg/kg, PO, bid; enrofloxa­ cin, 5--10 mg/kg, PO, bid for 14 days). Salmonella infections were historically common in guinea pigs in research colonies. With present standards of husbandry, rodent control, and good quality feed, the disease rarely occurs. It is most likely seen when guinea pigs are kept outside and wild rodents have access to their feed. Disease is more often seen in young or stressed animals. Wection may be subclinical, and diarrhea is rarely present. Clinical signs include conjunctivitis, fever, lethargy, anorexia, rough fur, palpable hepatospleno­ megaly, cervical lymphadenitis, and abor­ tion in pregnant sows. Mortality is often high in epizootic outbreaks. If aninlals recover, organisms may be shed intermit­ tently. Diagnosis is accomplished by isolating the organism from blood, ocular secretions, lymph nodes, or spleen. Because of zoonotic considerations and the potential for a carrier state, treatment is not recommended. Chronic dermatitis (especially of the forepaws) is a common condition usually seen in obese guinea pigs housed on wire or abrasive floors. Poor sanitation is also a predisposing factor. The feet are swollen

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RODENTS and hairless with ulcers and scabs 1-3 cm in diameter on the plantar surface. Staphylo­ coccus aureus is the usual causative agent and probably enters the foot through a cutaneous w0tmd. Awns and straw in the bedding can also cause foot puncttU"es. The inflanunation can progress to osteoa.ithritis and systemic amyloidosis secondary to chronic staphylococcal infection. Surgical treatment is often tmsuccessful, because there is rarely an abscess to be excised or drained but rather a diffuse cellulitis that infiltrates sw-rounding tissue. 'Treatment involves housing the affected guinea pig on clean, dry, soft bedding, topical or pa.i·enteral administration of antibiotics, and foot ba.i1da.ges as needed. Unfortunately, the condition may not respond to therapy. Chlan1ydial coajunctivitis is one of the most conunon causes of infectious coajunctivitis in guinea pigs. It is caused by Chlamydia caviae, an obligate intracellular ba.cteriwn. Clinical disease usually is found in young aninlals 4-8 wk old. Rhinitis, lower respiratory tract disease, and a.bo1tion ca.ii also occur. Concmrent ba.cte1ial infections can contribute to the respiratory symptoms. C caviae can rapidly spread through a breed­ ing or resea.i·ch colony. The orga.ilism infects primarily the mucosal epitheliun1 of the coajunctiva. and, less frequently, the ge1lital tract of guinea pigs. Asymptomatic infection can occur, but clinical disease most often results in mild inflanmiatory coajunctivitis with a slight, yellow-white discharge, co11iw1ctival hyperemia., chemosis, and even severe coajunctivitis with profuse, purulent ocula.i· exudate. Demonstration of intra.cyto­ plasmic inclusion bodies in Giemsa.-stained coajtmctival epithelial cells often confirms the diagnosis. The most sensitive and reliable method of diagnosis of chlamydiosis is PCR testing. Antichlamydial therapy with doXYcycline (5 mg/kg, PO, bid for 10 days) is the treatment of choice and usually results in complete recovery. Guinea pigs develop short-lived inunwlity to C caviae and, after a short petiod, may be susceptible to reinfection. Viral Infections: Adenovirus is species­

specific for guinea pigs and may ca.use a prinla.ry respiratory pnewnonia. The a.symptomatic carrier state is thought to be common, but prevalence is Lmknown. Clinical disease, while rare, can be initiated by stress or inhalation anesthesia. and occurs more often in i.J.1unw1ocompromised, young, or aged animals. Morbidity is low, but anin1als usually die suddenly without clinical signs.

2017

Other na.tttrally occurring viral infections of gui.J.1ea. pigs such as cytomegalovirus a.i1d parainfluenza. rarely ca.use detectable clinical disease. Serologic surveys indicate that guinea pigs will develop a.i1tibodies to rat and mouse pathogenic viruses but do not develop disease. Parasitic Infestations: Ma.i1ge, ca.used

by the sa.i·coptid mite 11-ixacarus ca.viae, is a common disease. The clinical signs are dra.inatic: intense pruritus, widespread alopecia., and hyperkeratosis. T caviae is tra.J1S1nitted through direct ani.J.nal-to-a.ilimal contact from sow to weanlings dwing feeding, and tlu-ough contact witl1 infested cage mate1ial such as bedding. The mites may be capable of existing subclinically, becoming active with stressors (such as sllipping or pregnancy), i.J.mnunosuppres­ sion, or otl1er underlying diseases. In affected ani.J.nals tl1a.t exhibit hematologic cha.i1ges such as heterophilia., monocytosis, eosi.J.1ophilia., and ba.sophilia, vigorous scratching may ttigger convulsive seizures. The seizw·es a.i·e controlled by diazepam (1-2 mg/kg, IM, as needed). The clinical prestm1ptive diagnosis should be confirmed with several skm scrapings, usually revealing a massive T caviae infestation. Treatment involves ivermectin (0.4-0.5 mg/kg, SC, repeated 2-3 tinles at inte1vals of 7-10 days), or spot-on dermal treatment with either selamectin (15 mg/kg for 800 g body wt). The guinea pig should also have a whole body washing with fipronil repeated twice at intervals of7-10 days. Fipronil should not be used when open skm wow1ds are present. Other ectopara.sitic diseases are infrequent in guinea pigs. Westation with the fur mite Chirodiscoides caviae may result in pruritus and alopecia. along the posterior trunk of the body, while underly­ ing skm is relatively Lma.ffected. SubclinicaJ cases may be a.symptomatic. Treatment is with sela.i11ectin (15 mg/kg for 800 g body wt) adminis­ tered twice at 2-wk intervals. Lice infestation with either Gyropus ovalis or Gliricola porcelli is usually a.symptomatic but in severe cases may lead to prwitus, alopecia, and flaky skin surfaces around the neck and ea.i·s. Lice may be obsetved di.J."ectly on ha.i.J.· shafts with a magnifying glass. A si.J.1gle application of 0.05 rnL of a topical solution containing l()OA, inlidacloprid and 1% rnoxidectin is an effective treatment fur lice infestations i.J.1 guinea pigs. Prevention is a.i.J.ned at i.J.11proving sanitary conditions in the aninlal's environment.

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Fungal Infections: Dennatophytosis is common in guinea pigs, and natural infection is always associated with Trichophylon menlagrophyles var menlagrophyles. Lesions typically begin as broken hairs and circular, scaly alopecia initially occurring at the tip of the nose, which spreads to the periocular, forehead, and pinna! areas. In severe cases, the dorsal sacrolumbar area is also affected, but the lin1bs and ventrum are usually spared. Pruritus is usually minimal or absent. Some animals have more inflam­ matory lesions characterized by erythema, follicular papules, pustules, crusts, pruritus, and occasional scar1ing. High temperature and humidity may contribute to a more severe infection. Tmentagrophyles can be isolated from the skin and fur in up to 15% of clinically normal guinea pigs. Guinea pigs can be tested for dennatophytes by using a new toothbrush to comb all parts of the hair coat and impress the bristles onto dennatophyte test medium (DTM) in several sites. In a healthy animal, dermatophytosis is generally a self-limiting disease, with full resolution after development of an appropriate cell-mediated immune response. In inummocompetent animals, this usually takes 100 days. Nevertheless, treatment is recommended because it will accelerate resolution of lesions caused by dermatophytes, thereby minimizing the tin1e course of the infection and mininlizing tile potential for spread to other animals or people. Whenever possible, c_uring the infection in the pet, while simultaneously decontanlinating the environment, is desirable. Environmental control should be performed every 14 days with enilconazole (0.2%) or concentrated chlorine laundry bleach (1:10) solutions.

Ringworm (Trichophyton) in a guinea pig. Dermatophyte infections on guinea pigs are often located on the face, back, or front feet. Courtesy of Dr. Louise Bauck.

Treatment is systemic therapy with or without topical treatment. Spot-on treatment products should not be used alone, because they may predispose individuals to chronic subclinical infection. Rather, whole-body shampooing, clipping, or rinsing with topical antifungal agents in conjunction with systemic therapy is preferred. For topical therapy, either enilconazole (0.2% at a dilution of 1:70) or miconazole shampoo (with or without chlorhexidine ), once or twice weekly, can be used. Enilconazole is licensed for use as an environmental disinfectant and is used off-label in treatment of dermatophytosis. Systenlic therapy is either itraconazole (10 mg/kg/day, PO) or terbinafine (30-40 mg/kg/day, PO) for 4-8 wk. Lesions may resolve in 2-3 wk, but antifungal therapy should be continued until two DTM cultures a.re negative, with a 2-wk inte1val between cultures. Often, dermatophyte infections of the skin require 2-3 mo of therapy. Metabolic and Nutritional Disorders

Guinea pigs of all ages require a dietary source of vitamin C. The stability of vitamin C in diets varies with composition of the diet, storage temperature, and hun1idity. The feed content of vitamin C is reduced by dampness, heat, and light. In fortified diets, approximately ha.If of the initial vitamin C may be oxidized and lost 90 days after the diet has been mixed and stored at tempera­ tures >22 ° C (71.6° F). Water in an open container may lose up to 500A, of its vitamin C content in 24 hr. Aqueous solutions of vitamin C will more rapidly deteriorate in metal, hard water, or heat and are more stable in neutral to alkaline solutions. Clinical signs of hypovitaminosis C include diarrhea, alopecia, and pa.in (from joints); animals are thin and unkempt. Petechiae on mucous membranes a.re not always seen, although hematuria may be present. Guinea pigs will show signs of vitamin C deficiency within 2 wk if it is not provided. Serum hypercholesterolemia (>60 mg/dL) and hypertriglyceridemia (>30 mg/dL) is seen in vitamin C--deficient guinea pigs after an overnight fast. Guinea pigs need -10 mg vitamin C/kg body wt daily for maintenance and 30 mg vita.min C/kg body wt daily for pregnancy. Vegetables high in vitamin C include red or green capsicwns, tomatoes, spinach, and asparagus. Metastatic calcification occurs most often in guinea pigs >1 yr old. Clinically, anin1als present with muscle stiffness and failure to thrive. Mineralization may be confined to soft tissues a.round elbows and 1ibs. Mineral

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deposition may also be more widespread, involving lungs, heart, aorta, liver, kidneys, uterus, and sclera. Dietary factors such as a low-magnesium and high-phosphorus diet, and high calcium and/or high vitan1in D intake have been implicated. Feeding conunercial, high-quality guinea pig diets has reduced the incidence seen in labora­ tory colonies. There are two other, similar syndromes in guinea pigs that affect either the skeletal muscles (muscular dystrophy) or the myo­ ca.rdiun1 and skeletal muscles (muscular degeneration and mineralization). These two conditions are associated with a vitamin E/selenium deficiency. A separate, incidental finding of multifocal mineraliza­ tion of individual muscle fibers may be seen in major muscles of hindlimbs. Affected anin1als are often asymptomatic. Spontaneous diabetes mellitus is common in guinea pigs. The clinical manifestations are mild or variable. Guinea pigs show polydipsia and weight loss while maintaining a good appetite. Hematology and urinalysis show glycosuria, hyperglycemia, and high serum triglyceride levels; ketonemia and ketonuria are not seen. Exogenous insulin is not required for survival. Reproductive and Iatrogenic Disorders Multiple cysts are often present on ovaries of females >l yr old. The cysts contain clear, serous fluid and may reach 2-4 cm in dian1eter. Cysts may be unilateral or bilateral. Clinically, ovarian cysts are associated with reduced reproductive performance, cystic endometrial hyperpla­ sia, mucometra, endometritis, and alopecia. Radiography and ultrasonography should be performed, especially if an abdominal mass is palpable. Diagnosis of the disease by plain radiography is difficult because of the similar opacity of ovarian cysts and abdominal neoplasms. Abdominal ultra­ sound allows differentiation by imaging the inner structure of the ovaiian cyst. Treatment is laparotomy and surgical removal of the ovary and cyst. Differential diagnoses include splenic, uterine, and ovarian tumors. Although the clinical signs ai·e sirnilai·, there are two recognized forms of pregnancy toxemia: the fasting/metabolic form and the toxic fom1. Both occur in late pregnai1cy. Affected sows show depression, acidosis, ketosis, proteinuria, ketonuria, and a lowered urinary pH (from -9 to 5----6). Metabolic pregnancy toxemia occurs in obese sows, especially females in their

2019

first or second pregnancy. The disease is caused by a reduced carbohydrate intake and mobilization of fat as a source of energy. Changes in feeding routine and stress may precipitate the crisis. Clinically, the sow stops eating and is initially depressed, then becomes comatose and usually dies within 5----6 days. Treatment is rai·ely successful in advanced cases. Aggressive treatment is necessary and involves administration of 5% glucose solution either IV or SC and/or propylene glycol orally, nub.itional supplementation, and cesarean section. Sows in late pregnancy can be given water within which a small ainount of glucose has been dissolved as a preventive measure. The circulatory or preeclai11psia fom1 of pregnancy toxemia is due to uteroplacental ischemia. The gravid uterus compresses the aorta, resulting in significant reduction of blood flow to the uterine vessels. Placental necrosis, hemorrhage, ketosis, and death follow. If suspected, emergency cesarean section and/or ovariohysterectomy are required to save the sow's life. Guinea pigs have a high perinatal mo1tality. Dystocia at1d stillbirths are related to large fetuses, subclinical ketosis, and fusion of the symphysis pubis. If females are first bred after 6 mo of age, the symphysis pubis often fuses and does not separate during parturition. Many stillbirths are often seen in prirniparous females. Pregnancy lasts 59-72 days ( average 63 days). If a female strains continually for >20 min or fails to produce young alter 2 hr of intermittent straining, dystocia may be occurring. Careful exainination of the cervix is necessary to assess how much separation of the symphysis pubis is present. There should be at least the width of the index finger to permit passage of the fetus. If adequate separation has occurred, oxytocin (1-2 units, IM) can be given. If the fetus is stuck, or parturition does not begin within 15 min of giving oxytocin, perform­ ing a cesarean section is necessary. The uterus should be opened close to the bifurcation of the horns. The guinea pig has a bicomuate uterus with one cervix. Neoplasia Spontaneous tumors are relatively unconm1on in guinea pigs and are usually seen in anin1als >3 yr old. Trichofolliculoma, a benign twnor of the hair follicle epithe­ liwn, is the most common skin twnor of guinea pigs. The tumor presents as a slow-growing, oval mass varying in diaineter from 0.5----7 cm and located pre­ dominantly in the subcutis of the dorsal

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lumbar or sacral region, or in the lateral femoral and lateral thoracic area Males are affected twice as frequently as females. The average age of affected animals is 3 yr. Epidennoid cysts arising from hair follicles are often associated with these tumors or may arise independently. Ulcerating tumors and ruptured cysts discharge caseous mate1i.al. Treatment of tJichofollicuJomas and epidermoid cysts is surgical excision. Tumors of the reproductive tract represent 25% of sponta.neolli? twnors in guinea pigs. Most are ovarian and uterine twnors, although manunary adenocarci­ noma is seen in both male and female guinea pigs. The prevalence of mammary twnors in males is higher than in otber species.

Miscellaneous Disorders Antibiotic Toxicity: The lethal sensitivity

of guinea pigs to antibiotic tl1erapy cannot be overemphasized. Antibiotics repo1ted to cause enterotoxemia are penicillin, ampicillin (amoxicillin), bacitJ·acin, erythromycin, spiramycin, stJ·eptomycin, lincomycin, clinda.mycin, vancomyci.n, and tetracycline. Topical antibiotics have also caused fatal enterotoxemia. The following tl1erapeutic dosages of antibiotics have been used clinically in guinea pigs (see TABLE 31). Trimethoprim-sulfamethoxazole, chJoran1phenicol, and enrofloxacin are safe to use in guinea pigs. Narrow-spectrwn antibiotics witl1 antibacterial activity against gram-positive bacteria should be avoided; the ca.use of deatli is a decreased gram-positive bacterial fiora and increased gram-negative fiora., with related bactere-

mia/septicemia. Paradoxica!Jy, clostridiaJ overgrowth (Clostridium difficile) has also been identified. C difficile is a pathogenic organism, not nonnally recoverable from intestinal contents. Treatment for antibiotic toxicity is p1irnarily supportive. The antibiotics should be stopped imrnectiately, fiuid therapy (IV or intJ·aosseous) should be administered, and analgesics should be provided to prevent abdominal discomfmt. High-fiber diets should be syringe fed to prevent ileus. Cholestyrarnine (1 g in 10 mL water, tid, for 5--10 days), an ion exchange resin, has been used experimentally to bind clostlidial toxins in clindan1ycin-induced enterotox­ emia. If the enterotoxemia is severe, the condition is life-threatening and the prognosis guarded.

Age-related Disorders: Urolithiasis is

a common problem in older guinea pigs, especially females, because of the proximity of the uretlu·al orifice to the anus and tl1e high risk of infection with fecal contan1i­ nants likeE coli. However, it may be seen in guinea pigs of both sexes and alJ ages. Clinical signs include dysuria, crying when attempting to urinate, and occasiona!Jy hematwia. Diagnosis is by abdominal radiology. The calculi are radiopaque and usually composed of calciwn carbonate or calciwn phosphate; calculi can also be composed of calciwn oxalate. Obstructive urolithiasis, hydroureter, hydronephrosis, and possible concun-ent septicemia can develop if the problem is not treated. ln addition to sex and age, diet may be related to urolithiasis. Foods high in calcium, eg, alfalfa hay, may result in a high

IM=Hili ANTIBIOTIC DOSAGES FOR USE IN GUINEA PIGS Antibiotic

Dosage

Azithromycin

15--30 mg/kg/day, PO ( discontinue if soft feces occur)

Ceftiofur

1 mg/kg/day, IM (for pneumonia)

Cephaloridi.ne

12.5 mg/kg, IM, once to three times daily for 5--14 days

Chlora.mphenicol

30-50 mg/kg, PO, SC, or IM, bid

Ciprofioxacin

10-20 mg/kg, PO, bid

Doxycycline

2.5-5 mg/kg, PO, bid

Enrofioxacin

5--10 mg/kg, PO or IM, bid

Gentamicin

6 mg/kg/day, SC (use cautiously)

Metronidazole

10-40 mg/kg/day, PO

Trin1ethoprim-sulfamethoxazole 30-50 mg/kg, PO, bid

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dietary calciwn:phosphorns ratio. Urinary ascorbate, if present at a high concentra­ tion, increases stone fonnation in guinea pigs given high-calciwn or high-oxalate diets. This may be both beneficial and deleterious, ie, needing to give enough vitamin C to prevent scurvy but not increase stone forn1ation. Surgical removal is standard treatment. However, it is often complicated by exuberant inflanmiatory reactions to suture material. Prophylactically, potassiwn citrate/ citric acid can be given as an inhibitor of crystal formation in urine. Citrate is not administered for its urine-acidifying effect as it is in dogs and cats, but because of its ability to bind calciwn into water-soluble calcium citrate. Dental Disease: The clinical signs and treatment of malocclusion in guinea pigs are almost identical to those in rabbits, except premolar teeth are more commonly affected (seep 1955). Alopecia: Alopecia develops to a degree in all guinea pigs in late pregnancy (60---70 days) and during nursing. It results from reduced anabolism of maternal skin associated with fetal growth. Hair loss usually begins on the back and progresses bilaterally on the flanks and ventral abdomen. Nursing guinea pigs may worsen the condition by pulling hair from their mothers. The alopecia resolves slowly either after parturition or when the sow stops nursing. Thinning hair is common in young anin1als at weaning. It is associated with a period of transition in which coarse guard hairs of the adult coat are developing and neonatal fur is being lost. Ear chewing and barbering are seen in group-housed guinea pigs that develop a social hierarchy. Often younger anin1als of lower rank develop hair loss from fur chewing by dominant older members. The hair loss is characterized by an in·egula.r, almost stepwise pattern. Treatment involves separation of the aggressive anin1al(s). Single-housed guinea pigs that become bored may inflict self-barbering. In these cases, areas the anin1al cannot reach such as the head, neck, and anterior shoulders are not affected. Changing the guinea pig's environ­ ment and providing large amounts of fresh hay often prevent boredom and stop this vice. Bilateral, symmetric alopecia may be seen in older females with ovarian cysts. Other differential diagnoses for alopecia are mite infections and dermatophytosis. Sebaceous glands are abundant along the dorsal surface of guinea pigs and around the anal orifice. The circumanal region contains

2021

a large accumulation of sebaceous glands. The sebaceous glands are testosterone dependent, and in adult males, excessive accwnulation of sebaceous secretions occurs in the skin arnund the base of the spine and the folds of the circwnanal and genital region. In areas covered by fur, the hair becomes thick, matted, and greasy. These folds can be periodically cleaned with surgical alcohol or a gel hand cleanser to preclude infection and unpleasant smell. Zoonotic Risk Pet guinea pigs carrying derniatophytes are a zoonotic risk for their owners, especially children, who are often the only affected members of a household. Risk factors for human dennatophytosis are young guinea pigs and recent acquisition of a new guinea pig. When treating ringworm in guinea pigs, environmental treatment should also be reconunended to the owners, with special attention given to the bedding and clothing of people in contact with infected or carrier anin1als. Contagious material may persist in the owner's clothing and bedding and is a common reason for a pet's relapse after an initial response. HAMSTERS The most common pet and research hamster is the golden or Syrian hamster (Mesocricetus auratus). All Syrian hamsters in captivity appear to have originated from a litter of eight hamsters collected near Aleppo in Syria in 1930. Four of the animals escaped, a male killed one female, and only one male and two females remained. From these three anin1als, litters were raised that were distributed to Europe and the USA for research and subsequently as pets. In 1971, an additional 12 Syrian hamsters were captured in the field by fanners and imported to the USA. Syrian han1sters have a head and body lengtl1 of 170---180 nun and tail length of 12 nun. They range in weight from 110---140 g, and females are larger than males. Wild Syrian hamsters have a light, reddish brown dorsal coat, and the underparts are white. The skin of Syrian han1sters is very loose. Other species now COilll11on as pets are the dwarf hamsters such as tl1e Djungarian (Plwdopus sungorus) and Roborovsky (P roborovskii) hamsters. They are small (2 yr. Clinical signs are highly variable. Initial infection commonly occurs without any clinical signs; early signs involve both the upper and lower respiratory tracts and may include snuffling, nasal discharge, polypnea, weight loss, hunched posture, ruffled coat, head tilt, and red tears. Dyspnea, the primary presenting complaint, is caused by ciliostasis, subsequent buildup of lysozyme-rich inflanunatory exudate in airways, bronchiectasis, and bronchiolecta­ sis from inflanunatory damage to bronchi­ olar membranes. Chronic disease often includes middle ear infection (via the eustachian tube). Antibiotic therapy may alleviate clinical signs but does not eliminate the infection. Enrofloxacin (10

mg/kg) and doxycycline (5-10 mg/kg) given orally bid for 14 days often alleviates severe clinical signs. Additional treatments such as daily nebulization therapy with 7% hyper­ tonic saline to break down the mucus biofilrn in respiratory passages, broncho­ dilators (theophylline 10 mg/kg, bid) to improve airway patency, and reducing ammonia levels in cages by daily removal of bedding and use of clean paper will ameliorate the disease. Chronic low dose doxycycline (5-10 mg/kg/day, PO) helps to prevent acute relapses. The doxycycline is both bactericidal for mycoplasma organisms and has a marked immuno­ modulatory effect on the chronic airway inflarnmation. The most important aspect of CRD for clinicians is that respiratory mycoplasmosis varies greatly in disease expression because of environmental, host, and organism factors tl1at influence the host-pathogen relationship. Examples of such factors include intracage ammonia levels; concurrent Sendai virus, coronavirus (sialodacryoadenitis vims), pneun10nia virus of mice, rat respiratory vims, and/or CAR bacillus infection; the genetic susceptibility of the host; the virulence of the Mycoplasma strain; and vitamin A or E deficiency. Although CRD is rarely seen in laboratmy rats, most pet rats have CRD to some degree. One survey of pet ratteries in the northwest USA showed vi.ttually all (95%) were positive for CAR-bacillus and M pulmonis, and approxin1ately half were positive for other viral respiratory agents. Bacterial pneumonia is nearly always caused by S pneumoniae, but seldom in the absence of some combination involving M pulmonis, Sendai virus, or CAR bacillus. Infection with C kutscheri also results in pneumonia but only in cortjunction with debilitation or inununosuppression. In pet rats, in1mtmosuppression can result from diabetes, neoplasia, or dietary deficiencies. C kutscheri pneun10nia is rare in pet rats. Pneun1onia caused by S pneumoniae can be of sudden onset. Young rats are more severely affected t11an older ones, and often tl1e only sign tl1ey exhibit is sudden death. Mature rats may demonstrate dyspnea, snuffling, and abdominal breathing. A purulent exudate may be seen around the nares and on the front paws from wiping of the nostJils. A tentative diagnosis is based on identification of nwnerous gram-positive diplococci on a Gram stain of the exudate or in a san1ple submitted for cytologic exanlination. Severe bacteremia is an important consequence of advanced disease and results in multiorga.n abscesses and

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infarction. Treatment is amoxicillin/ clavulanic acid (13.75 mg/kg, PO, bid) or f3-lactamase-resistant penicillins such as cloxacillin, oxacillin, and dicloxacillin, which can all be administered orally or parenterally. Ulcerative dern1atitis caused by Staphylococcus aureus infection results from self-tratm1a associated with fur mite infestation or, more commonly, from scratching of the skin over an inflamed salivary gland. Rats have a remarkable ability to resist infection with S aureus. Treatment consists of clipping the toenails of the hindpaws, cleaning the ulcerated skin, and applying a topical antibiotic. Systemic treatment is rarely necessary. The two most common causes of clinical respiratory disease in mice are Sendai virus and M pulnionis infection. Sendai virus is associated with an acute respiratory infection in which mice display chattering and mild respiratory distress. Neonates and weanlings may die. Adults generally recover within 2 mo. When the disease expression exceeds this pattern, the cause is most likely conctuTent mycoplasmal infection. M pulmonis is the cause of chronic pnemnonia, suppurative rhinitis, and occasionally otitis media. Chatte1ing and dyspnea are caused by accwnulations of purulent exudate in inflamed and thickened nasal passages. Survivors often develop chronic bronchopneLU11onia, bronchiecta­ sis, and pulmonary abscesses. Antibiotic therapy may alleviate clinical signs but does not eliminate the infection. Viral Infections: Viral diseases of mice and rats are common. However, most diseases are subclinical and important only in laboratory animals in which they have the potential to have a significant effect on research. Sialodacryoadenitis virus, a coronavirus, causes inflan1mation and edema of the cervical salivary glands in rats. Owners of infected rats often describe their pets as having mLU11ps. Sialodacryoadenitis virus infection is highly contagious. It initially causes rhinitis followed by epithelial necrosis and inflammatory swelling of the salivary and lacrimal glands. Cervical lymph nodes also become enlarged. There is no treatment for this disease. Glandular healing follows within 7-10 days, and clinical signs subside within 30 days, with minimal residual lesions remaining. During acute inflammation, affected rats are at high risk of anesthesia-related mortality because of the decreased diameter of the upper respiratory tract ILU11en. Ocular

2029

lesions such as conjunctivitis, keratitis, corneal ulcers, synechia, and hyphema can develop secondary to lacrimal dysfunc­ tion. The eye lesions usually resolve but occasionally progress to chronic keratitis and megaglobus. Parasitic Infections: Protozoa: Endoparasites are relatively common in mice. However, only two parasites regularly encountered in the diges­ tive tract, the protozoan parasites Spironu­ cleus muris and Giai·dia muris, are considered patl1ogenic, even though they are not associated witl1 clinical signs in imrnw1ocompetent hosts. Diagnosis is based on demonstration of characteristic trophozoites in wet mow1ts of fresh intestinal contents or feces. Treatment is metronidazole (10-40 mg/kg/day, PO, or 0.04o/o--O. l % drinking water solution for 14 days), but it does not completely elinlinate the infection. Nematodes: Pinwonns are ubiquitous and considered nonpathogenic in mice. Two are commonly encountered: Syphacia obvelata and Aspicularis letrnplera. Often, the only indication of pinworm infestation is rectal prolapse due to straining. To establish a diagnosis of S obvela.la infestation, a clear cellophane tape impression of the perianal skin can be made. Adults obvelata females deposit ova around tl1e anus. A letraptera does not deposit its ova in tllis area, and fecal smear or flotation is required to confirm a diagnosis. Ivem1ectin (2 mg/kg, PO, given twice at a 10-day interval) elinlinates pinwonns from nlice. The recommended label dosage for nlice with ectoparasites (0.2 mg/kg, given twice at a 10-day interval) does not eliminate pinworms. Mites: Most infectious causes of alopecia and dennatitis in mice are associated with fur nlites. Generalized thinning of the hair, especially on difficult-to-groom areas such as the head and trunk, is seen. The coat often has a greasy appearance and, in cases of heavy infestation, noticeable pruritus and self-inflicted dennal ulceration may occur. Three mites are commonly seen: Myobia musculi, Myocoples musculinus, and Radfordia affinis. M muscitli is tl1e most clinically significant mouse mite. Infesta­ tions are usually caused by more than one species. Mites are spread by direct contact with infected mice or infested bedding. Diagnosis is based on identification of adult mites, nymphs, or eggs on hair shafts with the use of a hand lens or stereoscopic microscope. Adults and nymphs appear

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RODENTS

pearly whlte and elongate; eggs are oval and can be seen attached to the base of hairs or inside mature females. Mite infestations are treated with ivermcctin (0.2 mg/kg, SC or PO, twice at 10-day intervals). Alternatively, a few drops of ivem1ectin solution ( diluted to 1:100 in equal parts of water and propylene glycol for tlrree treatments) can be placed on the mouse's head to allow spread by grooming and ingestion. Ectoparasitic infestation is less common in rats than in mice. Occasionally, the fur mite Radfordia ensifera is seen. Although R ensifera infestation produces few ill effects, heavy infestation may lead to self-trauma and ulcerative dennatitis. Ornithonyssus bacoti, the tropical rat mite or red mite, is a bloodsucking parasitic mite prin1arily found in wild rats such as the brown rat (Rattus noruegicus) or the black roof rat (Rattus rattus). It has a wide host range and occasionally infects pet han1Sters, gerbils, rats, and mice living in very old buildings or when building construction or renovations disturb colonies of wild rodents that had been on the premises and acting as hosts. 0 bacol'i can survive for long periods in the environment and travel considerable distances in search of new hosts. lf it does not find a suitable rodent host, it will feed on people. Its common nan1e is a misnomer, because it is found worldwide in tropical and temperate climates. Mites appear whlte before feeding and become red-brown after engorgement. Heavy infestations on pet rodents resemble fine sawdust within the fur. 0 bacoti typically does not cause clinical signs in pet rodents, but heavy infestations cause anemia, debility, weakness, pruritus, and death in small rodents. As well as causing discomfort, the mite is a vector for the rodent filarial nematode Litomo­ soides carinii and a potential vector of several human pathogens. Most infestations occur in late spring or early sU111mer when fledglings are leaving the nest and the mites are searchlng for another food source. Infestation of O bacoti is eliminated by a combination of bathing and treating the host anin1al with selamectin (15 mg/kg, one topical treatment), elin1ination of commen­ sal rodent reservoirs, and insecticide treatment of the pet's cage (pennetlrrin­ impregnated cotton balls 7.4% placed inside the cage weekly for 6 wk) and environment (fipronil spray or synthetic pyretlrroids). Fungal Infections: Dem1atophytosis is uncommon in pet mice and rats. It is caused by Trichophyton mentagrophytes. Lesions, when present, are most common on the face, head, neck, and tail. The lesions

have a scurfy appearance, with patchy areas of alopecia and va.iiable degrees of erythema and crusting. Pruritus is usually minimal to absent, and the lesions do not fluoresce under a Wood's la.inp. T menta­ grophytes can be isolated from the fur of clinically nom1al mice but is rare in rats. Neoplasia

The most common subcutaneous tumor in rats is fibroadenoma of the manm1ary glands. The distribution of the manunary tissue is extensive, and the tumors can develop anywhere from the neck to inguinal region. Tumors can reach 8-10 cm in dia.ineter and are seen in both males a.i1d females. The surgical technique for twnor removal is straightforward, and survival after mastectomy has been reported to be good if the tun10r is benign. The prevalence of manunary tumors, as well as that of pituitary tumors, is significantly lower in ovariectomized rats than in sexually intact rats. However, tl1e recurrence of fibroad­ enomas is common in W1involved ma.imna.i'Y tissue, and often several surge1ies are needed. In contrast, man1m3.!'Y tun10rs in mice are nearly always malignant a.i1d often a.i·e not amenable to surgical removal. The most common spontaneous tun1ors associated with the skin are ma.i11ma.i'Y adenocarcino­ mas, followed by fibrosarcomas. The incidence of mamrna.i'Y tun1ors varies according to the mouse strain and the presence or absence of mouse ma.I11mary tumor viruses; the incidence is as high as 700,6 in some strains. In wild and outbred ntice, the incidence of fibrosarcomas is lo/o--6%. Subcutaneous twnors are nearly always malignant and often have ulcerated by the time a diagnosis is made. Tumors can be treated by surgical excision, but the chance of recwTence is hlgh and tl1e prognosis is poor. Miscellaneous and Iatrogenic Disorders Dental Overgrowth: Dental problems

are cmmnonly seen in pet ntice and rats because of their continually erupting teeth. Overgrown incisors are seen most frequently in rats and ntice, in contrast with molar occlusion seen in guinea pigs and chlnchlllas. Overgrowth is easily treated witl1 a high-speed drill that cuts through the overgrown incisors without splitting or splintering them, leaving a clean, smooth surface. Cutting the teeth with rongeurs

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RODENTS

does not produce good longterm results, and problems may arise. The incisor may fracture longitudinally; the fracture may reach the apex and cause the animal discomfort. Bacteria can enter the fractured tooth, track down to the apex, and cause an apical abscess. Extraction of the incisors is an alternative to trimming; however, this procedure is difficult because of the incisors' long roots.

Age-related Disorders: Chronic

progressive nephrosis is a common age-related disease in rats. The kidneys are enlarged, pale, and have a pitted, mottled surface that often contains pinpoint cysts. Lesions consist of a progressive glomerulo­ sclerosis and widespread tubulointerstitial disease, primaiily involving the proxin1al convoluted tubule. Proteinuria often is> 10 mg/day. The disease occurs earlier and is of greater severity in males than in females. Dietary factors appear to have an inlportant role in the progression of renal disease. Caloric restriction, the feeding of low-pro­ tein diets (4%-7%), and limiting the source of dietary protein reduce the incidence and severity of the disease. Treatment is supportive and involves feeding a low­ protein diet. Avascular necrosis of the tail, or ringtail, is seen primarily in young rats, and occasionally in young mice, kept in low-humidity environments. If ringtail is diagnosed, treatment involves at11putation of the tail below the necrotic annular constriction.

Skin Disease in Mice: Most of the

diseases seen in pet mice are associated with the skin and represent >25% of all cases. Behavioral disorders, husbandry­ related problems, microbiologic/parasitic infections, and idiopathic skin diseases are seen. Behavioral, husbandry-related, and infectious causes of skin disease ai·e relatively straightforward to diagnose and treat. However, many skin diseases characterized by chronic or ulcerated skin (often secondarily colonized by bacteria) are diagnosed as idiopathic. This group is commonly unresponsive to treatment, topical or systemic, and affected mice are often euthanized. Barbering and fighting are manifestations of social dominance, a fonn of behavior relating to the social rank and dominance status of an individual mouse in a group. Barbering is a unique condition seen in group-housed mice in which the dominant mouse nibbles off the whiskers and hair around the muzzle and eyes of cagemates.

2031

There are no other lesions, and only one mouse, the dominant individual, retains all of its fur. Removal of the dominant mouse stops barbering; frequently, however, another mouse assw11es the dominant role. Barbering is often seen in female mice caged together. Male mice, except littennates raised together from bilth, are more likely to fight, often ve1y savagely, and inflict severe bite wounds on one another, especially over the rump, tail, and shoul­ ders. Mechanical abrasion resulting from self-trawna on cage equipment is a form of husbandry-related alopecia. Small patches of alopecia appear on the lateral surfaces of the muzzle. They result from chafing on metal feeders, poorly constructed watering device openings, and metal cage tops. Unlike barbering, dem1atitis may also be associated with alopecia. Treatment consists of replacing the poorly constructed equipment with nonabrading equipment. Individually housed mice can display aberrant stereotypic behavior such as polydipsia and bai· chewing that results in mechanical abrasion and alopecia. In these cases with one mouse, replacing the cage equipment does not help. Instead, environmental enrichment toys such as running wheels or hollow tubes should be provided. Nursing mice often have ventral abdominal and thoracic alopecia; this is nom1al and is nearly always associated with the extensive distribution of mammaiy glands. Sometil11es a pet mouse presents with clinical signs of mite infestation but no evidence of 1nites or known history of recent exposure to other aninlals. Biopsy sat11ples may be useful in these cases to distinguish active acariasis from dermal hypersensitivity to mites or other allergens such as tilnber chip bedding. Dem1al hypersensitivity is well desc1ibed in certain inbred strains of mice and is characterized by severe pruritus, the presence of fine dandruff all over the body, and occasionally ulcerative dermatitis. Idiopathic skin disease is characterized by ulcerative dermatitis with pruritus in mice that are negative for prin1aiy ectoparasitic, bacterial, or mycotic infections. Histopathologic examination and inununofluorescent microscopy of selected inbred strains of mice have revealed an underlying vasculitis attributed to immune complex deposition on dermal vessels. Dietary factors and dysregulated fatty acid metabolism have been inlplicated in the development of the ulcerative dem1atitis in these mice. This common

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disease of mice of a C57BL6 background is caused by an underlying inun une-mediated vasculitis, and the severity appears to be modulated by dietary fat and vitamin E content. Topical treatment twice daily with 0.2% cyclosporine in 2% lidocaine gel supplemented with gentamicin at 50 mcg/mL results in either complete heafu1g or near­ complete healing of the ulcerated skin, regardless of the size of the skin ulceration. Skin swellings in mice are usually tumors or abscesses. Needle biopsy often reveals the nature of the contents and allows diagnosis. Three opportmlistic pathogens,

Staphylococcus aureus, Pasteurella pneumotropica, and Streptococcus pyogenes, are isolated frequently and can

cause abscesses in other organs. Antibiotic therapy with penicillins or cephalosporins, concurrent with drainage and debridement of the abscess, is effective.

Chromodacryorrhea in Rats: The Harde1ian glands of rats are located behind the eyes and secrete porphyrins that are increased in response to stress and disease, coloring t11e tea.rs red. When porphyrin­ eruiched tear fluid d1ies around the eyes and external nares, it resembles crusts of blood. Owners often describe their rats as hemorrhaging from the eyes and nose. The porphyrins can be readily differentiated from blood witl1 a Wood's lan1p, because they fluoresce under ultraviolet light. Although chromodacryorrhea is not pathologic, it is a consequence of acute­ onset stress such as that caused by pain, illness, or restraint. It usually indicates a chronic tmderlying disease. Zoonotic Risk

As rats have become popular as pets, children now account for >50% of the cases of rat bite fever (RBF) in the USA; 14% of RBF cases in children involved exposm·e to a rat at school. RBF manifests as a bacteremia and septicemia characterized by fever, chills, myalgia, arthralgia, headache, and vomiting. A petechial rash develops over the extrenlities, in particular the palms and soles, but sometimes is present all over the body. The incubation period is 3-10 days (average 5 days). Wants and children may experience severe diarrhea resulting in weight loss. Mortality occurs in 7%-13% of untreated patients. After infection, a polyarthritis develops in 50o/o-70% of patients. Prognosis is good with treatment with parenteral penicillin early in the disease. Fatalities are associated witl1 late reporting or late recognition of the disease.

The nonspecific initial presentation combined with difficulties in culturing Streptococcus moniliformis produce a significant risk of delay or failure in diagnosis. Rats are not reconunended as pets for children. Adults with pet;rats should practice regular handwashing and avoid hand-to-mouth contact when handling rats or cleaning rat cages. There are sporadic but persistent reports of cases of Oniithonyssus bacoti dermatitis from pet rodents that manifests as an erythematous papular rash. It often excoriates because of intense pruritus. Occasionally, vesicles, wi:icarial plaques, diffuse erythema, or hemorrhage are seen. Affected areas of the skin are those usually covered by clothing (such as arms and tnmk), with the face and webs of fingers usually spared. There is considerable evidence that O bacoti carry and have the potential to transmit several human pathogens. Experiments have shown that O bacoti transmits Rickettsia akari (rickettsialpox), Yersinia pestis (plague), Coxsackie virus, Francisella tularensis (tularemia), and Trypanosoma cruzi (Chagas' disease). Researchers have also documented O bacoti specimens with Coxiella burnetii (Q fever), hantavirus, Bon·elia spp (Lyme disease), Bartonella spp, and Rickettsia spp. Mice are inapparent carriers of dennato­ phytes, and pet mice are a zoonotic risk for their owners, especially children.

MICE AND RATS AS LABORATORY ANIMALS Rodents used for research arc maintained in tightly controlled environments designed to reduce tl1e impact of unwanted variables in animal experiments. Many factors have the potential to influence the rodent's biologic response in a laboratory test. Besides a description of the experiment, research journals often require a description of the research rodent's source, nlicrobiologic status, and environment (eg, feed, water, temperature, humidity, light exposure) in the materials and methods section. Environmental conditions, husbandry procedures, and animals must be similar if research data generated from one laboratory is to be judged based on reproducibility and thus validation. If variables such as feed, housing, rodent genetic background and disease-free or microbiologic status are not properly controlled, then experin1ental results can be of limited use or even worthless. Although

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complete elimination of vaiiables in animal experiments is not possible, many factors that contribute to variation cai1 be signifi­ cantly reduced or eliminated. One of tlie most important variables is tlie effect of infectious agents on reseai·ch mice and rats. Few infectious agents found in laboratory mice and rats today cause overt, clinical disease. Distinguishing between infection and disease is critical to interpreting tlie microbiologic status of laboratory animals. Infection indicates the presence of microorgaiiisms, which may be patliogens, opportunists, or commensals, of wliich the last two are most numerous. Clinical disease does not need to be present for microorgaiiisms to affect research. Animals tliat appear normal and healtliy may be unsuitable as research subjects because of the unobservable but significant local or systemic effects of viruses, bacteria, and parasites witli which tliey may be infected. Knowledge of the varied and unwanted effects of natural patliogens in laboratory rodents has steadily increased over the past 130 yeai"S of conducting animal research. The historic struggle against patliogens of laboratory rodents is often divided into three periods. The first (1880-1950) was when mice and rats becaine common research animals. Many of these original stocks hai·bored a variety of natural, or indigenous, patliogens. During tliis period, improvements were made in saiiitation, nub.ition, environmental control, and oilier aspects of animal husbandry. The result was a great reduction in the range and preva­ lence of patliogens found in laboratory rodents. The second period (1950-1980) was one of gnotobiotic derivation, when cesarean rederivation was used to replace infected stock with uninfected offspring. Full-term fetuses were removed from an infected motlier and transferred to a

2033

gem1-free environment and foster care. This procedure was successful in eliminating many patliogens not transmissible in utero, eg, endoparasites, most bacteria, and some viruses. The third period (1980-present) has been one of eradicating indigenous rodent viruses. The reduction in known viruses infecting rodents was accomplished tlu·ough serologic testing of animals for antibodies to specific pathogens. A.ntibody­ positive colonies were subsequently eliminated or cesarean-rederived. Most modem reseai·ch animal facilities incorporate some fom1 of health monitoring into tlieir animal care progran1 (see TABLE 32). Since the 1980s, it has been based on serology, although moleculai· metliods of detection (eg, PCR) are rapidly increasing in use. The laboratories tliat perforrn serologic assays primarily test groups of reseai·ch rodents or tlieir sainples. The well-being of tlie animal colony is more important thai1 the well-being of an individual animal, and laboratory animal medicine is effectively a type of "herd medicine." Although healtl1 monitoring is costly, it results in significant longtem1 savings, because researchers can use fewer animals and the animals' daily care is not as labor intensive. Health monitoring allows laborat01y animal veterinariatlS to check tl1e health stat1.1s of a colony, inf01m researchers of their animals' patliogen status, prevent enb.y of patliogens into tlie facility by screening animals received from unknown sources, and promptly deal witli tlie presence of unexpected infectious agents in rodents. Undetected infection makes laboratory aiiimals unfit for research and renders experimental data unreliable. It is more cost-effective to prevent enb.y of infectious agents into a facility or to detect and eliminate tliem early than to discard months of research data.

INFECTIOUS AGENTS COMMONLY TESTED FOR IN LABORATORY RODENTS

Test

Agent

E cun

Encephalilozoon cuniculi

Description

Species

PROTOZOA

A sporozoan parasite of rabbits and rodents

Mice, rats

BACTERIA

C pil

Clostridium pilif01me

Agent ofTyzzer disease

Mice, rats

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INFECTIOUS AGENTS COMMONLY TESTED FOR IN LABORATORY RODENTS (continued) Test

Agent

Description

Species

CARB

Cilia-associatedrespiratory bacillus

A bacterial respiratory , pathogen of rodents and rabbits

Mice, rats

M pul

Mycoplasma pulmonis

Agent of mouse and rat pulmonary mycoplasmosis

Mice, rats

VIRUSES ECT

Ectromelia

A mouse poxvirus

Mice

TH-1

Toolan's H-1 virus

A rat parvovirus

Rats

Hantaan virus

A zoonotic hantavirus of rats; several types (HPS, NED) exist throughout world

Rats Mice

K -virus

Mouse pneumonitis virus

A mouse papovavirus

KRV

Kilham rat virus

A rat parvovirns

Rats

LCM

Lymphocytic choriomeni.ngitis virus

A zoonotic arenavirus

Mice, rats

LDEV

Lactate dehydrogenaseelevating virus

A mouse arterivirus

Mice

MADI (FL)

Rodent adenovirus strain 1

Mouse adenovirus,rodent adenovirus strain 1 (FL)

Mice,rats

MAD2(K87)

Rodent adenovirus strain 2

Mouse adenovirus, rodent adenovirus strain 2(K87)

Mice

MCMV

Mouse cytomegalovirus

A mouse herpesvirus

Mice

MHV

Mouse hepatitis virus

A mouse coronavirus

Mice

MNV

MuriJ1e norovirus

A mouse calicivirus

Mice

MPV

Mouse parvovirus

A mouse parvovirus

Mice

MTV

Mouse thymic virus

A mouse herpesvirus

Mice

MVM(MMV)

Minute virus of mice

A mouse parvovirus

Mice

PolyVM

Polyoma virus of mice

A mouse papovavirus

Mice

PVM

Pneumonia virus of mice

A rodent pneumovirus

Mice,rats

SDAV

Sialodacryoadenitis virus

A rat coronavirus

Rats

Reo3

Reovirus type 3

A rodent reovirus

Mice, rats

SenV

Sendai. virus

A type 1 paran1yxovirns

Mice,rats

RTV

Rat theilovitus

A rat picomavirus

Rats

TMEV (GDVII)

Theiler murine encephalomyelitis virus

Mouse poliovirus, strain GDVII

Mice

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SUGAR GLIDERS

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SUGAR GLIDERS Sugar gliders (Petawus breviceps) are small, nocturnal marsupials native to Australia, Indonesia, and New Guinea that live in eucalyptus and acacia forests. They belong to the family Petauridae, which includes the wrist-winged gliders. Gliders in this family possess a gliding membrane (patagiwn) that mns from the wrist of the forelimb to the ankle of the hindlimb and that allows them to glide as far as 50 m and forage for food using less energy. They use their tails as stabilizing rudders that enable them to change direction easily. The second and third toes on their hindfeet are fused to form a "grooming comb" that helps them clean their fur. Females are seasonally polyestrous and have a double vagina, two uteri, and a pouch containing four teats; they often have twin births. After 16 days of gestation, the young Uoeys), each weighing only 0.2 g, migrate to the pouch to develop further and finally leave the pouch after 70-74 days. They remain in the nest until 110-120 days of age, when they are weaned. They stay with the colony until 7-10 mo old. Males have a forked pettis (to match the female's double vagina) and a pendulous scrotun1 containing two testicles. Males do not urinate from the forked end of the penis but from the proximal end. Both males and females have paracloacal scent glands acljacent to the vent (the cloaca! opening or common opening of urinary, reproductive, and GI tracts) with which they mark territory and each other, and males also have frontal scent glands on their foreheads and glands on their throats and chests. Sparse fur and an oily discharge are nonnal

Forked penis of a male sugar glider. Courtesy of Dr. Laurie Hess.

on the frontal and sternal glands of post­ pubescent males. These glands give both sexes a musky odor. Sugar gliders have large, protmding, widely spaced eyes, giving them a wide field of vision, especially at night. Their ears move independently and are highly sensitive to sound. They also have a great sense of smell to locate food, sense preda­ tors, and recognize both their tenitory and their colony-mates. Wild gliders have gray fw- and a central black stripe dorsally on their heads; domesticated gliders may look sinlilar to the wild type but also come in several color variations. Sugar gliders are polygamous, territorial, and live in colonies of 5 to 12 individuals with a donlinant male. They sleep in tree hollows by day and between foraging trips at night. They toler­ ate a wide range of environmental temp­ eratw-es and go into torpor to conserve energy in very cold conditions. Sugar gliders are omnivorous and feed on sugar-1ich plant and insect exudates (sap, gw-n, nectar, manna, pollen) and invertebrates as a source of protein. They a.re hindgut fermenters and possess a well-developed cecum that utilizes bacterial fermentation to break down complex polysaccha.tides contained in gwn. See also TABLE 33, which sw11ma.tizes important biologic a.i1d physiologic data for suga.i· gliders.

Physical Examination: For a full clinical exanlination, anesthesia with isoflurane via face mask may be required if gliders are very stressed or biting. More docile animals may be exan1ined while wrapped in a small towel and cupped in the palm of the hand. Gliders inside fabric bags or pouches may be pa.tiially exposed, one body pa.it at a tin1e, for exa.nlina.tion. Because gliders are nocturnal, it may be best to schedule clinical exan1inations earlier in the day when they are less active. If possible, the animal should be first observed moving in its cage to assess posture, coordination, and demeanor. If the glider is anesthetized, cloa.cal temperature, hea.it rate, and respiration rate can be recorded, and the heart and lungs assessed with a pediatric stethoscope. The fur and skin should be exa.t11ined for ectoparasites, tra.wna.tic irtjury, fur loss, and degree of hydration; the oral cavity for broken teeth, dental abscesses, or tartar build up; and the eyes

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SUGAR GLIDERS

ittN•ii

SELECTED PHYSIOLOGIC DATA FOR SUGAR GLIDERS

Life span

9-12 yr

Adult male body wt

100-160 g

Adult female body wt

80-135 g

Respiratory rate

16-40/min

Heart rate

200-300 bpm

Body temperature

97.3 ° F (36.3 °C)

Thermoneutral zone

80° -88° F (27°-31 ° C)

Food consumption

15%-20% body wt/day

Dentition

Diprotodont

Dental fommla

2(13/1-2 C 1/0 P 3/3 M4/4)

Puberty

8-12 mo in females, 12-15 mo in males

Estrous cycle

29 days

Gestation period

15-17 days

Litter size

2 (81%)

Birth weight

0.2 g

Pouch emergence

70-74 days

Weaning

110-120 days

and ears for any abnormalities. The cloaca! area should be examined, and the penis of males extruded. The abdomen should be palpated, and the pouch in females exam­ ined. Major joints should also be palpated, and digits and toenails checked forevidence of trauma. Diagnostic and Treatment Techniques:

If animals are dehydrated, isotonic fluids up to l()OA, of body wt can be administered SC over the shoulder region. Care should be taken not to induce edema to the patagium. Fluids also may be administered intraosse­ ously in the proximal femur or tibia. SC injections may be given in the same area that SC fluids are administered. IM injections may be given in the epaxial muscles of the neck and dorsal thorax. IV injections are very difficult to perform but may be accomplished in cephalic or lateral saphenous veins in an anesthetized glider. Radiographs generally require the glider be anesthetized for proper positioning. Pulmonary diseases are easiest to detect with radiographs. Feces may be easily san1pled and checked annually with a fecal float and direct smear for parasites; aninlals with diarrhea should have their feces cultured and tested for appropriate antibiotic sensitivity.

Blood Collection, Hematology, and Biochemistry: Reference ranges for sugar

gliders are presented in TABLE 34. Chemical restraint, essential to allow blood collec­ tion, is most safely achieved with isoflurane/ oxygen administered via mask and T -piece. To assist in making clinical diagnoses, blood samples may be obtained from the cranial vena cava, jugular vein, medial tibial artery, or lateral tail vein. Blood volumes of up to 1% of body wt can be collected; typically 0.5-1 mL is obtained. To access the cranial vena cava, a 27- or 25-gauge needle on an insulin syringe may be inserted in the . thoracic inlet just lateral to the manubriurn, with the needle directed at a 30 ° angle from midline toward the opposite hindleg. The vena cava is not visualized directly during venipuncture but is accessed blindly using the manubriurn as a palpable landmark. The jugular vein can be visualized if the hair is clipped and the vein is forced to fill by apply­ ing gentle digital pressure at the thoracic inlet; it sits midway between the point of the shoulder and the mandibular ramus. The needle can be bent at its base to facilitate venipuncture at this site. The medial tibial artery, which runs very superficially just distal and medial to the stifle joint, is easier to access and can be sampled with a 27-or 25-gauge neeclle and 0.5-1 mL syringe.

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SUGAR GLIDERS Pressure after sampling is required to prevent hematoma fom1ation. The size of the lateral tail vein is most suited to skin prick and droplet collection into capillary tubes. Small blood samples (0.25 mL) may also be obtained from the cephalic, lateral saphe­ nous, femoral, and ventral coccygeal veins with a 27-gauge needle on an insulin syringe. Anesthesia and Surgery: Anesthesia in sugar gliders should be approached the san1e way it is in other small mammals.

2037

Gliders ideally should be fasted for at least 4 hr preoperatively. Preoperative analgesics, sedatives to reduce preoperative stress, and local and gas anesthetics all may be used. Care must be taken to keep gliders warm during surgery to ensure rapid recovery. Gliders undergoing surgeries that last> l hr or that require intra-abdominal access should be administered fluids intraosse­ ously (in the femur or tibia) throughout the procedure if IV access is impossible because of small size. Shorter, sin1ple

SELECTED HEMATOLOGIC AND SERUM BIOCHEMICAL VALUES FOR SUGAR GLIDERS Conventional (USA)Units

SI Units

HEMATOLOGY Hemoglobin

13-15 g/dL

Hematocrit

45%-53%

0.45-0.53 UL

RBCs

5.1-7.2 x lOG/µL

5.1-7.2 x 10 12 /L

Mean corpuscular Hgb concentration

30-33 g/dL

300-330 g/L

Mean corpuscular Hgb

18.2-20.6 pg

18.2-20.6 pg

WBCs

5-12.2 x 103/µL

5-12.2 x 109/L

Neutrophils

1.5-3 x 103/µL

1.5-3 x lQ9fL

Lymphocytes

2.8-9.2 x 103/µL

2.8-9.2 x 109/L

Monocytes

0.06--0.2 x 10 /µL

0.06--0.2 x 109/L

Eosinophils

0.02-0.14 x 103/µL

0.02-0.14 x 109/L

Basophils

130-150 g/L

3

0

0

5.6--6.9 g/dL

56-69 g/L

Albumin

3-3.5 g/dL

30-35 g/L

Globulin

2.2-3.6 g/dL

22-36 g/L

Plasma proteins

BIOCHEMISTRY ALT

50-106U/L

AST

46-179U/L

46-179U/L

Calcium

6.9-8.4 mg/dL

1.7-2. l mmol/L

50-106U/L

CK

210-589U/L

210-589U/L

Creatinine

0.2-0.5 mg/dL

17.7-44.2 µmol/L

Glucose

130-183 mg/dL

7.2-10 mmol/L

Phosphorus

3.8-4.4 mg/dL

1.2-1.4 mmol/L

Potassium

3.3-5.9 mEq/L

3.3-5.9 mmol/L

Sodium

135-145 mEq/L

135-145 mmol/L

Urea

18-24 mg/dL

6.4-8.6 mmol/L

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SUGAR GLIDERS

procedures may necessitate only SC fluids, Conunonly used preanesthetics include atropine or glycopyrrolate, midazolam, and either butorphanol or buprenorphine. Local anesthetic injections of a 50:50 mixture of 2% lidocaine with 5% bupivicaine may be used to infiltrate the incision site to help reduce the chance of postoperative self-mutilation. To facilitate castration, this mixture may be diluted with sterile water and infused into the base of the scrotal stalk nearest to the abdomen, while a low concentration of gas anesthetic is adminis­ tered. Both isoflurane and sevoflurane may be administered via small face mask or via a large face mask used as an induction chamber. For surgery, gliders may be maintained on gas anesthesia with a face mask or intubated with a 1-nun Cook endotracheal tube tlu·eaded with a stylet. During surgery, blood loss should be monitored carefully; use of radiosurgery may help minimize bleeding. Because sugar gliders tend to chew incisions after surgery, ideally subcuticular sutures and skin glue should be used to close skin incisions. Analgesics should be adminis­ tered before surgery to minimize pain inunediately after surgery. Gliders should recover from surgery in temperature­ controlled incubators. Orchiectomy and scrotal ablation are conunonly performed on male sugar gliders to prevent breeding and decrease sexual frustration. Hair is clipped around the base of the scrotal sac and stalk, and the skin is cleaned without alcol:)ol so as not to lower body temperature. A local anesthetic is administered at the base of the stalk, and with the glider under gas anesthesia, the incision is made over the scrotal stalk -2--3 mm from the body wall. The· spermatic cords are exposed by blunt dissection and are clan1ped and ligated with 5-0 polydiox­ anone suture or cut and cauterized with radiosurgery. The scrotal sac containing the testicles and distal spern1atic cord is then removed, and the ligated stalk can be sutured to the abdominal wall fascia to prevent herniation. The skin is then closed with tissue glue. Standard ovariohysterec­ tomy is not routinely perforn1ed because of the internal position of the female reproductive organs, which are difficult to access beneath the pouch. With ovariohys­ terectomy, the area around the pouch is clipped and scrubbed in a routine manner, and a 1-2 nun incision is made paramedian to the pouch. The linea alba is bluntly dissected and incised, and the bladder is exteriorized from the incision to reveal the ovaries beneath. The ovarian arteries are

ligated, as is the ute1us proxin1ally to the lateral vaginal canals. After resection of both ovaries and ute1i, the linea is closed, and the skin is sutured subcuticularly and closed with skin glue. Distal penile amputation is another conunon surgery. Sexually frustrated males may self-mutilate the distal end of their penises or develop paraphimosis. Because males urinate only from the proximal end, the distal, forked segment may be safely amputated. Other surgeries performed in sugar gliders include cystotomy to remove uroliths, urethros­ tomy to alleviate urinary tract obstruction from uroliths in males, and surgical removal of impacted paracloacal glands. The skin over impacted glands is infiltrated with a small volume of local anesthetic and incised; the gland is bluntly dissected and removed without rupturing it. The blood vessel supplying fue gland may be ligated with 5-0 or 6-0 polydioxanone or cut and cauterized with radiosurgery. The skin is closed with tissue glue. Drug Dosages: Very few phannacologic

studies have been performed in sugar gliders, and most published drug dosages have been extrapolated from those detern1ined for cats, fe1Tets, and hedgehogs. For drugs and dosages commonly used in sugar gliders, see TABLE 35. Nutrition and Housing: Ideally, sugar

gliders should be maintained as a group with one male and a number of females. If breeding occurs, the young should be removed soon after weaning, or violent attempts to disperse them may occur. Because sugar gliders are arboreal (tree-dwelling), a large cage (ideally of PVC-coated stainless steel) is best for nocturnal climbing. As large a cage as possible should be provided with a minimum size of36 x 24 x 36 in. Bar spacing should not be more than ·1 x 0.5 in. wide, or feet and heads may become entrapped. Caging containing vertical bars should be avoided, because vertical bars do not facili­ tate climbing. A wooden nest box (made for birds) or a fabric pouch positioned high up in the cage should be provided for hiding and sleeping. Cages should contain numerous branches (commercially available for bird cages) and horizontal shelves to promote climbing. Swings and chew toys made for birds are ideal for gliders to play with. Exercise wheels containing smooth interiors (so as not to entrap toes) should be provided for physical and mental stimulation. The cage bottom may be covered with newspaper or other

SUGAR GLIDERS

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IM=l!ifi

2039

COMMONLY USED DRUGS IN SUGAR GLIDERS

Drug

Dosage

Considerations

ANTIBIOTICS Amoxicillin

30mg/kg,PO or IM,once daily For dem1atitis or divided bid

Amoxicillin-clavulanic acid

12.5mg/kg/day, PO

Broad-spectrum against anaerobes and aerobes

Cephalexin

30mg/kg/day, PO

Enrofloxacin

2.5-5mg/kg,PO or IM,once or twice daily

Potential tissue necrosis when injected

Gentarnicin

1.5-2.5mg/kg,SC,IM,IV,bid

Nephrotoxic

Metronidazole

25mg/kg/day,PO

Penicillin

22,000-25,000ill/kg,once or twice daily

Sulfadin1ethoxine

5-10mg/kg,PO,once or twice Ensure hydrated daily

Trimethopri.rn/sulfa

10-20mg/kg,PO, once or twice daily

Carbary! 5%powder

Topically or in cage

Use small amounts to treat ectoparasites

Fenbendazole

20-50mg/kg/day, PO, x 3days

For roundworms,hook­ worms,whipworms, tapeworms

Iverrnectin

0.2mg/kg, PO, SC; repeat in 14days

For roundworms, hook­ worms,whipworms,mites

Metronidazole

25mg/kg/day x 3days; repeat in 14 days

For intestinal protozoa

Piperazine

100mg/kg,PO

Pyrethri.n powder

Topically

For ectoparasites

Selamectin

6-8 mg/kg,topically; repeat in 30days

For ectoparasites

ANTI PARASITICS

ANTI FUNGALS Itraconazole

5-10mg/kg,PO,bid

Nystatin

5,000ill/kg, tid x 3days

Acepromazine/ butorphanol

1.7 mg/kg/ 1.7 mg/kg,PO

Buprenorphine

0.01-0.03mg/kg,PO or SC, bid

Butorphanol

0.1-0.5mg/kg,SC or IM, every6-8hr

Meloxicam

0.1-0.2mg/kg/day,PO or SC

For Candida

ANALGESICS Postoperative analgesic and sedative to decrease self-mutilation of incision

Anti-inflammatory

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SUGAR GLIDERS

•t·Nii*i COMMONLY USED DRUGS IN SUGAR GLIDERS Drug

Dosage

(continued)

Considerations

PREANESTHETICS Atropine

0.02-0.04 mg/kg, IM, SC, IV

To lessen intraoperative secretions

Glycopyrrolate

0.01-0.02 mg/kg, IM, SC, IV

To lessen intraoperative secretions

ANESTHETICS Diazepam

0.5-2 mg/kg, PO, IM, IV

Sedative, anticonvulsant

Isoflurane

1%-5%

Via face mask or intubation

Ketamine

30-50 mg/kg, IM

Ketamine/medetomi­ dine

2-3 mg/kg/0.05-0.1 mg/kg, IM

Immobilization

Ketan1ine/midazolan1

10-20 mg/kg/0.35-0.5 mg/kg, IM

Give ketamine 10 min after midazolan1

Midazolam

0.25-0.5 mg/kg, IM or IV

Sedative, anxiolytic

Sevoflurane

lo/c,-5%

Via face mask or intubation; possible toxicity, use cautiously

Enalapril

0.22-0.44 mg/kg/day, PO

Furosemide

1-4 mg/kg, SC or IM, every 6-12 hr

Cisapride

0.25 mg/kg, PO, once to three times a day

GI motility enhancer

Metaclopramide

o'.05-0.l mg/kg, PO, bid-qid

GI motility enhancer

Calcitonin

50-lOOW/kg, SC or IM

Helps mobilize calcium

Prednisolone

0.1-0.2 mg/kg/day, PO, SC, IM

Corticosteroid

Calcium glubionate

150 mg/kg/day, PO

Calcium supplement

Vitamin A

500-5,000 IU/kg, IM, once

For dennatitis

Vitan1in E

25-100 ID/glider/day

Vitamin K

2 mg/kg, SC, every 1-3 days

CARDIAC DRUGS Diuretic

GI DRUGS

HORMONES

VITAMINS

recycled paper product that is nontoxic if ingested. Several food and water bowls should be provided throughout the cage, with designated areas for eating, drinking, exercising, and hiding. The recommended diet for captive sugar gliders includes calcium-loaded insects (c1ickets, mealwonns, waxwonns,

Intestinal and liver disease

cockroaches, moths) to promote dental health, as well as a daily nectar/sap substitute (eg, fructose/sucrose/glucose or honey diluted to lOOAiwith water). Nectar should account for -500Ai of the diet. Several nectar substitutes are conrn1ercially available, including Gliderade nectar supplement (Exotic Pet Nutrition Company, Newport

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SUGAR GLIDERS News, VA), acacia gmn powder, and nectar diets meant for Jory birds. Other protein sources in addition to insects include eggs, lean meat, newborn mice, and commercial pelleted diets meant for sugar gliders. Corrunercial diets or homemade insectivore or omnivore mixes should be provided in addition to live food, with insects and pelleted food accounting for nearly 50% of the total diet. Fruits, nuts, and vegetables should be offered only in moderation ( Uld be vaccinated 4-8 wk before paiturition to increase specific colostral immunoglobu­ lins. Neonates can be vaccinated at4 and 8 wk of age with Clostridium pe1fringe.:ns type C and D. Exotic sheep, goats, and cervids ai·e sometimes vaccinated beginning at 10-12 wk of age with multivalent clostridial bacterin-toxoids containing immunogens for Clostridium tetani, C perf1ingens (types B, C, D), C septicum, C chauvoei, C novyi, C sordellii, and C hamnolyticum in areas of high exposw·e risk. The initial dose is 5 mL followed in 6 wk by a 2-rnL dose, administered SC. A 2-mL booster dose should be given annually.

Miscellaneous: A nwnber of infectious diseases, including bovine viral diarrhea (BVD), bluetongue, malignant cata.J.Thal fever, epizootic hemorrhagic disease of deer, anthrax, encephalomyocarditis virus, cowpox, ai1d brucellosis, may appear as serious local problems but are not

widespread in zoos. Unfortunately, satisfactory vaccines for many infectious diseases are not available for exotic animals. Inactivated BVD vaccines are recommended in situations in which BVD has been a problem. Annual vaccination witl1 one sta.J.1dard bovine dose IM should begin at 3 mo of age. Satisfactory vaccines for bluetongue, epizootic hemorrhagic disease, malignant catarrhal fever, and encephalomyocarditis virus are not currently available in the USA. In contrast, a nun1ber of vaccines are available for extra-label use in exotic man1rnals, which may not be efficacious or necessary. These noncore vaccines for domestic carnivores include feline leukemia virus, feline im1mmodeficiency virus, Chlamydiafelis, feline infectious peritonitis, feline Giardia vaccine, coronavirus, and Lyme disease. If a collection has a history of these diseases or is in an ai·ea endemic for disease, vaccination may be considered. Antlrrax vaccine has been administered to cheetal1 (Acinonyxjubatus) and black rhinoceros (D·ice1·os bicornis) without apparent ill effect, and conference of protective inm1unity in some with a single booster was recommended. Vaccination of valuable animals could be considered in the event of an outbreak. Brucellosis affects both free-living and captive marine mammals, with minimal apparent zoonotic potential. No vaccination or oilier control methods for brucellosis are established for these or other exotic man1rnal species in captivity. Vaccination programs for free-living bison and cervi.ds are controversial. Although the MLV vaccine effectively prevents future abortions and the transmission of brucellosis, it does not protect from infection or seroconversion, may induce abortions in pregnant a.J.timals, and is infectious to people. The reemergence of brucellosis worldwide ai1d an increasing incidence of hun1a.n disease underscore the need for new and improved brucellosis vac­ cines. The vaccinia, cowpox, and smallpox (variola) viruses are closely related pox viruses that may have all evolved from a single ancestral virus. Cowpox virus has caused morbidity and mortality in canids, felids, equids, elephai1t, rhino, camelids, viverrids, rodents, primates, and hoofs­ tock; zoonotic disease has been reported. Vaccinia titers have been docWllented in free-living nonhwnai1 primates in Soutl1 An1erica. The CDC currently limits distribu­ tion of vaccinia. vaccine to health care and bioindust1ial laboratory workers witl1 exposure risk.

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MANAGEMENT AND NUTRITION INTRODUCTION

2066

BIOSECURI TY 2068

Principles of Biosecurity 2069 The Three Levels of Biosecurity 2071 Developing a Biosecurity Program 2071 Bioexclusion 2071 Surveillance 2073 Biocontainment 2073 Handling Disease Outbreaks 2074

2075 Technical Aspects of Cloning 2075 Status of Cloning Domestic Animals 2076 Rationale for Cloning 2077 Controversies 2077

CLONING OF DOMESTIC ANIMALS

COMPLEMENTARY AND ALTERNATIVE VETERINARY ME DICINE

Acupuncture 2079 Manual Therapy 2081 Laser Therapy 2083 Herbal Medicine 2084 Nutraceuticals and Dietary Supplements 2086 Homeopathy 2087

2087 Large Animals 2087 Failure of Passive Transfer 2088 Sepsis in Foals 2089 Specific Clinical Manifestations of Sepsis 2092 Neonatal Pneumonia 2092 Omphalitis, Omphalophlebitis, and Patent Urachus 2092 Neonatal Uveitis 2093 Septic Arthritis 1062 (MUS) Neonatal Encephalopathy 2094 Meconium Impaction 2096 Small Animals 2096 Care of Orphaned Native Birds and Mammals 2100

MANAGEMENT OF THE NEONATE

2104 Pain Perception 2104 Recognition and Assessment of Pain in Animals 2105

PAIN ASSESSMENT AND MANAGEMENT

2078

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MANAGEMENT AND NUTRITION

PainAlleviation 2106 Analgesic Pharmacology 2107 Opioids 2107 Nonsteroidal Anti-inflammatory Drugs and Corticosteroids 2110 a2-Agonists 2110 Ketamine 2110 OtherAnalgesicAgents 2111 Local and RegionalAnalgesic Techniques 2111 Chronic Pain 2112 Osteoarthritis Pain_ 2113 Cancer Pain 2113 STR AY V OLTAGE IN A NIMA L HOUSING

2113

2116 Air Quality 2116 The Dilution Effect of Ventilation 2117 Cold Weather Ventilation 2117 Wann Weather Ventilation 2119

VE NTILATION

HE ALTH-MANAGEMENT INTERACTION AQUA C ULTURE and AQUATIC SYSTE MS 1743 (EXL)

2119 Beef Cattle Breeding Herds 2119 Reproduction 2120 Cull Cow Selection andManagement 2120 NutritionalManagement 2121 Health and ProductionManagement Program 2122 Vaccinations 2122 · CalfManagement 2122 Replacement Heifers 2125 General HealthManagemeilt Considerations 2126 BeefFeedlots 2126 Economic Impact of Disease 2127 Implementing aFeedlotMedicine Program 2127 Feedlot Records 2128 Vaccination Protocols 2129 Nutritional Advice 2129 Disease Epidemics 2129 Control and Prevention of Disease 2130 Beef Quality Assurance and Beef Safety Programs 2133 Development ofAntimicrobial-resistant Bacteria 2134

BEEF CATTLE

2135 TheModem Dairy Industry 2135 Animal and Herd Productivity 2136 Interactions Between Health and Production 2139 The HealthManagement Program 2140

DAIRY CATTLE

MANAGEMENT AND NUTRITION

GOATS 2147 VetBooks.ir

HORSES 2151 PIGS 2160 SHEEP 2164 SMALL ANIMALS 2169 MANAGEMENT OF REPRODUCTION CATTLE 2171

Nutrition 2171 Breeding Program for Heifer Replacements andCows 2172 Bull ReproductiveManagement 2174 Breeding 2175 Artificial Insemination 2175 Pregnancy Determination 2176 Embryonic Death, Abortion, and Abnormal Fetal Development CalvingManagement 2178 Dystocia Management 2180 Cow-Calf PairManagement 2181

GOATS 2182

Puberty and Estrus 2182 Breeding Soundness Examination Breeding 2184 Induction of Estrus 2184 Pregnancy Determination 2185 Pregnancy 2186 Parturition 2186

HORSES 2187

2183

ReproductiveCycle 2187 Breeding Soundness Examination of theMare 2189 Pregnancy Determination 2194 ParasiteControl During Pregnancy 2195 Vaccinations 2195 Abortion 2195 Parturition 2196 Dystocia 2198 Examination of the FetalMembranes 2199 The Early Postpartum Period 2200 Breeding Soundness Examination of the Stallion 2200 Breeding 2201

PIGS 2201

Sow and GiltManagement 2202 BoarManagement 2203 BreedingManagement 2207

2177

2063

2064

MANAGEMENT AND NUTRITION

2212 Reproductive Physiology 2212 Measuring Reproductive Performance 2213 Factors Affecting Reproductive Performance 2214 Breeding Programs 2215 Pregnancy Determination 2216 Prenatal Losses 2216 Ram Management 2217 Artificial Insemination 2218

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SHEEP

2219 Breeding Soundness Examination 2219 Breeding Management 2221 Manipulation of the Estrous Cycle 2225 Pregnancy Determination 2225 Prevention or Termination of Pregnancy 2226 Whelping and Queening 2227 Labor and Delivery 2227 Postpartum Care 2228 Periparturient Problems 2228 Infertility 2229

SMALL ANIMALS

BREEDING SOUNDNESS EXAMINATION OF THE MALE

Bulls 2231 Rams 2233 Bucks 2234 Stallions 2234 Boars 2237 Dogs 2237

EMBRYO TRANSFER IN FARM ANIMALS

Cattle 2240 Sheep and Goats 2242 Pigs 2242 Horses 2242

HORMONAL CONTROL OF ESTRUS

Horses 2245 Cattle 2245 Goats and Sheep 2246 Pigs 2247 Dogs 2247 Cats 2248

2244

NUTRITION

2248 Nutritional Requirements 2248 Feeding and Nutritional Management The Breeding Herd 2263

BEEF CATTLE

2263

2239

2230

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MANAGEMENT AND NUTRITION

Stocker Cattle 2263 Finishing Cattle 2264 Performance Modifiers 2264 DAIRY CATTLE 2265

:Nutritional Requirements 2265 Feeding and Nutritional Management 2278 Feeding Young Calves 2280 Feeding Calves from Weaning Through Maturation 2282 Accelerated Calf-rearing Programs 2283 Feed Additives 2284 Nutrition and Disease 2284

2287 Birds 2288 Psittacines 2288 Passerines 2290 Columbiformes 2290 Raptors 2291 Piscivorous Birds 2291 Waterfowl 2292 Gallinaceous Birds 2292 Ratites 2292 Mynahs 2293 Toucans 2293 Managing Avian Zoological Collections 2293 Mammals 2293 Handrearing Zoo Mammals 2293 Bats 2294 Carnivores 2296 Insectivores, Edentates, and Aardvarks 2297 Marine Mammals 2297 Marsupials 2298 Primates 2299 Rodents and Lagomorphs 2300 Subungulates and Ungulates 2301 Reptiles 2302 Crocodilians 2306 Snakes 2306 Turtles 2306 Tortoises 2307 Lizards 2307 Fish 2307

EXOTIC AND ZOO ANIMALS

2308 Nutritional Requirements 2308 Herbage and Browse Utilization 2310 Nutritional Diseases 2311

GOATS

2065

2066

MANAGEMENT AND NUTRITION INTRODUCTION

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HORSES 2312

Nutritional Requirements 2313 Feeding Practices 2321 Nutritional Diseases 2323 Feeding the Sick Horse 2328 Feeding the Aged Horse and the Orphan Foal 2329

PIGS 2329

Nutritional Requirements 2329 Feeding Levels and Practices 2340 Major Feed Ingredients 2341 Feeding Management of Sows and Litters 2342 Feeding Management of Weanling Pigs 2342 Growth Stimulants 2342 Nutritional Diseases 2343

RABBITS 1937 (EXL) SHEEP 2345

Nutritional Requirements 2345 Feeding Practices 2348 Farm Sheep 2348 Ewes 2348 Lambs 2349 Mature Breeding Rams 2351 Range Sheep 2351 Nutritional Diseases 2353

SMALL ANIMALS 2354

Nutritional Requirements and Related Diseases Nutrient Classifications 2366 Dog and Cat Foods 2373 Pet Food Labels 2373 Pet Food Product Types 2374 Feeding Practices 2376 Nutrition in Disease Management 2379

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MANAGEMENT AND NUTRITION INTRODUCTION Almost all domesticated animals rely on their caretakers to maintain their health and well-being, to provide appropriate nutrition, and to meet behavioral needs and any special physiologic requirements. The success of proper management and nutrition is especially important to agricultural species that must sustain growth and production.

Genetic advancement has led to continual increases in productivity that place similar continual pressure on animal husbandry management to ensure it does not limit animal health, well-being, or productivity. Proper management and nutrition are also central to the prevention and control of infectious and noninfectious diseases.

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MANAGEMENT AND NUTRITION INTRODUCTION

Infectious diseases occur after colonization of an animal by microbes (eg, a bacterium, virns, rickettsia, parasite), but simple infection by a microorganism is not usually sufficient for disease to develop. Environ­ mental and host factors influence whether the animal will develop clinical or subclini­ cal disease or have impaired productivity. Management has a substantial impact on environmental and host conditions that contribute to disease susceptibility. Eradication and exclusion of specific organism(s) that cause disease is the only certain way to prevent infectious disease. This is usually impractical or impossible for many conrn1on diseases of agricultural animals. As a result, it becomes necessary to control rather than to prevent infectious disease by reducing circumstances that favor the presence or the spread of the infectious agent, by mitigating environmen­ tal circumstances that cont1ibute to develop­ ment of disease once animals have become infected, and by minimizing circumstances that increase host susceptibility. Circum­ stances that contribute to the development of a disease are called 1isk factors, and they can be related to the microbe, the environ­ ment, or the host. Identifying and mitigating the impact of risk factors is the goal of a management strategy to prevent specific diseases and to maintain productivity. A multifaceted approach to disease prevention and control through management practices is particularly important when dealing with many of the common infectious and noninfectious diseases seen in food animal production systems (eg, enzootic pneumonia in calves and piglets, neonatal diarrhea, bovine respiratory disease complex of feedlot cattle, infectious infertility in swine and cattle, metabolic disease in dairy cows) as well as in companion animals (eg, respirato1y disease in cattelies, kennel cough in canine boarding facilities, infertility and viral respiratory disease in horses). Many of these diseases are difficult to control without an integrated approach, because they either have a complex etiology involving the interaction of multiple microbes or are caused by pathogens for which there are no reliable treatments or effective specific preventive measures. Prevention and control of these diseases is best achieved by implementing manage­ ment practices to mitigate recognized risk factors for infection, disease development, and impaired productivity. Often, these are general management reconrn1endations that are not targeted at specific infectious organisms. Effective control may also require in1plementation of management practices to

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address risk factors unique to particular pathogens and diseases. The need to identify and implement multifaceted management strategies that will maintain health and enhance productivity is likely to increase in animal agriculture. This need for new strategies is driven by competitive and economic forces within the industry and by pressure for change from interested parties outside agriculture. Identifying and implementing these management changes requires collaborative efforts of all groups working in livestock production, including veterinar­ ians, animal scientists, and nutritionists, with consideration of economic and other forces acting on producers. All of agriculture, but particularly animal agriculture, is under pressure from consun1er and special interest groups to address concerns arising from some industry practices. These concerns include potential links between aglicultural practices and antimicrobial resistance in hun1an patho­ gens, relationships between envirornnental contanlination and intensive animal production, the role of agricultural management practices in reducing the risks of foodbome illnesses and risks of exposure to zoonotic pathogens, and the in1pact of ag1icultural practices on animal welfare. Even though there may be no conclusive evidence linking livestock production to these public health and public interest issues, livestock production management will likely change in response to the perception of such links. Any changes in current practices will require development of new approaches to maintain anin1al health and production, which will require a substantial investment in research and education. Increasingly, livestock production must ensure that management practices are implemented at the farm level as part of the industry-wide system to maintain the safety and wholesomeness of the food supply. Validated on-frum food safety progrruns are often based on Hazard Analysis and Critical Control Point (HACCP) principles. They emphasize that all stages of the food production chain have a role in ensuring food quality and safety. Developing, in1plementing, and auditing these management programs are essential to maintain consun1er confidence. These progranis require implementation and docU111entation of management practices that reduce the risk of physical, chemical, or mic­ robial hazards entering the hwnan food supply ttu·ough production practices on farms. Animal agriculture is also under pressure from within the industiy to better protect the industry itself. Well-publicized outbreaks of

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MANAGEMENT AND NUTRITION INTRODUCTION

disease such as bluetongue, Schmallenberg virus, avian influenza, and transmissible spongiform encephalopathies in several species (eg, bovine spongiform encephalopa­ thy, scrapie, chronic wasting disease) have focused the industry's attention on biosecu­ rity as a disease prevention and control strategy. Biosecurity is a set of management practices that aims to prevent the introduc­ tion of infectious or other disease-causing agents and/or to prevent the further spread of agents that are introduced or are already present (see ai,so below). Biosecurity programs can be implemented at a room, building, farm, regional, or national level. Similar to disease prevention programs, biosecurity programs often comprise a set of general practices and sets of management practices targeted at specific pathogens. Nutritional management is a subcategory of animal management. Proper nutrition is essential to health and productivity. Nutrition also plays a role in susceptibility to disease (eg, feline lower urinary tract disease) as well as in medical management of certain diseases (eg, diabetes in dogs and cats, equine metabolic syndrome, ketosis and hypocalcemia in dairy cattle). Rations/diets must be formulated to provide for basic physiologic needs (eg, energy, protein, fats, carbohydrates, vitamins, minerals) and to ensure optimal growth and productivity. Proper ration formulation considers age, sex, breed, physical activity, and lactation and gestational status.

Nutiitionally related diseases include diseases associated with a nutritional excess (eg, direct toxic effect, digestive upset), nutiitional deficiency (either primary or secondary), or nut1itional imbalance. In animal agriculture, health and production are also heavily influenced by feeding management in addition to ration fom1ula­ tion. Feed preparation and delivery are often as in1portant in ensuring anin1al health and productivity as the actual nut1itional value of the ration itself. Inadequacies in nutritional delivery can directly cause disease (eg, mminal acidosis, lan1initis) or increase susceptibility to disease (eg, Clostridium perj'ringens enterotoxemia). Nutritionally related diseases in companion animals also include both conditions of excess (eg, developmental orthopedic disease in dogs related to excess calcium and energy) and of deficiency (eg, blindness in cats related to taurine deficiency). Feeds and feeding management can also influence animal health if feeding results in exposure to physical hazards (eg, sharp objects), chemicals (eg, mycotoxins, toxic plants), allergens (eg, dust mites, mold spores), or microbes (eg, molds, Salmonella spp). Feeding and waste management practices are also important to prevent and control infectious disease spread through fecal-oral transmission (eg, salmonellosis, neosporosis, paratuberculosis, toxoplasmosis).

BIOSECURITY The tenets of biosecurity have been long recognized by veterinarians. However, throughout the past decades, interest in biosecurity as a scientific discipline has surged because of l ) disease outbreaks that have threatened to devastate agricultural economies, and 2) bioten-orism. In fact, the meaning of the tem1 biosecurity and the stmcture and focus of biosecurity programs have evolved throughout time to more accurately reflect the scientific commu­ nity's evolving perception of disease as well as the needs of the consumer, the veterinary profession, and producers and owners. In modern animal medicine, biosecurity is probably best defined as "all procedures implemented to reduce the risk and conse­ quence of infection with a disease-causing

agent." This broad definition recognizes that disease is a complex interaction between the host, the disease-causing agent, and the environment. Biosecurity can be considered in terms of individual animals or populations of animals (flocks or herds), economic entities (production facilities or companies), or geographic regions (counties, states, countries, or continents), thus facilitating compartmen­ talization for trade purposes. Importantly, it addresses strategies for both disease prevention (eradication) and control (limiting the consequence of infection). Benefits of an effective biosecurity program include optimized animal health and welfare and, in the case of food animal medicine, improved productivity and

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BIOSECURITY end-product value, as well as safe regional/ international trade. Although implementa­ tion of a comprehensive biosecurity plan or program has obvious benefits, alloca­ tion of resources must be economically (food animals) or emotionally (companion animals) justified. Unless a disease poses a specific risk to human health or animal welfare, its mere presence in an individual animal or population of animals is not significant. Intervention strategies are consequently chosen based on both their economic and biologic efficiency. A dynamic and integrated epidemiologic and economic analysis is required to determine and quantify the negative effect of a disease challenge, and the anticipated positive response to the proposed intervention strategy. Such integrated analysis has become significantly more important in intensive production systems. The economic impact of disease can be difficult to assess. This is particularly so in intensive production systems in which economic return is governed by not only animal productivity but also product quality. In addition, the consequential loss from disease challenge is, at best, only prutially recoverable. Using tl1e cost of disease to justify intervention overemphasizes the consequence of inaction, and it is useful only in justifying intervention strategies directed at preventing disease challenge.

PRINCIPLES OF BIOSECURITY Disease control and prevention relies on the interrelated processes of bioexclusion, surveillance, and biocontainment. Preven­ tion of disease is costly, difficult, ru1d time consuming and is primarily directed at preventing epidemic or exotic diseases. It invariably involves eradication of disease­ causing agents from a population of animals or geographic area. In contrast, control progrruns are less demanding and prin1arily focus on limiting endemic diseases to tolerable levels within a population of animals or geographic area. Although preventing exposure to disease-causing agents remains an objective of control strategies, strategies are primarily focused on limiting the consequence of disease.

Disease Prevention: Disease prevention

depends on 1) stringent bioexclusion to avoid contact between tl1e disease-causing agent and the host, 2) eru·ly detection of a breach in biosecurity through vigilant smveillance, and 3) rapid implementation of a ruthless biocontainment policy. This is feasible only if there is an effective merulS of detecting infection; containing the infection

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through slaughter, clean-out, and disinfec­ tion; and preventing dissemination of the disease-causing agent. Eradication is reserved for t110se diseases that pose a dire public healtl1 threat, that have a devastating effect on animal performance, or that severely compromise end-product quality.

Disease Control: In disease control

strategies, the emphasis shifts from preventing disease to reducing its conse­ quence or economic inlpact. Prevalence data are now use10,000 ohms for dry

hand-foot contact. The contact voltage to produce sensation can therefore be higher for people than for cows, depending on the conditions of the contact points. The stan­ dard measurement circuit used for field investigations uses a 500-ohm "shunt" resistor to simulate the combined resistance of a cow's body plus a conservative (lowest or worst case) estin1ate of the resistance of the two contact points (cow + contact resistance). A great deal of research on the effects of stray voltage on dairy cows has been conducted throughout the past 50 yr. The most sensitive cows ( 2 Vnns in dry locations. N wnerous studies have docwnented that avoidance behaviors occur at exposure levels well above tllis first behavioral reaction threshold. As tl1e current dose increases above 2 mA, an increasing percentage of cows show mild behavioral responses, and some cows start to show avoidance behaviors. The median avoidance tl1reshold for 60 Hz cun·ent flowing tJu·ough a cow is -8 mA (or 4 Vm1S contact voltage in wet locations and>8 Vnns in dry locations). Even when the tJu·eshold is exceeded, all cows do not respond behaviorally all the time, nor do they exhibit the saine signs; how­ ever, as the voltage increases, signs in the herd become more widespread and wlifmm. Cows have reswned normal behaviors within 1 day of removal of aversive voltage and cun·ent levels. The only studies tl1at have docun1ented reduced water or feed intake in cows had botl1 sufficient current applied to cause aversion ai1d forced exposures (ie, cows could not eat or drink witl10ut being exposed to aversive voltage and current). It is typical for voltage levels to vaiy considerably tJu·ough the normal daily operation of electJical equipment on a farm. Decreased feed and/or water intake will result only if cwrent exposure levels at wate1ing and feeding locations are sufficient to produce aversion at these locations and they occm often enough to interfere with drinking and eating behaviors. If an aversive cun·ent occurs only a few tin1es per day, it is not likely to have an adverse effect on cow behavior. The more often aversive cwrent exposmes occur in areas c1itical to drinking or feeding, the more likely it is to affect the cows. Studies investigating the effects of !ugh-frequency or short-duration tJ·ansient voltages on cows clearly indicate that as the

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STRAY VOLTAGE IN ANIMAL HOUSING

duration of a current pulse gets shorter ( or the frequency increases), more voltage and current is required to cause behavioral responses. The main cause of short-dur a ­ tion electric pulses on farms is improperly installed electric fences and electrified crowd gates. These devices are designed to produce a powerful electric impulse that is used to control animal behavior. Improper installation of these devices can cause these pulses to appear in unintended areas on the farm. The other common source of high-frequency events is a switching transient that occurs when electric equipment is turned on or off. These high-frequency pulses decay quickly and do not travel far from their source, and it is extremely rare for them to reach problem­ atic exposure levels. Research suggests that swine respond to voltage/crnTent exposure in a way similar to that of cows. Behavioral modification in swine has been seen above 60 Hz exposures of -5 Vrms, with avoidance behaviors at exposures >8 Vrms. The body plus contact resistance for swine appears to be some­ what higher than for cows, and 1,000 ohms appears to be a conservative value for measurement purposes. Ewes have been shown to avoid electrified feed bowls when 60 Hz exposure levels exceed 5.5 Vims, whereas lambs showed this same prefer­ ential behavior when exposure levels exceeded 5 Vrms. Exposures to voltages as high as 18 Vm1s had no effect on hens' production and behavior. This is likely because of the very high electrical resistance of poultry, which has been docU111ented to be between 350,000 and 544,000 ohms.

Clinical Findings: A wide variety of

behavioral signs have been reported in cows exposed to voltage and cUITent. No one sign is pathognornonic, however, because these behaviors can also be caused by other factors in the animal environment. The only way to determine whether stray voltage is a potential cause of abnormal behaviors is to perfom1 electric testing. The direct effects of stray voltage can range from mild behavioral reactions indica­ tive of sensation to intense behavioral responses indicative of pain. The severity of response depends on the amount of electric CUITent flowing through the animal's body, the pathway it takes through the body, and the sensitivity of the individual animal. The indirect effects of these behaviors can vary considerably depending on the specifics of the contact location, level of current flow, body pathway, frequency of occurrence,

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and many other factors related to the daily activities of animals. All of the docU111ented effects of excessive voltage exposure have been behaviorally mediated. Results of studies to investigate direct physiologic effects that may be produced at levels both above and below those required to produce behavioral responses have shown that blood cortisol concentrations and other stress hormones do not increase at levels below behavioral response levels. Increases in stress-related hormones have been docun1ented in some, but not all, cows at voltage/cUITent exposures substantially higher than the threshold required for behavioral modification. A large body of research clearly indicates that at levels of voltage exposure typically used as regulatory limits ( 1 volt at cow contact locations, or 2 rnA of CUITent flow through a cow) will not result in increased somatic cell counts or incidence of mastitis.

Diagnosis: Several common situations

are of concern in animal enviromnents, including 1) changes in drinking behavior, such as decreased number of drinks of water per day and increased length of time per drink; 2) avoidance of locations that may result in reduced feed or water intake; and 3) difficulty of moving or handling animals in some areas. If these behaviors are seen, electric testing indicating cow contact exposure in excess of 4 rnA (2 Vims in wet locations witl1 a 500 ohm cow+ contact resistor, or 4 Vrms in dry locations with a 1,000 ohm cow+ contact resistor) is necessary to confirm a stray voltage diagnosis. Signs in pigs, ewes, and poultry are similar, although threshold response levels are higher than for cows. It is critically important to use a realistic value of animal resistance to relate voltage exposures to the level of cUITent conducted through an animal and the resulting effects on nerve stimulation, sensation, and behavioral reaction. A competent field investigation will include voltage measure­ ments at cow contact locations both with an appropriate "shunt" resistor (cow contact voltage) and without a shunt resistor (open circuit voltage). The shunt resistor is meant to represent the resistance of the body resistance of a cow plus the contact resistance representative of the exposure location. Both animal-contact and open circuit voltage measurements are required to determine the "source resistance" of the electric parts of the circuit. Note that source resistance is different from the cow contact resistance and can be used as a diagnostic to detennine the voltage source.

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STRAY VOLTAGE IN ANIMAL HOUSING

Animal-contact voltage levels should be monitored at different times of the day and on different days to represent the nom1al operating conditions of the farm electrical system. Point-to-reference ground measurements can be useful for diagnostic purposes. A reference ground can be established with a copper-clad rod dtiven into the ground at least 25 ft (8.5 m) from any part of the gr0tmding network on the farm. The other contact point is typically the ground-neutral interconnection in the barn service entrance panel or some other prut of the grounded-neutral system. Cow contact measurements are typically Y2 to 1/, of point-to-reference voltage levels. Long, insulated meter leads (6--10 ft [2--3 rn]) facilitate measurements on the farm and give a reasonable estimate of power frequency (60 Hz and 50 Hz) events but introduce considerable noise to higher frequency measurements. The measurP­ ment of high frequency events requires proper equipment and careful measurement technique. Details on measurement techniques are available through elect1ic power suppliers and extension publications.

Prevention and Control: Off-fam1 sources of stray voltage are most often related to improper ftmction of the grow1ded-neutral system of the electric utility. On-farm sources of stray voltage are most often due to wiring systems that do not meet wi1ing codes and struldards. Deficien­ cies may include loose or c01Toded connections; ground faults (shorts); undersized wiling; or wiring damaged by animals, accidents, rnoistw·e, or corrosion. The first step in a competent stray voltage investigation is to detem1ine the source of neutral-to-eruth voltage. Faults or electric code violations that could pose an electrocution hazard should be corrected immediately to protect both animals and people. If stray voltage levels are excessive, a competent electrician should assess the situation to detennine the most practical, safe, and efficient way to reduce neutral­ to-eaith voltage. Equipotential pla11es are required at critical anilnal contact locations in animal confinement facilities a11d effectively eliminate contact voltage even if substa11tial levels of neutral-to-eaith voltage are present.

VENTILATION Ventilation is often associated with respirato1y health of anilnals; the quality of the air that animals breathe directly influences a11irnal health and disease. Ventilation, directly and il1directly, impacts many other aspects of anilnal health as well. Good ventilation in the lying area of lactating animals helps beddil1g stay dry, a factor in favor of good rna111maiy health. Good ventilation along alleys helps to keep walking surfaces dry, which contributes to healthy feet. Good ventilation may lead to greater productivity, eg, maintaining aiJ· movement in the eating area makes animals more comfortable, especially ilnportai1t during hot weather as an aid to maintaining dry matter intake. A comfo1table, well­ ventilated lying area encourages a11imals to lie down, an importrult contribution to many aspects of anilnal healtl1. During ventilation, outside aiJ· is brought into a barn where it collects moisture, heat, and other contarninai1ts. Air is then exhausted to the outside. To determine ventilation rates, the focus is on the

moisture content of the air, measured by relative humidity.

AIR QUALITY Air quality is not easily defined. It is related to ventilation a11d the absence (or presence) of contanlina11ts in the air. For anim104° F (40 ° C) may be treated with an antimicrobial. Treated anirnals may be tagged and n"oted in the individual a.ni.n1al database, or the total nw11ber of animals treated (total a.mmmt of drug administered) in a group or pen may be recorded. Vaccination: The value of vaccinating

feedlot cattle for common infectious diseases, particularly those of the respira­ tory tract, has been controversial since the vaccines were introduced. Nevertheless, a wide vai·iety of vaccines ai·e used in feedlot health programs. Vaccines are available for the following diseases or infections of feedlot cattle: infectious bovine rhinotracheitis, pneu-

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HEALTH-MANAGEMENT INTERACTION BEEF CADLE

monic pasteurellosis, parainfluenza 3 virus infection, bovine respiratory syncytial virus infection, Hislophilus somni disease complex, bovine viral diarrhea types 1 and 2, and clostridial disease. The vaccines available for clostridial diseases are highly effective. The nwnber of clostridial antigens to be used (2- to 8-way) depends on local prevalence of clostridial diseases, including blackleg (Closliidium chauvoei), malignant edema (C septicum), bacillary hemoglobinuria (C novyi, type D [haeino­ lyticum]), infectious hepatitis (C novyi, type B), tetanus (C lelani), and enterotox­ emia (C perfringens types B, C, and D). Leptospirosis (Leplospira serovars Hardjo, Pomona, Grippotyphosa, Canicola, and Icterohaemorrhagiae) bacterins are also used in some situations. A basic vaccination schedule for receiving calves should include a viral respiratory vaccine plus a clostridial vaccine. Additional vaccines should be included only if two criteria can be met: the disease is enough of a risk that prevention is necessary ( eg, leptospirosis in some ar·eas ), and data are available to support the use of vaccines to prevent disease. Castration and Dehorning: These

surgical procedures are best perfo1med well al1ead of entry to the feedlot, but invarfably there will be bulls and homed cattle offered for sale. When to castrate and dehom these mismanaged cattle is quite controversial, with studies showing that performing surgery at initial processing 24 hr after arTival was superior to delaying these procedures.

Anthelmintics and Insecticides: Anthel­

mintics ar1d insecticides are administered according to local conditions. Most incoming cattle will have been exposed to internal parasites, and appropriate dewonning methods should be imple­ mented. Young cattle raised on small farms in which tl1e stocking rate on pasture is high may harbor helminths. Yatmg cattle may also be affected by chronic vem1inous pneumonia caused by D'ictyocaulus vivipa­ nis. Most young cattle will be infected with coccidia, and having an appropriate anticoccidial agent in the feed is necessary.

Growth-promoting Agents: Growth­

promoting agents (s eep 2758) increase growth rate of animals without being used themselves to provide nut1ients for growth. They are generally administered in small an.10unts-often via implants or in feed-to

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alter metabolism so the ar1in1al increases body tissues and grows more rapidly. They include antibacterials, antinucrobials, steroids (eg, estrogens, androgens), and ionophores. They promote changes in composition, confonnation, mature weight, or efficiency of growth, along with changes in the rate of live weight gain.

BEEF QUALITY ASSURANCE AND BEEF SAFETY PROGRAMS The purpose of a beef quality assurance (BQA) program is to identify ar1d avoid areas in the feedlot where quality or safety defects car1 be seen. The goal of the BQA prograrn is to assure the consw11er that all cattle shipped from a feedlot ar·e healthy, wholesome, and safe and that their mar1agement has met all govenunent ar1d industry staildar·ds. The feedlot must be able to document all steps of production. Critical points in production must be monitored to ensure no residue violations or carcass defects. These critical points include, but are not limited to, incoming cattle, product and conunodities, cattle handling, ar1d evaluation of outgoing cattle. There is a built-in margin of safety for withdrawal tin1es in the feedlot industry, because most withdrawal tin1es for animal health products are shorter than the feeding periods. Feedlot personnel must be aware of situations that create high risk of residues. Nonperfom1ing cattle could have orgar1 dan1age, which could prevent normal clearance of a drug product, causing violative residues even after the preslaugtt­ ter withdrawal time has elapsed. The BQA program is based on the principles of the Hazard Analysis of Critical Control Points (HACCP) system. Each production step should be evaluated for potential quality or safety defects, including bacterial contamination, which car1 cause infectious disease in cattle or employees; chemical usage/contan1ination, which car1 lead to violative residues; and physical darnage, such as injection site dar11age, bruising, or broken needles in animal tissues. The ar1alysis should include sanitation staildard operating procedures (eg, finding ways to prevent or minin1ize fecal-oral contarnination). All relevar1t govenunent regulations on feedstuffs, feed additives, and medications (including route of administration ar1d withdrawal times) must be closely followed. Extra-label drug use must be prescribed only by the herd health vete1inarian. All owners of cattle treated witl1 medications adrninis-

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HEALTH-MANAGEMENT INTERACTION: BEEF CADLE

tered extra-label must comply with prescribed, extended withdrawal times that have been set by the herd health veterinarian under the guidelines of a valid veterinarian­ client-patient relationship. The Food Animal Residue Avoidance Databank is the primary resource to detennine the preslaughter withdrawal time when an animal has been treated in an extra-label manner.

Record Keeping: All records should be kept for �2 yr after cattle have been shipped from the feedlot. If a violative residue is found in any cattle shipped for slaughter, the feedlot must make applicable records available to the appropriate govenunent agencies. The source and cause of violative residue should be detennined and corrective action taken to prevent reoccurrence. Individual Records: Treatment records should be maintained for all cattle treated individually. This can be done using handwiit ­ ten records or a compute1ized record system. Essential information includes the individual animal identification, treatment date(s), diagnosis, drug administered, serial/lot nwnber, dosage used, approximate weight of animal, route and location of administration, and earliest date the animal could clear tl1e preslaughter witl1drawal period. The treatment history of cattle with clu·onic medical problems, or of tl1ose tl1at have a poor, unexplained growtl1 rate, should be scrutinized carefully. In many cases, residue screening, such as tl1e live a.t1in1al swab test, is advisable. Residue screening should be perfom1ed under tl1e supervision of tl1e herd healtl1 veterina.iian. The results of such testing detennine whether a.11 animal ca.11 be released for shipment. Group Records: All anin1als treated as part of a group (processing or mass medication) should be identified by group or lot, and tl1e treatment infommtion should be recorded. Records should include the animal lot or group identification, product used, serial/lot nwnber of the product, date treated, dosage used, route and location of administration, and withdrawal information. A preslaughter withdrawal time is assigned to the entire pen. Recording treatments under this system asswnes that every anin1al in tl1e lot or group received the treatment. The health records of cattle shipped to slaughter should be checked by feedlot personnel to ensure tl1at treated a.t1in1als have cleared tl1e appropriate witl1drawal times. All pesticides should be used in accordance with label directions, and their use and withdrawal time should be recorded.

Treatment Protocol Book: The herd health vete1inarian should provide a treatment protocol book specific to the feedlot operation. It should be reviewed regularly and updated at least every 90 days. One copy should be kept at the treatment facility and another copy should be maintained in the feedlot office. A wi·itten treatment protocol and cwTent prescrip­ tions are important docun1ents the feedlot must have if there is a govenunent inspection of the feedlot facilities, drug usage procedures, and residue avoidance plans. It also provides written guidelines for animal health progra.tns, thus minimizing chances of mistakes or misunderstandings.

Culling of Feedlot Cattle Culling may be done at any point between exa.tnination of the cattle on at-rival and a few weeks later, before the cattle a.i·e placed on a high-energy diet. Diseases that justify culling include clu·onic untluiftiness and inappetence of undetennined etiology, chronic la.tninitis, chronic la.tneness caused by footrot, clu·onic bloat, chronic pnewno­ nia, acute and chronic pulmonary abscess, and bovine viral dian·hea. Each of these diseases leads to untluiftiness, and a clinical exan1ination is necessary for diagnosis.

Animal Welfare in Feedlots Good feedlot design is in1portant to ensure animal comfort. Handling facilities must be modem and efficient and must not induce animal attendants to be cruel to a.ttlmals when they are being moved from one location to anotl1er; excessive force should not be used to get the a.ttlmals to move. The feedlot personnel must be educated in the teclutlques of low-stress cattle ha.t1dling and recognition of signs of pain and discomfort associated with certain illnesses. The vete1inarian should emphasize good feedlot design and equipment that will ensure comfort for the animals and minimize pain and stress associated witl1 handling procedures. The veterinarian must also be a vigila.t1t guardian, denouncing inhwnane practices and encouraging sound animal welfare management. (See also ANIMAL WELFARE, p 1579.)

DEVELOPMENT OF ANTIMICROBIAL-RESISTANT B ACTERIA IN FEEDLOT CATILE The use of antin1icrobials in feedlot cattle, as in all food anin1al species, has come under increased scrutiny because of

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HEALTH-MANAGEMENT INTERACTION DAIRY CADLE

concerns about the potential transfer of resistantzoonotic pathogens to people and also transfer of resistant genetic determi­ nants to human pathogens. A pathogen of concern related to resistance in cattle is Salmonella spp. Transfer of Escherichia coli O157:H7 through the food chain, while

2135

a valid zoonotic disease concern, is not related to an issue of resistance. The American Association of Bovine Practi­ tioners publishes Pr1tdent Drug Usage Guidelines, which provides guidelines for antimicrobial usage in cattle feedlot operations.

HEALTH-MANAGEMENT INTERACTION: DAIRY CATTLE The dairy industry is in a period of economic volatility of historic proportions. An era of modest fluctuation in milk and feed pricing in the late 1990s to the early 2000s was followed by increases in milk prices not seen before. The period of high dairy profitability in early 2008 was soon dampened because of substantial increases in production costs as a result of high fuel and feed costs as the USA government encouraged crop farmers to produce corn for ethanol distillation. Since then, milk prices have rebounded and dropped several times, although not to the san1e extent. USA dairy product exports have also fluctuated widely, contributing significantly to milk price volatility and overall profitability. As of early 2014, some 15% of USA dairy products are exported, milk prices are at an all-time high, and feed prices are somewhat lower.

THE MODERN DAIRY INDUSTRY The structure of the dairy industry in developed countries has continued to evolve as production efficiency has risen. Industry consolidation is the norn1, with reduced herd nun1bers, increased herd sizes, and adoption of specialized manage­ ment practices that encourage higher productivity. In the past, most dairy cows were housed in stall-barn facilities designed to maximize operator comfort. Today, free-stall facilities are built to maximize natural ventilation and cow comfort. Historically, barns were often placed in sheltered locations, whereas today they are usually located in open fields or on hilltops to ensure adequate airflow. The type of milking facility is also evolving; whereas in 2007, 49.2% of operations reported using tie-stall or stanchion milking facilities, almost 75% of cows are

now milked in parlors, reflecting the fact that most large herds are housed in free-stall or open facilities (and milked in parlors). Most parlors are highly mechanized and designed to minimize the amount of labor required, and economics dictate that milking proceed nearly around the clock to maximize the return on investment. Milk quality is traditionally defined by the somatic cell count (SCC) and bacterial count in prepasteurized bulk tank milk. In all developed nations, regulatory officials set allowable maximums for SCC. Since 1986, limits for sec and bacteria have been gradually lowered. The current upper lin1it for the bulk tank SCC is 750,000 in the USA and 500,000 cells/mL in Canada. The SCC maximwn in the EU is 400,000 cells/mL using geometric means as the basis for calculation. Artificial insemination (through the commercial distribution of frozen semen) is the preferred method of reproductive management in most dairy operations. In fact, 45% of USA dairy operators in 1996 reported that no breeding bulls were present on their farms. The use of genetically elite sires has contributed to increases of> 150 kg/ yr in genetic merit for milk production. Declining fertility has accompanied advancements in genetic merit. Dairy farms commonly record herd conception rates of 600A, of newborn heifer calves are hand-fed colostrwn within the first 24 hr of life to ensme adequate intake of immunoglobu­ lins. The feeding of waste milk from cows undergoing antibiotic treatment or with mastitis is economical but may transmit infectious diseases to the calf. To decrease the potential for disease transmission, some producers pastemize waste milk(15% of all calves in 2007) or feed milk replacer(>70% of calves in 2007). The an1ount of milk fed to heifers(typically 8%--10% of body wt at birth) has typically been restricted to encomage conswnption of high-protein calf sta1ters, with a goal of early rumen development and weaning by 8--10 wk of age. However, calf health was found to improve when calves were fed more milk than this, and current practice recom­ mends that calves be fed an increasing amoW1t of milk-up to 12%--15% of bo300 days after calving. 4) Fewer replace­ ment heifers are available. 5) Higher labor and treatment costs are associated with prolonged efforts to synchronize and breed open cows. Successful AI requires that cows be inseminated during estrus in a narrow range of optimal fertility, and that the semen be thawed properly, transported quickly to the cow, and deposited in the appropriate area of the reproductive tract. The most important factor affecting the success of an AI program is the detection of estrus: recent data from the USA indicate that fewer than 4()0A, of estrus periods were detected in lactating dairy cattle. Efforts to improve heat detection using estrus synchronization and artificial detection aids have been largely unsuccessful and are hampered by the reduced duration and intensity of estrus exhibited by modem USA Holsteins, and by the increasing size of farms making estrus observation more difficult. Because heat detection rates are so low, some dairy managers have returned to extensive use of natural service sires to ensure that cows conceive promptly. In these herds, breeding soundness examinations and bull manage­ ment programs should be included to ensure continued herd productivity. (See

also BREEDING SOUNDNESS EXAMINA'l10N OF' BULI.S,

p 2231.) However, the problems associated with natural service include reduced genetic in1provement of offspring; costs associated with purchase, raising, and feeding bulls; dan1age to facilities; and danger to people. Researchers in Wisconsin and Florida have developed hormonal synchronization protocols that allow timed insemination to be performed with acceptable conception rates. These programs have been widely adopted and have enabled herds to dramatically increase the nun1ber of pregnant cows throughout defined time periods. Many of the injections and t11e inseminations can be scheduled on a weekly basis, leading to more efficient use of labor. Replacement Management Herd productivity can be profoundly affected by the success of the replacement

program. The cost of raising heifers is a significant proportion of the overall cost of production; a replacement animal does not begin to earn a profit until midway through her second lactation. A wide range of mortality rates (5%-25%) is reported for replacement anin1als. The highest morbidity and mortality rates on dairy farms generally are seen before weaning. The most significant causes of preweaning death are infectious diseases of the digestive and respiratory systems. These disorders can be controlled by well-designed health management procedures that define the care and housing of the dan1 during the periparturient period, the calving process, feeding adequate quantities of high-quality colostrum, and the application of proper preventive measures (including sound nutritional programs) for newborn calves. Delayed age at first calving reduces dairy productivity by increasing the need for replacement animals and increasing the costs of raising the replacements because of longer feeding periods. Heifers should be 23-25 mo old at first calving, which means they should conceive when 14--16 mo old. Adequate nutrition is important to ensure that heifers are fertile and cycling at this stage and that continued growth occurs so that heifers are large enough at calving to limit dystocia and maximize mammary development and lactation. Herd Size, Composition, and Culling There is a well-demonstrated relationship between productivity and herd size. One reason for this is the greater willingness for larger operations to adopt production­ enhancing technologies. Government policies can also substantially influence herd size (eg, countries with supply manage­ ment systems effectively limit the annual income a farm can achieve from the sale of milk). The an10unt and productivity of pasture can influence tl1e size of herds that use grazing. ln these herds, productivity is detennined by balancing the ability of the pasture to produce nutJ.ients against the ability of the cows to produce milk. The size of both grazing and confinement herds are increasingly affected by competing demands for land. The proportion of the herd producing milk versus the nonproductive stock (dry cows, calves, heifers, and bulls) has an effect on total herd productivity. Herd composition is the result of a nwnber of interrelated management decisions, such as culling policy, rate of reproductive success, rate of disease, replacement management,

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and longtenn goals regarding herd size. The ability of a herd manager to cull animals can have a significant impact on herd composi­ tion. When numerous replacement heifers are available, culling may intensify, leading to a younger herd with improved genetic potential for future milk production. In countries such as the USA, where herd production is not limited, longterm plans regarding expansion often influence herd composition. In some growing or start-up herds, only nonlactating cattle are pUI0 chased to reduce the risk of purchasing animals with infectious diseases such as contagious mastitis or bovine viral diarrhea. These herds often consist of a high proportion of first-lactation animals. Decisions regarding cow removal can significantly impact productivity of the daily herd. Culling rates vaiy between herds and may be related to disease rates or disease control programs. Fertility, mastitis, and lameness ai·e common reasons for cow removal. Culling is an important aspect of controlling other diseases such as bovine tuberculosis, brucellosis, paratuberculosis, and chronic mastitis caused by some contagious mastitis pathogens.

Environmental Conditions Even with optimal housing situations, herd productivity ca.11 be affected by environmen­ tal conditions. High-producing cows have higher dry-matter intake, generate more internal heat, and are less tolerant of high ainbient temperature. Weather conditions that combine high atnbient temperature and high humidity without periods of cooling generaJJy depress dry-matter intake and reduce milk yield. The increased concentra­ tion of dairy farming in regions that experience considerable periods of high temperatures (eg, southwestern USA) has resulted in more seasonal variation in milk output. Farmers have adopted a variety of systems to combat heat stress. New facilities are constructed with lai·ge, open sides and ends (often >4.3 m high) and use fans and sprinkler systems to keep cows comfortable. Older, enclosed facilities can be retrofitted with tunnel ventilation systems to provide adequate air movement. (See also VENTILATION, p 2116.)

Drying Off and Dry Cow Management Risk factors for most postpartum diseases of dairy cows are present during the dry period, with clinical signs of disease

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becoming evident after calving. Diseases such as hypocalcemia (milk fever), hypomagnesemia, udder edema, ketosis, displaced abomasum, and mastitis often begin during the dry period. Dairy health management prograins focus on many preventive practices such as vaccination, hoof care, and nutritional monitoring during this period. The length of the dry period influences milk yield in the subsequent lactation. The recommended dry period is 6-8 wk. D1y periods of 2,000 cows) is employment of a full-time staff veterinarian to oversee and direct day-to-day issues regarding health and performance. The frequency of scheduled herd visits for grass-based seasonal dairy operations varies depending on the herd's stage of lactation. More frequent visits are .necessary in early lactation and during the breeding period. Activities at herd visits fall into four general categories: provision of individual animal health care and emergency services, scheduled technical activities, scheduled analytic and training activities, and provision of quality control programs. The frequency of individual activities varies. Individual Health Care and Emer­ gency Services: The examination and treatment of individual animals is an important activity during scheduled dairy visits. Frequent herd visits allow practition­ ers to examine cows early in the course of disease when the likelihood of successful treatment is higher. Routine visits also allow veterinarians to monitor the outcome of treatments and modify treatment protocols as needed. Ideally, monitoring programs include a system to detect cows not performing as expected. Special attention should be pa.id to the highest-risk cows, including frequent observation of anirnals during the peripartwient period. Some

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farms have adopted a system that ir1cludes routine daily monitoring of body tempera­ tme and rwnen activity of cows during the first 7 days after calving. A.nirnals that fall outside no1mal lin1its are treated according to predefined criteria or detained for examination by the herd veterinarian. All treatments administered to dairy cows should be recorded in treatment logs (either computerized or handwritten) to ensure adherence to proper meat and milk withholding periods. The frequency of unscheduled visits for emergency medical services usually diminishes in herds that have adopted a health and production management program. Scheduled, Traditional, and Technical Activities: Routine reproductive exan1ina­ tions account for much of the veterinarian's tin1e during scheduled herd visits. Attaining reproductive success is an essential detem1inant of herd productivity. For a description of reproductive programs, seep 2171. The end point of reproductive examinations should be to identify nonpregnant cows that can be returned to the breeding program and to generate data that can be used to detennine the success or failure of breeding programs. The imple­ mentation, success, and cost-effectiveness of scheduled breeding progran1s should be reviewed frequently. On smaller fa.ims, it is often customary for the veterina.iian to perfom1 routine ir1dividual anin1al treatments (such as IV injections), prophylactic activities (such as vaccinations), and some technical tasks (such as dehoming calves) during scheduled herd visits. It is appropriate for the veterina.i·ian, or a technician under the veterinarian's supe1vision, to perfom1 these tasks, because the farm staff may not perfom1 them often enough to become technically proficient. On larger farms, tl1ese tasks must often be performed on a daily basis; in this case, farm employees should be trained to accomplish these tasks. Scheduled Analytic and Training Activities: Conducting scheduled or unscheduled technical activities will not be effective unless a system exists to captme the results of the activities and allow for analysis and ongoing revision. The structure of the health and production management program must include time for the fa.imer and the herd veterinarian to analyze and discuss herd management issues. In herds that depend on hired personnel to implement designated tasks, time must be

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scheduled to observe and effectively train personnel ultimately responsible for perfonning the activities. Development of standard operating procedures is one method to ensure that agreed-on practices are implemented. Treatment protocols are used to define standard treatments for common diseases on dairy farms and should be used when multiple people have responsibility for administering antibiotic treatments to dairy cattle or when extra-label drng use is pre­ scribed. They also provide a mechanism for increased communication about treatment plans between the veterinarian and producer. The avoidance of residues in food products is a major responsibility of dairy practitioners. Increased scrntiny regarding antinticrobial use in food-producing anin1als has arisen because of concern about the development of antimicrobial resistance in food borne pathogens. Although the level of detected ai1tibiotic residues in meat and milk products is extremely low, antibiotic residues in bulk ntilk and carcasses are seen occasionally. In the USA, contan1ination of bulk milk is rare because of an effective sUIVeillance system based on rapid testing for selected antinticrobial agents of every load of raw milk Milk contantinated with antibiotics is discarded, and the producer is fined. The requirements for extra-label drng use in the USA have been defined by regulatory officials under the Aninlal Medicinal Drug Use Clarification Act and shm).id be closely followed. The An1erican Association of Bovine Practitioners has responded to societal and regulatory concerns about the use of antimicrobial agents by adopting recommendations for the prudent arid judicious use of antin1icrobial agents in dairy cattle. In response to concerns about the development of antimicrobial resistance in human medicine, the FDA is requesting that drng manufacturers begin the process of elintinating the labeling and use of certain antimicrobials for production pm-poses (to increase feed efficiency or weight gain). Specifically, antimicrobials of importance to hun1an medicine will no longer be pennitted to be provided in feed or water solely for production pm-poses, and no new antimi­ crobials will be approved for production pm-poses, although they can be approved for use in feed or water for treatment or prevention of disease. For producers to use an antimicrobial in feed or water, they must receive a feed directive from their veterinarian ( essentially a prescription);

over-the-counter sales of antin1icrobials for use in feed or water will no longer be allowed. See also TIIE VETElllNARY FEED UIHJ::GIWJ::, p 2634. Some dairy practitioners function as the nutritional specialists for the 'dairy farms they serve. TI1ey may collect feed samples for nutrient analysis, forn1ulate rations, and advise the farmer regarding crop and haivesting conditions. These veterinarians often devote a considerable ainolUlt of their professional time to nutritional manage­ ment. Other fam1s employ a professional nutritionist or use a nutritionist employed by a feed company or local cooperative to formulate the rations and submit feed samples for nutrient analysis. Regardless of the source of the dairy's nutrition progran1, the veterinariai1 can perform an essential oversight function simply by observing body condition and general health in cows in certain high-risk areas (peripaituricnt and high milk production), monitoring the incidence of nutrition-related diseases such as parturient hypocalcemia and displaced abomasun1, and ensuring that the diet described on paper is adequately formulated and delivered to the cows. Assessing pasture conditions by periodic inspection of pasture is an inlportant component of managing the nutritional progran1 of herds that use management-intensive grazing. These quality control activities should be conducted routinely as pa.it of the health and production management prograin. Quality Control Programs

Quality control refers to activities that ensure consistency in perforn1ing key management processes. Vital management areas for most herds include nutritional management, ntilking management, and ymmg-stock progran1s. Some fan11s may also develop quality control processes for environment and housing and farn1specific mai1agement of breeding bulls. Milking management should be a standard element of quality control prograins. Tasks such as observing the milking routine and scoring tl1e condition of teats should be performed at least quarterly. A scheduled system of routine screening for mastitis pathogens can be inlplemented as part of the milking management prograin. The veterinarian can teach farn1 personnel how to perform the Califontia Mastitis Test as part of a SUIVei!lance prograin. Animals routinely screened may include cows at dry off, fresh cows and heifers, and newly purchased cows. Milk sainples can be

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HEALTH-MANAGEMENT INTERACTION: DAIRY CATILE

collected and submitted for culture from quarters that show positive reactions. Newborn calves and replacement heifers are often housed separately from lactating cows and may not be observed routinely by the herd veterinarian. However, routine surveillance of critical management issues such as adequate delivery of colostrum to calves and growth rates of replacement heifers can be done as pait of scheduled herd visits. The environment of dairy cattle cai1 have considerable influence on health and productivity. Some veterinai·ians routinely schedule "walkabouts" through the housing ai·eas to assess factors related to anin1al comfort and hygiene. Udder cleanliness, hoof and hock lesions, and respiratory disease are often determined by housing conditions. Herd walkabouts should include ai·eas often ignored, such as dry-cow and heifer housing.

Performance Targets Performance tai·gets reflect herd standards of performai1ce that are perceived as indicators of successful herd management. They are useful as comparison values for herd perfonnance ai1d as a starting point to initiate discussions about potential ai·eas for improvement. To use a perfom1ance tai·get, it is necessary for a herd to have a record system that allows for generation of

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comparable herd indices. In many instances, pe1fom1ance targets have been calculated as arithmetic averages, which are useful indicators of herd pertonnance when the contributing data (such as milk, fat, and protein yields) are nonnally distributed and have a reasonable degree of vaiiation. However, many reproductive indices and values such as SCCs ai·e not distributed normally, and eIToneous conclusions about herd perfom1ance may be made if averages alone are used to make management decisions. Appropriate frequency distlibu­ tions are more useful for these types of data. Key indicators for perfom1ance targets should be defined. The monitoring system should specify the indices used, the anin1als included, ai1d the time interval to reassess progress made toward reaching each target. Typical performance indicators include milk production, reproductive perfor­ mance, milk quality, replacement manage­ ment, cow removal, animal health, ai1d special reports (see TABLE 4). Perfo1mai1ce targets should be reviewed at appropriate intervals with realistic expectations regai·ding the an10unt of time it takes to effect change in an index. For exai11ple, management actions taken to reduce days to first calving would require �9-10 mo to become appai·ent. A more tin1ely value such as age at conception would more rapidly reflect current management changes.

EXAMPLES OF ACTIVITIES FOR ROUTINE MONITORING·

Cow Monitoring

Environment Monitoring

Records Monitoring

Body condition

Stalls and bedding

Milk production

Rw11en fill

Barn climate

Milk quality features

Feces consistency

Milking method

Roughage analysis

Undigested fraction in feces

Milking parlor condition

Drinking water quality

Teat end callosity

Pasture management

Sire evaluations

Lesions of udder/teat/skin

Grass haivesting (silage) Soil analysis

Clinical disease cases

Maize haivesting (silage) Artificial insemination records

Reproductive exaininations

Floor design and maintenance

Disease and drug records

Ectopai·asites

Ration formulation

Fan11 economics report

Locomotion and claw score

Feeding management

Slaughter findings

Young stock growth

Hygiene practices

Laboratory findings

"From Noordhuizen JP, Dairy herd health and production management practice in Europe: state of the art. Proc 23rd World BuiaLrics Congress, Quebec, Canada, 2004.

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Record Keeping

A system of unique individual cow identifica­ tion is a prerequisite for a successful health management program. The most common methods of animal identification are ear tags, collars, and branding. Increasingly, farms are using electronic identification via transpond­ ers on ankle bands or neck straps. At a mi.J1imw11, data must be recorded on birth, breeding, and calving dates and periodic milk yield. Under ideal circwnstances, swnmarized data should be available for the nutritional progran1, disease occwTence, and financial performance. Record analysis is a necessary compo­ nent of the health management cycle. Most or all dairy herd i.Jnprovement (DHI) systems allow for electronic access to performance data, and various computer­ ized systems for herd management are used throughout tl1e industry. Most monitoring systems can be charactetized broadly as one of the following: 1) manual (handwrit­ ten) card systems, 2) on-farm computer progran1s, 3) DHI, or4) DHI and on-faim computer. Regardless of the type of system used, it should be easy to use and relevant to the day-to-day operations of the dairy. One in1portant function of record systems is tl1e generation of"action" lists (due to calve, due to dry, etc). This function is critical in large herds in which cattle ai·e not individually known by the animal handlers

and can be overlooked easily. Most systems also provide for a minimal level of herd analysis, such as the generation of timely perfom1ance reports for production, reproduction, and disease. Some prograins can also generate statistics. The record­ keeping system should allow the producer and veterinarian to understand and modify the fonnulas used to generate herd per­ fom1ai1ce indices. For paraineters and values used to monitor herd healtl1 and production, see TABLE 5. The vetetinarian should ensure tl1at collected data are used in a timely manner. Accurate data collection is most likely when the producer is using the data frequently and understands its value. The validity of data generated from both manual and automated data collection systems should be reviewed and critically assessed. Unusual results and deviations from normal perfonnance tai·gets should be challenged. The producer and the vetetinai·ian should agree on defined actions based on the herd status and goals. Actions are generally diagnostic, preventive, or treatment oriented. 'fypical activities might include listing animals for routine herd fertility or illness exan1inations, or selecting cows to obtain milk sainples for culture, to vaccinate, to consider culli.J1g, to breed, to receive body condition scori.J1g, or to receive treatments.

PARAMETERS USEFUL TO MONITOR HEALTH AND PRODUCTION OF DAIRY HERDS Parameter

Goal

Adult Cow Disease Average percent of herd Jaine

25 cm in mature bucks(> 14 mo old). Scrotal circumference can vary by season and decrease by as many as 3 cm outside the breeding season. Because scrotal circumference and body weight are positively correlated in bucks, scrotal circmnference measurements are of minimal value before 14 mo of age. The testicles and epididymis should be synrn1etJ.ical and finn on palpation. Any asyn1metry or changes in tone may indicate infection or injury and will likely adversely affect fertility. Orchitis a.i1d epididymitis are both ra.i·e, occuning in -1 % of breeding bucks, and affected bucks should be tested for Brncella melitensis, because bred does are at risk of stillbirths and abmtions. Other causes of orchitis and epididyn1itis are of minin1al concerns for transmission; however, treatJ.nents a.i·e generally unrewa.i·ding. Gaseous lyn1phadenitis (see p 63), spermatic granuloma, and calcifica­ tion of the testicles(which also may be due to Corynebacterium pseudo tuberculosis infection) all reduce or eliminate the buck's fertility, and infected bucks should be culled. In extreme cases, ultrasound may be used to detennine whether one or both testicles are affected and if herni-castration is an option. Evaluation of semen quality is another important part of the breeding sotmdness exanlination. Semen can be collected either by use of an artificial vagina or with an electroejaculator. The former yields a higher quality sa.inple but requires the presence of a doe in heat to perfom1. Electroejaculation is more convenient and, thus, used more commonly. Once semen is obtained, it should be maintained at 37°C (98.6° F) and evaluated as quickly as possible. Grossly, the semen should be cloudy, white, and free of urine, blood, pus, or dirt. Occasionally, semen will be an off-yellow color and may be normal but should be examined more closely for wine cont.an1ination. The semen should be evaluated microscopically for motility, morphology, and presence ofWBCs. Gross motility can be measured by placing a drop of undiluted semen on a wam1ed slide and

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MANAGEMENT OF REPRODUCTION: GOATS

evaluating on low-magnification. A satisfactory sample should exhibit anywhere from general oscillation to vigorous swirling. Sporadic oscillation to no motility at all indicates poor semen viability. Individual and progressive motility should also be measured by diluting the semen with an isotonic diluent (eg, 0.9% saline) and evaluating microscopically. Sperm cells should be counted to determine a percent­ age of progressively motile spem1, with a minimum of 30% being acceptable. Spem1 morphology should also be assessed microscopically, with a minimwn of 700/o normal being acceptable. (See ai,so BREEDING SOUNDNESS EXAMINATION OF THE MALE, p 2234.)

BREEDING Natural service is the easiest and most common breeding system. Most hobby operations have a low doe: buck ratio (5: l ) because of multiple breeds and different bloodlines. Bucks have a strong libido and can breed far more does than this, although as they get older, and especially during the off-season, they are less efficient. Aitificial insemination (Al) is increasingly being used by goat producers, because it allows for both dissemination of valuable genetics and control of sexually transmitted diseases. Proper heat detection ancVor hormonal synchronization of the estrous cycle is essential and may lead to increased labor and costs. Ovulation in does occurs toward the end of standing estrus; there­ fore, insemination must occur around this tin1e to be effective. The M1:PM rule is generally used: if the doe is first noticed to be in standing heat in the morning, Al should be pcrfonned in the evening (or vice versa). However, breed-specific.estrns durations should be considered when deciding the best time to inseminate. Vaginal (pericervical deposition) or cervical (intracervical deposition) insemination techniques are inexpensive and easy to perform and can result in acceptable pregnancy rates if fresh semen is used. However, if frozen semen is used, transcer­ vical or laparoscopic intrauterine insemina­ tion techniques must be used, which are more expensive and require more skilled personnel. Frozen semen in 0.25--0.5 mL straws may be purchased directly from buck owners or custom collectors. Semen can be collected for Al in an artificial vagina or with an electroejaculator. Most bucks will mount a doe in P.strus and ejaculate; with training tl1ey can ejaculate year round and even mount wethers. Older bucks are often reluctant to breed does that

have had estrus induced outside the nom1al breeding season; therefore, collections are more successful when young bucks are used. The optimal sperm concentrations depend on the individual buck and production settings but should be -200-400 million/mL to account for an approxin1ate 500/o death and damage rate during semen processing and thawing. There is no legislation or industry-wide standard in North America that governs the collection, processing, and sale of frozen semen, but country-specific legislations should be reviewed and followed before exporting semen. Embryo transfer allows for dissemination of valuable female genetics. Its application in goats is somewhat limited because of tl1e variable response of does to superovulation techniques. Control of tl1e estrous cycle is crucial to ensure adequate timing for induction of superovulation, which is achieved by treating witl1 conunercially available follicle-stimulating honnone (FSH) products. Lapa.roscopic insemination of semen is reconunended to confirm that superovulation occuned (via visualization of multiple corpora lutea) and to allow for the greatest conception rate. Embryo retrieval can be achieved surgically, laparoscopically, or transcervically, with surgical techniques providing tl1e highest recovery rates. Embryos can then either be transferred inunediately via laparoscopic or surgical techniques into synchronized does or frozen in liquid nitrogen.

INDUCTION OF ESTRUS Estrus can be induced in several ways, depending on the tin1e of year and the relationship to tl1e doe's natural breeding season. Out-of-season breeding is of interest to dairy goat owners, because it reduces seasonal fluctuation in tl1e herd's milk production. In meat production systems, increasing conception rates and litter sizes are important and can be manipulated using hom10ne therapy. The sudden introduction of an odorifer­ ous buck often advances the onset of cycling by a few weeks, and tl1e does also may show some synchronization. The buck should be housed well away from tl1e does (out of their sight and smell) for 2:3 wk before introduction. Even if tl1e whole group does not cycle, this method can get a few to conceive in the theoretically out-of-season period. Providing 20 hr of light per day in January and February (northern USA), witl1 a sudden return to available daylight on

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MANAGEMENT OF REPRODUCTION: GOATS March 1, will bring goats into estrus several weeks later. In this system, it is more difficult for the owner to pick out the does that are in estrus; consequently, running a young, vigorous buck with the does gives tl1e highest conception rate. If a po1tion of the herd is artiiicially synclU'onized, some of the remaining does also may come into estrus. The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) places limits on extra-label drug usage in food-producing anin1als in the USA and restricts extra-label use to animals that are suffering or in danger of death. Uncler AMDUCA, pharmaceuticals cannot be used to alter reproduction for production purposes, and the following comments about manipulating reproduction are provided for use in cotmtries outside the USA. If the corpus lutemn is fm1ctional, a synthetic PGF2a analogue will induce estrus; however, this is not effective clming anestrus. Additionally, it may provoke short cycles that tend to be seen normally at the beginning of the season. Melatonin in1planls may also be used to produce sho1t-day effects and induce sexual activity in both does and bucks. Progestagen treatment, followed by administration of FSH or pregnant mare sermn gonadotropin (PMSG), will cause out-of-season estrous activity. Good conception rates can be achieved with this system, and fixed-time insemination is feasible, but these products (FSH and PMSG) are not approved for use in goats. Progestagen treatment can be in the form of injections with an oily base every 3 clays, impregnated vaginal sponges (eg, fluroge­ stone acetate or methyl acetoxyprogester­ one), norgestomet implants, oral administration of melengestrol acetate, or a controlled intravaginal drug-releasing device, or CIDR (which is a fonn of progestagen-impregnatecl silastic for vaginal use). A commercial product marketed for use in swine containing both PMSG and hmnan chorionic gonadotropin will also cause does to cycle outside the nonnal breeding season when administered at the end of progestagen treatment.

PREGNANCY DETERMINATION Pregnancy detemtination can be performed using real-time ultrasonography and is very accurate with a skilled operator. Transab­ dominal ultrasound is quick and reliable and can detect pregnancy as early as 25 days, witl1 the fetal heart beat detectable by

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clay 27. Transrectal ultrasound is more difficult and time consmning but can diagnose pregnancy as early as 20 days. The accuracy of transabdominal ultrasound to differentiate the presence of a single fetus from multiples varies from 45o/o-55% (possibly higher with skilled operators). It is extremely difficult to accurately differentiate between twins, triplets, and quadruplets using ultrasound at any time during gestation. Fetal sexing may be perfom1ed by skilled ultrasonographers between clays 55 and 70 of gestation and is more accurate in singles versus multiples. Routine radiography can be used to detect pregnancy witl1 lO()OA, accuracy after day 70 and can detect the mm1ber of kids after day 75. Progesterone concentrations can be measured in milk or serum, but samples must be collected precisely one cycle after the doe was bred. Whereas low progester­ one levels can confim1 a nonpregnant status, high progesterone is not a positive pregnancy test, because it cannot differenti­ ate between midcycle, true pregnancy, or false pregnancy. Plasma progesterone levels in pregnant does have been reported to be higher in triplets versus twins versus single fetuses at 84--21 days before kidding. The estrone sulfate test, perfom1ed on plasma, milk, or urine, is another way to determine pregnancy. Between 15 and 20 days after conception, the level of estrone sulfate, a conjugated estrogen produced by the conceptus, increases substantially and stays increased throughout pregnancy. Higher concentrations of estrone sulfate have aeen repo1ted in does carrying twins or triplets than those bearing a single fetus. Abortion, fetal death, or resorption ca.uses tl1e estrone sulfate level to drop; therefore, the test also is a useful measure of fetal viability. Pregnancy-speciiic protein B (PSP-B), also known as pregnancy-associated glycopro­ tein, is produced by the placenta and can be detected in serum or plasma of pregnant does by ELISA at least 30 days after breeding. Precocious milking is conrn1on in heavy-milking strains of goats. It can be seen in a virgin doe or during the first pregnancy. Therefore, udder development is no guarantee of pregnancy. Hydrometra, or pseudopregnancy, is well documented in goats, although its ca.use is largely m1known. Aseptic fluid a.ccunrnla.tes within the uterus and is accompanied by high peripheral concentrations of progester­ one due to a failure of luteolysis. It can be both shorter or longer than a true pregnancy and occurs in 3o/o-3()0A, of dairy herds.

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MANAGEMENT OF REPRODUCTION GOATS

Approximately 500/o of pseudopregnancies occur as a result of early embryonic death at �40 days of gestation. An additional mechanism involves spontaneous persis­ tence of the corpus lutewn, which occurs more commonly in older goats, does bred out of the natural breeding season, or after induced ovulation. In some cases, ovaiian cysts may also be present; therefore, it is recommended to always treat for both. Usually, the udder enlarges, but tme filling does not occur. The doe may show behavioral signs of impending parturition, possibly even calling or searching for the nonexistent kid. The diagnosis can be made by excluding pregnancy coupled with the presence of clinical signs. This condition can be treated with prostaglandin to lyse the corpus luteum, and does may be able to conceive again if diagnosed and treated early. However, if the condition persists or recurs, the chances of future conception decline. For commercial dairy herds, this can produce moderate to severe economic losses. Goats tend to have a high incidence of abor­ tion, with chlamydiosis ( Chlamydia psiltaci) and toxoplasmosis (Toxoplasma gondii) being commonly identified causes in the USA ( see ABORrION IN GOATS, p 1340). In cases of abo1tion, the fetus and placenta should be submitted to a diagnostic laboratory to exclude infectious causes. Paired serum sainples should be obtained from the doe and saved in case serology is indicated. A thorough history, including nutrition and any recent changes in husbandry, should be taken.

PREGNANCY Gestation length is 145-155 days (average 150 days) and can be affected by breed, litter weight, environment, and parity. Generally, first-kidding does have one or two kids, and in subsequent kiddings, triplets and quadmplets are not w1common, especially in large, well-fed, heavy milkers. Quintuplets and sextuplets are rare. Progesterone production for maintenance of pregnancy is entirely dependent on the corpus luteum, with a drastic decline in progesterone occurring 12-24 hr before kidding. Induction of paitmition is a useful technique to increase survival in dairy goat kids and to catch and separate kids from 3 Y1) dairy goats, but not neai·ly so frequently, nor as severely, as in cattle. Treatment includes IV administration of calcium gluconate or calciw11 borogluco­ nate solution. Vaginal prolapse is fairly common (see p 1390) in does and is believed to have a hereditary component. It may intermittently occur dming late pregnancy due to increased intra-abdominal pressure. If complete vaginal prolapse occurs, intervention is required to prevent injmy, infection, or dystocia. Owners should be advised that vaginal prolapses will recur with each pregnancy, so they can decide whether to cull the anin1al.

PARTURITION Partm·ition tends to be W1eventful in goats, with the incidence of dystocia 25 mm) follicles but no luteal

structures. Courtesy of Dr. Patricia Sertich.

follicles or corpora lutea. The cervix may be closed but not fu111 and tight,.or it may be thin, shmt, and dilated. As the length of daylight increases, mares undergo a vernal transition and the ovaries become active, with nun1erous large (>25 nun) follicles. The cervix and uterus have minimal tone. Mares have tluee or four prolonged intervals of estrus (periods of sexual receptivity to the stallion) during the vernal transition, but ovttlation does not occur. The end of vernal transition is marked by a surge of luteinizing honnone and subsequent ovttlation. After this ovttlation, tl1e first 21-day interovttlatory period of that breeding season occurs and a regular estrous cycle is established. Although tl1e mare continues to ovulate regwarly every 21 days throughout the breeding season, the length of estrus varies, ranging from 2-8 clays, and the length of diestrus varies accordingly to maintain a 21-day interval. Early in the breeding season, estrus tends to be longer, whereas around the sununer solstice tl1e mare may be sexually receptive for only 2-3 days.

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MANAGEMENT OF REPRODUCTION: HORSES

Mares have two follicular waves each cycle. The first wave of follicular develop­ ment occurs dming diestrus, and these follicles become atretic. The second wave occurs after luteolysis and is associated with estrus. Early in estrus, the endometiial folds of the uterus are edematous, but the edema wanes as ovulation approaches. Usually, one follicle becomes dominant and ovulates when it is 30--35 mm is present or begirming on day 2--3 of estrns and every other clay until ovulation occurs or the mare goes out of heat. Mares ovulate 0-48 lu· before the end of estrus. Breeding should take place before ovulation. Ovulation can be induced by administration of cleslorelin if the mare has a dominant follicle. (See also MANIPULATION OF OVARIAN ACTIVITY, p 2188.) A tail wrap should be applied on the mare, and the perineum cleansed. The stallion's penis should be rinsed with water before breeding to remove smegma and to minimize contan1ination of the mare's reproductive tract. The mare should be slowly introduced to the stallion and teased until obvious signs of receptivity (tail raise, abduction ofhindlegs, eversion of vulvar lips, urination) are displayed. A nose twitch may be used for additional restraint but may intetfere with the mare's expression of sexual receptivity. For breeding, the stallion should be fitted with a well­ adjustecl halter with large rings that allow the chain shank to freely slide. During breeding, the stallion should be controlled adequately to prevent injury to the mare. After breeding, the penis can be rinsed with

2201

warm water to reduce contamination from the mare's genital tract. Artificial Insemination: Semen is obt.ained using an artificial vagina; motility, morphol­ ogy, and concentration of spem1 are detenninecl; and the number of morphologi­ cally normal, progressively motile spenn is calculated. Semen extender containing an antibiotic is then slowly added to semen to improve spem1 swvival. The temperature of the semen extender should be similar to the temperatlue of tl1e semen at the time of dilution. A commonly used semen extender is glucose skim milk extender (made with 4.9 g glucose, 2.4 g instant nonfat d1y milk, and 100 mL sterile distilled water). One of tl1e following antibiotics can be added: piperacil­ lin 100 mg (1 mg/mL); ticarcillin 100 mg (1 mg/mL); reagent grade gentamicin, which must be buffered with 2 mL 8.4% NaHC03, 100 mg (1 mg/mL); or arnikacin sulfate 100 mg (1 mg/rnL). Effective proptietmy semen extenders are also available conunercially. The mm·e is prepm·ed for insemination by application of a tail wrap and cleansing of the perinew11. If soap is used, it should be rinsed thoroughly to remove a11y residue. Mares should be inseminated with at least 250-500 x 106 progressively motile, morphologically nonnal spem1atozoa before ovulation. lnsemination is accomplished by depositing the semen into the body of the uterus using a sterile, plastic insemination pipette. Disposable sterile equipment is recom­ mended to prevent contamination. Nom1al spetm can be expected to remain viable in the mare's reproductive tract for at least'48 hr. Mares should be examined by palpation a11d ultrasonography per rectum to confum tl1at ovulation occurs. Stallion semen ca11 be extended, cooled to 4°C, and packaged for transpmt in a conunercial tra11sport device. If semen from fertile stallions is properly handled, good pregnancy rates can be achieved when tl1e semen is used up to 48 hr later.

MANAGEMENT OF REPRODUCTION: PIGS Management of conunercial swine breeding herds involves a thorough tmderstanding of reproductive physiology, genetics, nutrition, immunology, disease control, environment, and other factors. (See also ABORTION IN PIGS, p 1341.) The closed-herd concept, which emphasizes preventive medicine strategies

along with herd protection, minimizes the risk of disease loss when combined with intensive management, sound nutrition, and genetic selection. The breeding program should be evaluated at specified intervals to ensure that progress in both efficiency and productivity is being made. Several

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MANAGEMENT OF REPRODUCTION PIGS

efficiency/production parameters to review when analyzing herd reproductive pe1fom1ance are shown in TABLE 11. The postweaning perlormance of a breeding herd's offspring can be measured through assessment of such parameters as feed conversion ratio, average daily gain, total days to market, and postweaning death loss. Problems on a swine farm can have a single cause or be caused by a combination of genetic, nutritional, environmental, health, and management factors. When investigating a herd problem, the practi­ tioner can best benefit from remaining focused on the herd and not individual animals. Accurate, up-to-date records are essential when investigating a herd problem. When analyzing a herd and its records, a certain percentage of "abnormal" aninlals and/or reproductive problems are to be expected.

SOW AND GILT MANAGEMENT Selection: Gilt selection for genetic improvement should be indexed based on such categories as growth rate, disease status, sexual development, reproductive history (including dam's perlonnance as to wean-to-service and wean-to-estrus intervals, litter size, milking ability, and pigs weaned), structure/confonnation, and underline (including teat number [7 pair] and placement). Of potential replacements, up to 30%-400/o may be culled, with most eliminated because of problems with structure/conformation, teat issues, and genital defects. Prepubertal gilts are usually fed a sex-specific ration ad lib until they reach market weight (250-275 lb [ 113-125 kg]) or are 5-6 mo old. At that time, selected animals are then moved into gilt develop­ ment, where they are fed a diet formulated

REPRODUCTIVE BENCHMARKING INDICES USED IN COMMERCIAL SWINE HERDS

Reproductive Index

Target

Intervention Level

Wean-to-estrus interval (95% in estrus by 10 days postweaning)

9 days

Wean-to-service interval

�5 days

>7 days

Repeat services at 21 ( ± 2) days

11%

Abnormal returns to-service (25-37 days)

5%

Multiple matings (if not using fixed timed insemination)

>89%

86%

12.5

11.5

10.4

2.3

96% success rate in training boars to mount a dummy and to ejaculate. A nervous boar may not allow the penis to be locked into the hand, even after several attempts. Semen can be collected from many such boars by allowing them to achieve natural intromission and lock the penis into the sow's cervix to begin the ejaculation, then quickly retrieving the penis and locking it into the hand. The boar will continue to ejaculate, and the major portion of the ejaculate can be collected. A prewarmed (37 ° C) thermos or styrofoam cup is a convenient and economical collection vessel. The pre-sperm fraction, consisting of 5--15 mL of fluid, is usually ejaculated first and allowed to fall on the ground (ie, it is not collected). The boar then usually ejaculates a small amount of gel, which is filtered out of the ejaculate by a double layer of coarse gauze (placed over the mouth of the collection

2205

receptacle), because it coagulates into a semisolid mass that can interfere with subsequent evaluation of semen quality. The boar then ejaculates the milky to cream-colored, sperm-rich fraction. The final, sperm-poor fraction contains the largest volume of fluid and gel. Care should be taken to let the boar complete the ejacu­ lation, voluntarily withdraw the penis from the hand, and dismount. Some boars will go through two or more complete ejacu­ lations before voluntarily dismounting. Semen collection by electroejaculation is done only on an anesthetized boar. An iitjectable anesthetic that will allow for 15-30 min of general anesthesia is recommended. The rectum is cleaned out using a lubricated hand, and a lubricated rectal probe is inserted. The penis is then exteriorized with the aid of Bozeman sponge forceps and grasped with a surgical sponge wrapped around the penis 5--10 cm distal to the glans penis. Electrostimulation of the boar is performed as in the bull or ram, with the ejaculate collected in a clear, plastic bag that envelops the glans penis.

Semen Evaluation: Standard tests used to evaluate boar semen include sperm motil­ ity, morphology, concentration, total numbers, and ejaculate volume. The ejaculate should be protected from changes in temperature, osmotic pressure, and pH during handling and analysis. All equipment and materials that come into contact with ° semen should be warmed to 35 °-39 C. Sperm motility should be evaluated as soon as possible after collection. Estimating sperm motility in an ejaculate by examining the mass activity or swirl motion of a drop of semen on a slide is of limited value and is not recommended. Gross sperm motility is best estimated on prepared samples in which a monolayer of individual sperm can be visualized using light microscopy. To do this, a 5--10 µL drop of semen is placed on a prewarmed slide and overlaid with a coverglass. Sample motility is then subjectively estimated to the nearest 5% by viewing several random fields under 20x magnification. Sperm morphology can be a valuable indicator of fertility potential, especially in those ejaculates with a high percentage of abnormal sperm. When using bright­ light microscopy, stained slides are necessary to provide adequate contrast to. evaluate sperm morphology. When using higher resolution microscopy (ie, phase­ contrast, differential interference contrast), glutaraldehyde or buffered formalin preserved samples can be used. A minimum

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MANAGEMENT OF REPRODUCTION: PIGS

of 100 (preferably 200) spem1 should be assessed for morphology of the head, midpiece, and principal piece (ie, the tail distal to the midpiece). Sperm can be categorized into three groups: normal, spem1 with abnom1al heads, and spem1 with abnormal tails (midpiece, principal piece, including cytoplasmic droplets). Samples with a high number ofsperm defects can be examined further, and abnormalities classified as major and minor defects. Acrosome morphology should also be assessed if possible. Several techniques are available to determine spem1 concentration in a filtered boar ejaculate. A crude, subjective, qualitative estimation of spenn concentra­ tion can be done by assessing visual opacity of a raw ejaculate, either by direct examination or with the aid of a Karras sper­ miodensimeter. Analytical detennination of sperm concentration can be performed by measuring opacity via a calibrated (spectro) photometer on a diluted semen san1ple. It is essential that the photometer be calibrated for boar semen. Even with a calibrated photometer, estimates of spem1 numbers may be ±300A, from that of the actual concentration; this can be attributed, in part, to in1proper technique, human error, and/or the inherent opacity ofthe secretions of the accessory sex glands present in the boar ejaculate. Photometric readings can also be inaccurate if the reading is outside the calibration curve or optimal operating range. A second, more direct method to measure sperm concentration is with a hemocytometer or counting chamber. In this method, concentration can be detem1ined by diluting a portion ofthe filtered ejaculate to a 1:200 ratio-most easily done using a Unopette® system. The hemocytometer should be charged, and the charged unit allowed to set for 5 min, so that the spem1 settle into one visual field. Using microscopy, a sperm count is pe1fom1ed and calculated as nom1ally done for RBC determination. Determining spenn concentration using a counting chamber is tedious and ti.me consuming, making its use on a routine basis impractical in most commercial operations. After calculating spem1 concentration/ mL, total spem1 nun1bers in an ejaculate can be calculated by multiplying spem1 concentration with the total volume (in mL) of the gel-free ejaculate. Ejaculate volume can be measured by using a wam1ed measwing apparatus (eg, graduated cylinder, disposable plastic measuring cups) or by measuring the weight of the ejaculate (with 1 g equivalent to 1 mL). More

frequently, compute1°automated semen analysis systems are being used to objectively determine spenn motility, sperm morphology, and spem1 concentration. Interpretation of Findings: Semen values can be affected by frequency of boar use, age, environment, disease, level of nutrition, genotype, and method ofspem1 cell fixation. Therefore, boars that do not have acceptable semen values are not necessarily subfertile or infertile. Spemtio­ grams can change dramatically over a short period of time, and boars shottld not be culled on the evaluation ofa single ejaculate. Breed differences in onset of puberty, libido, mating ability, and conception rate have been seen. Environment can affect fe1tility over a short period of time, primarily because of disturbances in the them10regulation of tl1e testes. Boars exposed to cold or hot environmental temperatures may have abnormal spenniograms for ?.7 wk after the insult. Severe exposure may result in abnormal spem1iograms for a longer time or may even lead to permanent spermatogenic disruption. Any disease that increases body temperature, and tlrns disrupts thennoregu­ lation of the testes, also has the potential to cause temporary sub- or infertility. Guidelines for Boar Evaluation:

Ideally, libido, mating ability, semen quality (see TABLE 12), and breeding results (conception rate and litter size) should be considered. The duration of spem1atogen­ esis and spermatozoa! maturation is -51 days in the boar. If a boar produces an ejacu­ late of low or marginal quality when examined in vitro, additional ejaculates should be assessed at 1- to 2-wk intervals to ascertain whether quality has improved over tin1e. Boars with spenniograms that do not improve over 2-3 mo are wuikely to ever improve. Boars with azoospem1ia on two complete ejaculates or that are unable to achieve complete erection should be culled immediately. Those that have penile lesions or blood in the semen should be sexually rested for ?.2-3 wk and reevaluated. For boars with persistent frenulwn or that habitually masturbate in the diverticulwn, surgical correction is recommended; however, the progeny should not be kept for breeding, because these conditions are most likely heritable. All results ofthe fertility examination must be considered in relation to age, disease history, envirorunen­ tal stress, prior breeding usage, mating system, and the techniques of semen collection and handling.

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MANAGEMENT OF REPRODUCTION: PIGS

2207

SUGGESTED MINIMUM SPERMIOGRAM VALUES FOR BREEDING BOARS Parameter

Natural Service

Artificial Insemination

Color

Opaque to white (vulvar discharge)

Opaque to white

Total sperm numbers

>35 x 10 9 spenn/ejaculate >35 x 10 9 spenn/ejaculate

Gross motility (raw)

>600h

>70%

Abnormal morphology (including cytoplasmic droplets)

14% have been associated with infectious balanoposthitis due to Co1ynebacterium renale (seep 1372, also called pizzle rot). Mating activity can be monitored by using a breeding harness on the ran1s and

2217

changing the crayon color every 14-17 days. When fewer than expected ewes ai·e marked, poor ran1 libido, insufficient number of rains to breed the ewe flock, or anestrus is suspected. When ewes are serially marked with different colors, conception failure or eai·ly embryonic death is suspected. The ram to ewe ratio varies with breed, maturity of ran1, and whether synchroniza­ tion or induction of estrus is being practiced. Ratios of 1:40 ai·e common in fann flocks, but excellent fe1tility can be achieved with a lower ratio if ran1s from prolific breeds ai·e used (eg, Finnish Landrace). For rain effect, the ratio should be 1:20; for estrus synchronization, 1: 10 to 15 (in season); and for estrus induction (out of season), 1:5 to 1:7. Length of ram exposure dw'ing the ovulatory season should be limited to two or three cycles so as to tighten the lambing period to optimize lan1bing management and lamb survival. Excellent fertility can be achieved with a breeding exposure of 35-42 days (2-2 Y2 cycles). Poor fertility indicates ai1 issue with the breeding management. Flock dispersion should be avoided at mating, but n01mal hanclling should not affect mating. Because younger ewes have a shorter, less intense estrous period, they ai·e better mated separately from older ewes with expe1ienced, although not necessarily older, rains.

Collection of Semen: The artificial vagina is used most commonly for collection of ran1 semen. It is prepared for collection by the introduction of warm water (100°-l30°F (40°-55° C]) and air between the outer casing and soft inner sleeve, lubrication with petrolatwn in the end where intromission of the penis occurs, and attachment of a graduated collecting glass at the opposite end. Ranis quickly learn to m0tmt a restrained ewe, and intromission and ejaculation ai·e extremely rapid. The second method of semen collection is by electroejaculation, for which the ran1 may be restrained on its side. The lubricated bipolar electrode is inserted into the rectw11. The withdrawn penis is held with a piece of gauze to facilitate inse1tion of the glans into a 10- to 15-mm diaineter graduated collecting tube. Ejaculation usually occurs after a few short electrical stimulations; "stripping" of the w·ethra may be helpful when expulsion of semen seems incomplete. ElectToejaculation is less reliable than the artificial vagina; specimens vary in quality and can be contaminated with wine.

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MANAGEMENT OF REPRODUCTION: SHEEP

The volume of semen collected with the artificial vagina is 0.5---1.8 mL, and the concentration of the spemmtozoa is 2.5-6 x 109/mL. Semen obtained by electroejacula­ tion generally is of larger volume but lower concentration. Evaluation of Semen: Immediately after collection, the semen is assessed for contamination, volume, concentration of spem1atozoa, and sperm motility (wave motion and sperm progression). Extension of Semen: Semen can be

processed by extending or diluting, packaging, and storing. Semen may be extended 5-fold, depending on the initial concentration, the processing and storage method, and whether the semen will be used fresh, chilled, or frozen-thawed. Most semen extenders or diluents are based on Tris, egg yolk, and additional cryoprotec­ tants such as glycerol. Commercial extender concentrates contain cryoprotectants and require the addition of egg yolk and double-distilled water. These extenders can be used for either fresh or frozen semen. Extenders for fresh and chilled semen include whole, skin1med, or reconstituted cow's milk that has been heated to 92°-95° C for 8--10 min in a water bath to inactivate toxic factors, egg yolk/glucose/citrate (15% egg yolk, 0.8%glucose [anhydrous], 2.8% sodium citrate dihydrate in glass-distilled water). The addition of Tris or glycerol improves the sperm survival of frozen­ thawed semen. The reconstitution of frozen-thawed semen with fresh seminal plasma improves its fertilizing ability when used for intracervical insemination but not for intrauterine insemination. The number of motile spem1atozoa and the volume ofan insemination dose for the ewe depends on the site of insemination and the method of processing. For vaginal insemination, 0.3-0.5 mL with 300 million motile spermatozoa is used; for cervical insemina­ tion, 0.05---0.2 mL is used with 100, 150, and 180 million spermatozoa of fresh, liquid­ stored, and frozen-thawed semen, respectively. Intrauterine insemination by laparoscopy requires 0.08--0.25 mL (with a total of 20 million motile spennatozoa) into each uterine horn. Storage of Semen: Ram semen may be stored for up to 24 hr by cooling the extended semen to 2 °-5° C over 90-120 min and by holding at this temperature. Fertility decreases rapidly and is low by 48 hr. Freezing and storage of ram semen in 0.25---0.3 mL, three-dose pellets or in 0.25

mL, single-dose synthetic straws at liquid nitrogen temperature (196 ° C) is successful in maintaining sperm viability, but there may be a range in motility after thawing and in fertility between rams or processing batches. Use of frozen-thawed SE)men may result in lambing rates of 500A, with cervical insemination and 500/o-SOOA, with intrauterine insemination. Freeze-thawing reduces the numbers of motile sperm. Chilling results in membrane changes that reduce the longevity of sperm. The membrane changes are sinlilar to capacitation and acrosome reactions, and affected spem1 are thus ready to fertilize oocytes. Fresh seminal plasma mitigates the effects of some of the capacitation changes. ARTIFICIAL INSEMINATION

The optimal time for insemination with nonfrozen semen is 12-18 hr after the onset of estrns. When estrns has been synchro­ nized or induced using progestagens and gonadotropins and/or ram effect, most ewes are in estrns within 36-48 hr and ovulate at -60 hr. Insemination should be done 48--58 hr after pessary removal for cervical insemination, or 48--60 hr for intrauterine insemination with frozen-thawed semen, with highest conception at -53-54 hr. Extended fresh or chilled semen can be placed into the vagina or cervix, and extended fresh, chilled, or frozen-thawed semen can be placed into the uterns. Frozen-thawed semen reconstituted with fresh seminal plasma can be placed into the cervix with conception rates >500A.. Vaginal Insemination: An artificial insemination pipette with a 1 2 mL syringe attached is placed deep into the vagina. This method is quick and involves minin1al restraint of the ewe. For cervical insemina­ tion, the ewe is restrained to linlit move­ ment and to present the hindquarters at a convenient height for easy access to the vagina. After cleaning the vulvar region, the cervix is located with the aid of a speculum and suitable illumination, and the insemina­ tion made as deeply as possible into the cervical canal. A long, thin inseminating tube with attached syringe or a semiauto­ matic insenlinating device can be used. The relatively long, tortuous, and fum-walled cervical canal of the ewe usually precludes penetration by the tube for >1 cm. In old, multiparous ewes with cervical tissue distortion, the difficulty increases, and the semen is deposited into the posterior folds of the cervix. In periparturient ewes, the cervix may be fully penetrated. In maiden

VetBooks.ir

MANAGEMENT OF REPRODUCTION: SMALL ANIMALS

ewes, in which inse1tion of the speculwn and dilation of the vagina can cause injury, the semen should be deposited in the anterior vagina. Intrauterine Laparoscopic Insemina­ tion: Food and water should be withheld

from the ewe for -12 hr. Ewes should be sedated with 1.5---2 mg xylazine, IM, and placed in cradles that restrain and inve1t them, first in dorsal recwnbency for preparation of the abdomen. Local anesthetic may be injected SC at two sites ( -4 cm on each side of the ventral midline and -6 cm anterior to the udder). The cradle

2219

is then raised at the posterior end so that the ewe is tilted at -45° with the lateral abdomen presented to the operator. The anesthetized sites allow for entrance of two trocars and cannulae; carbon dioxide is insufflated through the first cannula to distend the abdomen. The laparoscope is inserted through the near cannula, the uterine horns are visualized, and a glass or plastic inseminating pipette or sheathed inseminating gun is inserted through the second cannula. Semen is deposited into the lwnen of the uterus. Conception rates are sinu.lar if semen is deposited into one or both horns of the uterus.

MANAGEMENT OF REPRODUCTION: SMALL ANIMALS BREEDING SOUNDNESS EXAMINATION Female: The breeding soundness exanlination should begin with a thorough reproductive and medical history, including inforn1ation on previous cycles (onset and regularity), breeding management (past and intended), outcome of any breeding(s), and relevant fanu.ly history, as well as routine medical infonnation (diet, medications, enviromnent, health status). A thorough physical exanli.nation, with particular attention given to the genitalia and manlffiary glands, should be perforn1ed. Vestibulovaginal defects (strictures) should be excluded by digital exanli.nation. Evaluation of the mammary glands should include inspection of the nipples for nom1al anatomy. Screening for hereditary defects common to the breed should be advised, which may require techniques such as radiography (eg, elbow dysplasia), ultrasonography (eg, renal dysplasia), ophthalmoscopy ( eg, cataract), specific DNA testing (eg, progressive rod-cone degeneration), as well as the physical exanli.nation (eg, patellar luxation). Digital vaginal exanli.nation and vaginoscopy of the bitch may detect strictures or other defects of the vulva or vagina that may !under copulation or whelping. Vaginal strictures are more commonly congenital than acquired and may be in the fonn of either a septate strand or a circumferential band. They most conunonly forn1 at the vestibulovaginal

junction, cranial to the urethral papilla. The heritability of such defects is unlrnown. Strictures of the vagina or vestibule are not uncommon in the bitch and usually prevent normal copulation, but if pregnancy ensues from mating without a tie or from artificial insemination, dystocia can result. Septate strands can be easily resected surgically, but circumferential strictures are difficult to resolve without episiotomy and major revision, and tend to reform. Elective artificial insemination and cesarean section may be preferable if the bitch has outstand­ ing breeding potential. Routine vaginal cultures are not advised because the vagina normally harbors a wide variety of bacte1ia, including j3-hemolytic streptococci and Mycoplasma spp. Bitches should be screened for brucellosis before each estrus when breeding is planned. A negative Brucella canis screening test is reliable; positive results warrant further specific (eg, agar gel inmumodiffusion [AGID]) serologic evaluation, culture, or PCR, because false-positives are conm1on. Clinicians should contact their commercial laboratory or veterinary school for updated screening protocols. Queens should be screened for feline leukemia virus and feline in1munodeficiency virus as medically indicated. Bitches and queens >5 yr old should also have their general health assessed by performing a CBC, serwn chemistries, and a urinalysis. Before an anticipated breeding, females should be in optimal body condition to improve conception rate and whelping

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MANAGEMENT OF REPRODUCTION: SMALL ANIMALS

outcome. Breeders commonly skip cycles between breedings; this is not optimal husbandry because the inevitable exposure to estrogen (queen) and progesterone (bitch, sometimes queen) dming the estrous cycle promotes cystic endometrial hyperplasia and may result in pyometra. Bitches and queens kept in optimal health can be bred sequentially and should be ovariohysterectornized or ovariectomized when no further breedings are planned. Proper nutrition and exercise strategies for pregnancy and lactation should be outlined. Bitches should be currently vaccinated for core infectious cliseases (canine distemper, paivovirus, adenovirus 2, ai1d rabies). Other noncore vaccinations should be administered only according to good medical practice (appropriate for the dog's age, health status, home and travel environment, and lifestyle). Queens should similarly be vaccinated approp1iately (based on duration of immUllity recommen­ dations) for feline distemper, rhinotrachei­ tis, ai1d calicivirus. Vaccination against rabies virus, feline leukemia virus, ai1d other noncore diseases should be done when indicated by good medical practice, based on risk factors associated with the cat's age alld husballdry. Unnecessary revaccination of bitches alld queens before breeding is not advised, because little improvement in immunity Call be expected ai1d adverse effects may be seen. Vaccination during pregnaI1cy is advised only when prior vaccination status is lacking or unknown, alld risk of exposure is high (eg, a shelter). In that case, the use of recombinant core vaccines is optimal. The use of preventive medication for heartwonn disease ai1d internal and external parasite control (according to • ma.Ilufacttll'ers' recommendations) during pregnancy alld lactation is advised. Appropriate isolation of the pregnallt female during the last half of pregnallcy for infectious disease prevention is important (eg, avoiding exposure to canine herpes­ virus in the bitch alld upper respiratory infections in the queen). Client education concerning normal whelping a.Ild queening events alld about the timely identification of dystocias is essential. Fetal alld uterine monitoring systems developed for routine use in tile bitch and queen improve neonatal survival witll reduced morbidity alld mortality for the dam. Male: The breeding soundness exainina­ tion for males should begin witll a tllorough reproductive alld general health history, including past alld intended breeding

mallagement, outcome of ally breedings ab'eady perfom1ed, relevai1t faI11ily history, as well as routine general history ( diet, medication, environment, ai1d healtll status). Screening for relevallt heritable defects of concern for the breed'should be advised. A thorough physical exainination should be performed, with particulai· attention given to the genitalia. The penis should be fully extruded from the prepuce alld exainined. This may require sedation in toms. lf hair accmnulates around the base of tile feline penis, it Call prevent copulation and should be removed. Prostate size ai1d symmetry should be assessed in dogs by sinmltai1eous abdo1ninal and rectal palpatjon or with ultrasonography; this is not generally necessary in cats because prostate disease is rare. Palpable abnor­ malities (pain or asymmetly) or semen abnom1alities always warrallt ultrasono­ graphic evaluation of tile prostate alld further clinical testing as indicated (eg, urinalysis, cytology, culture). The testes alld epididyrni should be palpated carefully for symmetJy alld nonnalcy-abnonnalities again warrallt ultrasonographic evaluation. The scrotun1 should be evaluated for evidence of dermatitis or ITauma, which Call impact fertility. A small ainow1t of mucoid discharge at the preputial opening is normal in dogs. (See also REPRODUCTTVE DISEASES OF THE MALE SMALL ANIMAL, p

1400.)

C1yptorchidism, a common genital defect in males, is diagnosed if either or both testes ai·e not present in the scrotum at puberty; testicles nom1ally descend into the scrotwn by 6-16 wk of age. Descent as late as 10 mo has been documented in dogs. Unilateral cryptorchidism does not result in infertility. In dogs, cryptorchidism is hereditary, alld affected aninlals should not be bred. Both late descent and failure of descent are heritable. Botll parents of affected individuals should be implicated as carriers. Because retained testes have a higher incidence of neoplasia ai1d torsion, bilateral orchiectomy is reconunended. Attempts at inducing descent with medical therapy with gonadotropins or testosterone have been tmsuccessful a.Ild ai·e not ethical. Orchio­ pexy is also considered unethical. Failure of one testis to develop (true monorchidism) may be seen in dogs but is rare. Serwn luteinizing hom1one (LH) levels ai·e high (>l ng/mL) if a dog or cat is completely neutered. A persistent penile frenulwn prevents protrusion of the penis from the prepuce alld thus copulation. Treatment is surgical. Deviation of the penis is uncommon; these

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animals require assistance in breeding or may be bred via artificial insemination. Hypospadias prevents n01mal sperm transport from the testes to the glans penis and is easily detected by physical examina­ tion. Small defects may close spontane­ ously, but some type of reconstmctive surgery involving urethrostomy and penile amputation is usually necessary. Phirnosis can be caused by stenosis of the preputial opening, which may be congenital or result from chronic inflammation (trauma or bacterial dem1atitis). Any underlying cause should be treated and then, if necessary, the opening enlarged surgically. Semen Evaluation: Ideally, a complete semen evaluation should be pe1ionned in male dogs intended for breeding and repeated at least annually in active stud dogs. Semen is readily collected from most dogs by manual stimulation; the presence of a teaser (estmal) bitch is advised to optimize results by improving libido. All equipment (artificial vagina, collecting tubes, pipettes, slides, and coverslips) should be room to body temperature, dry, and free of water and contaminants such as chemical disinfectants. The canine ejaculate consists of three fractions-the first and third are of prostatic 01igin, while the second is sperm-1ich. Spenn production is related to testicular size, so large dogs should produce higher spem1 counts than small dogs. Semen evaluation should include an assessment of libido, total spe1m count per ejaculate (nom1al in dogs is 200-400+ million), spe1m motility (normal >90% progressively motile, with moderate to fast speed), and morphology (>900Ai nonnal). The sperm count (sperm/mL) is usually determined with a hemocytometer or by spectrophotometry. Spem1 per ejaculate is calculated by multiplying the spenn count by the volume of semen collected. Motility is evaluated in an unstained sample as soon as the sample is collected, ideally using clean slides prewannecl on a slide warmer. Several commercially available stains are suitable for morphology exan1ination; eosin­ nigrosin and Giemsa stains are used most commonly. An adequate amount of the third fraction should be collected to ensure that the entire sperm-rich fraction has been acquired and to permit evaluation of the prostatic component, which should be clear (free of urine and cellular contan1ination). Subfertility or infertility should never be diagnosed based on one collection. If the sample is azoospennic, semen alkaline

2221

phosphatase can be measured in the ejaculate to assess whether the ejaculate was complete, because it is an epididy.mal marker. Levels >5,000 mcg/dL indicate the ejaculate included the second, nom1ally sperm-rich fraction. Levels 2 ng/mL, breeding should begin. Optimal ovulation timing should use quantitative progesterone assays from commercial laboratories (the cost difference is minimal). Regardless of which assay is used, an additional test should always be performed 2-4 days after the first rise is detected to indicate that the cycle has progressed as expected, a functional corpus luteum has been formed, and ovulation has occurred.

Use of Hormonal Evaluation to Time Breeding: Owners of breeding animals

should be advised to notify their veterinar­ ian when tl1ey first notice U1at a bitch for which timing is planned is in season, based on vaginal discharge or vulvar swelling/ attraction to males. Even the most astute owner may not notice the true onset of proestrus for a few days. Early proestrns should be documented with vaginal cytology ( 70% superficial cells. At that point, serial honnonal assays should begin. For routine breedings, progesterone testing may be clone every other day until a rise in progesterone >2 ng/mL is identified. The day of the initial rise in progesterone >2 ng/mL is identified as "day O." Breedings are advised on clays 2, 4, and6. When increased accuracy of ovulation ti.ming is necessaiy (eg, frozen or chilled semen breedings, infe1ti.lity cases, breedings with subfertile stud dogs), daily LH testing is recommended. Once tl1e LH surge is identified, breeding days may be planned. The clay of the LH surge is also "clay 0." It is useful to perform vaginal cytology every 2 3- days until comification is complete (generally >800/o-900/o superficial cells). This maximal cornification usually develops before the fertile period and continues until the onset of diestrus, which is usually a few clays after the end of the fertile period. Vaginal cytology may be continued until the diestral shift is

identified, which gives a retrospective evaluation of the breeding just completed. In addition, at least one progesterone assay should be performed after clay O is identified to document that levels continue to rise. This illustrates sustained corpti:, luteum function and strongly suggests tl1at an ovulatory cycle has occurred. Insemination with extended, chilled semen should be done on days 4 and6, or 3 and5, after day 0. The days chosen can depend on overnight shipping possibilities and the schedules of all involved paities. Frozen semen breedings should be done on day5 or6. Vaginoscopy may be perfo1med throughout tl1e cycle as an adjunct to vaginal cytology ai1d hormonal assays, especially when evaluating an unusual cycle. Behavior ai1d other observations should also be made. Ovulation timing is most accurate when information from several tests is pooled (vaginal cytologies, vaginoscopy, and progesterone or LH tests).

Artificial Insemination: Artificial insemination is becoming more common in cai1ine reproduction, permitting the use of shipped semen, assistance for ge1iatric or subfe1tile males, coverage of dominant females, and advanced reproductive technology such as intrauterine deposition of semen. Insemination may be performed with fresh, chilled, or frozen semen. All instruments should be clean and free of any chemical contan1ination. After semen has been collected and evaluated (seep 2221), it can be deposited in the cranial vagina of the bitch using a rigid insemination pipette of appropriate length, or into tl1e uterus via transcervical catheterization. Access to tl1e uterus via laparoscopy or lapai·otomy is less desirable because of invasiveness. Semen (the second fraction) may be diluted with extenders and chilled for later or distant use (witllin 48 hr), or extended and frozen in liquid nitrogen (in straws or pellets) for longtenn storage. Phosphate-buffered egg yolk diluent or Tris-buffered diluent is used most often; several commercial extenders ai·e available. A drop of chilled semen should be warmed for evaluation before use. Frozen semen should be tl1awed as directed by the c1yopreservation center, evaluated, and immediately insenlinated. Dogs should be screened for B1ucella canis when semen is collected for c1yoprese1vation. Cats The queen should be taken to the tom when showing signs of estrus. The breeding ai·ea

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should be familiar to the tom, quiet, and have good footing and a minimum of interference, while permitting observation. The courtship should not be inte1Tupted unless there is concern for the safety of either cat. Toms have been known to mate to the point of physical exhaustion, but queens n01mally go through a period of rolling and grooming after a breeding and may not let the tom remount for some time. Because ovulation is induced by vaginal-cervical stimulation, multiple breedings over 2 3 - days are advised. Periods of separation between matings prevent exhaustion and diminish the chances of fighting. The stress of transpor­ tation may affect reproductive functions in nervous queens. Evaluation for pregnancy can be perfonned 21-30 days after breeding by abdominal palpation and ultrasonogra­ phy.

MANIPULATION OF THE ESTROUS CYCLE The estrous cycles of dogs and cats are not as easily manipulated as in other species. Most protocols are not based on controlled studies, so manipulation of the estrous cycle in valuable breeding individuals is not advised. Although onset of a particular cycle may be delayed, return to n01mal cycling is highly variable. Induction of estrus is possible in late anestrus bitches by using prolactin inhibitors (eg, bromocriptine, cabergoline). Ovariohysterectomy or ovariectomy is the best method to prevent estrus in the bitch and queen. Longtern1 suppression of estrus by using androgens is not advised, because it is not documented to be safe in breeding bitches. Common adverse effects are breaktl1rough proestrus, clitoral hypertrophy, vaginitis ( especially in prepubertal bitches), increased activity of skin sebaceous glands, mild epiphora, and alterations in hepatic function studies. After treatment is discontinued, return to estrus is -70-90 days but variable. Conception rates are reportedly normal by the second cycle after treatment. If given to pregnant bitches, synthetic androgens induce severe developmental anomalies in the urogenital system of female puppies. The safety and efficacy of injectable testosterone, as is practiced commonly in racing Greyhounds, has not been supported by controlled studies and is not advised. Androgens should not be given to cats. The use of megestrol acetate, a synthetic progestagen, is not advised in breeding

2225

females because of the increased risk of cystic endometrial hyperplasia and pyometra, as well as other adverse effects (eg, mammary hyperplasia and neoplasia, hyperglycemia secondary to insulin resistance, and rebound hyperprolactin­ emia and lactation). Suppression (and induction) of estrous cycles by the use of synthetic GnRH in1plants has been described in the bitch; it can be successful, but the products are not universally available. Estrus induction in the bitch can be accomplished with oral prolactin inhibitors (cabergoline 2.5-5 mcg/ kg/day); anestrus of at least 2 mo duration must precede induction. Ovulation can be induced in estrual queens physically or, more reliably, honnonally to produce a luteal phase ( di.estrus or metestrus) of -45 days. Physical methods include mating with a vasectomized tom (very effective) or inserting a sterile swab or glass rod into the vagina. The latter should be performed repeatedly for best results. Hormonal methods include administration of human chorionic gonadotropin at 500 ill/cat or GnRH at 25 mcg/cat. Both are given JM, once daily for 2 days.

PREGNANCY DETERMINATION Fertilization occurs in the oviducts in both the bitch and queen. Implantation of zygotes in the uterus occurs at -18 days in the bitch and 14 days in the queen. This is accompa­ nied by the fonnation of small swellings along the uterine horns (deciduomata) by -21 days. These a.re palpable, assuming the anin1al is cooperative, at this time. Fetal growth is rapid during early pregnancy, and these swellings double in di.a.meter every 7 days. After day35-38, they become indistinct, and palpation becomes difficult until late pregnancy when fetal heads and rumps are palpable as firm, nodular structures in the ventral posterior abdomen. A commercial relaxin assay, specific and sensitive for pregnancy diagnosis in the bitch after30 days gestation, is available. Although the fetal skeleton begins to calcify as early as day 28, it is not detectable by routine radiography until approxinlately day 42-45 and is quite prominent by day 47-48. Radiography at this time is not teratogenic. Late gestational radiography (>55 days) is the best method to determine litter size. Fetal dentition becomes visible at term, and its appearance can be used to confirm fetal develpment adequate for an elective cesarean section when ovulation

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MANAGEMENT OF REPRODUCTION: SMALL ANIMALS

ltM!ii

GESTATIONAL AGE IN DOGS AND CATS

Dogs: Gestational Age ± 3 days

Cats: Gestational Age ± 2 days

40days

(6 x GSD") + 20

(15 x BP ) + 20

25'>< BP+ 3

(3 x CRU)+ 27

(7 x BDci)+ 29

11 x BD + 21

>40days

b

(6 x HD) + (3 x BD) + 30 Days before parturition = 64--6 6 minus gestational age

Days before parturition= 61 minus gestational age

"Gestational sac diameter (cm) bBiparietal diameter (cm) ccrown rump length (cm) d Body diameter at the liver (cm) timing is not available and breeding dates are vague or spread over many days. Ultrasonography is also useful in pregnancy determination and permits evaluation of fetal viability. Ultrasonography is best perfom1ed at 25----35days gestation. Before 21 days, "false-negative" results are seen. Doppler-type instruments allow one to "hear" the fetal heart, which beats 2----3 times faster than that of the dam. Placental sounds may also be heard. Ultrasonography is especially helpful in differentiating pregnancy from other causes of uterine distention (eg, hydrometra, pyometra, mucometra). Ultrasonographic measurements can be used to calculate gestational age (see TABLE1 7). Gestational age in cats can also be detemiined by the following formula: mean litter crown run1p length (in cm) = 0.242 3 x gestational age -4.21 65

PREVENTION OR TERMfNATION OF PREGNANCY Unplanned and unwanted mating of cats and dogs is a common concern. Pregnancy can be completely prevented or temiinated by ovariohysterectomy. Sixty percent of misbred bitches do not conceive, so confirmation of an undesired pregnancy is advised before proceeding. Postcoital douches are of no value in preventing unwanted pregnancy. Although injectable estrogens, when administered appropri­ ately, can prevent pregnancy, their use involves great risk of serious adverse effects, including pyometra and potentially fatal bone marrow suppression, and they are not advised. 1f used, they must be administered soon after copulation, before potentially fertilized ova reach the uterus. Oral estrogens given during diestrus greatly

increase the risk of pyometra, are unreliable in ten11inating pregnancy, and are not advised. Safe and effective tem1ination of pregnancy is possible in both the bitch and queen by administration of prostaglandin F,a (natural hormone) at0.1 mg/kg, SC, tid for 48 hr followed by0.2 mg/kg, SC, tid to effect (until all fetuses are evacuated as confirmed by ultrasonography). Treatment times can reach14 days. In the bitch, treatment time can be reduced (usually by 48 hr) by the concurrent administration of prostaglandin E (misoprostol) intravagi­ nally at1 3 mcg/kg/day. The adverse effects of prostaglandins at this dosage (panting, trembling, nausea, and diarrhea) are mild and transient. The therapeutic window for prostaglandins is narrow, and doses should be calculated carefully. Synthetic prostaglandins (cloprostenol 1 -3 mcg/kg every1 2 -24 hr to effect) more specifically target the myometrium, causing fewer systemic adverse effects, and are currently preferred. Pregnancy can also be reliably temiinated in the bitch by administration of dexametha­ sone at0.2 mg/kg, PO, bid to effect. The owner should be informed of the adverse effects of corticosteroid administration (eg, panting, polyuria, polydipsia). Combination drug protocols (cabergoline 5 mcg/kg, PO, divided every 24 hr for as long as10 days, cloprostenol l mcg/kg given SC twice at -2 8 and 3 2 days after the LH surge) have been reported to terminate pregnancy reliably with minimal adverse effects, shortest treatment times, and greatest sucess rates; their cost and need for compounding are disadvantages. Antiprogestins (aglepristone) are safe and effective abortifacients; availability remains problematic.

MANAGEMENT OF REPRODUCTION SMALL ANIMALS

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WHELPING AND QUEENING Normal gestation in the bitch is 56---58 days from the first day of diestrus, or 64-66 days from the initial rise in progesterone from baseline (generally >2 ng/rnL), or 58-72 days from the first instance that the bitch pem1itted breeding. Parturition in the queen occurs 64-66 days from the LH surge triggered by copulation. Predicting length of gestation without prior ovulation timing is difficult because of the disparity between estrual behavior and the actual time of conception in the bitch, and the length of time semen can remain viable in the reproductive tract (often ?:.7 days). Breeding dates and conception dates do not con-elate closely enough to permit accurate prediction of whelping dates. Additionally, clinical signs of tenn pregnancy are not specific-radiographic appearance of fetal skeletal mineralization varies at tenn, and fetal size varies with breed and litter size. A drop in rectal temperature to a mean of 98.8 ° F (range 98.1 °-100.0° F) (37.1 °C [range 36. 7°-37.8 °C]) is seen in most bitches 8-24 hr before whelping. Breed, parity, and litter size can also influence gestational length. Subtle signs of impending delivery include relaxation of the perineum, man1111ary engorgement, and a change in the appear­ ance of the gravid abdomen, but these changes are not sensitive or specific. Because there is no means to effectively manage prematurely bom puppies, premature intervention in the whelping process is undesirable. Likewise, an excessively conservative approach resulting in intrauterine fetal death is undesirable as well. Bitches typically enter stage I labor within 24 hr of a decline in serun1 proges­ terone to 24 hr without progression to stage II, if

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MANAGEMENT OF REPRODUCTION: SMALL ANIMALS

stage II labor does not produce a vaginal delivery within 1-4 hr, if fetal or maternal stress is excessive, if moribund or stillborn neonates are seen, or if stage II labor does not result in the completion of deliveries in a timely manner (within 12-24 hr). Uterine and fetal monitors can be used to detect and monitor labor and to manage dystocia. Unresponsive uterine inertia, obstructive dystocia, aberrant ute1ine contractions, or progressive fetal distress without response to medical management are indications for cesarean section. Medical management includes adminis­ tration of calcium gluconate and oxytocin based on the results of monitoring. Drugs are given only after 8-12 hr of an estab­ lished contraction pattern (stage I labor) as detected by the uterine monitor and only if inertia is detected when stage II labor is anticipated. Premature adminis­ tration of drugs results in suboptimal response. Generally, the administration of calcium increases the strength of myometrial contractions, while oxytocin increases the frequency. Calcium gluconate (Hl0Ai solution, 1 ml/22 kg body wt bid-qid) is given when uterine contractions are ineffective or weak. It can be given SC, avoiding the potential for cardiac irritability associated with IV administration. Oxytocin (0.5-2 U in bitches; 0.25-1 U in queens) is given when uterine contractions are less frequent than expected for the stage of labor. The most effective time for treatment is when ute1ine inertia begins to develop, before the contractions stop completely. High doses of oxytocin saturate the receptor sites and make it ineffective as a uterotonic. If fetal stress is evident (persistent bradycardia) and response to medications is poor, cesarean section is indicated. POSTPARTUM CARE Palpation and, if necessaiy, radiography should be used to detennine that all puppies or kittens have been delivered. The routine postpartum administration of oxytoxin or antibiotics is unnecessary in healthy dains with nursing neonates, unless the placenta has been retained. The dain's body temperature and the character of the postpartum discharge or lochia and milk should be monitored. Nmmally, the lochia is dark red to black and is heavy for the first few days after parturition. It is not necessary that the dain consume the placentas. Disinfection of the neonatal umbilicus with tincture of iodine helps prevent bacte1ial containination.

The neonate should be weighed accurately as soon as it is dry and then twice daily for the first week. Any weight loss beyond the first 24 hr indicates a potential problem and should be given immediate attention (eg, supplemental feeding, assisted nursing, evaluation for sepsis). Neonates should gain 1()% of their body weight daily. PERIPARTURIENT PROBLEMS Bitches and queens should deliver in a fainiliar area where they will not be disturbed. Unfainiliar surroundings or stran­ gers may impede delive1y, interfere with milk letdown, or adversely affect maternal instincts. This is especially true in young or primiparous animals. The dan1's apprehen­ sion or nervousness may subside in a few hours, but in the meantime the neonates must receive colostrun1 and be kept warm; nursing should be closely supervised. The use of acepromazine at low dosages (0.01 mg/kg, PO, bid-tid) can effectively relax nervous dains and does not sedate neonates detectably nor interfere with milk production. A nervous dain may ignore the neonates or give them excess attention. She may lick and bite at the umbilical stump, causing hemo1Thage or dan1age to the abdominal wall that may lead to evisceration. Excess grooming of the neonate may prevent it from nursing. If the dain's maternal instincts fail, she may assume sternal recumbency and not allow nursing, or leave the neonates w1attended. It is not unusual for the dan1 to pick up the pups and to reaITange them in the box, especially after delive1y of each pup; however, she should then asswne the no1mal nursing position. The principal metabolic disease associated with pregnancy is puerperal hypocalcemia (seep 992). It is rare in cats and most common in dogs weighing 700/o progressively motile spermatozoa. Sperm morphology is detemlined as for bulls (seep 2231). At least 800/o of the spem1 should be morphologically normal. The concentration is detemlined

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EMBRYO TRANSFER IN FARM ANIMALS using a hemocytometer. To do this, the sperm is diluted at 1: 100, and the number of sperm in the large central square (made up of 25 smaller squares) on the hemocytometer is counted. The nun1ber of sperm counted x 106 is the concentration of spermatozoa/mL. The total number of spenn in the ejaculate is calculated as volume x concentration. Total sperm nun1ber in the ejaculate ranges from 400 x 106 to> 1,000 x 106 and is correlated with body wt; as a general rule, a dog should produce -10 x l 06 spem1/J.b body wt. Every dog investigated for infertility should be screened for Brucella canis. (See also BRUCELLOSIS TN DOGS, p 1402.) Spenn quality may be nonnal or abnormal, or no sperm may be seen in the ejaculate. lnfertility is rare in dogs with a normal sperm evaluation and, if seen, the history should be reviewed for mismanage­ ment or bitch infertility. The presence of WBCs or RBCs in the ejaculate suggests inflanunation of the tract, most commonly prostatitis; culture of prostatic fluid and appropriate treatment may help fertility. If sperm quality is abnormal, the history should again be reviewed to detennine whether the dog has been sick recently or has received any drugs, especially anabolic steroids. Other recognized causes of abnormal sperm quality include inflanuna­ tion of the scrotum or other factors that may be causing a high scrotal temperature, testicular neoplasia (ultrasonography of the testes is recommended because many neoplasms of the testes are not palpable), trauma to the area of the scrotum, or brucellosis. However, most cases of low sperm quality in dogs are idiopathic. The dog's pituitary status can be investi­ gated but is usually unrevealing. Luteinizing hormone and follicle-stimulating hom1one are typically nonnal to high in dogs with abnormal semen quality, because the degenerating testes are not able to provide

2239

the feedback mechanism to the pituitary. Because abnonnal spem1 quality may be induced by a recent transient disease or exposure to toxins, and spem1atogenesis might resume, collections should be repeated about every 3 mo for -1 yr before a definitive prognosis for breeding can be given. Azoospemlia is relatively common in dogs. It may be due to failure of the clog's testes to produce sperm, or to failure of the sperm to exit the testes because of epidiclyrnal blockage or incomplete ejaculation. As in stallions, the ejaculate may be tested for the presence of alkaline phosphatase, which is secreted by the epididymis. A high value (5,000----40,000 ll!L) indicates fluid from the epidiclynlis was collected and thus is consistent with true azoospennia Low values (500Ai. Under the same management conditions and well-trained staff, the pregnancy rate of frozen-thawed embryos is expected to be lOOAi lower than that delived from transfers of fresh bovine embryos. Although increased pregnancy rates may be obtained with transfer of multiple embryos, the tisk of dystocia and retention of fetal membranes associated with twin pregnancies and the increased probability of producing freemartin calves preclude widespread use of this approacl1. The use of sexed semen in embryo transfer programs is considered economically viable, especially if attention is given to inseminate donor cows with spe1m numbers compara­ ble to those used in artificial inseminations with conventional nonso,ted semen.

SHEEP AND GOATS The amotmt of embryo transfers done in small ruminants are a fraction of those recorded for cattle. Globally, almost 900,000 embryo transfers were repmted for cattle in 2012, while only 12,458 were reported for sheep and 1,013for goats. In addition to commercial and market fac. tors limiting the production of emb1yos in small ruminants, current embryo transfer techniques in sheep and goats almost exclusively consist of surgical and/or laparoscopic methods for embryo collection and transfer. Donor and recipients are synchronized using progestagens with an i.Itjection of PGF2a given on the day the intravaginal progestagen device is inserted. Because of the additional superovulation honnonal treatment donor females receive, recipients come into estrus earlier than donor ewes and does; therefore, the progestagen source (typically an intravaginal device) in recipients is removed 12 hr before it is removed in donors. FSH is commonly used to superovulate small ruminants. As in cattle, FSH is commonly administered twice daily in a seties of decreasing doses administered over 3days (eg, day 1 = 5 and 5mg; day 2 = 3and 3 mg; day 3 = 2 and 2 mg). On the last day of FSH treatment, the progestagen source is removed and a luteolytic iltjection of PGF2a

given. Estrus is typically detected by vasectomized bucks/rams; artificial insemination should take place 12---24 hr after estrus is detected or 45---50 hr after progesta­ gen removal. Intracervical or transcervical aitificial insemination is difficult and requires advanced training and practice. Increased pregnancy rates are obtained by laparoscopic artificial insemination, because it allows the semen to be deposited in the cranial aspect of the utetine horns. Surgical embryo collection is still very common, but lapai·oscopic and nonsurgical transcervical catheterization procedures are consistently improving and yielding good results, albeit still lower than those obtained with surgical methods. Embryos are collected 7---8 days after estrus .

PIGS Embryo collection and transfer in pigs is not yet done commercially or as intensively as in ruminants. Until recently, embryo transfer in pigs was primarily perfonned for research purposes. In 2012, Canada, France, and Ireland were the only countries to report the commercial collection and transfer of 2,4 78 swine embryos. Owing to the high ovulatory rate in sows, superovula­ tion treatment may or may not be used in embryo transfer procedures. Embryo collection can be done soon after a geneti­ cally valuable sow is slaughtered and the reproductive tract is collected for embryo retrieval. Surgical collection of embryos is also performed using ventral laparot­ omy of the caudal abdomen. Most embryo transfers are performed using surgical techniques (abdominal ventral laparot­ omy under general anesthesia). Recently, nonsurgical techniques to collect and transfer porcine embryos have been developed ai1d proved successful, but they require specialized equipment and highly skilled individuals. Embryos are typically collected 4-7 days after ovulation. Current pregnancy rates with nonsurgical tech­ niques remain lower than those obtained after surgical embryo transfers. Embryos should not be transferred to the uterine body, because this results in low pregnancy rates. The transfer of 16---22 embryos per recipient is recommended to achieve optimal pregnancy rates.

HORSES Embryo transfer in the equine industry has been prin1arily used to obtain offsp1ing from mai·es with rest1icted reproductive potential (mares with undiagnosed subfe1tility,

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EMBRYO TRANSFER IN FARM ANIMALS uterine pathologies, or simply older mares) or from pe1fonnance mares that must remain nonpregnant to continue to compete. Most breed associations allow the registra­ tion of foals born by embryo transfer, and an increasing number now allow the registra­ tion of multiple foals born in the same year. Because of this recent increased acceptance by breed registries, many horse breeders have obtained several foals in one breeding season from a single donor mare. Superovulating mares with a purified form of equine follicle-stimulating horn1one extract preparation (eFSH) to increase ovulation and embryo recovery rates is no longer commonly done commercially. Difficulties with manufacturing suitable gonadotropins and the variable response of mares to FSH stimulation have pre­ cluded widespread commercial use of this approach to produce equine embryos. It was thought that the low embryo recovery rate in mares ovulating >4 follicles/ovary could be attJibuted to an inability of the ovarian fossa to accommodate multiple ovulations in that area, or alternatively, excessive response to the FSH stimulation could result in dysmatured oocytes. A recent advance in embryo transfer technologies in commercial settings has been the possibility of producing in vitro equine embryos using intracytoplasmic sperm injection (ICSI). Frozen semen from deceased stallions can be efficiently used to produce in vitro embryos by using only a portion of a frozen semen straw to provide spern1 for the ICSI procedure. The number of ICSI-derived equine embryos is expected to continue to increase sharply during the next few years. The horse embryo is notoriously challenging to cryopreserve, probably owing to its relatively large diameter and the presence of an embryonic capsule that limits interaction between cryoprotectant agents and the embryo. Embryos of mornla or early blastocyst stage (33 mm diameter) by administration ofhrn11an chorionic gonadotropin (hCG), 2,500 IU, IV; by administration of a deslorelin implant, 2.2 mg, SC; or by administration of deslorelin, 1-2 mg, IM, in a biorelease vehicle. Ovulation is seen in 85% ofma.res witllin 48 lu, typically 36-42 hr after hCG or injectable deslorelin treatment or 40--44 lu· after treatment with a deslorelin implant. Repeated use of hCG over a long period is associated with antibody formation and may decrease response to treatment; this has not been seen with deslorelin. Use of deslorelin in implant form has been associated with periods of anestrus in treated mares, especially if the corpus luteum of ovulation is lysecl with prostaglan­ din. For this reason, many veterinarians remove the implant after ovulation is seen; tlus is easily perfom1ed if tl1e in1plant is placed in Llle vulvar mucosa. Mares do not superovulate in response to equine chmionic gona.clotropin (eCG), and they do not respond well to follicle-stimulat­ ing hormone (FSH) derived from other species, but Ll1ey may be superovulatecl (average of tluee to fow· follicles ovulated) by treatment with equine FSI-1 (no longer commercially available in tlle USA). GnRI-1 given al 2-20 mcg/hr (by infusion ptm1p) throughout -10 days induced nonnal follicular growlll and ovulation in anestrous mares; the larger close induces superovula.­ tion (average of three follicles). Cyclicity has also been induced in anestrous mares by Lreat:ment with 200 mcg GnRH every 6 hr, 500 mcg GnRH every 12 hr, or by admillistra­ tion of a GnRH agonist, buserelin (10 mcg, SC), every 12 hr plus hCG (2,500 IU, IV) once a follicle has reached 35 nun in diameter. The clopan1ine receptor antago­ nist dompe1idone (1.1 mg/kg/day, PO) alone or in combination witl1 GnRH (250 mcg, SC, qid) has also been used to stimulate follicular development in mares witl1 quiescent ovaries.

CATILE In cows, ovulation may be syncluonized with a progestagen and estrogen combina­ tion treatment, a two-dose prostaglandin regil11en, or a GnRH and prostaglandin

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HORMONAL CONTROL OF ESTRUS

combination. Administration of PGF2ac (25 mg, IM) or prostaglandin analogue (clopros­ tenol at 500 mcg, IM) to cows with a corpus luteum from 5 days after ovulation results in estrus in -2-5 days. Two prostaglandin ir\jections given 12-14 days apart synchro­ nize estrus and ovulation in most cows. Time to estrns is more variable than with progesterone suppression, so insemination should be based on detection of estrus. Ovulation may also be synchronized by administration of GnRH, 100 mcg, IM (day 0), followed by prost.aglandin treatment on day 7 and a second GnRH treatment on day 9. Cows should be inseminated 0-20 hr after the second GnRH treatment. This GnRH and PGF2ac protocol is termed "ovsynch." There are many variations on this protocol, using additional steroids, prostaglandin, or GnRH treatments, that may increase the degree of synchrony or pregnancy rates after rutificial insemination. A progesterone-releasing intravaginal device (PRID) consists of micronized progesterone distJibuted homogeneously in an inert silicone rubber coated onto a cylindrical stainless spiral coil. The PRID is maintained in the vagina for 7 days, and a luteolytic dose of PGF2ac is administered 1 day before or at "pull-out" day. There are no milk or meat withdrawal requirements. In noncycling animals, an ir\jection of equine chorionic gonadotropin (eCG) is adminis­ tered when the PRID is removed. A controlled intravaginal drug-release (CIDR) device may also be used for estrus synchronization. A CIDR is an intravaginal device constrncted of a pi:ogesterone­ impregnated medical silicone elastomere molded into a T-shape. It is labeled for estrns synchronization in beef and dairy cattle. Cows are administered GnRH, and concomitantly a CIDR is inserted and maintained for 7 days. At the time of removal, cows receive an injection of PGF2ac. Cows can be inseminated, with or without another GnRH injection, 48-72 hr after PGF2ac injection. The most effective synchronization treatment, an IM i:Jtjection of a combination of 5 mg estradiol valerate and 3 mg norgestomet, with an ear i:Jnplant of 3 mg norgestomet left in for 9 days, is no longer commercially available in the USA because of the ban on the use of estrogens in food anin1als. Note that all estrns synchronization protocols are less effective in Bos indicus cattle and B indicus crossbreds than in Bos taurus cattle. Melengestrol acetate (MGA) is a steroidal progestagen used as a feed additive to promote growth and suppress estrus in heifers. MGA is used at a dosage of 0.5 mg/

head/day for 14 days for estJus synchroniza ­ tion. Fertility after this treatment is low, and females should not be bred. This protocol could be i:Jnproved by adrniniste,ing PGF2ac 17 days after the last feed containing MGA. The fertility of this estrns is reestablished. Ovulation may be induced in cows with matme follicles (10-15 mm dian1eter) by treatment with GnRH at 100-250 mcg, IM; luteinizing hormone (LH) at 25 mg, IM; or hCG at 5,000-10,000 IU, IM. Because the endogenous LH peak develops at the onset of estrns, this administration wiU not speed the time of ovulation in estrous cows but may be used to ensme luteinization in cows with histories of cystic ovarian disease or to i:J1duce ovulation in anestrous postpartum cows. Superovulation may be achieved in cows by treatJnent with eCG (not currently commercially available in the USA) in mid-di.estrus followed by prostaglandin­ induced luteolysis 2-3 days later, or by treatJ11ent with FSH (potencies differ, refer to label instructions), typically IM, bid for 4-5 days, at a decreasing or constant dose with administration of prostaglandin (25-35 mg, IM) usually on day 3 or 4 of treatment. FSH treat111ent is discontinued at t11e onset of estrns.

GOATS AND SHEEP In cycling goats, luteolysis may be induced by administration of PGF2ac (2.5-5 mg, IM) or cloprostenol (62.5-125 mcg, IM) as early as day 3. In sheep, PGF2ac (�15 mg) or cloprostenol (125 mcg) is effective after day 5 of the cycle (estrns is day 0). Estrus may be synchronized by two doses of prostaglan­ din, 11-13 days apart in does or 7-9 days apart in ewes. Estrns may also be synchro­ nized in cyclic or anestrous does and ewes by administration of progestagens; impregnated intravaginal sponges (medroxyprogesterone or fluorgestone) have been the most widely used agents for control of ovulation but are not currently available for clinical use ill the USA. In small ruminants, a controlled internal drug release (CIDR) intravaginal plastic device i:J11pregnated with progesterone (300 mg) can also be used. The CIDR is maintained in the vagina for 7 days, and a luteolytic dose of PGF2ac administered 1 day before or at device removal. The estrns response is high within 72-84 hr. A portion of a bovine norgestomet ear i:Jnplant (1.5--mg/goat) or ir\jection of progesterone in oil (10 mg/day, IM) has also been effective. In sheep and goats, the ear in1plant is placed subcutane­ ously near the base of the ear or the base of

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HORMONAL CONTROL OF ESTRUS

the tail and then removed 7-9 days later. Progestagen treatment is administered for 10-14 days in sheep and for 14--21 days in goats. Ewes should be joined with rams the day after cessation of treatment; does return to heat on the second or third day after treatment ends. Injection of equine chorionic gonadotropin (eCG; 100-500 IU) at the end of treatment increases synchroni­ zation of ovulation or ovulation rate. Alternatively, in does, progestagens may be given for 11 days with eCG and prostaglan­ din administered on day 9, and fixed-time insemination perfom1ed on days 12 and 13. In regimens involving treatments other than prostaglandin alone, fertility may be reduced on the first estrus after treatment in ewes but not in does. During the nonbreed­ ing season, melatonin implants (18 mg) induce fertile estrus 50-70 days after implant insertion. Better results are obtained when melatonin implants are inserted early or during the transitional period. The implant is biodegradable and does not need to be removed. Estrus synchronization may be improved by using an estrus synchronization protocol at the end of implant action. During the nonbreed­ ing season, a source of gonadotropin is also required. The most common gonadotropin used is eCG, administered at the end of a progestagen treatment ( or 24 hr before device removal). The dose of eCG depends on the season, breed, age, and postpartum interval, an10ng other factors. A high eCG dose is characterized by superovulation, low fertility, shortened estrous cycles, pregnancy loss, and problems with multiple lan1bs or kids. The repetitive use of eCG has produced antibodies against eCG in certain sheep and goats, resulting in modification in the time of ovulation and consequent reduction of fertility when artificial insemination at a fixed time is done.

PIGS In pigs, estrus synchronization may be easily achieved by synchronized weaning of lactating sows; estrus is seen 4--10 days later. Administration IM of a commercially available combination of equine chorionic gonadotropin (eCG; 400 IU) and human chorionic gonadotropin (hCG; 200 IU), per 5 mL dose, given as a single injection within 12 hr after weaning, tightens the synchroni­ zation, and estrus is seen 4--5 days after weaning. This eCG and hCG combination also induces estrus in gilts with delayed puberty and in sows with postweaning anestrus. Exogenous prostaglandin induces luteolysis of the porcine corpus luteurn only

2247

after day 12 of tl1e estrous cycle and, therefore, is not a practical agent for estrous cycle control; however, estrus may be synchronized by induction of abortion in sows pregnant>15 days by administration of PGF,a (15 mg, IM, then 10 mg, IM, 12 hr later) or cloprostenol (1 mg, followed 24 hr later by 0.5 mg); sows return to estrus 4--10 days after treatment. Oral altrenogest (15---20 mg/day, PO, for 14--18 days) may be used for estrus synchronization and for improvement of farrowing rate and litter size in mature sows. In lactating sows, one daily dose of altrenogest from the day of weaning until 5 days before the planned breeding day is also effective and results in estrus 4--9 days after completion of treatment. Estrus may also be synchronized by using bovine norgestomet implants (one implant followed by addition of a second implant 9 days later) removed 19 days after initiation of treatment; neither treatment is currently approved in the USA for swine. Combination eCG and hCG may be given on the day of progestagen withdrawal to hetter synchronize estrus.

DOGS In bitches, estrus suppression, for no more than 24 mo, can be accomplished by administration of mibolerone (an andro­ gen, 30-180 mcg/day, PO, depending on the weight of the bitch). To be effective, treatment must be started at least 30 days before estrus. Estrus is variable but typically develops soon after cessation of treatment; fertility should be normal by the second estrus after treatment. If the bitch has already entered proestrus, the progestagen rnegestrol acetate (2.2 mg/kg/day, PO, for 8 days) may be used to stop the cycle. Administration must start in the first 3 days of proestrus (vulvar bleeding). The next estrus usually develops 4--6 wk earlier than expected. To delay estrus, treatment with megestrol acetate (0.55 mg/kg/day, PO, for 32 days) is begun in late anestrus (up to a few weeks before estrus is expected). After treatment, estrus is seen in 2 9 mo (typically 5---6 mo), and fertility is not affected. Neither mibolerone nor megestrol acetate is recommended for use in bitches on their first estrus or in bitches pri.Jnarily used for breeding. Adverse effects of progestins such as megestrol acetate include cystic endometrial hyperplasia and pyometra; longtem1 treatment may result in obesity, diabetes mellitus, and neoplasia of the uterus and mammary glands. Mibolerone may cause skin, vaginal, and clitoral changes.

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HORMONAL CONTROL OF ESTRUS

Clinical use of deslorelin for estrus suppression is under investigation. Extended-release implants of deslorelin can suppress estrus for> 1 yr in bitches without apparent adverse effects and with full return to fertility. Estrus induction in bitches remains problematic, and none of the drugs presented below are approved for this use in the USA. Many methods have been proposed, but repeatability is low and fertility of the induced estrus is variable. Estrus induction in the bitch before endometrial involution is complete(135 days after the most recent estrus) can result in reduced fertility. The dopamine agonists cabergoline(5 mcg/kg/day, PO, until 2 days after onset of proestrus), metergoli.ne (0.56-1.2 mg/kg, IM, every third day until proestrus), and bromocryptine(0.3 mg/ bitch for 3 days followed by 0.6-2.5 mg per bitch for 3-6 days after onset of proestrus) are reported to induce fertile estrus in most bitches. Average length of treatment was 16-19 days. Two notable adverse effects of dopanti.ne agonist treatment in the bitch are vomiting and coat color changes. Use of deslorelin in1plants may also be effective for induction of estrus but has been associated witl1 low progesterone values during diestrus and, subsequently, prolonged estrus suppression. Removal of the implant 10 days after inse1tion may overcome this problem. Induction of estrus with GnRH analogues continues to be investigated. SyncJu·onous estrus using whole(2.1 mg) or half(l.05 mg) deslorelin implants after termination of diestrus with PGF2a has been reported. The PGF2a proto­ col started witil a low dosage(50 mcg/kg, SC, bid) on tl1e first day, followed by a moderate dosage(100 mcg/kg, SC;bid) on tile second day, and then a full dosage(250 mcg/kg, SC, bid) for 5 days. Encouraging results have also been repo1ted using a single 1.5-mg IM injection of a sustained-

release formulation of deslorelin marketed for use in mares. The most widely studied gonadotropin for estrus induction in canids is equine chorionic gonadotropin(eCG), which is available in tile USA only i11 a porcine product that contains a combination of80 IU eCG and 40 IU hCG/mL. A single 5-mL injection of tllis product was highly effective for inducing proestrus in89.5% of treated bitches, but ovulation rate was poor. However, whelping rates of 50%-84% have also been reported when eCG and hCG were used to induce estrus in bitches.

CATS Megestrol acetate may be used to suppress estrus in queens by treating with 5 mg/cat daily for 3 days, tilen 2.5-5 mg once weekly for a maximwn of 10 wk. Administration of megestrol acetate to queens is an extra­ label use of tl1e drug, and informed consent should be obtained from tile owners. The queen should be allowed an estrus before resuming tl1erapy. Mibolerone is also not approved for use in queens (because of hepato-toxicity) but is effective at 50 mcg/cat/day, PO. Longtem1 deslorelin implants have also suppressed estrus in cats, but the lengtll of suppression is variable. Estrus may be induced in queens witl1 follicle-stimulating hormone(FSH), 2 mg, IM, tile ftrst day, then 0.5-1 mg, IM, daily for 4 additional days. Recommended doses of hwnan chorionic gonadotropin(hCG) range from 25 to 500 IU. The higher doses are more effective at inducing ovulation but may also result in oocyte degenera­ tion. For queens with anovulation or for queens undergoing artificial insenti.nation, ovulation of mature follicles (present on day 2 of estrus) may be induced by treatment with hCG at 250 IU, IM, or GnRH at 25 mcg, IM. Ovulation is reported to occur 25-27 hr after hCG administration to queens.

NUTRITION: BEEF CATTLE NUTRITIONAL REQUIREMENTS Beef cattle production, whetl1er on range, improved pasture, or in ilie feedlot, is most economic when feedstuffs are used effectively. Young growing grass or otl1er high-quality pasture crops usually supply

ample nutrients, such that matw·e and young growing cattle can consun1e sufficient good-quality mixed pasture (grasses and legwnes) for nonnal growth and maintenance. However, mature pasture, crop residues, or forage crops harvested in a manner iliat results in shattering, leaching,

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NUTRITION: BEEFCATILE

or spoilage may be so reduced in nutritive value (particularly energy, protein, phosphorus, and provitamin A or !3-carotene) that they are suitable only in a maintenance ration for adult cattle. Such feedstuffs should be supplemented if used for any other purposes. The mineral content of forages is influenced by the corresponding mineral levels in the soil and by excess levels of some minerals that reduce the availability of others. Mature forages also may be lower in mineral content, especially phosphorus. Normally, supplemental minerals are supplied in a free-choice mineral mix or force-fed in the total mixed ration. Certain nutrients are required by beef cattle in the daily ration, whereas others can be stored in the body. When body stores of a nutrient are high, eg, vitamin A, dietary supplementation is unnecessary until such stores are depleted. However, it may be difficult to determine when body stores have been depleted until advanced signs of deficiency start to appear. The following are dietary requirements for maintenance, growth, finishing, reproduction, and lactation in beef cattle. Water: Water, although not considered a

nutrient per se, is required for regulation of body temperature, as well as for growth, reproduction, lactation, digestion, metabolism, excretion, hydrolysis of nutrients, transportation of nutrients and waste in the body,joint lubrication, plus many more functions. Restricting water intake results in impaired performance. An animal will expire more quickly from a water deficiency than from a deficiency of any nutrient. Because feeds themselves contain water, and the metabolism of ingested feeds releases water ( called metabolic water), not all of the anin1al's water needs have to be met by drinking water. Thirst is the result of need, and anin1als drink to meet this need. The need for water results from an increase in the electrolyte concentration in the body fluids, which activates the thirst mecha­ nism. Many factors, including temperature and body weight, affect water consumption in cattle. An 800-lb (364-kg) heifer at an environmental temperature of 4.4° C (40° F) can be expected to conswne 6.3 gal. (23 L) per day; at 21°C (70 ° F), this will increase to 9.2 gal. (34.8 L). At the same 4.4° C tempera­ ture, a 400-lb (182-kg) heifer will cunswne -4 gal. (15.1 L). Note that water consump­ tion and body weight are not correlated by a straight-line relationship. A 900-lb (409-kg)

2249

lactating cow at the 4.4° C temperatme will consume 11.4 gal. (43.1 L) per day. Energy: Productive animals need essentially two types of energy. Energy of maintenance is that needed to maintain respiration, circulation, digestion, etc. Therefore, in calculating total energy needs, the net energy for maintenance, or NE,,., must be considered. The energy required for growth and reproduction is called the net energy for production, or NE,. It is the amount of energy intake deposited as muscle and/or fat in animals gaining weight. (See TABLES 18---22.) Except for preruminant calves, beef cattle can meet their maintenance energy requirements from roughages of reasonably good quality (green, leafy, fine-stemmed, free of mold and weeds). A shortage of energy may exist on overstocked pastures, with inadequate feed allowance or poor-quality forages, or during a drought. For production, additional energy from concentrates or co-product feeds may be necessary, especially when forages of fair to poor quality are consumed. Especially in cold weather, roughages of vaiying quality may have similar mainte­ nance energy values. Heat released during digestion and assin1ilation-called "heat incrernent"-contributes to the mainte­ nance of body temperature for wintering stock Protein: Protein requirements currently are evaluated as metabolizable protein, which is interchangeable with absorbed protein. Metabolizable protein defines the protein more neai·ly as that which is available to the animal for maintenance and production. It is defined as the combination of the true protein absorbed by the intestine, supplied by microbial synthesized protein plus undegraded intake protein (UIP). The latter often has been called "bypass" protein. Energy deficiency due to low feed intake or intake of poor quality feed is the most common deficiency that limits growth, development in heifers and bulls, milk production, and reproduction, with protein deficiency being the next most common. Protein deficiency of long duration eventually depresses appetite, with eventual weight loss and unthri.ftiness, even when ample energy is available. Feedstuffs vary greatly in protein digestibility. Fur example, the protein of common grains and most protein supple­ ments is -75o/o--85% digestible, that of alfalfa hay -70%, and that of grass hays usually

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NUTRITION: BEEF CADLE

MEAN NUTRIENT CONTENT OF FEEDS COMMONLY USED IN BEEF CATILE DIETS•

Feedstuff

DE (Meal/kg)

ME (Meal/kg)

NE m (Meal/kg)

NE g (Meal/kg)

TDNs (%)

Alfalfa (Medicago saliva) Fresh

2.73

2.24

1.38

0.80

62

Fresh, late vegetative

2.91

2.39

1.51

0.92

66

Fresh, full bloom

2.22

1.81

0.97

0.42

50

Hay

2.65

2.17

1.31

0.74

60

Hay, sun-cured, early bloom

2.65

2.17

1.31

0.74

60

Hay, sun-cured, mid bloom

2.56

2.10

1.24

0.68

58

Hay, sun-cured, full bloom

2.43

1.99

1.14

0.58

55

Silage

2.78

2.28

1.41

0.83

63

Barley (Hordeum vulgare) Grain

3.84

3.03

2.06

1.40

88

Silage

2.65

2.17

1.31

0.74

60

Beet pulp, dried

3.26

2.68

1.76

1.14

74 64

Bermuda grass (Cynodon dactylon) Fresh

2.82

2.31

1.44

0.86

Hay, sun-cured

2.16

1.77

0.93

0.39

49

Brewer's grains, dried

2.39

2.39

1.51

0.91

66

Citrus pulp, dried

3.62

2.96

2.00

1.35

82

Com (Zea mays indentata) Distiller's grains, dried

3.88

3.18

2.18

1.50

90

Gluten feed

3.53

2.89

1.94

1.30

80

Grain, cracked

3.92

3.25

2.24

1.55

90

Silage, well-eared

3.17

2.60

1.69

1.08

72

Seed

3.97

3.25

2.24

1.55

90

Meal

3.31

2.71

1.79

1.16

75

Molasses, cane

3.17

2.60

1.70

1.08

72

Oats

3.40

2.78

1.85

1.22

77

Sorghum (Sorghum bicolor), grain

3.62

2.96

2.00

1.35

82

Cotton (Gossypium spp)

NUTRITION BEEF CADLE

2251

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MEAN NUTRIENT CONTENT OF FEEDS COMMONLY USED IN BEEF CATTLE DIETS• (continued) Crude Protein (%)

Crude Fiber

Ash

(%)

(%)

NDF (%)

ADF (%)

Ca

(%)

p

(%)

Dry Matter (%)

Alfalfa (Med'icago saliva)

10.5

47.1

36.8

1.29

0.26

23.4

24.2

10.2

30.9

24.0

1.71

0.30

23.2

30.4

10.9

3.7

l.19

0.26

23.8

18.6

26.1

8.6

43.9

33.8

1.40

0.28

90.6

19.9

28.5

9.2

39.3

31.9

1.63

0.21

90.5

18.7

28.0

8.5

47.1

36.7

1.37

0.22

91.0

17.0

30.l

7.8

48.8

38.7

1.19

0.24

90.9

19.5

25.4

9.5

47.5

37.5

1.32

0.31

44.2

18.1

5.8

0.05

0.35

88.1

18.9

26.5

22.2 19.3

4.79

Barley (Hordeum vulgare)

13.2 11.9 9.8

2.4

3.37 2.92 20.0

8.3

56.8

33.9

0.52

0.29

37.1

5.3

44.6

27.5

0.68

0.10

91.0

73.3

36.8

0.49

0.27

30.3

8.0

93.0

Bermuda grass (Cynodon dactylon)

12.6

28.4

8.1

7.8

2.7

76.6

38.3

29.2

7.8

4.18

48.7

31.2

0.29

0.70

90.2

6.7

12.8

6.6

23.0

23.0

1.88

0.18

91.l

46.0

21.3

0.26

0.83

90.3

Corn (Zea mays indentata) 30.4

6.9

4.6

23.8

7.5

6.9

36.2

12.7

0.07

0.95

90.0

9.8

2.3

1.5

10.8

3.3

0.03

0.32

90.0

3.6

46.0

26.6

0.25

0.22

34.6

4.2

51.6

41.8

0.17

0.52

89.4

28.9

17.9

0.20

1.16

90.2

0.4

1.00

0.10

74.3

8.7

19.5

Cotton (Gossypium spp) 24.4

25.6

46.1

13.2

7.0

5.8

0.5

13.3

13.6

12.0

12.6

2.76

3.3

29.3

14.0

0.01

0.41

89.2

1.9

16.1

6.4

0.04

0.34

90.0 (continued)

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NUTRITION: BEEF CATTLE

MEAN NUTRIENT CONTENT OF FEEDS COMMONLY USED IN BEEF CATILE DIETS• (continued)

Feedstuff Soybeans (Glycine max), meal

DE (Meal/kg)

ME (Meal/kg)

NE ,.. (Meal/kg)

N �" (Meal/kg)

3.70

3.04

2.06

1.40

TDNs

(%) 84

Wheat (1hticum aestivum) Wheat bran

3.09

2.53

1.63

1.03

70

Fresh, early vegetative

3.22

2.64

1.73

1.11

73

" Dry-matter basis; DE, digestible energy; ME, metabolizable energy; NE,,,, net energy for maintenance; NE,, net energy for gain; TDNs, total digestible nuu·ients; NDF, neu!Tal detergent fiber; AD�� acid detergent fiber. Adapted, with permission, from Nutrient Requ'i re,neuls qf'Be�f'Callle, 2000, National Academy of Sciences, National Academy Press, Washington, DC.

35%-500/ci. The protein of low-quality feeds, such as weathered grass hay, range grass, or cottonseed hulls, is digested poorly. Thus, even though total protein intake may appear to be adequate, metabolizable protein might be deficient. A lack of protein in the diet adversely affects the microbial protein production in the rumen, which in turn reduces the utilization of low-protein feeds. Thus, much of the potential nutritive value of roughages (especially energy) may be lost if protein levels are inadequate. Urea and other sources of nonprotein nitrogen (NPN) are used commonly in commercial protei11 supplements to supply one-third or more of the total nitrogen requirement. Such products are broken down readily by the ruminal microbial protein to anunonia and then synthesized to high-quality microbial protein. The use of NPN needs available sources of ample phosphorus, trace minerals, sulfur, and soluble carbohydrates for the microbial synthesis of utilizable protei11. The amow1t of crude protein (% N x 6.25) supplied by NPN must be stated on the feed tag accompanyil1g conunercial supplements. Toxicity is not a se1ious problem when w·ea is fed at recommended levels and mixed thoroughly with the other ingredients of the ration. However, rapid ingestion of urea at levels>20 g/100 lb (45 kg) body wt may lead to toxicity (seep 3043). Several urea-molas­ ses liquid supplements, containing as much as 100/c, urea, currently are self-fed to beef cattle. Caution should be exercised when cattle are started on such supplements.

Minerals: Qualitatively, beef cattle require the same mineral elements as do dairy cattle; however, the relative quantities of the several minerals are different (see TABLE 23, p 2262). The minerals most apt to be deficient in beef cattle diets are sodium (as salt), calcium, phosphorus, magnesiwn, zinc, copper, and seleniwn. In some areas, including the interior of the USA, iodine may be deficient in diets for pregnant cows; likewise, there are regional deficiencies (probably reflecting soil deficiencies) of several trace minerals, including copper, cobalt, and selenium. However, there are areas where some mineral elements (eg, selenium, molybdenwn) are present at toxic levels. Attempts have been made to correct natural soil deficiencies for trace minerals by soil fertilization practices. Thus, it is ilnplied that a beef producer needs to know the mineral and trace milleral coµtent of the feedstuffs used in cattle rations. A general approach to prevent such deficiencies is to feed a conunercial salt mineral mix developed for the geographic location of the herd. The salt (NaCl) requirement for beef cattle is quite low (0.2% of the dry matter); however, there appears to be a satiety factor involved-almost all animals appear to seek out salt if it is not readily available. Range cattle may consume 2-2.5 lb (1 kg) salt/head/mo when forage is succulent but about half that amount when forage is mature and drier. When salt is added to a free-choice protein feed to limit intake, beef cows might consume>1 lb salt/day over long periods of time

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NUTRITION: BEEF CATILE

2253

MEAN NUTRIENT CONTENT OF FEEDS COMMONLY USED IN BEEF CATTLE DIETS• (co11tin11ecl)

Crude Protein (%) 51.8

Crude Fiber (%) 5.4

Ash

(%)

6.9

NDF (%)

Dry Matter (%)

ADF (%)

Ca (%)

10.3

7.0

0.46

0.73

90.9

p (%)

Wheat (T' liticum aestivum) 17.4

11.3

6.6

42.8

14.0

0.14

1.27

89

27.4

17.4

13.3

46.2

28.4

0.42

0.40

22.2

without adverse effects if they have plenty of drinking water. Signs of a salt deficiency are rather nonspecific and include pica and reduced feed intake, growth, and milk production. Calcium is the most abundant mineral element in the body; --98% functions as a structural component of bones and teeth. The remaining 2% is distributed in extracel­ lular fluids and soft tissues and is involved in such vital fw1ctions as blood clotting, membrane permeability, muscle contrac­ tion, transmission of nerve impulses, cardiac regulation, secretion of certain hormones, and activation and stabilization of certain enzymes. Most roughages are relatively good sources of calciwn. Cereal hays and silages and such crop residues are relatively low in calciwn. Although leguminous roughages are excellent sources of calcium, even nonlegwne roughages may supply adequate calciw11 for maintenance of beef cattle. When cattle are fed such roughages produced on low-calcium soils, or when finishing cattle are fed high-grain diets with limited nonlegume roughage, a calcium deficiency may develop. Because lactating beef cows do not produce nearly the amount of milk that dairy cattle do, their calcium requirement is much less. Nevertheless, it is sound management to provide a free-choice salt mineral mixture tailored to the environment and production class of the grazing cattle. Salt should always be mixed with mineral, because salt drives intake. Cows have almost zero "nutritional wisdom," ie, they do not seek out feedstuffs or minerals when they are deficient, with the exception being sodium, o adding mineral to the salt generally improves intake among cattle with free-choice access to the mineral mix.

The total ration should provide a calcium: phosphorus ratio of 1.2 to 2: 1, with cows at minin1w11 of 1.2: 1 and feedlot steers at minimum of 2: 1. Wider ratios appear to be tolerated if the minimum requirements for each mineral element are met and if adequate vitamin D (exposure to sunlight) is available. Range cattle should be provided a mineral supplement that has as much or more phosphorus I han calcium, because green forage is many times higher in calcium. Research has shown that intake among cattle receiving free-choice mineral mix is highly variable. One study showed that 14 %--15 % of cows with free-choice access to mineral in block or loose fonn conswned zero mineral. The only time cattle should be offered mineral free choice is when they are grazing and no other feed is being fed. If cows are consuming any other feed, the salt and mineral should be mixed with the ration so all cattle will ingest the prescribed an10unt of mineral. Approximately 800Ai of the phosphorus in the body is found in the bones and teeU1, with the remainder dist1ibuted among the soft tissues. Phosphorus may be deficient in some beef cattle rations, because roughages often are low in phosphorus. F\uthermore, as forage plants mature, their phosphorus content declines, making mature and weathered forages a poor sow·ce. Phospho­ rus has been described as the most prevalent mineral deficiency for grazing cattle worldwide. Most natural protein supple­ ments are fairly good sources of phospho­ rus. Because adequate phosphorus is critical for optinlal pe1fom1ance of beef cattle, including growth, reproduction, and lactation, a phosph01us supplementation program is reconunendecl using eiilier a free-choice mineral mixture or direct

2254

NUTRITION: BEEF CADLE NUTRIENT REQUIREMENTS OF PREGNANT REPLACEMENT BEEF

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cows•

Months Since Conception 2

3

4

5

6

7

8•

9

6.14 2.36 0.07 8.57

6.30 2.42 0.16 8.87

6.46 2.48 0.32 9.26

6.61 2.54 0.64 9.79

6.77 2.59 1.18 10.55

6.92 2.65 2.08 11.65

7.07 2.71 3.44 13.23

7.23 2.77 5.37 15.37

303 119 4 425

311 119 7 437

319 119 18 457

326 119 27 472

334 117 50 501

342 115 88 545

349 113 151 613

357 110 251 718

11 9 0 20

11 8 0 20

12 8 0 20

12 8 0 20

12 8 12 33

13 8 12 33

13 8 12 33

8 3 0 12

9 3 0 12

9 3 0 12

9 3 0 13

10 3 7 20

10 3 7 20

10 3 7 20

1

NE,,, required(Meal/day) Maintenance 5.98 Growth Pregnancy Total

2.29 0.03 8.31

MP required(g/day) Maintenance 295 Growth Pregnancy Total

118 2 415

Calciwn required(g/day) Maintenance 10 Growth Pregnancy Total

9 0 19

11 9 0 19

Phosphorus required (g/day) Maintenance 8 Growth Pregnancy Total

4 0 12

8 4 0 12

Average daily gain(kg/day) Growth

0.39 0.03 0.42

0.39 0.05 0.44

0.39 0.08 0.47

0.39 0.12 0.51

0.39 0.19 0.58

0.39 0.28 0.67

0.39 0.40 0.79

0.39 0.57 0.96

0.39 0.77 1.16

Shrunk body 332

343 3

355 4

367 7

379 12

391 19

403 29

415 44

426 64

346 761

359 790

374 823

391 860

410 902

432 950

459 1,010

490 1,078

Pregnancy Total Body wt(kg) Gravid uterus mass Total(kg) Total(lb)

333 733

a Mature weight, 533 kg (1,173 lb); calf birth weight, 40 kg (88 lb); age at breeding, 15 mo; breed code Angus; see TABLE 18 for abbreviations. The concentration of vitamin A in all diets should be 2,200 lU/kg (1,000 lU/lb) of dry matter. Adapted, with permission, from Nutrient Requirements of Beef Cattle, 2000, National Academy of Sciences, National Academy Press, Washington, DC.

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NUTRITION BEEF CADLE

supplementation in the diet. In a phosphorus deficiency, reduced growth and efficiency of feed conversion, decreased appetite, impaired reproduction, reduced milk production, and weak, fragile bones can be expected. There does not appear to be any advantage to feeding more phosphorus than is recommended. Furthern1ore, feeding excess phosphorus contributes to increased environmental pollution. Good somces of supplemental phosphorus include steamed bone meal, mono- and dicalcium phosphate, deftuorinated rock phosphate, and phos­ phoric acid. Corn co-products like corn gluten and distillers grains with solubles are also high in phosphorus. Because most grains are relatively good somces of phos­ phorus, feedlot cattle rarely suffer a phos­ phorus deficiency, although phytic acid chelation of phosphorus in grains may render up to one-half of it unavailable­ especially for monogastric animals such as swine and poultry. Magnesium maintains elect1ical potentials across nerve endings. In a deficiency, the lack of control of muscles is obvious. However, nonnally deficiencies are not anticipated. A magnesium deficiency in calves results in excitability, anorexia, hyperemia, convulsions, frothing at the mouth, and salivation, but such a condition is uncommon. Usually, a magnesiw11 deficiency is seen in the spring in more mature grazing cattle under field conditions (ie, grass tetany, seep 996). The initial signs are nervousness, reduced feed intake, and muscular twitching about the face and ears. Animals are uncoordinated and walk with a stiff gait. In advanced stages, affected cows fall to the ground, convulse, and die sho1tly after. A blood sample from affected cows would show a serum magnesium level of 250 kg) conswne 1.5%--2% of their weight in dry matter daily. Smaller species ( 900A, of the supplemental protein fed to pigs in the USA. It is very palatable and has an excellent amino acid profile that complements the amino acid pattern in cereal grains. Ground, full-fat soybeans can also be fed to swine but only after they are heated (by extrusion or roasting) to inactivate the trypsin inhibitors and other heat-labile antinutri­ tional factors. Canola meal also is an excellent protein source. Low-gossypol cottonseed meal ( 4.5 kcaVg should be corrected for energy density.

2006 NRC NUTRIENT REQUIREMENTS FOR ADULT DOGS (MAINTENANCE)• Nutrient (Amount/1,000 kcal ME)h Protein (g)

Minimum

20

Maximum

Recommended Allowance

25

Arginine (g)

0.70

0.88

Histidine(g)

0.37

0.48

Isoleucine(g)

0.75

0.95

Leucine(g)

1.35

1.70

Lysine(g)

0.70

0.88

Methionine(g)

0.83

Methionine + cystine(g)

0.65 1.30

Phenylalanine(g)

0.90

1.13

1.63 (cont-inued)

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NUTRITION: SMALL ANIMALS

2359

2006 NRC NUTRIENT REQUIREMENTS FOR ADULT DOGS (MAINTENANCE)• (continued) Nutrient (Amount/1,000 kcal ME)b

Minimum

Maximum

Recommended Allowance

Phenylalanine + tyrosine(g)

1.48

Threonine(g)

0.85

1.08

Tryptophan(g)

0.28

0.35

Valine(g)

0.98

Fat(g)

1.85

1.23 82.5

Linoleic acid(g)

16.3

13.8 2.8 0.11

o:-Linolenic acid(g) Eicosapentaenoic + docosahexaenoic acid(g)

2.8

0.11

0.5

0.75

Minerals Calcium (g)

0.50

Phosphorus(g)

1.0

Potassium (g) Sodium(g)

1.0 75

200

Chloride(mg) Magnesium (mg)

300 45

150

lron(mg)

7.5

Copper(mg)

1.5

Manganese(mg)

1.2

Zinc(mg) Iodine (mcg)

15 220

175

Selenium (mcg)

87.5

Vitamins Vitamin A(retinol equivalents)

16,000

Cholecalciferol (mcg)

20

379 3.4

Vitamin E(o:-tocopherol, mg)

7.5

Vitamin K(menadione, mg)

0.41

Thiamine(mg)

0.56

Riboflavin (mg)

1.05

1.3

Pantothenic acid(mg)

3.75

Niacin(mg)

4.25

Pyridoxine(mg)

0.375

Folic acid(mcg) Vitamin B,2(mcg) Choline(mg)

67.5 8.75 425

• Reprinted with permission from the National Academies Press, copyright 2006, National Academy of Sciences. " ME ; metabolizable energy

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2360

NUTRITION SMALL ANIMALS

2006 NRC NUTRIENT REQUIREMENTS FOR PUPPIES AFTER WEANING• Nutrient (Amount/1,000 kcal ME)h

Minimum

Maximum

Recommended Allowance

PROTEIN, GROWING PUPPIES 4-14 WK OLD 45

Protein(g)

56.3

Arginine (g)

1.58

1.98

Histidine (g)

0.78

0.98

Isoleucine (g)

1.30

1.63

Leucine (g)

2.58

Lysine (g)

1.75

Methionine (g)

0.70

0.88

Methionine+ cystine (g)

1.40

1.75

Phenylalanine (g)

1.30

1.63

Phenylalanine+ tyrosine (g)

2.60

3.25

Threonine (g)

1.63

2.03

Tryptophan (g)

0.45

0.58

Valine (g)

1.35

1.70

3.22 >20

2.20

PROTEIN, GROWING PUPPIES 2:14 WK OLD Protein(g)

35

43.8

Arginine (g)

1.33

1.65

Histidine (g)

0.50

0.63

Isoleucine (g)

1.00

1.25

Leucine (g)

1.63

2.05

Lysine (g)

1.40

1.75

Methionine (g)

0.53

0.65

Methionine + cystine (g)

1.05

1.33

Phenylalanine (g)

1.00

1.25

Phenylalanine+ tyrosine (g)

2.00

2.50

Threonine (g)

1.25

1.58

Tryptophan (g)

0.35

0.45

Valine (g)

1.13

1.40

FAT, MINERALS, AND VITAMINS, ALL PUPPIES Fat(g) Linoleic acid (g)

330

21.3

65

3.3 0.2

cx-Linolenic acid (g) Arachidonic acid (g) Eicosapentaenoic+ docosahexaenoic acid (g)

0.08 11

0.13 (continued)

NUTRITION: SMALL ANIMALS

2361

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2006 NRC NUTRIENT REQUIREMENTS FOR PUPPIES AFTER WEANING• (continued) Nutrient (Amount/1,000 kcal ME)b

Minimum

Maximum

Recommended Allowance

Minerals Calcium (g)

2.0

18

Phosphorus (g)

3.0 2.5

Potassium (g)

1.1

Sodium (mg)

550

Chloride (mg)

720

Magnesium (mg)

45

100

Iron (mg)

18

22

Copper (mg)

2.7

Manganese (mg)

1.4

Zinc (mg)

10

25

Iodine (mcg) Selenium (mcg)

220 87.5

52.5

Vitamins Vitamin A (retinol equivalents)

3,750

Cholecalciferol (mcg)

20

379 3.4

Vitamin E (cx-tocopherol, mg)

7.5

Vitamin K (menadione, mg)

0.41 0.34

Thiamine (mg) Riboflavin (mg)

l.05

l.32

Pantothenic acid (mg)

3.75

Niacin (mg)

4.25

Pyridoxine (mg) Folic acid (mcg) Vitamin B 12 (mcg) Choline (mg)

0.375 68 8.75 425

" Reprinted with pennission from the National Academies Press, copyright 2006, National Academy of Sciences. b

ME = metabolizable energy

seizures, and death. Macadan1ia nuts are also potentially toxic to dogs and cats and can cause weakness, depression, vomiting, ataxia, muscle tremors, hyperthermia, and tachycardia. As few as six macadarnia nuts can be toxic to dogs. Onions and garlic contain thiosulfate, which can cause oxidative damage to RBCs and result in anemia. Onions are more toxic than garlic. Guatemalan avocados contain a substance

called persin, which can cause dyspnea, pulmonaiy edema, and pleural ai1d pericardia] effusion in goats and possibly dogs. Food high in fat, such as chicken skin, can result in some dogs developing pancreatitis. Broccoli toxicity has been reported to occur in dairy cattle, but it is a poorly documented problem in dogs and cats. Sugar-free foods containing xylitol can cause liver dainage in dogs. Raw food diets

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2362

NUTRITION: SMALL ANIMALS

2006 NRC NUTRIENT REQUI REMENTS FOR ADULT CATS (MAINTENANCE)• Nutrient (Amount/1,000 kcal ME)b Protein(g)

Minimum

Maximum

40

Arginine(g) Histidine(g) Isoleucine(g) Leucine(g) Lysine(g) Methionine(g) Methionine + cystine(g)

0.68 0.34 0.68

Phenylalanine(g) Phenylalanine+ tyrosine(g) Threonine(g) Tryptophan(g) Valine(g) Taurine(g)

0.080

Fat(g)

82.5 13.8 0.5

Linoleic acid(g) Arachidonic acid(g) Eicosapentaenoic+ docosahexaenoic acid(g)

Recommended Allowance

50 1.93 0.65 1.08 2.55 0.85 0.43 0.85 1.00 3.83 1.30 0.33 1.28 0.10 22.5 1.4 0.015 0.025

Minerals Calcium(g) Phosphorus (g)

0.40 0.35

0.72 0.64 1.3 170 240 100 20 1.2 1.2 18.5 350 75

Potassium(g) Sodium(mg)

160

Chloride(mg) Magnesium (mg)

50

Iron(mg) Copper(mg) Manganese(mg) Zinc(mg) Iodine(mcg)

320

Selenium(mcg) Vitamins Vitamin A(retinal equivalents) Cholecalciferol(mcg)

25,000 188

250 1.75 (continued)

NUTRITION: SMALL ANIMALS

2363

VetBooks.ir

2006 NRC NUTRIENT REQUIREMENTS FOR ADULT CATS (MAINTENANCE)• (continued)

Nutrient (Amount/1,000 kcal ME)b

Minimum

Maximum

Recommended Allowance 10

Vitamin E(a-tocopherol, mg) Vitamin K(menadione, mg)

0.25

Thiamine(mg)

1.40

Riboflavin(mg) Pantothenic acid (mg)

1.0 1.15

1.44

Niacin(mg)

10.0

Pyridoxine (mg) Folic acid(mcg)

0.5

0.625

150

188

510

637

Vitamin B,2 (mcg) Choline (mg)

5.6

a Reprinted with permission from the National Academies Press, copyright 2006, National Academy of Sciences. " ME = metabolizable energy

2006 NRC NUTRIENT REQUIREMENTS FOR KITTENS AFTER WEANING•

Nutrient (Amount/1,000 kcal ME)b Protein (g)

Minimum

Maximum

45

Recommended Allowance 56.3

Arginine(g)

1.93

Histidine(g)

0.65

>5.5

0.83

Isoleucine (g)

1.08

>21.7

1.4

Leucine (g)

2.55

>21.7

3.2

Lysine(g)

1.70

>14.5

Methionine (g)

0.88

Methionine + cystine (g)

1.75

Phenylalanine(g)

1.00

>7.25

1.3

Phenylalanine + tyrosine(g)

3.83

17

4.8

>12.7

1.6

Threonine (g)

1.30

Tryptophan(g)

0.33

Valine (g)

1.28

Glutamic acid (g) Taurin e(g) Fat(g) Linoleic acid (g)

8.75

3.25

2.4

2.1 1.1 2.2

4.25 >21.7

0.40 1.6

18.8 0.080

>2.22

0.10

82.5

22.5

13.8

1.4 (continued)

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2364

NUTRITION: SMALL ANIMALS

2006 NRC NUTRIENT REQUIREMENTS FOR KITTENS AFTER WEANING• (conUnued)

Nutrient (Amount/1,000 kcal ME)h

Minimum

Maximum

Recommended Allowance

a-Linolenic acid(g)

0.05

Arachidonic acid(g)

0.05

Eicosapentaenoic + docosahexaenoic acid(g)

0.025

Minerals Calciwn(g)

1.3

2.0

Phosphorns(g)

1.2

1.8

Potassium(g)

0.67

1.0

Sodium(mg)

310

Chloride(mg)

190

225

Magnesium(mg)

40

100

Iron(mg)

17

20

Copper(mg)

350

2.1

l.l

Manganese (mg) Zinc(mg)

1.2 18.5

12.5

Iodine(mcg) Selenium(mcg)

450 30

75

Vitamins Vitamin A (retinol equivalents) Cholecalciferol (mcg).

20,000 0.70

Vitamin K(menadione, mg)

0.25 1.1

Riboflavin(mg) Pantothenic acid(mg)

Folic acid(mcg)

1.15

1.43 10

0.5

0.625

150

188

510

637

Vitamin B 12(mcg) Choline(mg)

1.40 1.0

Niacin(mg) Pyridoxine (mg)

1.4 9.4

Vitamin E(a-tocopherol, mg) Thiamine(mg)

188

250

5.6

" Reprinted with permission from the National Academies Press, copyright 2006, National Academy of Sciences. b ME � metabolizable energy

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NUTRITION: SMALL ANIMALS

2365

DAILY MAINTENANCE ENERGY REQUIREMENTS FOR DOGS AND CATS Animal

MERa (kcal/day)

Healthy adult dogs Intact

1.8xRERb

Neutered

1.6 xRER

Obese prone

1.4 x RER

Healthy puppies 4mo old

2xRER

Healthy adult cats Intact

1.4xRER

Neutered

1.2xRER

Obese prone

1.0xRER

Healthy kittens

2.5xREW

• MER = maintenance energy requirement b RER = resting energy requirement c Kittens can alternatively be fed free choice

(see p 2375) are also not recommended for dogs and cats. Raw meat products may contain pathogens. (See ai,so FOOD HAZARDS, p 2964.) Nutrient deficiencies have also been seen in dogs and cats fed "natural," "organic," or "vegetarian" diets produced by owners with good intentions. Many published recipes have been only crudely balanced by computer, if at all, using nutrient averages. In addition, most homemade diets do not undergo the scrutiny and rigorous testing applied to conunercial complete and balanced diets. If pet owners wish to feed their pets homemade diets, the diets should be prepared and cooked using recipes fommlated by a veterinary nutritionist. Some nutritional diseases are seen secondary to other pathologic conditions or anorexia, or both. Owner neglect is also a frequent contributing factor in malnutrition. Energy: The most useful measure of energy for nutritional purposes is metaboliz­ able energy (ME), which is defined as that portion of the total energy of a diet that is retained within the body. It is typically measured in calories or joules. The caloric content of pets foods is usually expressed in kilocalo1ies (kcal), which is 1,000 calories. Dogs and cats require sufficient energy to

allow for optimal use of proteins and to maintain optimal body weight and condition through growth, maintenance, activity, pregnancy, and lactation. Energy requirements for dogs and cats are not a linear function of body weight. Recent evidence indicates that dogs maintained in households require fewer calories per day than dogs kept in kennels, but considerable variability exists. Breed differences also affect caloric needs independent of body size, eg, Newfound­ lands appear to require fewer calories/day than Great Danes. Other factors that determine daily energy needs include activity level, life stage, percent lean body mass, age, and environment. Even when specific fom1ulas are used, any given anin1al may require as much as 300A, more or less of the calculated amount. Consequently, general recommendations may need to be modified within this 300A, range, and body condition scoring should be regularly perfom1ed. The precise ME values for many dog food ingredients have not been experimentally determined and are often estimated using those for other rnonogast1ic species (such as pigs) or calculated using Atwater physiologic fuel values modified for use with typical dog food ingredients. Likewise,

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NUTRITION SMALL ANIMALS

the precise ME values for many cats are not !mown, although it is believed that the factors used for dogs may apply. The modified Atwater ME values for dogs are 3.5 kcal/g for carbohydrate and protein and 8.5 kcal/g of fat. The impact of vaiious envirorunental temperatures is described in the recent NRC publication on nutrient requirements of dogs and cats and has been documented under certain conditions. For exainple, energy requirements increased from 120 to 205 kcaJ/kgO·75 in Huskies as ainbient temperatures decreased from 14°C in summer to ---20°C in winter. Effects of environmental temperature are not well characterized in cats, because most of the reseai·ch was done under thermoneutral (68°---72° F (20°---22°C]) conditions. However, unacclimatized adult cats increased their daily caloric intakes nearly 2-fold when environmental temperatures of 23°C and 0°C were studied. Caloric Requirements: Energy require­ ments are quite variable ainong dogs and cats. Animals with the saine body weight can have 3-fold variation in daily kcal require­ ments, which ai·e affected by age, neute1ing status, physiologic status (growth, gestation, lactation, etc), physical activity, environ­ mental temperature, and any underlying abnom1alities. Any reconunendations for kcal requirements are only starting points and may need to be modified based on the response of the individual dog or cat. Many formulas are available to calculate caloric requirements for dogs and cats. A simple method for healthy dogs and cats struts with calculating the resting energy requirement (RER). The RER is the energy requirement for a healthy but fed aiumal, at rest in a thermoneutral envirot1ment. It includes energy expended for recovery from physical activity and feeding. There is an exponential a.Ild a linear fom1ula for calculating RER. The exponential formula (RER = 70 [body wt in kg0 751) ca.Jl be used for anin1als of a.J1y body weight, whereas the linear fom1ula (RER = 30 x [body wt in kg] + 70) is restricted for use in anin1als that weigh >2 kg and 14 wk old need a minimum of9.7 g and 12.5 g of protein of high biologic value per kg metabolic body wt/day, respectively. The cat has a higher protein requirement than most species, and healthy adult cats need a .mininlwn of 3.97 g of protein of high biologic value per kg metabolic body wt/day. Healthy kittens need a minimun1 of9.4 g of protein of high biologic value per kg metabolic body wt/day. The biologic value of a protein is related to the nwnber and types of essential amino acids it contains and to its digestibility and metabolizability. The higher the biologic value of a protein, the less protein is needed in the diet to supply the essential amino acid require­ ments. Egg has been given the highest biologic value, and organ and skeletal meats have a higher biologic value than plant­ based proteins. General guidelines for dietary protein requirements in dogs and cats exist, but requirements vary depending on the digestibility of the protein in the diet. If an animal is consuming a diet containing predominantly plant protein sources, protein requirements may be higher than if the animal is consunling a diet containing predominantly animal protein sources. The dietary requirement for protein in healthy adult dogs is satisfied when the dog's metabolic need for amino acids and nitrogen is satisfied. Optimal diets for growing puppies should contain a minimum of 22% protein as dry matter (AAFCO guidelines) or 45 g protein/1,000 kcal ME for puppies 4-14 wk old and 35 g protein/1,000 kcal ME for puppies >14 wk old (NRC guide­ lines). Adult clogs require a nlinimwn of 18%

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protein as dry matter (AAFCO guidelines) or -20 g protein/1,000 kcal of ME required (NRC guidelines). Optimal diets for growing kittens should contain at least 24%-28% ME as protein or 30% protein as dry matter (AAFCO guidelines) or 45 g protein/1,000 kcal ME (NRC guidelines). Optimal diets for adult cats should contain -200A, ME as protein or 26% protein as dry matter (AAFCO guidelines or 40 g protein/1,000 kcal ME (NRC guidelines). Growing kittens are more sensitive to the quality of dietary protein and anlino acid balance than are adult cats. Protein suitable for cats must supply >500 mg of taurine/kg diet dry matter. Unless synthetic essential anlino acids are added, some animal protein is necessaiy in the diet to prevent taurine depletion and develop­ ment of feline central retinal degeneration or dilated cardiomyopatl1y. Without sufficient energy from dietai-y fat or carbohydrate, dietary protein ordinarily used for growth or maintenance of body functions is less efficiently converted to energy. Too little high biologic protein in the diet, relative to the energy density, can cause an apparent protein deficiency. Signs produced by protein deficiency or an in1proper protein:calorie ratio may include any or all of the following: reduced growth rates in puppies and kittens, anemia, weight loss, skeletal muscle atrophy, dull unkempt hair coat, anorexia, reproductive problems, persistent Wlfesponsive parasitism or low-grade microbial infection, impaired protection via vaccination, rapid weight loss after injury or during diseas�, and failure to respond properly to treatment of injw-y or disease. High protein intakes per se do not cause skeletal abnormalities in dogs (including osteochondrosis in large breeds) or renal insufficiency later in life in dogs or cats.

Fats: Dietary fat consists mainly of triglyceride witl1 varying amounts of free fatty acids and glycerol. Lipids can either be simple (triglycerides, wax) or complex (containing many other elements). Triglycerides are divided into sh01t, medimn, and long chain based on the number of carbon atoms in the fatty acid chain. Essential fatty acids are long-chain fatty acids that cannot be synthesized in the body; most fatty acids consumed in the diet are long-chain fatty acids. Most nutrients conswned are digested and absorbed in the small intestines, where they then enter the blood supply via the portal vein and are delivered to the liver. When long-chain fatty acids are conswned, tl1ey are digested and

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absorbed into the small-intestinal epithelial cells; however, they are not transp01ted directly into the blood supply but rather enter the lymphatics first. There are conflic t ­ ing studies regarding the fate of dietary medium-chainfatty acids. Most studies suggest that medium-chain fatty acids do not require initial transport in the lymphat­ ics and instead can be absorbed from the intestines directly into the blood supply via the portal vein. Fatty acids are either saturated, indicating there are no double bonds, or unsaturated, indicating there are one or more double bonds. Fatty acids that contain more than one double bond are called polyunsaturated fatty acids (PUFA). PUFA are designated as either omega-3, omega-6, or omega-9fatty acids, depending on the location of tl1e first double bond. The more double bonds a fatfy acid contains, the more prone it is to rancidity if not properly preserved. Saturated fatty acids m·e used primarilyfor energy in the body, whereas unsaturated fatty acids m·e found in cell membranes 3lld blood lipoproteins. Dietary fatty acid profiles are reflected in the fatty acid composition of tissues 3lld cell membrfilles. In general, as the fat content of a diet increases, so does the caloric density 3lld palatability, which promotes excess cal01ie consumption 3lld obesity. Fat is a concentrated source of energy, yielding -2.25 times the ME (as fill equal dry-weight portion) of soluble carbohydrate or protein. The addition of too much dietm,1fat relative to other nutrients may result in excessive energy intake and subsequent suboptin1al intakes of protein, minerals, 3lld vitmnins. Dietary fats alsofacilitate the absorption, storage, and trfillsport of the fat-soluble vita­ mins (A, D, E, 3lld K). They m·e also 1'I. source of essential fatty acids (EFA), which maintain functional integrity of cell membra11es 3lld m·e precursors of prostaglfilldins and leukotrienes. Dietary fats, especially the unsaturated variety, require a protective (natural or synthetic prese1vatives) filltioxidation system. If 3lltioxid3llt protection from a natural preservative system (eg, vitmnin C or mixed tocopherols) or from synthetic preservatives (eg, BHA, BH1� ethoxyquin) in the diet is insufficient, dietm,1 3lld body polyunsaturatedfats become oxidized 3lld lead to steatitis. Rfillcid fats in the diet can also result in fat-soluble vitmnin deficiency. Dietary fat requirements vm,1 with age filld species. Optimal diets for growing puppies should contain a minimum 8% fat as dry matter (AAFCO guidelines) or 5.9 g of fat per kg metabolic body wt/day (NRC

guidelines) or 21.3 gfat/1,000 kcal ME (NRC guidelines). Optimal diets for adult dogs should contain a minimum 5%fat as dry matter (AAFCO guidelines) or 1.3 g of fat per kg metabolic body wt/day (NRC guidelines) or 10 gfat/1,000 kcal ME (NRC guidelines). Optimal dietsfor growing kittens 3lld adult cats should contain a mininlum go1ofat as dry matter (AAFCO guidelines), 4. 7 g offat per kg metabolic body wt/day for kittens, 4.7 g offat per kg metabolic body wt/day for kittens, 2.2 g of fat per kg metabolic body wt/day for adult cats (NRC guidelines), or 22.5 gfat/1,000 kcal MEfor growing kittens 3lld adult cats (NRC guidelines). Dogs 3lld cats have a dietm,1 requirement for specific EFA, including linoleic acid, fill unsaturated EFAfound in appreciable 3ll1ounts in com and soy oil. Cats also have a dietary requirement for fillother unsatu­ rated EFA, m·achidonic acid. Unlike dogs, cats Cfilillot readily convert linoleic to arachidonic acid, which must be obtained from anin1al sources. Recommendations for dietary intake of both linoleic acid 3lld arachidonic acid are -5 g 3lld 0.2 g/kg diet, respectively,for kittens 3lld adult cats. Both linoleic acid 3lld m·achidonic acid are omega-6 fatty acids. Recent studies suggest that o:-linolenic acid (fill omeg a -3fatty acid) is also essential in dogs filld possibly in cats. This omega-3 fatty acid is found primarily in flaxseed oils. The 3ll1ount of dietary a-linolenic acid needed likely depends on the linoleic acid content. Although the required 3ll10unts of this omega-3 fatty acid are presently unknown, current minimal recommend a ­ tions include 0.8 g/kg diet of o:-linoleic acid when linoleic acid is 13 g/kg diet (dry-matter basis) for puppies 3lld 0.44 g/kg diet of o:-linoleic acid when linoleic acid is 11 g/kg diet (d1,1-matter basis) for adults. In addition, the longer chain omega-3fatty acid, docosaliexaenoic acid (Olli\), may be conditionally essentialfor normal neurologic growtl1 3lld development of puppies 3lld kittens. Puppiesfed diets containing DHA perform better in learning experiments filld are easier to train thfill puppies fed diets without DHA. Eicosapen­ taenoic acid (EPA) is fillother longer chain omega-3 fatty acid that has been shown to be beneficial in tl1e diet for treatment of certain skin, renal, and GI conditions, as well as cancer, arthritis, and hyperlipidemia. These longer chain omega-3 fatty acids are found primarily in marine sources of lipids. Very little o:-linolenic acid gets converted to DHA/EPA in dogs 3lld cats. Therefore, when choosing omega-3fatty acids to treat certain

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medical conditions, it is best to choose marine somces. NRC recommends a level of 0.025 g/1,000 kcal ME of a combination of DHA and EPA for both kittens and adult cats. NRC recommends levels of DHA and EPA in the diet of 0.13 g/1,000 kcal ME for puppies and 0.11 g/1,000 kcal ME for adult dogs. Most commercial adult dog foods typically contain 5o/o-15% fat (dry-matter basis). Puppy diets usually contain 8o/o-20"A, fat (dry-matter basis). One reason for this wide range of fat content is the pmpose of the diet; work, stress, growth, and lactation require higher levels than maintenance. As much as 60% of the calories in a cat's diet may come from fat, although diets that contain 8%-40% fat (d1y-matter basis) have also been fed successfully. Because fat can add considerably more calories to a finished diet, the an10w1t of protein relative to energy must be balanced appropriately to the life stage and typical intakes expected for an animal's size and needs. EFA deficiencies are extremely rare in dogs and cats fed properly preserved complete and balanced diets formulated according to AAFCO profiles. Deficiencies of EFA induce one or several signs, such as a dry, scaly, lusterless coat; inactivity; or reproductive disorders such as anestrus, testicular underdevelopment, or lack of libido. Fatty acid supplements are often recommended for dogs with dry, flaky skin and dull coats, but underlying metabolic conditions should always be evaluated first.

Carbohydrates and Crude Fiber:

Carbohydrates in pet foods include low- and high-molecular-weight sugars, starches, and various cell wall and storage nonstarch polysacchaiides or dietary fibers. The four carbohydrate groups functionally are absorbable (eg, monosaccharides such as glucose, galactose, ai1d fructose), digestible (eg, disacchatides, some oligosaccharides), fem1entable (eg, lactose, some oligosaccha­ rides), and poorly fem1entable (eg, fibers such as cellulose, which is an insoluble fiber). Although there is no minimum dietaiy requirement for simple carbohydrates or starches for dogs and cats, certain tissues, such as the brain and RBCs, require glucose for energy. If inadequate ai11otmts of dietaty carbohydrates are available, the body will synthesize glucose from glucogenic ainino acids and glycerol. Cats n01mally use glucogenic an1ino acids and glycerol to synthesize glucose, which is one reason why cats are classified as true carnivores. However, dogs usually synthesize glucose

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from dietary cai·bohyd.rates. The use of dietaty protein to synthesize energy in dogs diverts ainino acids away from ftmctions such as SY11thesis of nonessential amino acids and building muscle. Carbohydrates cai1 become conditionally essential when energy needs are high, such as during growth, gestation, and lactation. Different cai·bohydrate somces have vaiying physiologic effects. In cats, cai·bohydrates apparently are not essential in the diet when an1ple protein and fats supply glucogenic atnino acids and glycerol. However, properly cooked nonfibrous carbohydrates are utilized well by botl1 cats and dogs. In both dogs and cats, if starches ai·e not cooked, they ai·e poorly digested ai1d may result in flatulence or diarrhea. Except for t11e occasional case of lactose or sucrose intolerance, most cooked cai·bohydrates ai·e well tolerated in botl1 dogs and cats. Fiber: Fiber is defined as the edible parts of plants or analogous cai·bohydrates tl1at are resistant to digestion and absorption in the small intestine and have complete or paitial fermentation in the Jai·ge intestine. AJtl10ugh tl1ere is no dietaiy requirement for fiber in clogs and cats, there ai·e health benefits of having certain fiber somces in the diet. Fiber is resistant to hydrolysis by mainmalian digestive secretions but is not an inert traveler through t11e GI tract. Increased levels of fiber in diets increase fecal output, normalize transit time, alter colonic microflora and fermentation patterns, alter glucose absorption and insulin kinetics, and, at high levels, can depress diet digestibility. The diverse natme of fiber has led to nwnerous classification methods. One way fiber is classified is based on its solubility. Soluble fibers have greater water-holding capacity than insoluble fibers. Fiber somces such as beet pulp, cellulose, and rice bran have low solubilities, while gum arabic, methylcellulose, and inulin have high solubility. Psyllium contains both low-solu­ ble and high-soluble fiber. Although tl1e classification of fiber based on its solubility is sWI used, fiber is better classified based on its rate of ferment.ability. Fermentation is defined as the capacity of fiber breakdown by intestinal bacteria, and this definition more accmately assesses the potential benefits of fiber in the GI tract. Fem1enta­ tion of fiber produces the short-chain fatty acids acetate, propionate, and butY)·ate. Short-chain fatty acids have nwnerous benefits, including supplying energy to the large-intestinal epithelial cells, stimulating intestinal sodiwn and water absorption, and

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lowe1ing the pH in the large intestines-an environment that favors survival of benefi­ cial bacte1ia in the GI tract. Conversely, fermentation also produces less desirable substances such as gases anunonia, and phenols. Highly fem1en�ble fibers are rapidly metabolized by intestinal bacteria and produce large amounts of gas that can result in cramping and diarrhea. Production of less desirable fermentation products can be minimized by using a moderately fem1entable fiber source· examples include beet pulp, inulin, ru\d psyllium. Beet pulp provides good fecal quality in dogs without affecting other nutrient digestibility when included at s7.5% (dry-matter basis). Dietary ferrnentable fiber also functions as a prebiotic in dogs and cats. Prebiotics are defined as nondigestible food ingredi­ ents that selectively stimulate the growth or activity of beneficial bacteria in the intestines, such as Bijidobacterium and Lactobacillus. They also inhibit the survival and colonization of pathogenic bacteria. The beneficial bacteria produce short-chain fatty acids and some nutrients (eg, some B vitamins and vitanli.n K). Beneficial bacteria also function as inlrnw10modulators and reduce liver toxins (eg, blood anline and ammonia). Dietary fructooligosaccharides (FOS) and marmanoligosaccharides (MOS) also promote the survival and growth of beneficial bacteria in the GI tract. FOS are nondigestible oligosaccharides consisting of chams of fructose molecules. Dietary sources of FOS include beet pulp, psyllium, and chicory. Beneficial bacteria are able to use FOS as a metabolic fuel, whereas pathogenic bacteria cannot. FOS also enhance the effectiveness of the GI inlrnune system. MOS are sinli.Iar to FOS, except the predominant sugar molecule in MOS is mannose instead of fructose. Dietary sources of MOS include natural fibers found in yeast cells. MOS use a different mecha­ nism than FOS to inhibit the growth of harmful bacteria. Pathogenic bacteria attach to the intestinal wall using finger-like projections called fin1briae. Fimbriae bind to specific mannose residues on intestinal cells. Fimb1iated mannose-specific pathogens can also bind to MOS instead of adl1ering to the intestinal epithelium, and harmful bacte1ia are then excreted in the feces. Several chemical methods are used to determine the fiber level of a food· all extract the components of fiber t� different degrees, which results in different estimates of fiber level for the same feedstuff. Crude

fiber, which is what is listed on pet food labels, quantifies insoluble dietary fiber, which is primarily cellulose, some ligni.n, and a small amount of hemicellulose. However, it does not measure a large portion of insoluble dietary fiber, nor any of the soluble dietary fiber. Therefore, crude fiber is not an accurate measure of total dietary fiber. The physiologic effects of fiber are not wli.form across all fiber types, and relymg solely on fiber content listed on pet food labels does not accurately reflect either fiber content and fiber types in commercial pet foods, or the physiologic effects from a diet.

Vitamins: Most commercial dog and cat

foods are fortified with vitamins to levels that exceed minin1al requirements. There is no AAFCO dietary requirement for vitamin C for dogs and cats, because they are able to synthesize it in the liver. Although dogs and cats can synthesize vitan1in C in levels sufficient to prevent signs of deficiency, supplementation may provide additional health benefits because vitanli.n C functions as a free radical scavenger and an antioxi­ dant in the body. There is also no AAFCO dietaly requirement for vita111i.n Kfor dogs and cats, because intestinal bacteria are able to synthesize it. However, any condition that alters the intestinal nli.croflora, such as antibiotic therapy, may result in vitanli.n K deficiency. As a result, NRC rec0111.111ends vitaimn Kat 0.33 mg/1,000 kcal ME in puppies, at 0.45 mg/1,000 kcal ME in adult dogs, and at 0.25 mg/1,000 kcal ME in kittens and adult cats. Deficiencies of fat-soluble vitamins (A, D, and E m dogs; A, D, E, and Kin cats) and some of the 11 water-soluble B-complex vitanli.ns have been produced experimen­ tally. Water-soluble vitamins are usually readily excreted if excess amounts are consumed and are thought to be far less likely to cause toxicity or adverse effects when ingested in mega.doses. Vitanli.n B 12 is the only water-soluble vitainin stored in the liver, and dogs may have a 2- to 5 y- r depot. Fat-soluble vitanli.ns (except for vitamin K in cats) are stored to an appreciable extent in the body, and when vitanli.ns A and D are ingested in large amounts (10-100 times daily requirement) throughout a period of months, toxic reactions may be seen. Only clinically relevant vitan1in-related in1bal­ ances are descrihecl below. Vitamin A: Excessive consun1ption of liver can lead to hypervitanli.nosis A and may produce skeletal lesions, including

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NUTRITION: SMALL ANIMALS deforming cervical spondylosis, ankylosis of vertebrae and large joints, osseocartila­ genous hyperplasia, osteoporosis, inhibited collagen synthesis, decreased chrondrogen­ esis in growth plates of growing dogs, and narrowed intervertebral foramina. Unlike most other mammals, cats cannot convert 13-carotene to vitamin A, because they lack the intestinal dioxygenase enzyme necessary for 13-carotene cleavage. Therefore, cats require a preformed source in their diet, such as that supplied by liver, fish liver oils, or synthetic vitamin A. Signs of a vitamin A deficiency in cats are similar to those in other species, except that classic xerophthalrnia, follicular hyperkera­ tosis, and retinal degeneration are rarely seen and usually are associated with concomitant protein deficiency. Nonethe­ less, cats fed diets deficient in vitamin A exhibited cortjunctivitis, xerosis with keratitis and corneal vascularization, retinal degeneration, photophobia, and slowed pupillary response to light. Certain of these alterations also result from the retinal degeneration that is seen in taurine deprivation. Hypovitaminosis A in cats may exhaust vitamin A reserves of the kidneys and liver; affect reproduction to cause stillbirths, congenital anomalies (hydrocephaly, blindness, hairlessness, deafness, ataxia, cerebellar dysplasia, intestinal hernia), and resorption of fetuses; and cause the same changes in epithelial cells noted in other anin1als. Squamous metaplasia of tl1e respiratory tract, cortjunctiva, endome­ trium, and salivary glands has been noted. Changes such as subpleural cysts lined by keratinizing squamous epithelium and extensive infectious sequelae are frequent in tl1e lungs and are occasionally noted in the cortjunctiva and salivary glands. Focal dysplasia of pancreatic acinar tissue and marked hypoplasia of seminiferous tubules, depletion of adrenal lipid, and focal atrophy of the skin have been reported. Borderline deficiency is more common, especially in chronic ill health. Rctinol at 9,000 IU/kg of diet should meet dietary needs for vitamin A dwing gestation and lactation and exceed the needs of growing kittens. See TABLES 58, 61, and 62 for dietary levels of vitamin A and otl1er nutrients reconunended by AAFCO and NRC. Vitamin D: Vitan1in D deficiency results in rickets in young anin1als and osteomala­ cia in adult anin1als. Classic signs of rickets are rare in puppies and kittens and most often are seen when homemade diets are fed without supplementation. Rickets has

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been reported in kittens fed diets deficient in vitamin D, even though dietary amounts of calciwn and phosphorus were normal. In rickets, serum calcium and phosphorus are decreased or low nom1al with a correspond­ ing high parathyroid hormone level; bone mineralization is decreased, and tl1e metaphyseal areas are enlarged. Osteomala­ cia rarely causes clinical signs in dogs or cats. Hypervitaminosis D causes hypercal­ cemia and hyperphosphatemia with irreversible soft-tissue calcification of the kidney tubules, heart valves, and large­ vessel walls. Death in dogs is either related to chronic renal failure or acutely due to a massive aortic rupture. Death in cats is related to chronic renal failure. Vitamin E: In cats, steatitis results from a diet high in PUFA, particularly from marine fish oils when these are not protected with added antioxidants. Kittens or adult cats develop anorexia and muscular degenera­ tion; depot fat becomes discolored by brown or orange ceroid pigments. Lesions are seen in cardiac and skeletal muscles and are sinlilar to tl1ose described in otl1er species. Thiamine: Thiamine deficiency generally does not develop in cats fed properly prepared, conunercial, complete, and balanced diets. Thian1inase, which tends to be high in uncooked freshwater fish, can produce a deficiency by rapid destruction of dietary thian1ine. Although canned conu11ercial cat foods may contain fish, the heat associated with canning is sufficient to destroy thiaminase. Destruction of thiamine has also resulted from treatment of food with sulfur di.oxide or overheating during drying or canning, but deficiencies are now rare. Thiamine-deficient cats develop anorexia, an unkempt coat, a hunched position, and with time, convulsions that become more severe, leading later to prostration and death. At necropsy, small petechiae may be found in the cerebrum and rnidbrain. Diagnosis can be confirmed in the early stages by giving 100----250 mg thian1ine, PO or IM, bid for several days. Recovery occurs in minutes to hours but, if the diet is not supplemented after this treatment, relapse can be expected. Thiamine deficiency may cause a nwnber of other neurologic disorders, including impairment of labyrinthine 1ighting reactions, seen as head ventroflexion and loss of tl1e ability to maintain equilibrium when moving or jumping; in1pairment of the pupillary light reflex; and dysfunction of the cerebellum, suggested by asynergia, ataxia, and dysmetria.

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Minerals: Minerals can be classified into three major categories: macrominerals (sodium, potassium, calcium, phosphorns, magnesium) required in gram amounts/day, trace minerals of known importance (iron, zinc, copper, iodine, fluorine, selenium, chromium) required in mg or mcg amounts/ day, and other trace ntinerals important in laboratory animals but that have an unclear role in companion anin1al nut1ition (cobalt, molybdemun, cadmiun1, arsenic, silicon, vanadium, nickel, lead, tin). A balanced amount of the necessary dietary minerals in relation to the energy density of the diet is in1portant. As intake of a mineral exceeds the requirement, an excessive amount may be absorbed, or a large amount of the unabsorbed mineral may prevent intestinal absorption of other minerals in adequate amounts. Indiscriminate mineral supple­ mentation should be avoided because of the likelihood of causing a mineral imbalance. Mineral deficiency is rare in well-bal­ a.nced diets. Manipulation of dietary intake of calcium, phosphorns, sodiun1, magne­ sium (dogs and cats), and copper (dogs) for therapeutic effect is common. Limited evidence exists for the recommendations of dietary mineral requirements for cats in TABLES 61 and 62; many are based on the mineral content of successfully fed diets. Macrominerals: Calcium and phospho­ rns deficiencies are uncommon in well­ balanced growth diets. Exceptions may include high-meat diets high in phosphorns and low in calciwn and diets high in phytates, which inhibit absorption of trace minerals. In dogs and cats, the requirements for dietary calciun1 and phosphorus are increased over maintenance during growth, pregnancy, and lactation. In dogs, the optimal calcium:phosphorus ratio should be -1.2-1.4: l; however, minimun1 and maximum ratios by AAFCO are 1:1 to 2.1:1. Less phosphorns is absorbed at the higher ratios, so an approp1iate balance of these two minerals is necessary. Also, insufficient supplies of calciwn or excess phosphorus decrease calciun1 absorption and result in initability, hyperesthesia, and loss of muscle tone, with temporary or permanent paralysis associated with nutritional secondaiy hyperpai·athyroidism. Skeletal demineralization, paiuculai·ly of the pelvis and vertebral bodies, develops with calciun1 deficiency. By the time there is a pathologic fracture and the condition can be confirmed radiographically, hone demineralization is severe. Often, there is a history of feeding a diet composed almost entirely of meat, liver, fish, or poultry.

Excess intakes of calcium are more problematic for growing (weaning to 1 yr) lai·ge- and giant-breed dogs. Excessive supplementation (>3% calciun1 [ dry-matter basis]) causes more severe signs of osteochondrosis and decreased skeletal remodeling in young, rapidly growing large-breed dogs thai1 in dogs fed diets with lower dietaiy calciwn (1o/o--3"A, [ dry-matter basis]). The clinical signs of lai11eness, pain, and decreased mobility have not been reported in small-breed dogs or more slowly growing breeds fen the higher calciwn an1ow1ts. Magnesium is ai1 essential cofactor of mai1y intercellular metabolic enzyme pathways ai1d is rarely deficient in complete ai1d balanced diets. However, when calciun1 or phosphorns supplementation is excessive, insoluble and indigestible mineral complexes form within the intestine and may decrease magnesium absorption. Clinical signs of magnesi1-m1 deficiency in puppies are depression, lethargy, ai1d muscle weakness. Excessive magnesiwn is excreted in the wine. In cats, there is evidence that magnesium concentrations >0.3% (dry-matter basis) may be detrimental if the diet is too alkaline. Trace Minerals: Iodine deficiency is rai·e when complete and balanced diets are fed but may be seen when high-meat diets ai·e used (dogs and cats) or when diets contain saltwater fish (cats). Kittens with iodine deficiency show signs of hyperthyroidism in the ,"rly stages, with increased excitability, followed later by hypothyroidism and lethai·gy. Abnormal calcium metabolism, alopecia, and fetal resorption have been reported. The condition can be confirmed by thyroid size (>12 mg/100 g body wt) ai1d histopathology at necropsy. The cause of hyperthyroidism that develops in older cats with increased blood thyroxine and triiodothyronine is unknown. Iron and copper found in most meats are used efficiently, ai1d nutritional deficiencies ai·e rare except in anin1als fed a diet composed almost entirely of milk or vegetables. Deficiency of iron or copper is mai·ked by a microcytic, hypochromic anemia and, often, by a reddish tinge to the hair in a white-haired animal. Deficiency of zinc results in emesis, keratitis, achromotrichia, retarded growth, and emaciation. Decreased zinc availability has been noted in canine diets containing excessive levels of phytate, which emphasizes the value of feeding trial tests over laborat01y nutrient analyses of pet foods.

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NUTRITION SMALL ANIMALS

Manganese toxicity has been reported to produce albinism in some Siamese cats; a deficiency of manganese in other species results in bone dyscrasia.

DOG AND CAT FOODS Pet Food Labels Current regulations require that all labels of pet foods manufactured and sold in the USA must contain the following items: 1) product nan1e,2) net weight of the product, 3) name and address of the manufacturer, 4) guar­ anteed analysis, 5) list of ingredients, 6) the words "dog or cat food" (intended animal species), 7) statement of nutritional adequacy, and 8) feeding guidelines. The AAFCO has also adopted an amendment that will require all pet food labels to contain information on the calorie content of the diet, expressed both in kcal ME/kg and per fanli.liar household unit (eg, cups, cans). The product name is the primary means by which a specific pet food is identified. The way ingredients are listed in the product name may also indicate the percentage of that ingredient present in the product, eg, using the tem1 "beef' in the product nan1e requires that beef ingreclients must be at least 700;6 of the total product or �95% of the total weight of all ingredients, excluding water. Using the tem1 "beef dinner," "beef entree," or "beef platter," etc, implies that beef must be at least 10016 of the total product, and at least25% but not more than 95% of the total weight of all ingredi­ ents, excluding water. Using the term "with beef' means at least 3% of the total product must be beef, and using the tenn "beef flavor" in1plies that there is only enough beef in the product to be detected by taste (25%. A certain vaiiance above or below a minimum or maxinuun should be expected. Conse­ quently, whenever possible, the mai1ufac­ turer's average nutrient profile should be used to evaluate a food. Direct product comparisons made between like (similai· water content) products (ie, dry vs dry, or cairned vs carmecl) ai·e generally valid. However, comparisons across different food types should be made on a cl1y-matter or caloric basis. As a general rule, dry-food analyses can be conve1ted to a dry-matter basis by simply adding 10% to the as-is value, because most diy foods contain -10016 water ( eg, a dry-food protein content of25% on ai1 as-fed basis is equal to27.5% d1y-matter basis). Cairned food analyses can be conve1ted to a d1y-matter basis by simply multiplying by 4, because most carmed foods contain -75% water (ie, a canned-food protein content of 6% on an as-feel basis is equal to24% dry-matter basis). Alterna­ tively, the approximate percent d1y matter of a nutrient in a product can be calculated from tl1e infonnation in the guai·anteed analysis. First, dry matter in t11e diet is calculated by subtracting the moisture level from 100%. Next, the percent of the nutrient of interest on a dry-matter basis is calculated using the following equation: (% nutrient [as fed],% dry matter in diet) x 100 = -% of nutrient (dry matter) Ingredient List: 1n the USA, all pet foods sold must be registered witl1 state feed control officials and must contain approved ingredients generally regai·ded as safe, unless they are for specialized purposes such as the amelioration or prevention of disease. Such foods are considered to be drugs and must be approved by the FDA. Ingredients ai·e listed in descending order of weight, on an as-fed basis, in the food. Although a food ingredient (eg, chicken) may be listed first, if that ingredient is 75% moisture, it will contribute a much smaller percentage of total nutrients to the food dry matter. 1n addition, an ingredient such as corn may be listed by individual types, eg, flaked com, ground com, screened com, kibbled com, etc. In this case, the total corn amount may be a significant an10unt of the total food dry matter, but when presented as individual types, each type appeai-s lower on the ingredient list. This is referred to as ingredient splitting.

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No reference to quality or grade of an ingredient is allowed to be listed; therefore, it is difficult to evaluate a product solely on the basis of the ingredient list. The value of this list is limited to determining the sources of the proteins and carbohydrates for dogs or cats. This kind of information is useful when evaluating animals experienc­ ing an adverse reaction to a food, possibly due to an allergy or intolerance to one or more ingredient sources such as beef, wheat, etc. Product formulations can be either fixed or open. In a fixed formula, combinations of ingredients and nutrient profiles do not change regardless of fluctuating market prices of the ingredients. In an open formula, ingredients, and possibly actual nutrient profiles, change depending on availability and market prices. Most commercial complete and balanced diets have a fixed fom1ula.tion. Statement of Nutritional Adequacy:

This statement indicates how the food was tested (feeding versus laboratory analysis or fonnula.tion) and for which life stage the food is intended. AAFCO recognizes only fow- life stages: growth, maintenance, gestation, and lactation. The tem1 "all life stages" is frequently used on a label and indicates that the product has been either formulated or tested for growth. By default, it is anticipated that such a food would also pass a maintenance protocol, because testing a food for growth generally includes gestation and lactation. There a.re no AAFCO-a.pproved nutrient profiles for ge1ia.t1ic, senior, or weight loss stages. The statement "complete and balanced" indicates the product contains all nutrients presently known to be required by dogs or ca.ts and that these nutrients a.re properly balanced to the energy density of the diet. The "complete and balanced" clainl must be substantiated by successfully completing AAFCO feeding trials, or the food must contain at least the minimal a.mount of ea.ch nutrient recommended by AAFCO. There a.re cautions "against the use of these requirements Oevels) without demonstra­ tion of nutrient availability" because some of the requirements a.re based on studies in which the nutrients were supplied as plllified ingredients and, therefore, a.re not representative of ingredients used in commercial pet foods. Laboratory analysis does not address the issue of bioa.vaila.bility. Supplements, snacks, treat products (ie, those intended for intennittent or supple­ mental feeding), and therapeutic or dietary products (ie, those intended for use under

the direction of a veterinarian) a.re exempted from AAFCO testing. Feeding Guidelines: These must be expressed in common tem1s, such as "feed (weight/unit of product) per body wt of dog or cat." They a.re general recommendations at best, and body weight and body condition must be monitored to prevent over- or underfeeding. Pet Food Product Types

Conunercial dog and cat foods a.re available in three principal fonns: canned, dry, and semin1oist. The classifications used depend on the processing method and water content more than on the ingredient content or nutrient profile. Complete and balanced commercial dog and cat diets a.re fomlll­ lated to provide adequate quantities of ea.ch required nutrient without an intolerable excess of any nutrient. Supplementation of particular nutrients to conunercially produced complete and balanced dog and cat foods should be done carefully and only with a.pprop1iatejustifica.tion. Dog foods a.re not satisfactory for ca.ts because most dog foods a.re lower in protein, often do not contain assw-ed concentrations of tallline, and a.re not designed to produce a. mina.ry pH of 20 yr old) who have a body mass index(BMI) �30 kg/m2 .

ESSENTIAL PUBLIC HEALTH FUNCTIONS Under the auspices of DHHS, the USPHS developed(and adopted in 1994) the follow­ ing ten essential public health functions to assist state and local health agencies achjeve their mission of promoting physical and mental health and preventing disease, injury, and disability. 1) Monitor health status to identify community health problems. A generally accepted defmition of public health smveillance is "the ongoing systematic collection, analysis, interpretation, and djssemination of outcome-specific data essential to the planning, implementation, and evaluation of public health practice." Without Ws type of activity over tin1e, base­ line data cannot be analyzed for adverse events and trends. 2) Diagnose and investigate health problems and health hazards in the community. As an adjunct tp surveillance, public health agencies conduct targeted screening programs ancl/or surveys to detect problems and hazards in the community. When detected, they are inves­ tigated to determine their magnitude, and results are used to inform public educa­ tion and prevention efforts. 3) Inform, educate, and empower people about health issues. Once priorities have been established through swveillance, detection, and investigation, educational activities that promote improved health should be disseminated. 4) Mobilize conm1unity partnerships to identify and solve health problems. Public health agencies at all levels can mobilize conununity partnerships to solve health problems. Of particular importance is identi­ fication of potential stakeholders who can contribute to or benefit from public health interventions.

5) Develop policies and plans that support individual and community health efforts. Policies and laws can effectively modify human behavior and reduce negative health outcomes. Examples include limiting access to high-calorie beverages in school-age children and "dram shop liability" to discourage overconsumption of alcoholic beverages in public establishments. 6) Enforce laws and regulations that protect health and ensure safety. The existence of policies and laws is not enough; compliance must be enforced to ensure the overall safety and health of the community. Ongoing assessment and education efforts are undertaken to ensure that these policies and laws remain relevant and known to the public. 7) Link people to needed personal health services and assure the provision of health care when otherwise unavailable. Having access to care when it is needed is important in helping individuals prevent and avoid unfavorable health outcomes and medical costs. Components of these efforts are ut1dertaken at the local, state, and federal levels to provide a coordinated system of health care. 8) Assure a competent public health and personal health care workforce. Competent health care workers provide care more effectively and efficiently than those less competent. This is facilitated by licensing and credentialing processes, incorporating core public health competencies into personnel systems, and adopting continual quality improvement opportunities for public health workforce members. 9) Evaluate effectiveness, accessibility, and quality of personal and population­ based health se1vices. Given scarce resources, it is imperative to assess whether programs and policies achieve intended outcomes. Cost-effectiveness analyses have been proposed as one strategy to infom1 policymakers on how best to allocate health care resources. 10) Support/sponsor research for new insights and innovative solutions to healtll problems. From the evidence-based results of coordinated research programs, healtl1 and health care problems can be better understood and in1proved over time.

PUBLIC HEALTH FOCI OF PREVENTION When considering opportunities and methods to address healtl1 problems, til!'ee stages of prevention are generally recognized: 1) Ptirnary prevention-focuses on avoid­ ing development of a disease by preventing

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PUBLIC HEALTH PRIMER it before exposure. Examples of primary prevention strategies include immunization programs, health education, and smoking cessation interventions. Because disease is largely avoided by these strategies, prin1ary prevention is generally regarded as the most cost-effective forn1 of prevention. 2) Secondary prevention-focuses on early disease detection and intervention, ideally before the onset of clinical signs. Examples include screening programs against various forn1s of cancer (eg, breast, colon, prostate, etc), postexposure rabies prophylaxis, tuberculosis skin tests, and infectious disease contact investigations. 3) Tertiary prevention-focuses on the treatment and rehabilitation of individuals with disease(s). Examples include antimi­ crobial therapies, hypertension drugs, and heart attack and stroke rehabilitation. Because this stage focuses its effmts after a disease is established, tertiary prevention has proved the most expensive form of prevention.

BASIC PRINCIPLES OF EPIDEMIOLOGY The definition of epidemiology is "the study of disease in populations and of factors that determine its occurrence over time." The purpose is to describe and identify opportuni­ ties for intervention. Epidemiology is con­ cerned with the distribution and detern1i­ nants of health and disease, morbidity, ir\jury, disability, and mortality in populations. For veterinary epidemiology, this intervention is to enhance not only healtl1 but also productivity. Distribution implies tl1at diseases and other health outcomes do not occur randomly in populations; determi­ nants are any factors tl1at cause a change in a health condition or other defined characteris­ tic; morbidity is illness due to a specific disease or health condition; mortality is deatl1 due to a specific disease or healili condition; and tile population at risk can be people, animals, or plants. Epidemiology is applied in many areas of public healili practice. Among tl1e most salient are to observe historical health trends to make useful projections into the future, discover (diagnose) current health and disease burden in a population, identify specific causes and risk factors of disease, differentiate between natural and inten­ tional events (eg, bioterrorism), describe the natural history of a paiticular disease, compare vaiious treatment and prevention products/techniques, assess the impact/ efficiency/cost/outcome of interventions, p1ioritize intervention strategies, and provide fow1dation for public policy.

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Epidemiologic Terms and Concepts The natural history of a disease in a population, sometimes termed the disease's ecology, refers to tile cow"Se of the disease from its beginning to its final clinical endpoints. The natural history begins before , infection (prepathogenesis period) when the agent sinlply exists in the environment, includes tl1e factors that affect its incidence and distribution, and concludes with either its disappearance or persistence (endem­ nicity) in that environment. Although knowledge of the complete natural history is not absolutely necessary for treatment and control of disease in a population, it does facilitate the most effective interventions. An in1portant epidemiologic concept is that neither health nor disease occlli'S randomly iliroughout populations. Innumerable factors influence the temporal waxing and waning of disease. A disease is considered endemic when it is constantly present wiili.in a given geographic ai·ea. For instance, ani.n1al rabies is endemic in tl1e USA An epidemic occw'S when a disease occlli'S in larger nwnbers tl1an expected in a given population and geographic area. Raccoon rabies was epidemic throughout tile eastern USA for much of ilie 1980s and 1990s. A subset of an epidemic is an outbreak, when tile higher disease occurrence occurs in a smaller geographic area and shorter period of tinle. Finally, a pandemic occW'S when an epidemic becomes global in scope (eg, influenza, IIlV/AIDS). The population at risk is an extremely important concept in epidemiology anti includes members of the overall population who are capable of developing tile disease or condition being studied. This concept seems sinlple at first, but misinterpretations can lead to erroneous study results and conclusions. As a sinlple exainple, a study of testicular cancer among residents in a population should not include women in tl1e population at risk (frequently expressed as tile "denominator" in an epidemiologic ratio). A ratio is the value obtained from dividing one quantity by another (X/Y). The nwnera­ tor and denominator may be independent of each oilier. In fact, in epidemiology, the term ratio is applied when the nwnerator is not a subset of the denominator. For example, in a class of veterinary students in which 88 are female and 14 are male, the sex ratio of female students to male students is 88/14, or6.3 to 1. A proportion is a type of ratio in which the nwnerator is part of the denominator (N[A + Bl). Therefore, they are not independent. For example, suppose that, among domestic dogs testing positive for

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internal parasites in Glendale, Arizona, 889 were male and 643 were female. The propo1� tion of female dogs among those found to have parasite infections would be 643/(889 + 643), or 0.42. A rate is another type of ratio in which the denominator involves the passage of time. This is in1portant in epidemiology, because rates can be used to measure the speed of a disease event or to make epidemiologic comparisons between populations over tin1e. Rates are typically expressed as a measure of the frequency with which an event occurs in a defined population in a defined time (eg, the number of foodbome Salmonella infections per 100,000 people annually in the USA). Incidence is a measure of the new occurrence of a disease event (eg, illness or death) within a defined time period in a specified population. 1\vo essential components are the number of new cases and the period of time in which those new cases appear. In an exan1ple regarding the class of veterinary students, if 13 of them developed influenza over the course of 3 mo (one quarter), the incidence would be 13 cases per quarter. An incidence rate takes the population at risk into account. In the previous exam­ ple, the incidence rate would be 13 cases per quarter/102 students, or 0.127 cases per quarter per student. Incidence rates are usually expressed by a multiplier that makes the nun1ber easier to conceptualize and compare. In this example, the multiplier would be 100, and the incidence rate would be 12.7 cases per quarter per 100 students (or 12.7"/o). An attack rate is an incidence rate; however, the period of susceptibility is very short (usually confined to •a single outbreak). A similar concept to incidence is preva­ lence. Prevalence (synonymous with "point prevalence") is the total nun1ber of cases that exist at a particular point in time in a particular population at risk. Again using the influenza example from above, if 7 students had influenza at the same time during the academic quarter, the prevalence would be 7/102 or 0.069 cases per class (or 6.9%). Measures of disease burden typically describe illness and death outcomes as morbidity and mortality, respectively. Morbidity is the measure of illness in a population, and numbers and rates are calculated in a sinillar fashion as with incidence and prevalence. Mortality is the corresponding measure of death in a population and can be applied to death from general (nonspecific) causes or from a specific disease. In the latter case, cause-­ specific mortality is expressed as the case

fatality rate, which is the number of deaths due to a particular disease occurring among individuals afflicted with that disease in a given time period. In another example, consider a large veterinary practice in the southwest USA that frequently sees dogs with coccidioidomycosis. The practice diagnosed 542 clinical cases in a particular year, 83 of which died from the disease in the course of that year. The month in which the most cases were diagnosed was September, in which 97 cases were diagnosed. Further, at a single point in time (perhaps based on the results of a serosurvey of dogs in the practice area), 237 dogs of 6,821 dogs with active records in the practice had the disease. In this scenario, the prevalence of coccidioidomycosis at the time of the serosurvey would be 237/6,821 or 0.035 (3.5%); the incidence in September would be 97 cases, and the incidence rate would be 97/6,821 or 0.014 ( l.4%). Finally, tl1e annual mortality rate due to coccidioidomycosis would be 83/6,821 or 0.013 ( l .3%), and the case fatality rate would be 83/542 or 0.153 (or 15.3%). Public health surveillance is defined as the ongoing systematic collection, analysis, interpretation, and dissemination of outcome-specific data essential to the planning, implementation, and evaluation of public health practice. In epidemiology, health surveillance is accomplished in either passive or active systems. Passive surveil­ lance occurs when individual healtl1 care providers or diagnostic laboratories send pe1iodic reports to the public health agency. Because this reporting is voluntary (some­ times referred to as being "pushed" to health agencies), passive surveillance tends to underreport disease, especially in diseases witl1 low morbidity and mortality. Passive surveillance is useful for longtenn trend analysis (if reporting criteria remain consistent) and is much less expensive than active surveillance. An example of passive surveillance is the system of officially notifiable diseases routinely reported to CDC by select health departments across the USA. Active surveillance, in contrast, occurs when an epidemiologist or public health agency seeks specific data from individual health care providers or laboratories. In tl1is case, the data are "pulled" by the requestor, usually during emerging diseases or significant changes in disease incidence. Active surveillance is usually much more expensive and labor intensive; it typically is lin1ited to sh01t-tem1 analyses of high-in1pact events. An example is tl1e 1 y- r surveillance conducted by CDC of the rapid increase in incidence of coccidioidomycosis among people in Arizona in 2007-2008.

PUBLIC HEALTH PRIMER

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Descriptive Epidemiology

Given that neither health nor disease is equally distributed throughout a population, epidemiologists use various methods to study and desclibe their occurrence. In descnptive epidemiology, diseases are classified according to the valiables of person, place, and time. Person: Who is affected by this disease? This is relevant, because certain variables may highlight changes in disease status and can be used to focus additional studies and interventions. Common person variables include age, sex, race, socioeconomic status marital status, religion, smoker/ nons1�oker etc. In the case of animals, equivalent �ariables may include species, breed, reproductive status ( eg, intact vs neutered, pregnant vs nonpregnant), function (eg, meaUmilk/fiber production, race horse vs working horse vs pleasure horse, companion dog vs mili�y working dog), and wild/feral vs domesticated (cats). Place: Where does this disease occur? Place valiables commonly illustrate geo­ of a graphic differences in the occurrence _ particular disease. Focused studies can help epidemiologists to detennine why those differences have occurred and to identify specific lisk factors. Common place valiables include comparisons across national, state, and municipal boundalies and between urban and rural conununities. For animal populations, "place" may refer to housing (eg, indoors vs outdoors, pen nun1ber or stall) or type of herd management (eg, . intensive feedlot confinement vs extensive grazing). Place may also relate to lisk of exposure to infectious a.ilinlals at sale barns or during shipment or to external factors such as severe weather and natural disasters. Time: When and over what time period (hours, days, weeks, day vs night) does this disease occur? Tinle valiables are in1portant to describe when disease occurs in relation to va.iious factors of potential exposure and vulnerability. In aninlals, time may refer to milking shift, breeding season, la.inbing/ calving season, at weaning, during shipment, on anival at the feedlot, dry vs wet season, etc. Common time valiables include seculat' trends (changes over long periods of time), seasonal/cyclic periods, and specific pomts in time (eg, outbreaks, epidemics, clusters, etc). When a particular disease is observed relative to the variables of person, place, and time, it is often systematically described to facilitate more in-depth study. These systematic descriptions commonly take the form of case reports, case series, or cross-sectional studies.

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Case reports are accounts of single or a few noteworthy health-related incidents (eg, an epidemiologic description of a case of hun1an rabies). Case series are listings of a la.i·ger number of cases usually presented consecutively (eg, a characteiization of dog bite incidents in a population of veterinarians and/or technicians over time). Case series articles are useful for comparing variables of person, place, or tin1e as they appear to affect tl1e ocCUITence of a pa.iticulat' disease. Cross-sectional studies are one-time assessments of the incidence or prevalence of a disease in a defined population, which is usually selected at random from a larger population at risk (eg, a serosurvey of . veterinariatlS for the presence of antibodies to Bartonella henselae organisms to detem1ine risk factors and for cat scratch disease). Cross-sectional studies are especially useful in forming hypotheses _to be addressed by follow-on analytic studies. Two main types of bias in desc1iptive epidemiology at'e selection bias and obser­ vation bias. Selection bias results from the identification of subjects/cases from a subset that is not representative of the entire population at risk A nonmedical exa.i11ple of selection bias would occur in a voter survey, intended to predict tl1e outcome of a political election, but drawn from _a sa.inple of voters from either high-or low-income status neither of which would be represent­ ative �f the overall voting population. Observation bias arises from systematic differences in the method of obtaining infonnation from subjects/cases. Consider a study comparing library usage between students at two universities. Sigrii.ficant differences might result if students from one university were queried over the phone regarding libra.iy visits, whereas students at the other university were directly observed for actual usage. In general, bias in descriptive studies is not as prevalent or sigrii.ficant as bias in analytical studies. In sununa.iy, descriptive epidemiology _ serves to describe the occurrence of disease in a population. Descriptive methods are conunonly applied to little-known diseases; they use preexisting data, address the . questions of who/where/when, �d identify potential associations for more in-depth analytical studies.

Analytical Epidemiology

Analytical studies at'e applied to study the etiology of disease, to identify a causal relationship between exposures and health outcomes. They are typically used when

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insights of a particular health issue are available, commonly from previous descriptive studies. In evaluating the causality of disease associations, analytical studies address the question of "why" as opposed to the "person/place/time" of descriptive studies. Once potential associations have been observed between those who have a particular disease and those who do not, further investigations are undertaken to determine causality and identify effective interventions. The first step in an analytic study is to fom1 some conjecture regarding observed exposures and health outcomes. In analytical studies, this conjecture is tem1ed the null hypothesis, meaning that the default assumption is that there is no association between the exposure in question and the disease outcome. Note that this asswnption of no association is made even though the epidemiologist often thinks that some association actually exists. Once the null hypothesis is generated, studies are designed to test it and either reject it (by finding that some association actually does exist between exposure and disease outcome) or accept it (by finding that no association exists). Analytical epidemiology is accomplished tl1rough either observational studies or inte1ventional studies. In the former, the investigator does not control the exposw-e between the groups under study and typically cannot randomly assign subjects to study groups.

Observational Studies:

Ecologic Studies: The unit under study is a group of people or animals versus an individual. The group has no size limitation but must be able to be defined. For instance, the group could be a kennel of dogs, a class of veterimuy students, or the citizens of an entire country. Once defined, the group is analyzed against some exposure to see what outcome(s) ensue. Examples of ecologic studies include Dr. John Snow's analysis of the association between the incidence of cholera in London and where people obtained their drinking water, an analysis of how tobacco taxes affect tobacco usage, and an analysis of certain occupations for resultant hearing loss. Ecologic studies have several advantages over other types of observational studies. They are relatively quick, easy, and inex­ pensive. Individual data are not necessary, only aggregate data for the group(s) under study. Finally, tl1ey are useful in generating information about the overall context of health, especially how it is affected by

variables such as demographics, geography, and the social enviromnent. Ecologic studies also have several disadvantages. First, tl1e measw-ement of many exposw-es is in1precise, especially of large groups in which the influence(s) of tl10se exposw-es is difficult to define or not equally exe1ted. This phenomenon of unequal variable exertion results in another potential drawback to ecologic studies. Known as ecologic fallacy, it is described by "associa­ tions observed at the group level do not necessarily hold true at the individual level." As an example, one could determine that the average IQ of a class of veterinary students is above average (which, by definition, would be 100). lf a particular· student was randomly selected from that class, could it be infen-ed tl1at that student's IQ was above 100? The answer is no, because of the difference between average and median. If the class had only a few people above average, but these students were significantly above average, and the rest of the students were only slightly below average, tl1e distribution would be skewed towar·d a higher IQ when, in actuality, many members of tl1e class would be below average. Cohort Studies: In tl1is type of study, a group of individuals (tem1ed a cohort) is obse1ved over time for changes in health outcomes. When the period of the study is from the present into the future, the study is a prospective cohort study. In tlus case, the cohort is assw11ed to share a particular exposure and is followed over time to docun1ent the occurrence of new instances of a particular disease or outcome. Obviously, each member of the cohort must not have the disease or outcome at tl1e beginning of the study. One of the most famous medical prospective coho1t studies is the Franung­ hain Heart Study. Researchers began the study in 1948 by recruiting 5,209 men and women, 30-62 yr old, from the town of Franungharn, Massachusetts. Since that tin1e, they have accomplished extensive serial physical exar11inations and swveys relating to the development of cardiovascular disease. The major advantage of the prospective cohort study is that many different exposures can be considered and ar1alyzed for influencing tl1e outcome under study. Disadvantages include the high cost in terms of money and time dwing the period of the study and the inability to study very rare diseases or health outcomes unless the cohort is extremely large. When the period of the study is from the past to the present, the study is a retrospec­ tive cohort study. The methodology is very

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similar to that of the prospective cohort study, except that all the events (exposures and outcomes) have already occurred; the investigator is merely looking back rather than forward. Retrospective studies are conceived after some individuals have already developed the outcomes of interest. The investigators jwnp back in time to identify a cohort of individuals at a point in time before they developed the outcomes of interest, and try to establish their exposure status at that point in time. They then determine whether the subject subsequently developed the outcomes of interest. If so, they can analyze the exposure(s) that may have contributed to those outcomes. Retrospective cohort studies have several advantages over prospective cohort studies. They typically take less time and are less expensive. Additionally, they can address rare outcomes, because the cases are selected after having already developed the disease or outcome. Disadvantages include a potentially high possibility of selection bias, the fact that individuals may have difficulty recalling certain exposures (termed recall bias), and the requirement for the existence of medical and/or exposure records. Regardless of being retrospective or prospective, the measure of association of all cohort studies is the relative risk (RR). Relative risk is calculated by dividing the incidence rate of the disease or outcome in the exposed individuals by the incidence rate in the unexposed individuals. An RR of 1 means there is no difference in risk between the two groups. An RR 1 means the outcome is more likely to occur in the exposed group than in the unexposed group. Consider an example in which the incidence of prostate cancer among neutered male dogs was found to be 1.37%,

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and the incidence in intact male dogs was 0.36%. ln this case, the relative risk would be 1.37/0.36 or 3.8. This could be stated as "Neutered male dogs would be nearly four times as likely as intact male dogs to develop prostate cancer."

Case-Control Studies: ln this type of study, subjects are selected as either having a particular outcome (cases) or not having the outcome (controls). They are then compared in a retrospective way to identify differences in their exposures that might explain the differences in outcomes. Ideally, cases and controls should be as similar as possible in all characteristics except the outcome in order to make the compaiisons simpler and more meaningful. That is why some investigators "match" cases and controls. ln one notable example, a very large case-control study in 1950 studied people with lung cancer and demonstrated a very positive association between smoking and lung cancer. Although it did not prove causality alone, it "'-as instrun1en­ tal in the U.S. Surgeon General's now-stand­ ai-d warnings. Case-control studies have several advantages. They are inherently retro­ spective, so they are relatively quick and inexpensive. Because the cases have already been identified, they are appropriate for studying rare diseases and exan1ining multiple exposures. Disadvantages include the fact that, like cohort studies, they are prone to selection, recall, and observer bias. Additionally, their application is limited to the study of one outcome. The most conunon measurement of association in case-control studies is the odds ratio. The odds ratio (OR) represents the odds that an outcome will occm from a particular exposure, compared with the odds of the outcome occurring in tl1e absence of that exposure. ORs are calculated using a 2 x 2 frequency table (TABLE 1).

CALCULATING AN ODDS RATIO Outcome Status +

Exposure Status

+

a = Number of exposed cases b = Number of exposed non-cases c = Number of unexposed cases d = Number of unexposed non-cases

a

b

c

d

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ad OR= ale= b/d be An OR of 1 means the exposme did not affect the odds of the outcome. An OR > 1 means the exposure is associated with a higher odds of the outcome, and an OR 500A., and up to 25% for wound infections

Rare/absent to epidemic in different regions; one focus along USA Gulf Coast in shellfish

Ingestion

Mild to severe, voluminous diarrhea, vomiting, dehydration; severe cases fatal if untreated, but low mortality if treated

Worldwide

Ingestion; wound infection

Gastroente1itis, usually mild and self­ limited; wound infections; septicemia, usually in imrnunosuppressed or those with liver disease (case fatality rate for sepsis 47%---600A. or higher)

Agent probably worldwide; prevalence may vary between regions

Ingestion of contami­ nated water, food (includ­ ing meat [especially pork], vegetables); fecal-oral (animal contact); dog bite (rare)

Gastroenteritis (enterocolitis); pseudoappendicitis (with mesenteric lymphadeni.tis, tenninal ileitis, fever, abdominal pain); severe GI bleeding possible in some cases of colitis; pharyngitis; sequelae may include erythema nodosum, reactive arthritis; sepsis, especially in elderly or imrnuno­ compromised

Worldwide; Ingestion prevalence of human disease may vary between regions ( commonly reported in Europe)

Gastroenteritis with watery diarrhea especially in young children, bloody feces uncommon; pseudoappendici­ tis; sequelae may include erythema nodosum, reactive arthritis; sepsis, other syndromes

RlCKETTSIAL DISEASES Southeastern and south central USA; has been detected in South America

Ticks, including Amblyomma ameri­ canu1n

Few cases described; fever, headache, malaise, myalgia, nausea, vomiting; many patients were irnrnunosuppressed

N01th America; also reported in South America, Asia, and Africa

Ticks, including Amblyomma ameri­ caniim

Asyn1ptomatic to nonspecific febrile illness; rash in many pediatric cases, some adults; may progress to prolonged fever, renal failure, respiratory distress, hemorrhages, cardiomyopathy, neurologic signs, multiorgan failure; more severe in immunosuppressed, elderly; estimated case fatality rate 2o/o--3% (continued)

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ZOONOSES

•ttH•i•

GLOBAL ZOONOSES• (continued)

Disease

Causative Organism

Animals Involved

RICKETISIAL DISEASES {continued) Human granulocytic anaplasmosis (formerly human granulocytic ehrlichiosis)

Anaplasma, phagocy­ tophilum (formerly Ehrlichia phagocytophi­ lum and E equi)

Wild rodents, deer may be reservoirs in North America; livestock, wild ungulates, wild rodents may be reservoirs in Europe; many other animals (eg, equids, ruminants, dogs, cats, birds) can also be infected

Infection by other

E canis, E muris-like

Dogs and other canids thought to be reservoirs for E canis, might also occur in felids; rodents may be reservoirs for E muris

Q fever (Query fever,

Coxiella burnetii

Sheep, cattle, goats, cats, dogs, rodents, other mammals, birds, ticks

Sennetsu fever

Ne01ickettsia sennetsu

Uncertain, possibly fish

-African tick bite fever

R afticae

Ungulates

-Mediterranean spotted fever; Boutonneuse fever; Tick bite fever;

R conorii subsp conorii

Dogs, rabbits implicated as reservoirs; other animals can be infected

-Israeli spotted fever, Astrakhan spotted fever, Indian tick typhus

R conorii subsp israelensis (Israeli spotted fever), R conorii subsp caspia (Astrakhan spotted fever), R conoiii subsp indica (Indian tick

Reservoir hosts uncertain

Ehrlichia species

seep 623)

organism implicated rarely in human illness

Spotted fever group of Rickettsia

typhus)

-Fleabome spotted Rfelis (synonym fever; Cat flea typhus ELB agent)

Unknown; dogs have been suggested as possible amplifying hosts

ZOONOSES

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•§:iii• GLOBAL ZOONOSES• Known Distribution

2435

(continued)

Probable Means of Spread to People

Clinical Manifestations in People

RICKETTSIAL DISEASES (continued) Worldwide

Tick bites (Jxodes spp)

E canis worldwide; E muris Eastern Europe to Asia; E muris-like organism in North Ame,ica

Ticks (E canis transmitted Rare cases of febrile illness, in both by Rhipicephalus sangui­ healthy and immunosuppressed neus, E muris by Haerna­ physalis.fwva and lX'Odes persu/.catus complex)

Worldwide

Mainly airborne; exposure to placenta, birth tissues, anin1al excreta; occasion­ ally ingestion (including unpasteurized milk); tickborne infections probably rare or nonexistent in people

Febrile influenza-like illness; atypical pneumonia, hepatitis, endocarditis in some; possible pregnancy complica­ tions; overall case fatality rate 1o/o-2% if untreated

Japan, Malaysia, Laos, possibly other Asian count1ies

Thought to be ingestion of raw fish

Relatively mild, nonspecific, febrile illness, resembles infectious mononucleosis

Sub-Saharan Africa, eastern Caribbean

Bite of infected tick (mainly Amblyomma hebraeum, A variega­ tum, also A lepidum, possibly Rhipicephalus decoloratus, Rhipicepha­ lus appendiculatus)

Nonspecific febrile illness; painful regional lymphadenopathy in many; eschars often multiple; nuchal myalgia; sometimes sparse maCttlo­ papular and/or vesicular rash; deaths do not seem to occur

Europe, especially Mediterranean; cases reported in sub-Saharan Afiica

Bite of infected ticks (mainly Rhipicephalus sanguineus, also others), crushing tick

Nonspecific febrile illness; eschar (typically single) may or may not be present; rash, often maculopapular, in most; life-threatening dissemi­ nated disease or neurologic signs possible but uncommon; case fatality rate 1o/o-3% if untreated

Resembles human monocytic ehrlichiosis; often asymptomatic to mild in immunocompetent; rash uncommon; estimated case fatality rate MIC (T is the time for which plasma concentration exceeds MIC, expressed as a percentage of the dosage interval); and for fluoroquinolones, which act by concentra­ tion-dependent killing mechan.isms, AUC/ MIC ratio (AUC is the area under the plasma drug concentration-tin1e cwve) is selected. The objective of PK/PD modeling is to define the three key pharmacodynamic

2507

properties that define any drug, namely Emax or Imax (efficacy); ECw (or ECM or EC00) (potency); and slope (n) in the Hill equation, which indicates sensitivity and selectivity. PK/PD modeling permits breakpoint values to achieve a bacteriostatic or bactericidal effect, or bacterial eradication to be computed, which are used to optimize efficacy and mini.Jnize resistance. Time-effect Relationships: The ability

of cl.rugs to reach the receptor is detennined by pharmacokinetic parameters that characterize the absorption, distribution, and clearance of a drug. There may not be a simple temporal correlation between plasma concentration of a drug and its therapeutic effect. Plotting plasma concentrations (x-axis) versus therapeutic effect (y-axis) in chronologic order displays the data as a loop for some drugs. This phenomenon is referred to as hysteresis in the concentration-effect relationship. The effect of most drugs lag behind the plasma concentration. This results in a counter­ clockwise hysteresis loop. For example, the NSAID robenicoxib has prolonged local effects after blood concentrations have decreased below effective levels. A clockwise hysteresis loop is obse1vecl for cocaine and pseucloephedrine when tachyphylaxis develops (see below). The temporal correlation between plasma concentration and therapeutic effect also varies for the different classes of antago­ nists. For instance, the extent and duration of action of a competitive antagonist depends on its concentration in plasma; which depends (in part) on its rate of elimination. This requires that the close be adjusted accordingly to maintain plasma concentrations in the therapeutic range. By contrast, the duration of action of an irreversible antagonist is relatively independent of its rate of elin1.ination and, therefore, plasma concentration, and more dependent on the rate of turnover of receptor molecules. Down-regulation and Up-regulation of Receptors: The density of most

receptors is not constant with time, which has important therapeutic implications. Down-regulation of receptors may occur as a result of continual stin1ulation by an agonist and manifests as tl1e development of tachyphylaxis, which demonstrates a clockwise hysteresis loop in the concentra­ tion-effect relationship. Conversely, additional receptors can be synthesized in response to chronic receptor antagonism­ a phenomenon known as up-regulation.

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PHARMACOLOGY INTRODUCTION

Because more receptors are now available, a hyperreactive response occurs when the cell is exposed to an agonist.

ROUTES OF ADMINISTRATION AND DOSAGE FORMS A diverse range of dosage fonns and delivery systems has been developed to provide for the care and welfare of animals. The development of dosage forms draws on the discipline of biopharrnaceutics, which integrates an understanding of fonnula­ tions, dissolution, stability, and controlled release (pharmaceutics); absorption, distribution, metabolism, and excretion (pha.rmacokinetics, PK); concentration­ effect relationships and drug-receptor interactions (pha.rmacodynamics, PD); and treatment of the disease state (therapeu­ tics). Formulation of a dosage fonn typically involves combining an active ingredient and one or more excipients; the resultant dosage form detem1ines the route of administration and the clinical efficacy and safety of the drug. Optimization of drug doses is also critical to achieving clinical efficacy and safety. Increasingly, a PK/PD mod.el that describes U1e drug response is U1e basis of dose optimization. The PK and PD phases a.re linked by the premise that free drug in the systemic circulation is in equilibrium with the receptors. The PD phase generally involves interaction of the drug with a receptor, which triggers post-receptor events and eventually leads to a drug effect (see p 2503). Drug delive1y strategies for veterinary formulations are complicated. by the diversity of species and breeds treated, the wide range in body sizes, different husbandry practices, seasonal vruiations, cost constraints associated. with the value of the anin1al being treated, the persistence of residues in food and fiber (seep 2518), and the level of convenience, among other factors. Innovative solutions have been developed to meet many of these challenges (eg, the convenient dosing option offered by topical spot-on formulations to treat external and internal pru·asites on clogs and cats, the rnicroencapsulation of NSAIDs as a way to mask taste when these agents ru·e acid.eel to the rations of horses). The ru1atomy of the GI tract of rwninru1ts presents unique opporl1.1nities for con­ trolled-release drug clelive1y systems, and many such systems a.re on the mru·ket. For exrunple, controlled-release boluses have been developed. to deliver antimicrobials, ru1thelmintics, production enhancers, nut1itional supplements, and other drugs.

Oral Route of Administration and Dosage Forms The oral route of ad.ministration is fre­ quently used in botl1 companion at1cl food animals. In clogs ru1cl cats, tablets, capsules, solutions, and suspensions ru·e administered orally; pastes ru·e also applied to the forelimbs of cats from which they a.re licked at1cl ingested. In horses, solutions and suspensions ru·e administered by nasogas­ tric tubes, pastes ru·e applied to the tongue, and granules a.re added to rations for ingestion. The oral route of ad.ministration is the most widely used in cattle, pigs, and poultry. Forn1ulations range from premixes ru1cl drinking water additives to licks, pastes, drenches, tablets, capsules, and boluses. Oral dosage fonns a.re usually intended for systemic effects resulting from drug absorption from the GI tract; however, some oral suspensions, eg, kaolin, ru·e intended to produce local effects, at1d. these ru·e not absorbed.. Disadvantages of the oral route of administration include the relatively slow onset of action, the possibilities of irregular absorption, the destruction of acid-labile drugs in the stomach, and tile wisuitability of this route for many high-moleculru·­ weight drugs. Oral dosage forms require careful phatrnaceutical forn1ulation. Oral dosage fom1s comprise liquids (solutions, suspensions, emulsions, elixirs, and syrups), semisolids (pastes), and solids (tablets, capsules, powders, granules, premixes, at1d medicated blocks). These dosage forms together with exrunples of modified-release delivery systems for ruminants ru·e discussed below. A solution is a. mixture of two or more components tllat form a single phase that is homogeneous down to tile molecular level. Solutions offer several advantages over oilier dosage fonns. Compared with solid dosage fom1s, solutions are absorbed faster and generally cause less irritation of the GI mucosa. Moreover, phase sepru·ation on storage is not a concern with solutions, as it may be for suspensions ru1d. emulsions. The disaclvru1tages of solutions include susceptibility to microbial contamination at1d tile hydrolysis in aqueous solution of susceptible active ingredients. In addition, the taste of some drugs is more unpleasant when in solution. A range of additives is used in the formulation of oral solutions, including buffers, flavors, antioxidants, and preservatives. Oral solutions provide a convenient meat1s of dn1g administration to neonates at1d young animals. A suspension is a coarse dispersion of insoluble drug patticles, generally with a

VetBooks.ir

PHARMACOLOGY INTRODUCTION

diameter>1 µrn, in a liquid (usually aqueous) medium. Suspensions are usefi.Ll to administer insoluble or poorly soluble drugs or when the presence of a finely divided form of the material in the GI tract is required. An example of the latter is the treatment of"frothy bloat" with dimethyl polysiloxanes, which relies on a dispersion of finely divided silica in the forestomach of rnminants. The taste of most drugs is less noticeable in suspension than in solution, because the drug is less soluble in suspen­ sion. Particle size is an important detenni­ nant of the dissolution rate and bioavailabil­ ity of drugs in suspension. In addition to the excipients described above for solutions, suspensions include swfactants and thic­ kening agents. Surfactants wet the solid paiticles, thereby enswing the pai1:icles disperse readily throughout the liquid. Thickening agents reduce the rate at which particles settle to the bottom of the container. Some settling is acceptable, provided the sediment can be readily dispersed when the container is shaken. Redispersion of the suspension may not be achievable if the sediment has packed closely to fom1 a hard mass, a process !mown as"caking." An emulsion is a system consisting of two immiscible liquid phases, one of which is dispersed throughout the other in the forn1 of fme droplets; droplet diaineter generally ranges from 0.1-100 µm. The two phases of an emulsion are !mown as the dispersed phase and the continuous phase. Emulsions ai·e inherently unstable ai1d are stabilized through the use of an emulsifying agent, which prevents coalescence of tl1e dispersed droplets. Creaining, as occurs with milk, also occw-s with phamiaceutical emulsions. However, it is not a serious problem because a unifo1m dispersion returns upon shaking. Creanling is, nonetheless, w1desirable because it is associated with an increased likelihood of the droplets coalescing and the emulsion "breaking." Other additives include buffers, antioxidants, and prese1vatives. Emulsions for oral administration are usually oil (the active ingredient) in water, ai1d they facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form. An elixir is a sweetened, usually hydroalcoholic solution of a bitter or nauseous drug intended for oral administra­ tion. The hydroalcoholic character of elixirs allows, within lim.its, both water�soluble and alcohol-soluble medicinal substances to be mainta.ined in solution. The proportion of alcohol in elixirs vai·ies widely, a characte,�

2509

istic used to advantage to solubilize medicinal agents. If the active ingredient is sensitive to moistw-e, it may be formulated as a flavored powder or granulation and reconstituted in water immediately before oral administration. Noru11edicated elixirs ai·e used as the vehicles for phai·maceutical formulations. A syrup is a concentrated aqueous solution of sugai· or a sugai· substitute with or without flavoring agents and a water­ soluble drug. Sucrose is the most frequently used sugar, and syrnps usually contain 600/o--800/c,. Syrups may also conta.in cosol­ vents, solubilizing agents, thickeners, or stabilizers. Norunedicated syrups are used as vehicles for water-soluble drugs. A paste is a two-component semisolid in which drug is dispersed as a powder in an aqueous or fatty base. The paii;icle size of the active ingredient in pastes can be as Jai·ge as 100 µrn. The vehicle containing tl1e drug may be water; a polyhydroxy liquid such as glycerin, propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral oil. Other fomrnlation excipients include thickening agents, cosolvents, adsorbents, htunectants, and preservatives. The thickening agent may be a naturally occwTing material such as acacia or tragacanth, or a synthetic or chemically modified derivative such as xanthum gum or hydroxypropylmetl1yl cellulose. The degree of cohesiveness, plasticity, ai1d syTingeability of pastes is attributed to U1e thickening agent. It may be necessary to include a cosolvent to increase the solubility of the drug. Syneresis of pastes is a fom1 of instability in which the solid ai1d liquid components of the formulation separate over time; it is prevented by including an adsorbent such as microcrys­ talline cellulose. A hW11ecta.nt ( eg, glycerin or propylene glycol) is used to prevent the paste that collects at the nozzle of the dispenser from forn1ing a hard crust. Microbial growtl1 in the formulation is inhibited using a preservative. It is critical that pastes have a pleasant taste or ai·e tasteless and ai·e able to be used throughout a wide temperature rai1ge. Pastes are a popular dosage form to treat cats and horses and can be easily and safely administered by owners. A tablet consists of one or more active ingredients and nun1erous excipients and may be a conventional tablet that is swallowed whole, a chewable tablet, or a modified-release tablet (these ai·e com­ monly refe1Ted to as modified-release boluses when the unit size is large). Conventional and chewable tablets are

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PHARMACOLOGY INTRODUCTION

used to administer drugs to dogs and cats, whereas modified-release boluses are administered to cattle, sheep, and goats. The physical and chemical stability of tablets is generally better than that of liquid dosage forms. The main disadvantages of tablets are a relatively slow onset of action because of the need to pass into the intestine and then undergo disintegration and dissolution before absorption across the gut wall, the low bioavailability of poorly water-soluble drugs or poorly absorbed drugs, and the local irritation of the GI mucosa that some drugs may cause. A capsule is an oral dosage form usually made from gelatin and filled with an active ingredient and excipients. Two conunon capsule types are available: hard gelatin capsules for solid-fill fonnulations, and soft gelatin capsules for liquid-fill or semisolid­ fill fonnulations. Soft gelatin capsules are suitable to forn1ulate poorly water-soluble drugs because they afford good drug release and absorption by the GI tract. Gelatin capsules are frequently more expensive than tablets but have some advantages. For example, paiticle size is rai·ely altered during capsule manufacture, and capsules mask the taste ai1d odor of the active ingredient and protect photolabile ingredients. A powder is a formulation in which a d.rng powder is mixed with other powdered excipients to produce a final product for oral administration. Powders have better chemical stability than liquids and dissolve faster than tablets or capsules because disintegration is not an issue. This translates into faster absorption for those drugs characterized by dissolution rate-limited absorption. Unpleasai1t tastes can be more pronounced with powders than With other dosage forms and can be a paiticular concern with in-feed powders, leading to variable ingestion of the desired dose. Moreover, sick ani.nlals often eat less and ai·e therefore not ainenable to treatment with in-feed powder formulations. Drug powders ai·e principally used prophylacti­ cally in feed or formulated as a soluble powder for addition to drinking water or milk replacer. Powders have also been formulated with emulsifying agents to facilitate their administration as liquid drenches. A granule is a dosage forn1 consisting of powder paiticles that have been aggregated to form a lai·ger mass, usually 2-4 mm in diaineter. Grai1ulation overcomes segrega­ tion of the different particle sizes during storage and/or dose administration, the latter being a potential source of inaccurate

dosing. Granules and powders generally behave sinlilarly; however, granules must deaggregate before dissolution and absorption. A premix is a solid dosage form in which an active ingredient, such as a coccidiostat, production enhai1cer, or nutritional supplement, is fonnulated with excipients. Premix products are mixed homogeneously with feed at rates (when expressed on an active ingredient basis) that range from a few milligrains to -200 g/ton of feed. They are administered to poultry, pigs, and ruminants. The density, paiticle size, and geometry of the premix paiticles should match as closely as possible those of the feed in which the premix will be incorpo­ rated to facilitate u.niforn1 mixing. Issues such as instability, electrostatic charge, and hygroscopicity must also be addressed. The excipients present in premix fonnulations include caniers, liquid binders, diluents, anticaking agents, and antidust agents. Caniers, such as wheat middlings, soybean mill run, and rice hulls, bind active ingredients to their swfaces and are in1po1tant in attaining uniform mixing of the active ingredient. A liquid binding agent, such as a vegetable oil, should be included in the formulation whenever a caiTier is used. Diluents increase the bulk of premix formulations, but unlike caniers, they do not bind the active ingredients. Exan1ples of diluents include ground limestone, dicalciwn phosphate, dextrose, and kaolin. Caking in a premix fonnulation may be caused by hygroscopic ingredients and is addressed by adding small an1ounts of anti­ caking agents such as calciwn silicate, silicon dioxide, and hydrophobic starch. The dust associated with powdered premix formulations can have serious implications for both operator safety and economic losses and is reduced by including a vegetable oil or light mineral oil in the forn1ulation. An alternative approach to overcoming dust is to granulate the premix fonnulation. A medicated block is a compressed feed material that contains an active ingredient, such as a dr11g, anthelmintic, swfactant (for bloat prevention), or a nutritional supple­ ment, and is commonly packaged in a cardboard box to feed to livestock. Ruminants typically have free access to the medicated block over several days, ai1d vai"iable conswnption may be problematic. This concern is addressed by ensuring the active ingredient is nontoxic, stable, palatable, and preferably of low solubility. In addition, excipients in the fonnulation modulate conswnption by altering the

VetBooks.ir

PHARMACOLOGY INTRODUCTION

palatability and/or the hardness of the medicated block. For example, molasses increases palatability, and sodium chloride decreases it. Additionally, the incorporation of a binder such as lignin sulfonate in blocks manufactured by compression, or magnesium oxide in blocks manufactured by chemical reaction, increases hardness. The hygroscopic nature of molasses in a fonnulation may also impact the hardness of medicated blocks and is addressed by using appropriate packaging.

Oral Modified-release Delivery Systems for Ruminants Several modified-release delivery systems have been developed that take advantage of the unique anatomy of the ruminant forestomach. Prominent among these systems are intraruminal boluses, which contain a range of active ingredients including parasiticides, nutritional supplements, antibloat agents, and production enhancers. They a.re adminis­ tered using a balling gun. Most of the commercially available intraruminal boluses are continuous-release devices that rely on erosion, diffusion from a reservoir, dissolution of a dispersed matrix, or an osmotic "driver" to release the active ingredient. The pay-out period for intraruminal boluses is commonly> 100 days. Regurgitation during rumination is prevented by the bolus having a density of -3 g/cm3 or a variable geometry. Other types of oral modified-release delivery systems are also available for ruminants. For example, sustained-release boluses that deliver sulfonamides through­ out a period of -72 hr are available to treat cattle. In addition, sustained-release boluses containing methoprene or diflubenzuron are approved for the control of manure­ breeding flies in cattle. The intraruminal devices to supplement ruminants with selenium, cobalt, or copper include soluble glass boluses and intraru­ minal pellets. Boluses of soluble glass containing selenium, cobalt, and copper are available for cattle and sheep. Because glass is susceptible to sudden changes in temperature, glass boluses should be at least 15 °-20 °C at the time of administration to avoid fracturing, which in turn may lead to regurgitation. Glass boluses are designed to dissolve in ruminal fluids, thereby releasing the incorporated elements. The composition of the glass detennines the solubility of the bolus, with an increase in the ratio of monovalent to divalent cations resulting in an increase in solubility. The

2511

glass boluses are retained in the rumen for up to9mo. Intraruminal pellets containing seleniwn or cobalt are available for sheep. Selenium or cobalt is released throughout a period of -3 yr from the pellet matrix, which consists of compressed iron grit. When selenium or cobalt intrarwninal pellets are administered alone, a "grinder" is usually coadministered to prevent the formation of calciw11 phosphate coatings on the surface of the pellets. Copper capsules, which contain oxidized copper wire particles encapsulated in gelatin, are available for adult sheep and goats. After oral administration, the gelatin capsule dissolves in the rW11en and releases the particles of copper oxide. The particles progress to the abomasrn11, where some are trapped in the mucosa! folds and release copper.

Parenteral Route of Administration and Dosage Forms A drug given parenterally is one given by a route other than the mouth (topical dosage forms are considered separately). The three main parenteral routes of drug administra­ tion are IV, IM, and SC, and in all cases administration is usually via a hollow needle. Injectable preparations are usually sterile solutions or suspensions of drug in water or other suitable physiologically acceptable vehicles. Volwnes delivered can range from milliliter to liter quantities. The time of onset of action for IV administration is seconds, and for IM and SC injections is minutes. Depot injectable preparations achieve prolonged release and maintain therapeutic concentrations of drug throughout 2-5 days. The bioava.ilability of a drng, particularly from prolonged-release fommlations, can be influenced by the location of the IM injection site. SC implants and pellets also achieve prolonged release of drug. A number of recombinant proteins and peptides are orally inactive and must be given by the parenteral route. Specialized dosage fom1s, usually for parenteral administration, are required for vaccines. In food animals, intramarnmary infusions and intravaginal devices a.re adnlinistered by the parenteral route. Parenteral dosage fonns and delivery systems include irtjectables (ie, solutions, suspensions, emulsions, and dry powders for reconstitution), intraman1mary infusions, intravaginal delivery systems, and implants. These dosage forms and delivery systems as well as the special considera­ tions relating to intra-articular injections,

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PHARMACOLOGY INTRODUCTION

recombinant proteins and peptides, and vaccines are discussed below. A solution for injection is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. "Water for injection" is the most widely used solvent for parenteral formulations. However, a nonaqueous solvent or a mixed aqueous/nonaqueous solvent system may be necessaiy to stabilize drugs that are readily hydrolyzed by water or to improve solubility. A range of excipients may be included in parenteral solutions, including antioxidai1ts, antimicro­ bial agents, buffers, chelating agents, inert gases, and substances to adjust tonicity. Antioxidants maintain product stability by being preferentially oxidized over the shelf life of the product. Anti.microbial preserva­ tives inhibit the growth of any microbes accidentally introduced when doses are being withdrawn from multiple-dose bottles, and they act as adjw1cts in aseptic processing of products. Buffers ai·e necessai-y to maintain both solubility of the active ingredient and stability of the product. Chelating agents are added to complex and thereby inactivate metals, including copper, iron, ai1d zinc, which generally catalyze oxidative degradation of drugs. Inert gases are used to displace the air in solutions and enhance product integrity of oxygen-sensitive drugs. Isotonicity of the formulation is achieved by including a tonicity -adjusting agent. Failing to adjust the tonicity of the solution can result in the hemolysis or crenation of erythrocytes when hypotonic or hypertonic solutions, respectively, ai·e given IV in quantities> 100 mL. Injectable formulations must be sterile and free of pyrogens. Pyrogenic substances are prin1artly lipid polysaccharides derived from microorgan­ isms, with those produced by gran1-negative bacilli generally being most potent. Injectable solutions are very commonly used, and aqueous solutions given IM result in immediate drug absorption, provided precipitation at the injection site does not occur. A suspension for injection consists of insoluble solid paiticles dispersed in a liquid medium, with the solid particles accoW1ti.ng for 0. 5o/o-30% of the suspension. The vehicle may be aqueous, oil, or both. Caking of injectable suspensions is minimized through the production of flocculated systems, comprising clusters of paiticles (floes) held together in a loose, open strncture. Excipients in injectable suspensions include antimicrobial preservatives, surfactants, dispersing or

suspending agents, and buffers. Surfactants wet the suspended powders and provide acceptable syringeability while suspending agents modify the viscosity of the formula­ tion. The ease of injection and the availabil­ ity of the drug in depot therapy are affected by the viscosity of the suspension and the paiticle size of the suspended drug. These systems afford enhanced stability to active ingredients that are prone to hydrolysis in aqueous solutions. Injectable suspensions are commonly used. Compared with that of injectable solutions, the rate of rlrug absorption of injectable suspensions is prolonged, because additional time is required for disintegration and dissolution of the suspended drug particles. The slower release of drug from an oily suspension compared with that of an aqueous suspension is attributed to the additional time taken by drug paiticles suspended in an oil depot to reach the oil/water boW1dai-y and become wetted before dissolving in tissue fluids. An emulsion for injection is a heteroge­ neous dispersion of one immiscible liquid in another; it relies on an emulsifying agent for stability. Parenteral emulsions ai·e rare, because it is seldom necessary to achieve an emulsion for drug administration. Untowai·d physiologic effects after IV administration may occur, including emboli in blood vessels if the droplets are> 1 µm in dian1eter. Formulation options for injectable emulsions ai·e also severely restricted, because suitable stabilizers and emulsifiers are very limited. Exan1ples of parenteral emulsions include oil-in-water, sustained­ release depot preparations (given IM), and water-in-oil emulsions of allergenic extracts (given SC). A dry powder for parenteral administra­ tion is reconstituted as a solution or as a suspension inunediately before injection. The principal advantage of this dosage form is that it overcomes the problem of instability in solution. Proteins and other materials that are extremely heat sensitive caimot be dried in phai,naceutical driers. Rather, freeze-drying, or lyophilization, is used to produce a porous powder that reconstitutes readily. Intramammary infusion products to treat mastitis are available for lactating and nonlactating (dry) cows. Lactating cow intrainainma1-y infusions should demon­ strate fast and even distribution of the drug and a low degree of binding to udder tissue. These properties result in lower concentra­ tions of drug residues in the milk In contrast, it is desirable for nonlactating cow fonnulations to demonstrate prolonged

VetBooks.ir

PHARMACOLOGY INTRODUCTION

drug release and a high degree of binding to mammary secretions and udder tissues. Particle size is particularly important, because it affects both the rate of release of the active ingredient and irritancy to the udder tissue. Drug paiticle size in nonlactat­ ing intrainammary fom1Ulations is usually smaller than in those for lactating cows, which is critical to reduce iITitancy during prolonged retention in the udder. Thicken­ ing agents are added to modify the rate of release of the suspended particles from oil fonnulations, and antioxidants ai·e commonly incorporated to prevent rancidity. Mastitis infusion products are often tenninally ste1ilized by irradiation. Intravaginal delivery systems include controlled il1temal drug-release (CIDR) devices, progesterone-releasing intravaginal devices (PRIDs), and vaginal sponges. These systems ai·e used for estrus synchro­ nization in sheep, goats, and cattle. Silicone is used in the manufacture of the T-shaped CIDR device and the coil-shaped PRID, whereas intravaginal sponges are made from polyurethane. The active ingredients in these systems are synthetic or natural hormones such as progesterone, metl1ylace­ toxy progesterone, fluorogestone acetate, or estradiol benzoate. An applicator consisting of a speculum and a separate plunger is used to insert sponges into the vaginal cavities of sheep and goats, and PRIDs into the vaginal cavities of cattle. A different type of applicator is used to insert CIDR devices into the vaginal cavities of sheep, goats, and cattle. Retention in the vagina depends on either tl1e wings (CIDR device) or the entire device (sponges and PRIDs) expanding. With all three devices, gentle pressure is exerted on the vaginal wall. Retention of the device is >95%. Most implants used in veterinaiy medicine are compressed tablets or dispersed matrix systems in which the drug is uniformly dispersed within a nondegrada­ ble polymer. Drug release from dispersed matrix systems involves dissolution of the drug il1to tl1e polymer, followed by diffusion of t11e drug tl1rough the polyn1er and partitioning from the surface of the polymer into tl1e surrounding aqueous environment. Implants are available to il1crease weight gain ai1d feed conversion efficiency in food anilnals. These implants are typically prepared in a maimer similai· to tablets. One controlled-release ilnplant consists of a cylindrical core of silicone, surrounded by an outer layer of estradiol-loaded silicone. A range of implants is available to enhance reproductive performance in breeding attimals. These include ear implants

2513

containing norgestomet dispersed in polyethylene methacrylate or silicone, a biocompatible tablet implant containing deslorelin (a GnRH agonist) for use in mai·es that does not require removal, and a sustained-release pellet of melatonin, which is implanted in the ear of ewes to enhance breeding performance. Testosterone pellets are available to implant il1 the ears of wethers at doses of 70-100 mg eve1-y 3 mo for the prevention of ulcerative posthitis. Special Dosage Form Considerations with Intra-articular Injections: The

dosage forms used in intra-articular administration are sterile aqueous solutions. In horses, the two most common reasons for intra-articulai· injections ai·e to anesthetize or "block" a joint during a lameness examination and to treat noninfectious inflan1matory joint diseases such as synovitis and capsulitis. Drugs, including glucocorticoids, pentosan polysulfate sodium, and hyaluronic acid, are administered intra-articularly in inflanm1a­ tory joint disease. The intra-aiticular administration of glucocorticoids avoids the adverse effects associated with large systemic doses. In dogs, hyaluronate sodium is administered by intra-articular injection for adjunctive treatment of synovitis. Special Dosage Form Considerations with Recombinant Proteins and Peptides: Recombinant proteins and

peptides are used in some countries to increase feed conversion efficiency and milk production in cattle (bovine growth hormone), increase feed conversion efficiency and produce leaner carcasses in pigs (porcine growth hormone), for the chemical shearing of sheep (epidennal growth factor), to reduce the incidence of skeletal weaknesses leading to leg injruies in horses (equine growth hormone), and for other uses. Recombinant proteins and peptides have been fom1Ulated as solutions, lyophilized powders, implants, and microparticles. The chemical and physical instability of recombinant proteins and peptides is a special consideration during formulation development. The major causes of chemical il1stability are proteolysis, deamidation, oxidation, and racemization. Causes of physical instability are aggrega­ tion, precipitation, denaturation, and adsorption to surfaces. A range of strategies has been reported to stabilize formulations containing recombinant proteins and peptides, including the choice of carrier vehicle (eg, oleaginous vehicles), the use

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of lyophilization excipients, the use of stabilizers such as sugars and detergents, chemical modification of the proteins and peptides, and the use of site-directed mutagenesis to synthesize more stable proteins. Special Dosage Form Considerations with Live Vaccines, Inactivated and Subunit Vaccines, and DNA Vaccines:

The organisms in live vaccines are subjected to freeze drying and, less commonly, to deep freezing at or below -70°C. To maintain the viability of organisms under these conditions, formulations include complex mixtures of proteins, peptides or amino acids, sugars, and mineral salts. The viability of organisms is additionally protected using stabilizers such as lactose or other saccharides, skim milk, and senun. Formulations used for inactivated and subunit vaccines consist of antigen(s), adjuvants, stabilizers, and preservatives (in the case of multiple-dose products). Inactivating agents such as phenol, thiomersal, and formaldehyde are used to kill the virus or bacteria without destroy­ ing the critical integrity of the antigens necessary to induce a protective immune response. Adjuvants enhance the immunogenicity of antigens by stimulat­ ing the immune system and prolonging antigen release. In this respect, aluminum hydroxide, aluminum phosphate, and oil emulsions are generally preferred to confer antibody-mediated immunity, whereas saponin, qui! A, and immunity­ stimulating complexes are preferred to confer cell-mediated immunity. Plasmid DNA vectors have been used to express antigens in vivo to generate inunune responses. Two delivery S:','Stems for DNA vaccines have been reported. In one system, the segment of DNA is coated with gold and administered to the patient using a "gene gun." The other delivery system uses a viral vector or plasmid to carry the DNA segment into the patient. Topical Route of Administration and Dosage Forms

The topical route of administration is used for local treatment of skin, control of external and internal parasites, and transdern1al delivery of therapeutic agents. Drugs applied to the skin for local effect include antiseptics, antifungals, anti-inflan1matory agents, and skin emollients. The rate of d1ug release from ointments, creams, and pastes is principally detennined by the semisolid base used. In dogs and cats, an

extensive range of topical formulations is used in the control of fleas, lice, mites, and ticks. These include insecticidal and acaracidal soaps, foams, shampoos, sprays, and rinses. Also available are topical delivery systems such as spot-on formula­ tions and flea and tick collars and medal­ lions. In food anin1als, a diverse range of topical dosage forn1s and delivery systems are used to control external parasites. For example, most pow"on formulations, plunge and shower dip concentrates, and jetting fluids are suspension concentrates or emulsifiable concentrates. In addition, many pour-on formulations display endecto­ cidal activity in cattle. The efficacious systemic concentrations attained with these preparations result from the animal's licking behavior and, to a lesser extent, percutane­ ous absorption of the active ingredient. Nun1erous methods are used to apply parasiticides to farm animals (see below). A special consideration relating to the use of topical dosage fo1ms is the potential for residues in wool and mohair to occur. The topical route of administration is also used to deliver therapeutic agents systemically. Transdennal patches, for instance, are used to deliver analgesics to the systemic circulation. The topical dosage forms available to treat animals include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures). These dosage forms as well as the specialized topical dosage fo1ms and delivery systems for transdern1al drug delivery and parasite control are discussed below. A dusting powder is a finely divided insoluble powder containing ingredients such as talc, zinc oxide, or starch. Coarse powders often have a gritty feel, whereas powders containing paiticles that are 6 wk) is done to control lice, keels, mites, and sheep blowflies. The pesticides used include rotenone, synthetic pyre­ throids, organophosphates, insect growth regulators, and macrocyclic lactones. Hand-jetting involves the use of a hanclpiece (or wand) to "rake" a pesticide solution into the wool along the dorsal midline and sometimes into tl1c breech, crutch, and poll. The solution is applied under pressure and penetrates to the skin. Some pour-on products on the market are formulated to deliver an active ingredient percutaneously. The macrocyclic lactones ivem1ectin, moxiclectin, cloramec­ ti.n, and eprinomectin are formulated as pow0on preparations for application to cattle. These formulations are usually solutions or emulsi.fiable concentrates for dilution with water before use. The principal route of percutaneous absorption for most drugs in people is the intercellular pathway, making the intercellular lipid matrix the primaiy banier to absorption. However, this may not be the case in species in which the emulsifying properties of skin secrPtions and the lai·ge nw11bers of follicles and glands per unit surface area must be considered (eg, cattle and sheep). Ionized solutes, for example, are reported to cross the skin of animals via shunt pathways (sweat ducts, follicles). Pour-on products ai·e fom1ulated to spread without run-off when applied to the skin and to be resistant to rain. The formulation also facilitates the partitioning of the drug out of the vehicle and into the skin and transpo1t of the drug across tl1e skin. The control of tl1ese processes is ctitical, because some drug is required to remain at the skin i.fthe drug is to be active against external parasites that are not blood sucking. In addition, too rapid passage of drug tl1rough tl1e skin may result in w1acceptable chemical residues in tissues or milk. The plunge dipping of sheep and cattle for external parasites requires a clipping vat, which may be a pottable unit or a perma­ nent in-ground structure shielded from

2517

direct sunlight by roofing. A draining pen located at the exit of the vat allows dip wash that drains off treated animals to return to the vat. Dip chemicals ai·e usually formu­ lated as aqueous solutions, emulsifiable concentrates, or suspension concentrates, all of which ai·e diluted with water before use. The high costs associated with plunge clipping relate principally to the costs of chemicals for chai·ging large vats, labor, and the disposal of the hazardous wastes. Plunge dips must be managed properly and the pesticide maintained at the concentra­ tion recommended by the manufacturer. Dipping of sheep and cattle is associated with "stripping" of tl1e active ingredient from the dip wash (eg, pesticide loss from the dip wash occw·iing at a greater rate tl1an water loss) and is categorized as mechatli­ cal or chemical. In the case of sheep, mechatlical stripping results from tl1e fleece acting as a sieve toward the active ingredient, with the degree of filtration being primai·ily cletem1ined by paiticle size. Chemical stripping is clue to the preferential absorption of pesticide by the fleece. To counteract stripping, a complex clip management regimen that involves reinforcement and "topping-up" is used. Reinforcement refers to the addition of undiluted chemical product to the dip without the addition of water, whereas topping-up refers to the addition of water and undiluted chemical product to the dip vat to return the volilllle to the slatting level. Proper clip management also minimizes contanlination of the dip with orgatlic matter. This requires that the race leading to the vat is constructed of concrete or slats to remove ditt from the a.tlitnals' feet and that anitnals be held in a yard overnight before dipping, during which time they are offered water but no feed. Hand spraying generally results in Wleven coverage of a.tlitnals and is considered an inefficient method of application. By compai·ison, recirculating and nonrecit·culating spray races facilitate whole body spraying and wet cattle to the skin. The situation with sheep is different­ the very short contact titne in a spray race litnits tl1e uptake of insecticide, which means the fleece seldom becomes saturated. Because of this, spray races should be used as an adjunct to shower or plunge dippit1g of sheep. Shower dips ai·e less labor intensive than plunge dips and are cheaper to operate. A typical shower dip consists of a swnp containing the dip wash, a pun1p, and a showeting pen constructed with a concrete floor a.t1d fitted with rotating and fixed

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nozzles. There are two types of shower dips: a conventional shower dip in which the swnp volwne is periodically maintained by adding fresh dip wash, and a constant replenislm1ent shower dip i:n which a smalJ-volwne sump is continually filled from a large-volume supply tank to maintain dip levels. Proper dip management requires attention to the factors described above for pltmge clipping. In addition, all equipment must be functioning properly for the fleece to become satmated. Sheep should not be dipped (by either the plunge or shower method) until shearing wounds have healed to avoid closbidial infections or caseous lymphaclenitis caused by Co1ynebacterium pseudotuberculosis. Moreover, the correct use of bacte1iostats is recommended to prevent post-dipping lan1eness caused by

Erysipelothri.x insidiosa.

Insecticidal collars are plasticized polymer resins in1pregnated with an active ingredient. CoUars for the contI·ol of ticks and fleas on clogs and cats release the active ingredient as a vapor, a dust, or a liquid, depending on the physicochernical properties of the chemical. Volatile liquid insecticides such as dichlorvos or naled ar·e used in vapor-release coUar'S. The insecti­ cide disbibutes through the collar· matrix as a vapor before being released. Powdered insecticides such as phosmet, sti..rofos, carbaryl, ar1d propoxur are used in dust-release coUars. Translocation of the active ingredient within the collar matrix leads to deposits fom1ing at the swiace; distribution of the insecticide to the animal depends on the animal's physical activity. Nonvolatile liquid insecticides such as chlorfenvinphos or diazinon are used in liquid-release collars. The active ingredient disbibutes as a liquid in the collar matrix and to the swiace, where it is released. The animal's activity plus the dissolution of lipophilic insecticides in skin secretions are in1portantfactors in translocation of the insecticide from the collar· to the artimal. Two types of insecticide-releasing ear tags to control flies on cattle are available. One is constructed from a polymer that provides structmal support and acts as a release rate-controUing matrix. The other is a membrane-based ear tag that consists of an insecticidal reservoir with a relatively in1perrneable backing on one side ar1d a rate-cono·olling membrane on the other. Both types rely on the animal's ear and head movements and groonting to transfer insecticide from the swface of the ear tag to the anin1al's skin or to other anin1als. Back rubbers typically consist of bmlap supported across lanes, gateways, or areas

where cattle congregate. Back rubber'S are charged by soaking thoroughly in oil-containing pesticide, typically a synthetic pyTeth.roid, ar1 organophosphate, or a combination of the two. The oil retards evaporation of the insecticide and enhances adherence to the animal's coat. Dust bags facilitate the self-treatinent of cattle to contI·ol flies and lice. They are consb'Ucted of an inner porous bag containing the active ingredient, which is commonly a synthetic pyreth.roid or an orgar1ophm;µhate, and an outer weatl1e1° proof ski.rt. Dust bags ar·e hung in lanes or gateways so that passing cattle brush against them and receive a topical application of pesticide.

Inhaled Dosage Forms and Delivery Systems lnhalational anesthetics ar·e critical in management of ar1estl1esia CwTently, enfiw·ar1e, halot11ane, isoflw·ane, methoxy­ tlurane, and nio·ous oxide are tl1e most commonly used inhaled anesthetic agents. These agents are usually delivered to anin1als in a car'!ier gas that includes oxygen, using an anestl1etic machine fitted with one or more vaporizers and a patient breathing circuit. lnllalational therapy of airway disease is used to deliver !ugh concentrations of drugs to the Iungs while avoiding or minimizing systentic adverse effects. 1b be delivered into the ai1ways, a drng must be presented as an aerosol, either as solid particles or liquid droplets in air. Particle or droplet size Jar·gely detennines the extent to which t11e drng penetrates t11e alveoli. Particles too small or too large for optin1al delivery into alveolar· sacs ar·e either exhaled or deposited on larger bronchial airways. Compared witl1 delivery by tl1e oral or par·enteral routes, tl1e on�et of pham1aco­ logic action of inhaled agents is faster and the doses adntinistered smaller, tl1ereby reducing the potential incidence of adve1'Se systemic effects. The delivery systems used for inhalational tl1erapy of airway disease in artimals are nebulizers ar1d metered-dose inhalel'S. In the poultiy industiy, inhalation of aerosolized vaccines is a common way to in1mwtize flocks of birds.

CHEMICAL RESIDUES IN FOOD AND FIBER Veterinary drugs and pesticides are used routinely in animal production to marrnge diseases ar1cl control par·asites, ar1d crop protection chemicals are used in production

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PHARMACOLOGY INTRODUCTION

of animal feeds. It is possible, therefore, for foodstuffs of animal origin to be adul­ terated with residues of veterinary drugs and pesticides, and for animal fibers to be contaminated with residues of ectopara­ siticides. Veterinarians must consider the in1plications of both possibilities when providing for the health and welfare of animals. First, animals and animal products destined for human consumption must not contain residues of drugs or pesticides that exceed legally permitted concentrations. Second, pesticide residues in fiber have potential implications for public health, occupational health and safety, and environmental safety.

Chemical Residues in Foodstuffs of Animal Origin

Chemical residues can be found in anin1al tissues, milk, honey, or eggs after ad.minis­ tration of veterinary drugs and medicated premixes, application of pesticides to animals, or consumption of stockfeeds previously treated with agricultural chemicals.

Residues Resulting from Veterinary Drugs, Medicated Feeds, or Applica­ tion of Pesticides: Extensive regulatory

and monitoring systems have been esta­ blished to ensure that chemical residues in food do not constitute an unacceptable health risk. The premarket approval process undertaken by regulatory authorities for new veterinary drugs and medicated feeds evaluates the quality, safety, and efficacy of these products. For veterinary medicines intended for administration to food-produc­ ing animals, an additional consideration is the safety of edible tissues and products (milk, honey, eggs) derived from treated animals. Regulatory authorities establish maximum residue lin1its (MRLs) or tolerances and set withdrawal times that ensure residues of the active constituent will not exceed the MRL when the label instrnctions for the product are followed. Residue programs consist of two principal activities: monitoring and surveillance. Residue-monitoring progran1s randomly sample food commodities from anin1als. San1ples are assayed for residues of specific veterinary drugs, pesticides, and environmental contaminants, and the residues are assessed for compliance with the applicable MRL or environmental standard. The number of samples taken for monitoring purposes typically provides a 95% probability of detecting at least one violation when 1 % of the animal population

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contains residues above the MRL. Surveil­ lance programs, by comparison, take san1ples from animals suspected of having violative residues on the basis of clinical signs or herd history. Food from animals identified with violative residues of veterinary drugs or pesticides do not enter the food chain. Residue monitoring is also a trade requirement, either mandatory or as an expectation, of impo1ting countries allowing market access to food products derived from animals. Compliance with the national standards of impo1ting countries becomes more difficult when the health standards, regulatory policies, and MRL-setting approaches of the exporting country and importing country differ. The situation is further exacerbated when patterns of use differ across countries or when the minor status of a disease or pest in a country does not warrant product registration, in which case MRLs are unlikely to be established. Regulat01y autho1ities w1de1take premarket approval assessments of applications in suppo1t of new veterinary drugs and medicated feeds. These assessments consider scientific data submitted by the sponsor. In the case of veterinary medicines proposed for use in food-producing animals, the data must demonstrate the safety of any residues remaining in the edible tissues or products from treated animals. These data describe the compound's toxicology, metabolism, pharmacokinetics, residue depletion, and dietary exposure. The key paran1eters de1ived in the safety and residue evalua­ tions are defined below. The acceptable daily intake (ADI) is the amount of a vete1inary drug, expressed on a body weight basis, that can be ingested daily over a lifetime without an appreciable risk to human health. The ADI is established based on a review of animal studies on toxicologic, pharrnacologic, or microbio­ logic effects as appropriate. Conservative safety factors are built into the ADI. The safe concentration is the maximal allowable concentration of total residues of toxicologic concern in edible tissue. The safe concentration is calculated from the ADI and considers the weight of an average person and the amount of meat, milk, honey, or eggs consumed daily by a high-consun1ing individual. An MRL, or tolerance, is the maximal concentration of residue resulting from the use of a vete1inary drug (expressed in mg/kg or mcg/kg on a fresh-weight basis) that is legally permitted as acceptable in or on a

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food. It is based on the type and an1ow1t of residue considered to be without any toxicologic hazard for hwnan health as expressed by the ADI. Other relevant public health risks and aspects relating to food technology, good practice in the use of veterinaiy drugs, and ai1alytical methodolo­ gies are also considered when establishing theMRL. The marker residue is the parent drug, its metabolites, or any combination of these, with a known relationship to the concentra­ tion of the total residue in the last tissue to deplete to the safe concentration. When the marker residue in the target tissue has depleted to theMRL, the total residue will have depleted to the safe concentration in alJ edible tissues. The target tissue is the edible tissue with residues that deplete to a concentra­ tion below theMRL at a slower rate than that in other edible tissues. It is considered suitable for monitoring compliance with the MRL of each edible tissue from a treated ai1itnal. The tai·get tissue is frequently liver or kidney for the purpose of domestic monitoring, and muscle or fat for monitor­ ing meat or cai·casses in international trade. The withdrawal time is the period of time between the last administration of a drug and the detection of residues of that drug to levels below theMRL in food from a treated a.Illinal. Compliance with the preslaughter withdrawal titne ensures the total residues deplete to below the safe concentration, ai1cl the mai·ker residue depletes to below theM�L. Failure to observe the correct withdrawal titne is the most common cause of violative residues of veterinaiy cl.rugs it1 food. Regulatory authorities determine withdrawal titnes based on resiaue depletion data that has been generated using healthy aiilinals representative of those typically treated with the specific product. The drug formulation used in these trials is identical to the market formulation, which is administered at the maximal label rate. The withdrawal titne is usually cletennmed statistica.lJy, taking into account variability ai11ong ai1it11als in drug disposi­ tion. Unlike anMRL, which applies to a veterinary drug regai·dless of the dosage fo1m, route of administration, or dosage regitnen, the withdrawal tit11e stated in the product labeling applies only to that paiticulai· formulation when administered by the recommended route and in accordance with the dosage regitnen. Altering ai1y of these factors modifies the pharmacokinetic behavior of the drug in

the animal and invalidates the stated with­ drawal titne. In addition, a rai1ge of physio­ logic and pathologic factors may modify the drug's disposition in the ai1i.mal and prolong drug elimit1ation. In the USA, some veterinaiy or hwnan drugs can be used extra-label (off-label) in food-producing anitnals under the Animal Medicmal Drug Use Clarification Act, provided ce1tain conditions are met (more information can be obtained on the FDA website, www.fda.gov). Veterinarians must be mindful, however, that the extra-label use of a small number of veterinaiy drugs is prohibited by the FDA Extra-label use refers to use in a species not included m the product labeling or at a dosage rate higher thai1 that stated m the product labeling. For drugs used m this ma.I111er, data are inadequate to demonstrate the safety of food products derived from the treated anm1al. An understanding of phannacoki­ netic principles a.lJows extended with­ drawal times to be estimated both when vete1inai-y drugs are used ill ai1 extra-label mai1ner and in situations that may lead to changes ill the kinetic behavior of a drug m an mdiviclual animal. The pharmacokinetic principles involved as well as two relevant practical examples that demonstrate such occw-rences ai·e discussed below. The elitnination half-life is the time requit·ecl for the concentration of a drug to be reduced by 50%. Therefore, 99.9"A, of an administered dose is eliminated over 10 half-lives. In food-producing a.Illinals, the residues of drugs with longer tem1inal elitnination half-lives take longer to deplete to below the MRL. The pharrnacokinetic behavior of the drug dete1mmes whether the elm1iI1ation half-life m tissues will exceed the elimination half�life m plasma. In food-proclucmg a.Illinals, the tenninal elitnination half-life for the slow elimination phase, or "I phase, of the residue concentra­ tion versus titne profile determmes the withdrawal time. Half-life is cletenninecl by both cleai·ance (Cl) and volwne of distribu­ tion (Ve!) as shown by the relationship: t 112 = 0.693 x

Vd Cl

Clearance is the blood volun1e cleai·ecl of drug per unit titne and refers to the irreversible elitnination of a drug from the body. The principal organs of elimination are the liver and kidneys; orgai1 clearance is related to blood flow ai1d the efficiency of drug removal. To clete1mit1e hepatic cleai·ai1ce, for exan1ple: ClH = QI! X E11

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PHARMACOLOGY INTRODUCTION

in which Q = blood flow and E = the extraction ratio. Factors that affect hepatic clearance include hepatic function, hepatic microsomal enzyme activity, and hepatic blood flow. Volume of distribution relates the amount of drug in the body to the concen­ tration of drug in plasma. For a drug administered IV, the relationship is: Vd =

an1ount of drug in body (dose) concentration (Cma.J

Vd is a characteristic property of the drug rather than the biologic system. A drug confined to the vascular compartment has a minimal value of Vd equal to plasma volume. Factors influencing Vd include the size of the drug molecule, lipid solubility, drug pKa, and tissue blood flow. Certain disease states effect changes in the Vd of a drug, particularly changes in drug binding. If it is necessary to administer a drug to a healthy animal at twice the reconunended rate, the elimination half-life of the drug is unchanged. Assuming the pharmacokinetic behavior of the drug demonstrates first-order kinetics, which is generally the case, doubling the administered dose will increase the depletion tin1e by one half-life. Thus, the withdrawal time should be extended by one hall�life to arrive at the same concentration as observed for the reconunended rate. However, if a drug is administered to an unhealthy animal with impaired drug excretion in which clearance is reduced by 50%, it can be seen from the relationship for half-life shown above that reducing clearance by 50% will double the half-life. Accordingly, the withdrawal time should be doubled to arrive at the same concentration as seen in an arumal with a fully functional excretory system. The predicted result should always be verified using a rapid-screening test. The detection of residues is likely to signal that the withdrawal time should be extended and the rapid-screening test repeated. Residues Resulting from Consump­ tion of Stockfeeds Treated with Agricultural Chemicals: The use of

agricultural chemicals can result in residues in crops and pastures that are subsequently consumed by animals. During drought conditions, the feeding of potentially contaminated crop byproducts, such as stubbles and fodder, and processed fractions, including grape mare, citrus pulp, fruit pomace, and cannery wastes, is likely to become more prevalent. In all cases, chemical residues may result in the edible

2521

tissues, milk, honey, or eggs derived from these animals. For approved uses of crop protection chemicals that ar·e likely to result in dietary exposure of food-producing arumals, regulatory authorities establish animal conrn1odity MRLs. The approach adopted for establishing these MRLs is fundamen­ tally different from the one that applies to veterinary drugs. Animal transfer studies, which allow detem1ination of the relation­ ship between the level of chemical in the ai1in1al diet and the concentration of residue found in edible tissues, milk, honey, and eggs, ar·e pivotal in determining MRLs. MRLs for animal tissues, milk, honey, and eggs are established at concentrations that cover the highest residues expected to be found from the estimated livestock dietary exposure. Human dietary exposure assessments are also performed to verify that food complying with MRLs is safe for consumption. In animal production systems, compliance with aiumal conrn10d­ ity MRLs relies on adherence to a stipulated period to allow residues in the crop to deplete before it is fed to animals, a stipulated period to allow residues in the arumal to deplete before slaughter, or a combination of both. Chemical Residues in Animal Fibers

From an economic standpoint, the major animal fibers are wool and mohair. Although this discussion primarily focuses on pesticide residues in wool, many of the concepts apply equally to mohair. Flies, lice, keds, and mites adversely affect wool production and have animal welfar·e implications for the sheep industry. Ectoparasiticides have been the mainstay to manage infestations of these parasites in sheep flocks for mar1y year·s. Two i.mportai1t manifestations of chenucal application to sheep ar·e the emergence of resistant strains of par·asites and the contamination of wool with pesticide residues. These two factors are linked, because the application of pesticides to resistant strains of flies or lice increases the likelil10od of treatment failure and the need to re-treat later in the wool-growing season. Higher residues in both the wool on treated sheep and in harvested fleeces are possible conse­ quences. Nonetheless, late-season applications are justified in some situations on aiumal health and welfare or economic grotmds. In view of community health and safety expectations and changing environ­ mental standards, wool producers are seeking ways to manage external parasites

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on sheep that rely less on chemicals. Integrated pest management (IPM) approaches may involve various husbandry options, such as shearing and crutching to combat flystrike; genetic improvements, such as selecting against animals suscepti­ ble to fleece rot and flystrike; biologic and environmental controls, such as the use of fly traps; and the selective use of chemicals. Pesticide residues in wool are influenced by many factors, including the chemical and formulation used, the method of application, the rate and timing of the chemical application, and the length ofwool at the time ofapplication. (See a.Isa ROUTES OP ADMINISTRATION AND DOSAGE FORMS, p 2508 .) The product types and chemical groups commonly used in the management of flies and lice on sheep include off-shears backline or spray-on products containing insect growth regulators (IGRs), organophosphate pesticides (OPs), and synthetic pyrethroid pesticides; short-wool plunge or shower dips that use IGRs, magnesium fluorosilicate, OPs, and spinosad; long-wool backline or spray-on products containing IGRs; and long-wool jetting products containing IGRs, macrocyclic lactones, OPs, or spinosad. Wool producers must ensure that pesticides are applied in accordance with the label directions. With some chemicals, application to sheep with >6 wk wool growth results in unacceptably high residues remaining in wool to the next shea.iing. Repeat applica­ tions ofpesticides may also result in higher wool residues at the next shearing, and backline products conunonly leave higher residues at the site of application. Although the use of sheep ectoparasiti­ cides can result in significant chemical residues on treated wool, any risk to public health is successfully mitigatetl by the following steps. First, scouring removes residual pesticide from processed wool destined for the manufacture of woolen garments. Second, in the case of lanolin used in pharmaceuticals and cosmetics and as nipple emollients by nursing mothers, any residual pesticide associated with the wax component is removed during refining ofthe lanolin. Additional assurance regarding the quality of low-pesticide grades of lanolin is provided by compliance with the applicable regulatory standards. With respect to occupational health and safety, residual pesticide in wool wax poses a hazard to shearers and other wool handlers during wool harvesting. For instance, nervous disorders and dermal irritation have allegedly occurred in shearers after shearing sheep treated with certain OPs and synthetic pyrethroid

pesticides, respectively. In addition, long-wool backline applications of synthetic pyrethroid pesticides can result in residue concentrations at the tips ofbackline staples high enough to cause dem1al erythema in shearers and wool handlers. In Australia, such occupational health risks are managed by prescribing a sheep rehandling period in the product labeling. The sheep rehandling period is the time that must elapse between the application ofthe ectoparasiticide a.i1d safely handling the treated a.ilimal. Ifsheep must be handled during the rehandling period, personal protective equipment should be used. Chemical residues on treated wool may pose a risk to the environment when effluent is discharged during processing (eg, into rivers). This concern has led to the enactment of legislation to protect the environment. For some pesticides, environmental quality standards at concentrations that will not harm the most sensitive organisms in aquatic ecosystems have been established. In the EU, textile products are subject to eco-label require­ ments. In Australia, environmental risks posed by residues of ectoparasiticides on treated wool are mitigated by assigning a wool-harvesting interval (also referred to as a wool withholding period). The wool­ ha.ivesting interval is the ti.me that must elapse before treated sheep may be shorn, ensUiing that harvested wool meets the prescribed environmental residue limits. The depletion ofpesticide residues in wool has been mathematically modeled to predict the likely consequences of treatments at different ti.mes during the wool-growing season and to detennine how late a pesticide may be applied to sheep without resulting in excessive residues at shea.iing. Modeling is a useful tool to determine wool-harvesting intervals and to help wool producers choose a pesticide and method ofapplication. Test kits to quantify pesticide residues in wool are also available.

NANOTECHNOLOGY Nanotechnology is a new enabling tech­ nology with the potential to revolutionize animal health. A nanomaterial has been defined as a material engineered to be < 100 ru11 in one or more dimensions. A nanometer is one one-billionth of a meter; to put the nanoscale into perspective, a hUinan hair is -80,000 nm in dia.ineter. Chemicals at the nanoscale display physical and chemical behaviors that can differ markedly from those of the bulk chemical (eg, in optical properties, conductivity, or electromagne-

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PHARMACOLOGY INTRODUCTION

tism). These behaviors are attributed to a combination of the small size, chemical composition, physicochemical properties, and swface structw·es of nanomaterials. Of major importance to the development of nanotechnologies for anin1al health will be a thoughtful, thorough, and balanced assessment of the benefits and risks involved. Risks can originate from any novel hazards of nanomaterials, the distribution profiles of nanomaterials in animals, the exposure of people to nanomaterials, and tl1e toxicity and fate of nanomatelials in the environment. Additional challenges relate to the detection and analysis of nanomatelials. This discussion focuses on the applic a ­ tion of nanotechnology in the delivery of veterinary drugs and vaccines, a field predicted to expand. Many of the benefits of nanotechnology in drug delivery are the result of improved apparent solubility or stability or both; an increased concentration of drug at the site of action (increased efficacy); a decreased concentration of drug at locations in the body remote from the site of action (reduced systemic toxicity); and modified pharrnacokinetics, including controlled release. There are nwnerous "drivers" of nanotechnology-based drug delivery. Pharmaceutical considerations are one such dliver (see drug nanocrystals, below); another is the need for vete1inary nanorned­ icines that overcome problems refractory to conventional therapy. One objective of "smart" drug delivery is to target specific sites. This strategy allows the use of smaller quantities of drug than would otherwise be possible. The passive targeting of intrave­ nously administered drug, for example, depends on the enhanced permeability and retention (EPR) effect, a phenomenon whereby nanoparticles extravasate at sites of increased vascular pern1eability, such as twnors, infections, and areas of inflanm1a­ tion, and then accwnulate at these sites. Swface modification of nanoparticles is used to prolong the circulation time and enhance the EPR effect. For example, coating nanoparticles with the hydrophilic substance polyethylene glycol lessens opsonization through a steric effect, thereby reducing the subsequent uptake of nanoparticles by the reticuloendothelial system. Conversely, uncoated nanoparticles are rapidly phagocytosed, a process used to advantage to treat intracellular parasites and infections located in phagocytic cells. In a separate process known as active drug targeting, nanoparticles with targeting moieties (eg, antibodies, ligands) attached to their swfaces are able to bind to specific

2523

tissues or cell types. Similarly, magnetic nanoparticles under the inf!uence of an alternating magnetic field transport drugs to their sites of action. Individualized and targeted drug therapy across animal species is an extension of the "smart" drug delivery concept. With this approach, miniature sensing and delivery devices, some with embedded PK/PD algoritluns or using nanodelivery platforms that provide local feedback on delivery mechanisms, are envisioned. Also envisioned are nanoscale devices with tl1e capability to detect and treat an infection, nutrient deficiency, or other health problem before symptoms are evident. In the case of antibiotics, the envisioned system would use less drug, thereby relieving concerns surrounding the potential development of antibiotic­ resistant strains of bacteria and thus increas­ ing food safety for consumers. Exciting advancements in the field of vaccine delivery are also being made (see vaccine delivery and vaccine adjuvants, below). The ratio of swface area to volwne of a drug nanocrystal is orders of magnitude greater than that of its microscale or macroscale dl-ug cow1terpart. Poorly water soluble drugs with a bioavailability that is dissolution-rate limited demonstrate markedly improved bioavailability when administered in a nanoform. Another advantage is that drug nanocrystals demonstrate reduced valiability in bioavailability for the fed and fasted states. Nanosized drug crystals are produced either by top-down technology, in which micronized particles are subjected to milling or grinding, or by bottom-up tech­ nology involving nanoprecipitation. Drugs and proteins conjugated to polymers such as polyethylene glycol degrade more slowly than do drugs or proteins alone. As a consequence, conjugates remain in the circulation longer than the parent drug or protein. A prolonged circulation tin1e allows for less frequent administration and results in increased extravasation of drug due to the EPR effect and, consequently, a higher drug concentra­ tion at the site of action. Dendrimers are highly branched polymers consisting of an initiator core; interior layers composed of repeating units; and tern1inal moieties that can be functionalized to modify solubility, miscibility, and reactivity of the resulting macromolecule. From a drug-carrying perspective, dendrimers are relatively new. High loadings of dl-ug can be incorporated into the dendrin1er core or attached to the tenninal moieties on the dendrin1er surface.

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PHARMACOLOGY INTRODUCTION

Dend1irners are particularly attractive for ocular, pulmonary, and oral drug delivery. Polyplexes are complexes of polymers and DNA with promising benefits for gene therapy. Polymeric micelles comprise an internal zone known as the "core" and an external zone known as the "sheU" formed by amphiphilic block copolymers such as poly(propylene oxide), poly(L-an1ino acids), and poly(esters). Tl1e advantages of polymeric micelles for dmg delivery include solubilization of poorly soluble molecules and sustained drug release due to drug encapsulation protecting the drug from degradation and metabolism. Polymeric micelles can also enhance the delivery of drugs to desired biologic sites, thereby improving therapeutic ef'ficacy and attentuating unwanted adverse effects. Liposomes are self-assembled vesicles that possess a central aqueous cavity smTounded by a lipid membrane fmmed by a concentric bilayer(s) (also known as a lamella[ e ]). When liposomes come in contact with biologic cells, they tend to unravel and merge with the membrane of the cell, releasing their payload of drugs or other agents. Liposomes can be designed to achieve various functions, including the protection of the active ingredient from degradation in the GI tract, the transport of drugs to sites of action, and prolongation of the residence time of the active ingredient in vivo. Solid lipid nanoparticles are synthe­ sized from solid lipids. The�e nanoparticles demonstrate excellent physical stability and protect the incorporated dmg from chemical degradation; however, low drug loading capacity is a disadvantage. Studies suggest it will be possible to develop a range of dosage forms, allowing solid lipid nanoparticles to be delivered by most routes of administration. Polymeric nanoparticles consist of two main fo1ms: polymeric nanocapsu.les and polymeric nanospheres. Polymeric nanocapsules can be prepared from natural and synthetic materials such as chitosan and poly(lactide-co-glycolide), respectively. From a drug delivery perspective, polyn1eric nanocapsu.les demonstrate a hlgh dmg loading capacity and facilitate increased drug bioavailability and controlled dmg release. Other applications of polymeric nanocapsules include the detection, diagnosis, and treatment of disease, and imaging. Polymeric nanospheres differ from polyn1eric nanocapsules, because drug is physical.ly and unifonruy dispersed in a dense polyn1eric matrix with the fotmer.

Magnetic nanoparticles have two therapeutic applications: drug delivery and therapeutic hyperthermia. The former application involves drug-coated magnetic nanopaiticles that are general.ly >50 nm in size. After IV administration, these nano­ paiticles are directed to the site of drug action using a magnetic field. Subsequent retention of the nanopaiticles at the site of action is also achieved using a magnetic field, and this facilitates localized drug release. By comparison, magnetic nan­ opaiticles for therapeutic hype1thermia are smaller in size (-5 run). I-lyperthermia via hysteresis energy loss results when an external alternating magnetic field is applied to the magnetic nanoparticles. A typical outcome oft.11erapeutic hyper­ t.11e1mia is tUlllor cell necrosis. An example of a nanoteclmology-based device for vaccine delivery is the Nanopatch®, used in people to deliver vaccines detmally. The Nanopatch® is a silicon wafer the size of a postage stamp with thousands of projections (>20,000/cm3), each of whlch is -100 µrn long and with a tip diameter of -1 µm. The tips of the projections are dry coated with vaccine at t.11e nanoscale; hence, there is no requirement for refrigeration of the vaccine during storage and transport. When t.11e device is applied to a patient's skin, the projections protrude into the wet cellulai· envirorunent below the skin smiace; on wetting, t.l1e vaccine is delivered in 900A, bound to plasma protein. The steady state volun1e of dist1ibution of pimobendan is 2.6 Ukg, and the tem1inal elin1ination half-lives of pimobendan and its active metabolite are 0.5 and 2 hr, respectively. Oral bioavailabil­ ity is reduced by food rn1til steady state is reached in a few days. Consequently, pimobendan should be administered on an empty stomach at least 1 hr before feeding for maximal effects when starting therapy. Hemodynamic effects after PO administra-

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SYSTEMIC PHARMACOTHERAPEUTICS OF THE CARDIOVASCULAR SYSTEM

tion on an empty stomach peak in l hr and last 8-12 hr; therefore, pimobendan can provide rapid short-term support to dogs with acute or decompensated heart failure. IV preparations are available in some countries. Pimobendan is approved for treatment of CHF due to dilated carcliomyopathy (DCM) and chronic degenerative mitral valvular disease (DMVD) in clogs. It has also been shown to prolong symptom-free survival in Doberman Pinschers with occult DCM. Pimobenclan has an excellent safety profile, and clinical data suggest that it is safe when administered concomitantly with other medications commonly used in treatment of canine CHF. Rep01tecl adverse effects are minimal, but the main one is GI intolerance of tl1e chewable tablet formulation. Pimobendan is contraindicated in clogs with known outflow tract obstruction (eg, subaortic stenosis). Pimobenclan is not approved for use in cats. A nwnber of retrospective studies in cats, using dosages similar to those used in dogs, suggest it is well tolerated, but there is no definitive proof of efficacy. The mechanism of action of the bipyridine derivatives amrinone and milrinone is probably in11ibition of PDE and increased levels of intracellular cAMP. Both anrrinone and milrinone are available for IV administration and are suitable only for sho1t-term management of CHF. However, with the wide availability and known efficacy of pin10bendan, these medications have fallen out of favor for treatment of CHF. jl-Adrenergic Agonists These drugs cause a positive inot;ropic effect by activating 13-receptors with subsequent stimulation of aclenylate cyclase and increased cAMP. Dopamine is an endogenous catechola­ mine precursor with selective 13 1 activity. However, it also stimulates release of norepinephrine. At low closes, it stimulates renal cloparninergic receptors, which causes increased renal blood flow and diuresis. It is rapidly metabolized by the body and has a half-life of 2 wk. Feline and Canine Rickettsial Infection: Anterior and posterior uveitis

and chmioretinitis secondary to infection with Ehrlichia or Rickettsia spp (see p 803) is common. Tetracyclines (doxycycline at 5---10 mg/kg, once to twice daily for dogs, and 10 mg/kg, bid, for cats, for 14-21 days) are tl1e drugs of choice and have excellent intraocular penetration. ln a dog from an area associated with rickettsial disease, it is rational to empirically treat uveitis with doxycycline pending serology. Enrofloxacin (3 mg/kg, PO, bid for 7 days) can also be used, although care should be taken not to exceed the dosage associated with retinal toxicity in cats (>5 mg/kg/day). Chloran1phenicol is not recommended, because it directly interferes with heme and bone marrow synthesis. Appropriate topical and systemic NSAID therapy is also recom­ mended to control ocular inflan1mation. When the intraocular inflammation is severe or tl1ere is a serous retinal detachment, short-term (2-7 days) corticosteroids (0.25---0.5 mg/kg, PO, once to twice daily) may be used concun·ently 24-48 hr after the start of oral antibiotic therapy. Animals can regain some vision after reattaclunent of the retina; the an10unt depends on the duration of the detachment and degree of inflanunation. Canine and Feline Ocular Mycoses:

Dogs and cats diagnosed witl1 ocular mycoses require systemic treatment. Along with systemic antifungals, topical and systemic anti-inflan1rnatories and topical mydriatics/cycloplegics are needed to control the secondary and potentially blinding intraocular inflan1mation. Blastomycosis (seep 634) is more conunon in dogs than cats. Up to 40% have ocular signs, usually anterior uveitis. Treatment options include parenteral an1phote1icin B deoxycholate or PO or IV triazoles. ln clogs, itraconazole is used at 5 mg/kg, PO, bid for 5 days, then continued at 5 mg/kg/day, PO, for a minimun1 of 60 days

2567

or 1 mo after all signs of the clisease have resolved. Adverse effects include anorexia, which is associated with liver toxicity. Cats can be treated with 10 mg/kg/day or 5 mg/kg, bid; however, there are few published cases of successful treatment in cats. Ketocona­ zole may also be used to treat blastomyco­ sis, but because the onset of effect is so slow, other triazoles should be used initially. Arnphotericin B deoxycholate is also effective but is nephrotoxic. The dosage (dogs: 0.5 mg/kg, IV; cats: 0.25 mg/kg, IV) is given three times weekly until the anin1al becomes azotemic or a cumulative dose of 4-6 mg/kg in dogs or 4 mg/kg in cats is reached. An1photericin B lipid complex used at the san1e or a slightly higher dosage is less nephrotoxic. The predominant lesion of histoplasmo­ sis (seep 639) is granulomatous choroiclitis, but anterior uveitis, retinal detachment, and optic neuritis can be present. Treatment options are itraconazole (10 mg/kg, PO) or fluconazole (2.5---5 mg/kg, PO) once to twice daily for 4-6 mo, or amphotericin B deoxycholate (0.25---0.5 mg/kg, IV, every 48 hr) until a cun1ulative dose of 5---10 mg/kg (dogs) or 4-8 mg/kg (cats) is reached. Because of its lipophilic nature and ability to cross the blood-ocular ba.niers, fluconazole is recommended for use in ocular disease, although anin1als have also had complete resolution when treated with the more hydrophilic triazole itraconazole. Ocular signs are present in 15% of cryptococcosis (seep 637) cases and are more common in cats than in dogs. Treatment can be with an1photericin B deoxycholate (0.1-0.5 mg/kg, JV, three times per wk) alone or in combination with flucytosine (30---75 mg/kg, bid-qicl for up to 9 mo). Ketoconazole, itraconazole, and fluconazole are also effective. In cats, ketoconazole is administered PO at either 5---10 mg/kg, bid, or 10---20 mg/kg/day for 6-10 mo. lf toxicity occurs, the dosage can be changed to 50 mg/kg/cat, PO, every other clay. 1n clogs, dosages are either &---15 mg/kg, PO, bid, or 30 mg/kg/day, PO, for 6-10 mo. Systemic absorption from the GI tract is significantly enhanced by food. Adverse effects of ketoconazole include anorexia, cliarrhea, vomiting, and increased liver enzY1nes. Because of poor CNS penetration, ketoconazole is not reconunenclecl for use as the sole agent in ocular cryptococcosis. Itraconazole (cats: 5---10 mg/kg, PO, bid, or 20 mg/kg/day, PO) is less likely to cause adverse effects than ketoconazole, and its GI tract bioavailability is enhanced by fatty food. Like ketoconazole, its hydrophilic nature leads to poor clistribution into the

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SYSTEMIC PHARMACOTHERAPEUTICS OF THE EYE

CNS, but it has been successful in treating CNS and ocular cryptococcosis. Adverse effects are mainly associated with the GI tract (anorexia and vomiting), buL liver disease can also develop. Liver enzymes (ALT) should be monitored every 2 wk for the first mo.nth of treatment and monthly thereafter. Fluconazole is more lipophilic and has better bioavailability than itraconazole. It also penetrates the CNS better (60"1olizecl (eg, ciprof1oxacin, enrof1oxacin), and a few 31·e completely degraded. Metabolites 31·e sometimes active; enrof1oxacin is de-ethyl­ atecl to form ciprof1oxacin. Ch31·acteristi­ ca1ly, phase I reactions result in a nwnber of prin1a.Iy metabolites (up to six have been described for some quinolones) that retain some antibacte1ial action. Conjugation with

l&HifH

glucuronic acid then ensues, followed by excretion. In contrast, only -100/o of ma.rbofloxacin is metabolized. Excretion: Renal excretion is the major route of elimination for most quinolones. Both glomerula.r filtration and tubular secretion a.re involved. Urine concentra­ tions a.re often high for 24 hr after adminis­ tration, and crystals may form in concentrated acidic urine. The clinical significance of this finding is tmclea.r. In renal failure, clearance is impaired, and reductions in dose rates are essential. Bilia.Iy excretion of pa.rent drug, as well as conjugates, is an in1portant route of elimination in some cases (eg, ciproftoxa­ cin, ma.rbof1oxacin, di.floxacin, pef1oxacin, nalidbdc acid). Quinolones appear in the milk of lactating animals, often at high concentrations that persist for some tin1e. Pharmacokinetic Values: The clearance and volwne of dist1ibutions of the drugs Va.IY a.Inong species, resulting in differences in plasma half-lives. Plasma concentrations attained a.re usually directly proportional to the dose administered but also Va.IY with volume of distribution and oral bioavailabil­ ity. Package inserts should be consulted for C,,,.Lx for those drugs approved for use in the target species. Therapeutic Indications and Dose Rates

Quinolones a.re indicated for the treatment of local and systemic infections caused by susceptible microorganisms, particularly against deep-seated infections and intracellular pathogens. Therapeutic success has been obtained in respi.rato1y, intestinal, mi.na.Iy, and skin infections, as well as in bacterial prostatitis, meningoen­ cephalitis, osteomyelitis, 3.I}d arthritis.

PHARMACOKINETICS OF SELECTED FLUOROQUINOLONES Elimination Half-life (hr)

Volume of Clearance Distribution (Ilkg) (mUmin/kg)

Drug

Species

Enrof1oxacin

Cats

7

Dogs

4.4

3.7

11

Mares

4-7

2

0.5-4

Ma.rbof1oxacin

Dogs

12

2

1.5

Orbif1oxacin

Cats

4.5

1.3

Dogs

5.4

1.2

4.3

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ANTIBACTERIALAGENTS

Because of their lipid solubility and ability to accumulate in phagocytic WJ3Cs, quinolones should be considered for use in infections located in tough to penetrate tissues. Therapeutic failure is iil0.5 mcg/mL for --72 hr. Tetracyclines usually are administered PO bid-tid (every 12--24 hr for doxycycline ru1d minocycline). Therapeutic Indications and Dose Rates The tetracyclines ru·e used to treat both systemic ru1d local infections. However, resistance ru1d their bacteriostatic nature suggest caution with empirical use for bactetial infections, particulru·ly in dogs ru1d cats. Specific conditions include infectious keratoconjunctivitis in cattle, chlru11ydiosis, heruuvater, ru1aplasmosis, actinomycosis, acti.nobacillosis, nocardiosis (especially minocycline), ehrlichiosis (especially doxycycline), Wolbachia, eperythrozoono­ sis, ru1d haemobartonellosis. Minocycline ru1d doxycycline are often effective to a somewhat lesser degree against resistru1t strains of StaphylococC'us aureus. In addition to ru1timicrobial chemother­ apy, tl1e tetracyclines are used for other purposes. As additives in ru1in1al feeds, U1ey serve as growth promoters. Because of the affinity of tetracyclines for bones, teeth, and necrotic tissue, they cru1 be used to delineate tumors by fluorescence.

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ANTIBACTERIALAGENTS

•th•ii•

ELIMINATION, DISTRIBUTION, AND CLEARANCE OF TETRACYCLINES

Tetracycline

Species

Elimination Half-life (hr)

Volume of Distribution (mIJkg)

Clearance (mIJkg/min)

6

3,000

4.23

10-13

1,500-2,400

3.45

Cattle

7-10

800-1,000

3.33

Horses

8 10 -

1,100

2.89

2,000

3.21

Oxytetracycline Dogs Calves (5 min) or by pretreatment with IV calciwn gluconate. The IV administration of undiluted propylene glycol-based preparations leads to intravascular hemolysis, which results in hemoglobinmia and possibly other reactions such as hypotension, ataxia, and CNS depression. Because tetracyclines interfere with protein synthesis even in host cells and therefore tend to be catabolic, an increase in BUN can be expected. The combined use of glucocorticoids and tetracyclines often leads to a significant weight loss, particu­ larly in anorectic anin1als. Hepatotoxic effects due to large doses of tetracyclines have been reported in pregnant women and in other animals. The mortality rate is high. The tetracyclines are also potentially nephrotoxic and are contraindicated (except for doxycycline) in renal insuffi­ ciency. Fatal renal failure has been repm'Led in septicemic and endotoxemic cattle given high doses of oxytetracycline. The administration of expired tetracycline

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ANTIBACTERIAL AGENTS

itM•iH

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DOSAGES OF TETRACYCLINES

Tetracycline

Species

Dosage, Route, and Frequency

Tetracycline

Cats, dogs

7 mg/kg, IM or IV, bid

Oxytetracycline

Cats, dogs

20 mg/kg, PO, tid 7 mg/kg, IM or IV, bid 20 mg/kg, PO, tid Cattle, sheep, pigs

Doxycycline

5--10 mg/kg/day, IM or IV

Calves, foals, lambs, piglets

10-20 mg/kg, PO, bid-tid

Horses

5 mg/kg, IV, once to twice daily

Dogs

5-10 mg/kg/day, PO 5 mg/kg/day, IV

Before heartworn1 adulticide therapy products may lead to acute tubular nephrosis. Swelling, necrosis, and yellow discolora­ tion at the ir\jection site almost inevitably are seen. Phototox.ic de1matitis may occur in people treated with demethylchlortetra­ cycline and other analogues, but this reaction is rare in other animals. Hypersen­ sitivity reactions occur; for example, cats may develop a "drug fever" reaction, often accompanied by vomiting, diarrhea, depression, inappetence, fever, and eosinophilia. The tetracyclines can inhibit WBC chemotaxis and phagocytosis when present in high concentrations at sites of infection. This clearly hinders normal host defense mechanisms and compounds the bacterio­ static activity of tetracyclines. The use of immunosuppressive drugs such as glucocorticoids impairs immunocompe­ tence even further. Doxycycline administered in tablets has been associated with esophageal erosion in cats. The incidence is reduced if administra­ tion is followed by a 5-mL volume of fluid. Doxycycline may be associated with GI upset; this might be reduced by administer­ ing the drug with food.

Interactions: Absorption of tetracyclines from the GI tract is decreased by milk and milk products (except for doxycycline and minocycline), antacids, kaolin, and iron preparations. Tetracyclines gradually lose activity when diluted in infusion fluids and exposed to ultraviolet light. Vitamins of the B-complex group, especially riboflavin, hasten this loss of activity in infusion fluids.

10 mg/kg, PO, bid, for 30 days

Tetracyclines also bind to the calcium ions in Ringer's solution. Methoxyflurane anesthesia combined with tetracycline therapy may be nephro­ tox.ic. Microsomal enzyme inducers such as phenobarbital and phenytoin may sho1ten the plasma half-lives of minocycline and doxycycline. Except for minocycline and doxycycline, the presence of food can substantially delay absorption of tetracy­ clines from the GI tract. The tetracyclines are less active in alkaline urine, and urine acidification can increase their antimicro­ bial efficacy.

Effects on Laboratory Tests: Tetracy­ clines may increase amylase, BUN, bromsulphthalein (BSp@), eosinophil count, AST, and ALT. Tetracyclines used in combination with diuretics are often associated with a marked rise in BUN. Cholesterol, glucose, potassiun1, and prothrombin time may be decreased. A false­ positive urine glucose test is also possible. Drug Withdrawal and Milk Discard Times: Regulatory requirements for

withdrawal times for food a.ninlals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health in1plications. The withdrawal tin1es listed in TABLE 46 se1ve only as general guidelines.

PHENICOLS Chlora.mphenicol is a highly effective and well-tolerated broad-spectrum antibiotic. However, because it ca.uses blood

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ANTIBACTERIAL AGENTS

hth•it·I

DRUG WITHDRAWAL AND MILK DISCARD TIMES OF TETRACYCLINES

Tetracycline

Species

Ox:ytetracycline•

Cattle Pigs Poultry

Ox:ytetracycline (lon g a- cting)•

Cattle

Chlortetracycline

Cattle Pigs

Withdrawal Time (days)

15-22 22 5

28

10

1-7

"Not for use in lactating dairy cows dyscrasias, it is prohibited for use in food-producing anin1als in several countries, including the USA and Canada. Thiamphenicol is less effective but safer than chloran1phenicol; flotienicol, a thiamphenicol derivative, is significantly more active in vitro than chloran1phenicol against many pathogenic strains of bacteria. Florfenicol is approved for use in cattle.

General Properties Chloramphenicol is a relatively simple neutral nitrobenzene detivative with a bitter taste. It is highly lipid soluble and is used either as the free base or in ester fom1s (eg, the neutral-tasting pa.Imitate for administra­ tion PO and the water-soluble sodium succinate for parenteral illiection). Chloramphenicol is a relatively stable compound and is unaffected. by boiling, provided that a pH of 9 is not exceeded. The nitrophenol group of chloramphenicol is replaced by a methyl sulfonyl group for thiamphenicol and florfenicol; florfenicol also contains a fluorine molecule. These structural changes m1prove efficacy, reduce toxicity, and for tlorfenicol, the fluorme molecule reduces bacterial resistance.

Antimicrobial Activity Mode of Action: The phenicols inhibit

microbial protem synthesis by binding to the 508 subunit of the 708 tibosome and m1pairing peptidyl transferase activity. Because peptide-bond formation is inhibited, peptides cannot elongate. The effect is usually bacteriostatic but, at high concentrations, chloramphenicol may be bactericidal for some species. Protem synthesis is inhibited m both prokaryotic and eukaryotic (mitochondrial) ribosomes.

Bacterial Resistance: Resistance against chloramphenicol develops slowly and in a stepwise fashion. In clinical

bacterial isolates, high-level plasmid­ mediated resistance reflects the produc­ tion of chloramphenicol acetyltransferase (encoded for by the cal gene) and results in acetylation of the molecule, which can no longer bind to the ribosome. Other inactivating enzymes also may be involved. In resistant gran1-negative bacteria, chloran1phenicol acetyltransferase is a constitutive enzyme; in gram-positive organisms, the enzyme is inducible. The fluorine atom of florfenicol prevents acetylation, thus enhancing the efficacy of this drug. InPseudomonas aeiuginosa and m strains of Proteus and Klebsiella spp, resistance is also nonenzymatic and is based on an inducible pem1eability block that is both chromosomal and plasmid­ mediated. Reduced permeability contrib­ utes to low level resistance. Very rarely, resistance may reflect altered ribosomal subunit structure and bindmg. Resistance to chloramphenicol often develops togeU1er with resistance to tetracycline, erythromycm, streptomycin, ampicillin, and other antibiotics because of multiple genes beiI1g carried on the same plasmid.

Antimicrobial Spectra: Many genera of

gram-positive and gran1-negative bactetia and several anaerobes such as Bacteroides fragilis, as well as Rickellsia and Chla­ mydia spp are susceptible. Chlorampheni­ col is notable for its anaerobic spectnun. Of special note is the efficacy against many Salmonella spp but the resistance of most strains of P ae ruginosa.

Pharmacokinetic Features Absorption: Absorption occurs promptly and rapidly from the upper GI tract when chloramphenicol base is administered PO to nonruminant animals. Blood concentrations usually are maximal in 1-3 hr. Because ruminal microflora

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ANTIBACTERIAL AGENTS

readily reduce the nitro group, chloram­ phenicol is inactivated in the ruminoreticu­ lum and is not available for absorption. The larger ester forms of chloramphenicol require hydrolysis by lipases to release the antibiotic for absorption from the GI tract; thus, the systemic availability of chloran1phenicol is delayed when the palmitate and other ester preparations are used. Generic inequivalence has been seen with oral dosage forms. The presence of food and intestinal protectants does not interfere with absorption of chloramphenicol, although drugs that depress GI motility do. Florfenicol is rapidly absorbed after admin­ istration PO, although milk interferes with absorption. Chloran1phenicol sodium succinate may be injected both IV and IM. However, hydrolysis is required in the body because only free chloran1phenicol base is active. The kinetics of this hydrolysis reaction may be slow and incomplete, with considerable individual and species variability. The absorption of chloramphenicol base itself from IM injection sites is notably restricted. For example, in horses, the therapeutic blood concentration of 5 mg/mL is achieved at a dosage of 50 mg/kg body wt, IM, after only 6-8 hr. Chloran1phenicol base is absorbed after IP injection. Florfenicol is available as an injectable solution intended for IM use. Distribution: Approxinlately 40%--60% of chloramphenicol in plasma is reversibly bound to albumin, and the free fraction readily diffuses into almost all tissues (including the brain); highest concentra­ tions are reached in the kidneys, liver, and bile. Substantial concentrations ( --500!., of plasma values) are also reached in many body fluids such as the CSF and aqueous humor. Milk concentrations are --500,,(, those of plasma but may be higher in mastitis. Transplacental diffusion is seen in all species, with concentrations of --75% being reached in the fetus as compared with the dam. Chloramphenicol does not attain effective concentrations in normal synovial fluid but does so in septic arthritis. The blood-prostate barrier is an exception to the extensive intracorporeal distribution of chloran1phenicol, and concentrations in the inflan1ed prostate are low to nil. Approxi­ mately 15%--200!., of peak serum concentra­ tions are seen within abscesses. Florfenicol also penetrates most boc1y tissues, although penetration of CSF and aqueous humor is less than that of chloramphenicol. Florfenicol does penetrate the milk of lactating cows.

2685

Biotransformation: Unlike many other

antibacterial agents, chloramphenicol undergoes extensive hepatic metabolism. Although some nitroreduction and other phase I reactions occur, free chloram­ phenicol is biotransformed primarily by glucuronide conjugation. Urinary products after administration of chlor­ amphenicol sodium succinate include inactive forms, mainly the unhydrolyzed sodium succinate and the glucuronide; only 5%-15% appears as biologically active chloramphenicol. There are several clinical concerns with respect to the biotransformation of chloramphenicol. In cats, a characteristic genetic deficiency in glucuronyl trans­ ferase activity leads to plasma half-lives that are often considerably longer than those in other species (eg, cats, 5.1 hr; ponies, 54 min), and dosages need to be adjusted accordingly. Phase I metabolism may also be deficient in cats. Very young animals frequently do not have full microsomal enzyme capabilities, and the plasma half-lives of chloramphenicol in the young ( 3 hr, and the apparent volume of distribu-

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ANTIBACTERIAL AGENTS

tion is> 1 J.lkg. They are usually adminis­ tered bid. In dogs, clindamycin has an elimination half-life of 3.9 hr and a volume of distribution of 1.4 J.lkg.

T herapeutic Indications and Dose Rates The lincosamides are indicated for infections caused by susceptible gram-positive organisms, particularly streptococci and staphylococci, and for those caused by anaerobic pathogens. Clindamycin is approved for use in cats and clogs for treatment of infected wounds, abscesses, and dental infections. Clindan1ycin has also been used to treat selected protozoa] diseases, including toxoplasmosis, but usually in combination with other antimicrobials. A selection of general dosages for some lincosarnides is listed in TABLE 51. The close rate and frequency should be adjusted as needed for the individual animal.

Special Clinical Concerns Adverse Effects and Toxicity: No

serious organ toxicity has been repottecl, but GI distw·bances do occw·. Clinclamycin­ inducecl pseudomembranous enterocolitis ( caused by toxigenic Clostridium dif[u;ile) or disruption of GI flora is a se1ious adverse reaction in a nwnber of species and can be lethal; thus, clindan1ycin is contraindicated for use in some in horses, guinea pigs, han1sters, rabbits, chinchillas, and mrninants. Lincosamicles are contraindi­ cated in horses, because severe and even fatal colitis may develop. Skeletal muscle paralysis may be seen at high concentra­ tions. Hypersensitivity reactions occasion­ ally are seen. Lincosanlides shouldJ'lot be used in neonates because of their limited ability to metabolize clmgs.

Interactions: Lincosanlicles have additive new·omuscular effects with anesthetic

agents and skeletal muscle relaxants. Kaolin-pectin prevents their absorption from the GI tract. They should not be combined with bactericidal agents or with the macrolides.

Effects on Laboratory Tests: Alkaline phosphatase, AST, and ALT may be increased. Drug Withdrawal T imes: In several countries, there is a 2-clay withdrawal time for pigs.

A number of antinlicrobiaJ agents are used periodically for several diverse purposes. Several of these are discussed below.

POLYMYXINS This group of polypeptide antibiotics includes polymyxin B and polymyxin E, or colistin. Because of toxicity, these drugs are most commonly used topically, or PO for treatment of intestinal infections. Colisti­ methate is a form of colistin intended for parenteral admi.Ilistration. Polymyxins are bactericidal; they interact strongly with phospholipids in bacterial cell membranes and radically dismpt their pem1eability and function. The polymyxins are more effective against gram-negative than gram-positive bacteria. Their rather narrow spectt·w11 includes Enterobacter, Klebsiella,

Salmonella, Pa.steurnlla, Bo'!'detella, Shigella, Pseudomonas spp, and Esche1i­ chia coli. Most Proteus or Neisserla spp

are not susceptible. Although intrinsic bacterial resistance to polymyxins is recognized, resistance is w1comrnon and is chromosome-dependent only. Polymyxins act synergistically when combined with potentiated sulfonamides, tetracyclines,

IM=i!iii

DOSAGES OF LINCOSAMIDES

Lincosamide

Species

Dosage, Route, and Frequency

Lincomycin

Cattle

10 mg/kg, IM, bid

Pigs

10 mg/kg, IM, bid 7 mg/kg, in-feed

Dogs

20 mg/kg/day, PO

Cats

10 mg/kg, IM, bid 25 mg/kg, PO, bid

Dogs, cats

5--10 mg/kg, PO, bid

Clindamycin

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ANTIBACTERIALAGENTS

and some other antibacterials; they also reduce the activity of endotoxins in body fluids and may be beneficial in endotox­ cmia. Their action is inhibited by divalent cations, unsaturated fatty acids, and quaternary ammonium compounds. Polymyxins are not absorbed after PO or topical administration; plasma concentra­ tions peak -2 hr after parenteral administra­ tion. Blood concentrations usually are low, because polymyxins bind to cell mem­ branes as well as tissue debris and purulent exudates. The polymixins undergo renal elimination mostly as degradation products, and their plasma half-lives are 3-6 hr. They are notably nephrotoxic and neurotoxic and, as such, systemic tl1erapy at antimicro­ bial doses should be avoided. Neuromuscu­ lar blockade can be seen at higher concentrations. Intense pain at sites of irtjection and hypersensitivity reactions also can be expected. Polymyxin B is a potent histan1ine releaser. The main indication for parenteral use of polymyxins is life-threat­ ening infection due to gram-negative bacilli or Pseudomonas spp that are resistant to other drugs. Polymyxins are also used PO against susceptible intestinal infections. Anti-endotoxin binding activity is an additional therapy via slow IV bolus. Topical application is common, eg, for otitis externa. Recommended dose rates for polymyxins vary considerably. A general guideline is 20,000 U/kg, PO, bid; 5,000 U/kg, IM, bid; 50,000-100,000 U by intramanm1ary infusion; 100,000 U intrauterine in cattle. IV administration of polymyxins is potentially dangerous.

BACITRACINS Bacitracins are branched, cyclic, decapep­ tide antibiotics. Bacitracin A is the most active of the group and the main compo­ nent of the commercial bacitracin preparations used either topically or PO. These antibiotics are bactericidal. They interfere with cell membrane function, suppress cell wall formation by preventing the fom1ation of peptidoglycan strands, and inhibit protein synthesis. Bactericidal activity requires the presence of divalent cations, such as zinc. The spectrum of bacitracins is described as broad, but it is used primarily to treat gram-positive infections. Resistance is rare. Bacitracins are often used in combination with neomycin and polyn1yxins to enhance the antibacterial spectrun1. Bacitracins are not appreciably absorbed from the GI tract and are not used systemi-

2693

cally because of their pronounced nephrotoxicity. However, they are used locally in wound powders and ointments, dermatologic preparations, eye and ear ointments, and as feed additives in swine and poultry rations for growtl1 promotion. In antibiotic-associated pseudomembra­ nous colitis caused by Clostridium difficile cytotoxin, bacitracin (given PO) is considered an alternative to vancomycin. Hypersensitivity reactions to bacitracins are seen occasionally.

GLYCOPEPTIDES Vancomycin is a complex glycopeptide that binds to precursors of the peptidoglycan layer in bacterial cell walls. This effect prevents cell wall synthesis and produces a rapid bactericidal effect in dividing bacteria. Its efficacy is time dependent. Vancomycin is active against most gram-positive bacte1ia but is not effective against gram-negative cells because of their large size and poor penetrability. Resistance to vancomycin does not readily develop. The drug is widely clistributecl in the body. Excretion (in active form) is via the kidneys; in renal insuffi­ ciency, striking accumulations may develop. The plasma half-life in dogs is 2-3 hr. The only indication for use of parenteral vancomycin is serious infection clue to

methicilli.n-resistantStaphylococcus aure1£S. Although poorly absorbed, oral

vancomycin is used to treat antibiotic-asso­ ciated enterocolitis, especially if caused by Clostridium difficile. Febrile reactions and thrombophlebitis (because of tissue irritation) at injection sites may be seen. Hypersensitivity reactions are seen infrequently. Ototoxicity and nephrotoxicity were fairly common in the past but are rare today because of fewer impurities in the final form.

FOSFOMYCIN Fosfomycin, a phosphonic acid iliat contains a carbon-phosphorus bond, is a natural antibiotic produced by Streptomy­ cesfmdiae. It is a phosphoenolpyruvate analogue that irreversibly inhibits phosphoenolpyruvate transferase, an enzyme that catalyzes the first step of pepticloglycan synthesis of microbial cell walls. Its in vitro spectrum is broad, with potential efficacy toward isolates express­ ing multidrug resistance, including E1;cherichia coli and methicillin-resista.nt staphylococci. As a cell wall inhibitor, fosfomycin is bacte1icidal when present at the site of infection at therapeutic

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ANTll:lACTERIALAGENTS

concentrations. Cell wall inhibition is time dependent, but fosfomycin also exhibits a concentration-dependent effect. Resistance to fosfomycin is unconm10n and reflects the FosX or FosA enzyme, which hydrolyzes the drug. The gene for this protein is chromo­ somally mediated. When resistance occurs, it generally is not associated with multi­ drug resistance. Studies in people have demonstrated that fosfomycin distributes well to soft tissues, reaching tl1erapeutic breakpoints. Adverse effects of fosfomycin appear to be limited to diarrhea. Approved for human use in the USA as the trometh­ an1ine salt, its indication is as a one time (or up to 3 days) treatment of uncomplicated urinary tract infections in people. Fosfomy­ cin has been added to the World Health Organization's list of critically important drugs. Accordingly, its use should be reserved, along with other critically important drugs, to situations in which lower-tier drugs are no longer appropriate.

NOVOBIOCIN SODIUM Novobiocin is a narrow-spectrwn antibiotic that may be bacteriostatic or bactericidal at higher concentrations. It is active mostly against gran1-positive bacteria but also against a few gram-negative bacteria. There is a synergistic effect with tetracyclines. Many species of bacteria can develop resistance to novobiocin. Adverse reactions are quite frequent after administration. Its main use is in combination with other agents for treatment of bovine.mastitis.

TIAMULIN FUMARATE Tiamulin hydrogen fumarate is a sernisyn­ thetic derivative of pleuromutilin. Tiamulin is active against gram-positive bacteria, mycoplasmas, and anaerobes, including Brachyspira hyodysentmiae. It is also clinically effective in treatment of swine dysentery and mycoplasmal arthritis. Tiamulin is well absorbed when adminis­ tered PO. The dosage is 8.8 mg/kg/day for 3-5 days, in either food or water. The parenteral dosage for mycoplasmal pneumonia in pigs is 15 mg/kg. 1n poultry, tiamulin interferes with monensin and salinomycin metabolism, and if the drugs are fed together, they become toxic. Generally, however, tianutlin has few adverse effects.

IONOPHORES Ionophores are lipid-soluble molecules that transport ions across lipid cell membranes.

The subsequent disruption of cell mem­ brane permeability results in antibacterial effects. Monensin is an ionophore antibiotic derived from Streptornyces that forms complexes with monovalent cations, including sodiwn and potassiwn. The complexes are transported in a nonpolar manner across the bacterial cell membrane. As such, it acts as an Na+fH+ antiporter. Monensin blocks intracellular protein transpo1t, resulting in antibacterial and antin1alarial effects. Monensin is used extensively in the beef and dairy industries in feed to prevent coccidiosis and improve feed efficiency. Monensin also increases the production of propionic acid and thus prevents bloat.

RIFAMYCINS Several semisynthetic derivatives ( rifan1y­ cin SV, 1ifampin [1ifampicin], tifamide) of natural rifamycins have been used as extended-spectr1m1 antibiotics. Rifamycins interfere with the synthesis of RNA in microorganisms by binding to subw1its of sensitive DNA-dependent RNA polymerase. They are active against gram-positive organisms, some mycobacteria, a few strains of gran1-negative bacteria (mostly cocci; bacilli are more resistant), some anaerobes, and chlamydiae. At high concentrations, they are also active against several viruses. Ftmgal and yeast infections resistant to rifampin alone often respond when a rifamycin is added to an antifungal agent (eg, amphotericin B). Resistance to rifan1ycins may develop rapidly as a 1-step process. For this reason, they should be administered in combination with other antimicrobials, such as penicillins, erythromycin, miconazole, and an1pho­ tericin B. The primary use of the rifamycins in people has been to treat tubercul9sis. Rifan1pin has been used in foals to control Rhodococcus equi pneun1onia. Because 1ifamycins penetrate tissues and cells to a substantial degree, they are particularly effective against intracellular organisms. Rifampin is readily but incompletely ( -40%) absorbed from the GI tract, and plasma concentrations peak within 2-4 hr. Concun-ent feeding may reduce or delay absorption. Rifan1pin may also be adminis­ tered IM or IV. Approximately 75'Yer-80% of rifampin is bound to plasma proteins. It is widely distributed in body tissues and fluids because of its high lipid solubility. Rifampin is biotransformed to several metabolites, some of which are active, and is primarily excreted in bile ( used for cholangitis in

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ANTIBACTERIAL AGENTS

people) and to a lesser degree in urine. Enterohepatic cycling of the parent drug and its mam metabolite (desacetylrifampin) conunonly occurs. The elimination half-life of rifa.mpin is dose dependent: in horses it is -6 hr; in dogs, -8 hr. The plasma half-life progressively sho1tens by -400A, during the first 2 wk of treatment because of the induction of hepatic microsomal enzymes; conversely, it is increased with hepatic dysfunction. Rifan1pin is usually well tolerated and produces few adverse effects. GI distur­ bances and abnormalities in liver function (icterus) have been reported in people. Hypersensitivity reactions can also result from 1ifampin administration, and renal failure is a possible consequence when intennittent dosage schedules are followed. Partial, reversible imrnunosuppression of lymphocytes develops. Urine, feces, saliva, sputum, sweat, and tears are often colored red-orange by rifampin and its metabolites. CNS depression after IV administration and temporary inappetence are seen in horses. The dose range for rifampin in horses is 10-25 mg/kg/day, PO or parenterally. NITROFURANS Nitrofurans are synthetic chemotherapeutic agents with a broad antimicrobial spectrun1· they are active against both gram-positive and gran1-negative bacteria, including Salmonella and Giardia spp, trichomo­ nads, amebae, and some coccidial species. However, when compared with other antimicrobial chemotherapeutic agents, their potency is not of particular note. The nitrofurans appear to inhibit a number of microbial enzyn1e systems, including those uwolved m carbohydrate metabolism, and they also block the initiation of translation. However, their basic mechanism of action has no� yet been clarified. Their primary action IS bacteriostatic, but at high doses they are also bactericidal. They are much more _active in acidic environments (pH5.5 1s optimal for nitrofurantoin activity). Resistant mutants are rare, and clinical resistance emerges slowly. Among themselves, nitrofurans show complete cross-resistance, but there is no cross­ resistance with any other antibacterial agents. Because of very slight water solubility, the rutrofurans are used either PO or topically. No nitrofuran is effective systemically. They are either not absorbed at_all from the GI tract or are so rapidly elimmated that they reach inhibitory concentrations only in the urine. Toxic

2695

signs seen with excessive doses of nitrofuran derivatives include CNS involve­ ment (excitement, tremors convulsions peripheral neuritis), GI disturbances, po�r weight gam, and depression of spennato­ genesis. Various hypersensitivity reactions can also be seen. Some nitrofurans are carcinogenic, and their future use is in doubt. Nitrofurans are among the drugs for which extra-label use is prohibited in food animals in the USA. Nitrofurantoin The mechanism of action of nitrofurantoin is unique. It is reduced by bacte1ial flavoproteirlS to reactive intennediates that inhibit bacterial ribosomes and other macromolecules. Protein synthesis aerobic energy metabolism, DNA �d RNA synthesis, and cell wall synthesis are inhibited. Nitrofurantoin is bactericidal in urine at therapeutic doses. Resistance is rare. Nitrofurantoin is used to treat urinary tract infections caused by susceptible bacte­ ria, such as Esche'lichia coli, Staphylococ­ cus aureus, Streptococcus pyogenes, and Aerobacter aerogenes. Pro/,eus spp, Pseudomonas aeruginosa, and Streptococ­ cus faecalis are usually resistant. After administration PO, nitrofurantoin is rapidly and completely absorbed (the macrocrystal fonn takes longer) and is swiftly elinlinated by the kidneys, mainly by tubular secretion ( -400A, in the unchanged form). Sen1111 concentrations are low, and little unbow1d drug is available for diffusion into the tissues. The plasma half-life is only -2 0 min. Nitro­ furantoin is concentrated in acid urine. When the pH reaches -5, the drug becomes supersaturated without precipitation, and its antibacterial action is maximal. Nitrofurantoin can be administered PO or parenterally. The dosage for dogs and cats 1s4.4 mg/kg, PO, tid for4-10 days. Adverse effects are not common at usual dosages, but nausea, vomiting, and diairhea can develop. CNS disorders have been seen and polyneuropathy is a serious effect seen in people. Animals with decreased renal function have a predisposition for polyneuritis. Various manifestations of hypersensitivity reactions can be seen. Yellow discoloration of teeth occasionally has been reported in very young aninlals. Nitrofurazone Nitrofurazone is only slightly soluble in water but, in general, corresponds to nitro­ furantoin in tem1s of its mechanism of action, antimicrobial spectrun1, potency,

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ANTIBACTERIALAGENTS

and physicochemical characteristics. Its main indications include the treatment of bovine mastitis, bovine metritis, and wounds. However, pus, blood, and milk reduce the antibacterial activity. Nitrofura­ zone is also used as a feed additive (0.05%) to control intestinal bacterial and coccidial infections. The withdrawal time for nitrofurazone in pigs is 5 days.

Furazolidone This is a nitrofuran with a wide range of antimicrobial activity that includes

Clostri.dimn, Salmonella, Shigella, Staphy­ lococcus and Streptococcus spp, and E coli. It is also active against Eimeria and Histomonas spp. It is usually administered

PO to treat intestinal infections but may also be applied topically. The usual oral dose of furazolidone in calves is 10-12 mg/kg, bid for 5--7 days. Caution should be exercised when treating small calves (eg, Jersey breed) to avoid excessive dose rates, lest neurotoxicity result; signs include head tremors, ataxia, visual impairment, and convulsions.

Miscellaneous Nitrofurans Nifuraldezone, like furazolidone, is used to control bacterial enteritis in calves. Nifurprazine is used only topically as an antibacterial agent. Furaltadone is used both PO to prevent intestinal infections and directly into the teat to treat mastitis.

NITROIMIDAZOLES The 5-nitroirnidazoles are a group of drugs that have both antiprotozoal and antibacte­ rial activity. Nitroimidazoles with activity against trichomonads and arriebae include metronidazole, tinidazole, nin1orazole, flunidazole, and ronidazole. Metronidazole and nimorazole are effective in treatment of giardiasis, whereas din1etridazole, ipronidazole, and ronidazole control histomoniasis in poultry. Several nitroimida­ zoles have activity against trypanosomes. Metronidazole, ronidazole, and other nitroin1idazoles are active against anaerobic bacteria. Metronidazole is the compound that has been the most studied and is discussed as the prototype of the group. Extra-label use of nitroimidazoles is prohibited in food anin1als in the USA.

Metronidazole Metronidazole has been used for many years in therapeutic management of tricho­ moniasis, giardiasis, and amebiasis. It is

active against obligate anaerobic bacteria. It is not active against facultative anaerobes, obligate aerobes, or microaerophilic bacteria other than Campylobacterfetus. At concentrations readily attained in serun1 after PO or parenteral administration, metronidazole is active againstBacteroides

fragilis, B melaninogenicus, F'usobacte­ iium spp, and Clostridium pei.fringens and other Clostridium spp. It is generally

less active against nonsporefomling, gram-positive bacilli such as Actinomyces, Propioniba.cterium, Bifidobacterium, and Eubacterium spp. Metronidazole is also somewhat less active against gram-positive cocci such asPeptostreptococcus and Peptococcus spp, but the less sensitive strains are usually not obligate anaerobes. Metronidazole is bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentration. The precise mode of action is unclear, but reduction in an anaerobic environment yields a compound that then binds to DNA, causing loss of the helical structure, strand breakage, and impairment of DNA function. Only susceptible organisms (bacte1ia and protozoa) appear to be capable of metabo­ lizing tl1e drug. The pharrnacokinetic pattern of metronidazole generally follows that expected of a highly lipid-soluble basic drug. It is readily but vaiiably absorbed from the GI tract (bioavailability 60%-100%), with seflil1l concentrations peaking within 1-2 hr, and becomes widely distributed in all tissues. Metronidazole penetrates the blood­ brain barrier and also attains therapeutic concentrations in abscesses and in empyema fluid. It is only slightly bound to plasma proteins. Biotransfom1ation is quite extensive, and parent drug and metabolites are excreted by both the renal and biliary routes. The elimination half-life in dogs is -4.5 hr, and in horses, 1.5-;3.3 hr. The principal clinical indications for metronidazole include the treatment of specific protozoa] infections (amebiasis, trichomoniasis, giardiasis, and balantidia­ sis) and anaerobic bacterial infections such as those that may be seen in abdominal abscesses, peritonitis, empyema, genital tract infections, periodontitis, otitis media, osteitis, arthritis, and meningitis, and in necrotic tissue. Metronidazole has been successfully used to prevent infection after colonic surgery. Nitroimidazoles also act as radiosensitizers, and metronidazole has been used as an acljunct to the radiotherapy of solid tun1ors. Adverse effects are not commonly associated with metronidazole. High doses

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ANTIFUNGALAGENTS

may induce signs of neurotoxicity in dogs, such as tremors, muscle spasms, ataxia, and even convulsions. Reversible bone marrow depression has been repo1ted. The drug should not be used in pregnant animals, particularly during the first trimester, although the evidence for carcinogenicity and mutagenicity is still tenuous. Metroni­ dazole may produce a reddish brown discoloration of the urine due to unidenti­ fied pigments. Recommended dose rates for metroni­ dazole in dogs are 44 mg/kg, PO, followed by 22 mg/kg, qid, for anaerobic infections; 25 mg/kg, PO, bid, for giardiasis; and 66 mg/kg/day, PO, for trichomoniasis. Courses of therapy are generally 5-7 days. Both PO and IV preparations are available.

2697

HYDROXYQUINOLINES The 8-hydroxyquinolines are a group of synthetic compounds with antibacterial, antifungal, and antiprotozoal activity. The best-known compounds of this class are iodochlorhydroxyquin (clioquinol), diiodohydroxyquin (iodoqu.i.nol), broxyquino­ line, and hydroxyquinoline. Because they are not absorbed from the GI tract to any degree, their main use has been to treat intestinal infections caused by bacteria or protozoa (such as Giardia). Hydroxyquinolines are also used topically for skin infections caused by bacteria and fungi. Hydroxyquinolines are potentially neurotoxic when used for prolonged periods. The dose for a 455-kg horse is 10 g/day, PO, using a decreasing dosage regimen to discontinue medication.

ANTIFUNGAL AGENTS Pathogenic fungi affecting animals are eukaryotes, generally existing as either filamentous molds (hyphal forms) or intracellular yeasts. Fungal organisms are characterized by a low invasiveness and virulence. Factors that contribute to fungal infection include necrotic tissue, a moist environment, and irnmunosuppression. Fungal infections can be primarily superficial and irritating (eg, dermatophyto­ sis) or systemic and life threatening (eg, blastomycosis, cryptococcosis, histoplasmo­ sis, coccidioidomycosis). See also DERMATO­ PHYTos,s, p 872, and FUNGAL INPECTIONS, p 632. Clinically relevant dimorphic fungi grow as yeast-like forms in a host but as molds in vitro at room temperature; they include Candida spp, Blastomyces dermatitidis,

Coccidioides immitis, Histoplasma capsulatum, Sporothrix schenckii, and Rhinosp01idium.

Several factors can lead to therapeutic failure or relapse after antifungal therapy. Drug access to fungal targets is often com­ promised. Host inflan1matory response may be the first barrier, followed by location in sanctuaries (brain, eye, etc) as a second barrier for some infections, and the organisms themselves as a third barrier. The fungal cell wall is rigid and contains chitin, which along with polysaccharides, acts as a barrier to drug penetration. The cell membrane contains sterols such as ergosterol, which inffuences the efficacy

and potential resistance to some drugs. Cryptococcus and occasionally Sporothrix schenckii produce an external coating or slime layer that encapsulates the cells and causes them to adhere and clump together. Finally, regarding drug access, most infections are located inside host cells, the lipid membrane of which can present a final barrier. Discontinuing therapy after clinical signs have resolved but before infection is eradicated also leads to therapeutic failure. Therapy should extend well beyond clinical cure. Once drugs reach the site of action, therapeutic success is impeded by the nature of fungal infections. Fungal growth is slow, yet most anti.fungal drugs work better in rapidly growing organisms. Likewise, most anti.fungal agents are fimgistatic in action, with clearance of infection largely dependent on host response. As such, the duration of therapy is long, and the "get in quick, hit hard, and get out quick" recom­ mendation for antibacterial therapy is not appropriate for anti.fungal therapy; care must be taken to not discontinue therapy too early. However, longer duration of therapy contributes to another conunon cause of therapeutic failure: host toxicity. Because both the anti.fungal target organism and the host cells are eukaryotic, the cellular targets of fungal organisms are often similar to the host structures. Therefore, as a class, antifungal drugs tend to be more

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ANTI FUNGAL AGENTS

toxic than antibacterial drugs, and the number of antifungal drugs approved for use are markedly fewer than the number of antibacterial drugs. Drugs that can be used locally (including topically) or character­ ized by distribution to sites of infection (eg, liposomal products) may decrease this risk. The slow growth that characterizes fungal infections means that acquired resistance occurs less commonly than in bacterial infections. Therapeutic failure may also reflect the inability of the immunocompro­ mised host to overcome residual fungal populations inhibited by the drug; those antifungals that are also (positive) immunomodulators may be more effective. A nwnber of serious systemic fungal diseases are well recognized in several parts of the world (seep 632). Antifungal agents have greatly reduced previously recorded human mortality rates due to systemic mycoses. A relatively na1Tow selection of dtugs is used in these cases.

POLYENE MACROLIDE ANTIBIOTICS Arnphotericin B is the model polyene macrolide antibiotic and is the sole member of this class used systemically. Polyene anti.fungal antibiotics are large molecules, consisting of a long polyene, lipid-soluble component and a markedly hydrophilic component. Amphotericin B acts as both a weak base and a weak acid, and as such is amphoteric. The polyene macrolides have been isolated from various strain� of bacteria; amphotericin B is an antibiotic product of Stre'J)tomyces nodosus. Amphotericin B, nystatin, and pimaricin (natan1ycin) are the only polyene macrolide antibiotics used in veterinary medicine."The polyenes are poorly soluble in water and the common organic solvents. They are reasonably soluble in highly polar solvents such as dimethylformamide and dimethyl sulfoxide. In combination with bile salts, such as sodium deoxycholate, amphotericin B is readily soluble (micellar suspension) in 5% glucose. This colloidal preparation has been used for IV in.fusion. The polyenes are unstable in aqueous, acidic, or alkaline media but in the dry state, in the absence of heat and light, they remain stable for indefinite periods. They should be adminis­ tered parenterally (diluted in 5% dextrose) as freshly prepared aqueous suspensions. Lack of stability indicates that labeled expiration dates should be adhered to once the product is diluted. Amphotericin B is also prepared as liposomal and lipid-based preparations, enhancing its safety without loss of efficacy.

Antifungal Activity Mode of Action: The polyenes bind to sterol components in the phospholipid­ sterol membranes of fungal cells to form complexes that induce physical changes in the membrane. The number of conjugated bonds and the molecular size of a particular polyene macrolide influence its affinity for different sterols in fungal cell membranes. Amphotericin B has a greater affinity for fungal ergosterol, the major sterol in fungal membranes, than for eukaryotic (host) cell membrane cholesterol. The long polyene structure causes the formation of channels in the fungal cell membrane. The resultant loss of membrane permeability results in the loss of critically important molecules. Potassiw11 ion efflux from the fungal cell and hydrogen ion influx cause internal acidi­ fication and a halt in enzymatic functions. Sugars and amino acids also eventually leak from an arrested cell. Fungistatic effects are most often evident at usual polyene concentrations. High drug concentrations and pH values between 6.0 and 7.3 in the surrounding medium may lead to ftmgicidal rather than fungistatic action. In addition to these direct effects on susceptible yeasts and fungi, evidence suggests that amphotericin B may also act as an i.m.mtmopotentiator (both humoral and cell mediated), thus enhancing the host's ability to overcome mycotic infections. Fungal Resistance: Polyene macrolides are inherently resistant to dermatophytes. Acquired resistance to the polyene antifungal macrolides is rare both clinically and in vitro. Pythium, a pseudofungus, is less susceptible, because it contains limited ergosterol in its cell membranes. Resistance has been documented for Candida spp, which are among the more rapidly growing fungal organisms. In general, resistance develops slowly and does not reach high levels, even after prolonged treatment. Antifungal Spectra: The polyene antibiot­

ics have broad antifungal activity against organisms ranging from yeasts to filamen­ tous fungi and from saprophytic to pathogenic fungi, but tl1ere are great differences between the susceptibilities of ilie various species and strains of fungi. They are ineffective against dern1atophytes. In vitro susceptibilities (both resistant and highly susceptible) do not always correlate well with the clinical response, which suggests that host factors may also play a role. Many algae and some protozoa

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ANTIFUNGALAGENTS

(Leishmania, 1'1ypanosoma, Trichomonas, and Ent,amoeba spp) are sensitive to the polyenes, but these compounds have no significant activity against bacteria, actinomycetes, virnses, or animal cells. Amphotericin Bis effective against yeasts (eg, Candid.a spp, Rhodotorula spp, C?yptococcus neojormans ), dimorphic fungi (eg, Histoplasma capsulatum, Blastomyces de rmatil'idis, Coccidioides immitis), de1matophytes (eg, 'l'richophyton, Microsporum, and Epidermophyton spp), and molds. It also has been used successfully to treat disseminated sporotiichosis, pythiosis, and zygomycosis, although it may not always be effective. Nystatin is mainly used to treat mucocutaneous candidiasis, but it is effective against other yeasts and fungi. The antimicrobial activity of pimaiicin is similar to that of nystatin, although it is mainly used for local treatinent of candidi­ a5is, trichomoniasis, and mycotic keratitis. Preparations: Amphotericin Bis available as an IV solution complexed to bile acids but also as several different preparations complexed to lipid mixtures. Because reticuloendothelial cells phagocytize the lipid component, directed delivery to the site of fungal infection is facilitated, reducing renal exposure. Prolonged antifungal activity (compared with nonliposomal prepai·ations) has been documented. Pharmacokinetic Features Absorption: The polyene macrolide antibiotics are poorly absorbed from the GI tract. Amphotericin Bis usually administered IV or topically and occasion­ ally locally, intrathecally, or intraocularly. Nystatin and piran1ycin are mostly applied topically. Nystatin is given PO to treat intestinal candidiasis. Absorption is minimal from sites of local application. Distribution: Amphotericin Bis widely distributed in the body after IV infusion. It associates with cholesterol in host cell membranes throughout the body and is subsequently released slowly into the circulation. Penetration into the CSF, saliva, aqueous humor, vitreous humor, and hemodialysis solutions is generally poor. Amphotericin B becomes highly bound to plasma lipoproteins ( -95%). Complexing ainphotericin B with various lipid-based products alters the distribution. Biotransformation and Excretion: The disposition of ainphote1icin Bis not well described in companion ariin1als.

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Approximately 5% of a total daily dose of an1photericin Bis excreted unchanged in the urine. Over a 2-wk period, -200,1, of the drug may be recovered in the urine. The hepatobiliary system accounts for 200/o-300,1, of excretion. The fate of the remainder of an1photericin Bis unknown. Pharmacokinetics: Amphotericin Bhas a biphasic elimination pattern. The initial phase lasts 24 hr, during which levels fall rapidly (700,1, for plasma and 500,1, for urine). The second elimination phase has a 15-day half-life, during which plasma concentra­ tions decline very slowly. Arnphotericin Bis usually infused IV, every 48-72 hr, w1til the total cunrnlative dosage has been reached. The disposition of the various lipid-com­ plexed ainphotericin B products is vaiiable. Because of its small size, AmBisome® is chai·acterized by the slowest uptake by reticuloendothelial cells and thus the highest plasma drng concentrations of ai11photericin B. However, the ainount of free versus complexed ainphotericin Bis not cleai·. AmBisome also was able to achieve CNS concenti·ations and was associated with the least nephrotoxicity in hwnan studies. ArnBisome has been studied in Beagles. Achievable amphotericin concentrations were much higher at equivalent doses of AmBisome compared with other products; further, dogs were able to well tolerate 4 mg/kg for 30 days. Amphotericin concentrations accumulate with multiple dosing when administered as ArnBisome. Therapeutic Indications and Dose Rates Arnphotericin Bis used principally to treat systemic mycotic infections. Despite its ability to cause nephrotoxicity (seep 2702), ainphotericin Bremains a commonly used antifungal agent because of its effective­ ness. Multiple approaches to delivery have been described in an attempt to minin1ize nephrotoxicity. In addition, dosing continues until a maximal cumulative dose is reached, with the ainount varying with the fungal organism. Nystatin is primarily indicated for treatl11ent of mucocutaneous (skin, oropharynx, vagina) or intestinal candidiasis; pimaricin is mainly used in therapeutic management of mycotic keratitis. General dosages for some polyene macrolide antibiotics are listed in TABLE 52. The dose rate and frequency should be adjusted as needed for the individual animal.

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ANTIFUNGALAGENTS

l&N•iti

DOSAGES OF POLYENE MACROLIDE ANTIBIOTICS

Polyene Macrolide

Dosage, Route, and Frequency

Amphotericin B (0.1 mg/mL in 5% dextrose)

0.1-1 mg/kg, given IV slowly, 3 times/wk Total dose: 4--11 mg/kg

Amphotericin B lipid complex injection 1-3 mg/kg, IV, every other day or 3 times/wk (Abelcet®) Total dose: 12-24 mg/kg Amphotericin B liposome (AmBisome®)

3- 4 mg/kg, IV, every other clay or 3 times/wk Total dose: 12-30 mg/kg

Nystatin

50,000-150,000 U, PO, tid (dogs)

Pimaricin (5% ophthalmic solution)

l drop, instilled into the eye, every 1-2 hr

Special Clinical Concerns Adverse Effects and Toxicity: Oral

administration of nystatin can lead to anorexia and GI disturbances. The IV infusion of amphotericin B can cause an anaphylactoid reaction due to direct mast cell degranulation. A pre-test dose is recommended to detect this reaction, and pretreatment with H 1 antihistamines and short-acting glucocorticoids may be appropriate. Th.rombophlebitis may occur with perivascular leakage. The primary toxicity associated with amphotericin B is nephrotoxicity. Within 15 min of IV administration of amphotericin B, renal aiterial vasoconstriction occms and lasts for 4--6 hr. This leads to diminished renal blood flow and glomerular filtration. Because ainphotericin B binds to the cholesterol component in the membranes of the distal renal tubules, a change in penneability occurs in these cells, leading to polymia, polydipsia, concentration defects, ai1d acidification abnormalities. The net result is a distal renal tubulai· acidosis syndrome. The metabolic acidosis leads to bone buffering, U1e excessive release of calcium into the circulation, and ultin1ately neph.rocalcinosis due to calciw11 precipita­ tion in the acidic environment of U1e distal tubules. Almost eve,y animal treated with an1photericin B develops some degree of renal impairment, which may become permanent depending on the total cumulative dose. The ad.ministration of ainphotericin B can lead to a nw11ber of other adverse effects, including anorexia, nausea, vomiting, hypersensitivity reactions, drug fever, nom10cytic normochromic anemia, cardiac arrhythmias (and even aITest), hepatic dysfunction, CNS signs, ai1d thrombophlebitis at U1e injection site. A number of acljuvant Ll1erapies ai·e used to minimize adverse events of ai11photericin

B. Pretreatment with antiemetic and antihista.minic agents prevents the nausea, vomiting, and hypersensitivity reactions. Giving corticosteroids IV also limits severe hypersensitivity reactions. Mannitol (1 g/kg, IV) with each dose of amphotericin B, and sodium bicai·bonate (2 mEqlkg, IV or PO, daily) may help prevent acidification defects, metabolic acidosis, and azotemia; however, clinical evidence of efficacy has not been proved. Saralasin (6-12 mcg/kg/ min, IV) and dopamine (7 mcg/kg/min, IV) infusions have prevented oliguria and azotemia induced by ainphote1icin B in dogs. Administering IV fluids or fu.rosemide before ainphotericin B prevents pro­ now1ced decreases in renal blood flow and glomerular filtration rate. Newer prepara­ tions in which an1photericin B is mixed with lipid or liposomal vehicles (particularly liposomes) ai·e safer ai1d have maintained efficacy.

Interactions: A.mphotericin B may be combined with otl1er antin1icrobial agents with synergistic results. This often allows both the total dose of ainphotericin B ai1cl the length of therapy to be decreased. Exainples include combinations of 5 f-lucytosine and ainphotericin B for treatment of cryptococcal meningitis, minocycline and ainphotericin B for coccidioidomycosis, and irnidazole ai1cl an1photericin B for several systemic mycotic infections. Rifainpin may also potentiate the antifungal activity of ainphotericin B. Drugs that should be avoided clming ai11photericin B therapy include aininogly­ cosides (nephrotoxicity), digitalis drugs (increased toxicity), curai"izing agents (neuromuscular blockade), mineralocorti­ coids (hypokalemia), thiazide diuretics (hypokalemia, hyponatremia), anti.neoplas­ tic drugs (cytotoxicity), and cyclosporine (nephrotoxicity).

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ANTIFUNGALAGENTS

Effects on Laboratory Tests: Treat­ ment with polyene macrolide antibiotics increases plasma bilirubin, CK, AST, ALT, BUN, eosinophil count, and urine protein, and decreases plasma potassium and platelet count. IMIDAZOLES Imidazoles may have antibacterial, antifungal, antiprotozoal, and anthehnintic activity. Several distinct phenylimidazoles are therapeutically useful antifungal agents with wide spectra against yeasts and filamentous fungi responsible for either superficial or systemic infections. The anthehnintic thiabendazole is also an imidazole with antifungal properties. Clotrin1azole, miconazole, econazole, ketoconazole, itraconazole, and fluconazole are the most clinically important members of this group. Posaconazole and voricona­ zole are among the newer drugs; v01icona­ zole is approved for use in people to treat aspergillosis. lrnidazoles generally are poorly soluble in water but can be dissolved in organic solvents such as chlorofonn, propylene glycol, and polyet110xylated castor oil (prepa­ ration for IV use but dangerous in dogs). An exception is fluconazole. lmidazoles are weak di basic agents. Alterations in side-chain structure determine antifungal activity as well as the degree of toxicity. Antifungal Activity Mode of Action: Imidazoles alter the cell membrane permeability of susceptible yeasts and fungi by blocking the synthesis of ergosterol (demethylation of Janosterol is inhibited), the primary cell sterol of fungi. The enzyme targeted is a fungal cytochrome (CYP450). Other enzyn1e systems are also impaired, such as those required for fatty acid synthesis. Because of the drug-induced changes of oxidative and peroxidative enzyn1e activities, toxic concentrations of hydrogen peroxide develop intracellularly. The overall effect is cell membrane and internal organelle disruption and cell death. The cholesterol in host cells is not affected by the in1idazoles, although some drugs impair synthesis of selected steroids and drug-metabolizing enzymes in the host. Because in1idazoles impair synthesis, a lag tin1e to efficacy occurs. This lag ti.me may be prolonged because of the long half-life of t11ese drugs. Fungal Resistance: Sensitivity to the imidazoles varies greatly between various

2701

strains of yeasts and fungi, but neither natural nor acquired resistance appears to be prevalent. Antimicrobial Spectra: The antifungal imidazoles also have some antibacterial action but are rarely used for this purpose. Miconazole has a wide antifungal spectrun1 against most fungi and yeasts of veterinary interest. Sensitive organisms include

Blastomyces clermatiticlis, Paracoccicli­ oicles brasiliensis, Histoplasma capsula­ tum, Canclicla spp, Coccidioides immitis, C1yptococcus neoforrnans, andAspergillus Jwnigatus. SomeAspergillus and Madurella spp are only marginally

sensitive. Ketoconazole has an anti.fungal spectrwn similar to that of miconazole, but it is more effective against C immitis and some otl1er yeasts and fungi. ltraconazole and fluconazole are the most active of the antifungal i.rnidazoles. Their spectrum includes din1orphic fungal organisms and dennatophytes. They are also effective against some cases of aspergillosis (60%-700A,) and cutaneous sporotiichosis. Clot1·in1azole and econazole are used for superficial mycoses (de1matophytosis and candidiasis); econazole also has been used for oculomycosis. Thiabendazole is effective againstAspmgillus and Penicillium spp, but its use has largely been replaced by the more effective intidazoles. Voriconazole is approved for hmnan use in treatment of Aspei·gillus but is effective against many other fungal organisms.Posaconazole may be more effective than itraconazole or fluconazole but may be associated with more adverse effects.

Pharmacokinetic Features Absorption and Distribution: The imidazoles are rapidly but sometimes erratically absorbed from the GI tract; plasma levels peak witllin 2 hr after adminis­ tration PO. Fluconazole is an exception, being close to 100% bioavailable after administration PO. Except for fluconazole, an acidic environment is required for dissolution of the in1idazoles, and a decrease in gastric acidity can reduce bioavailability after administration PO. The rate of absorption appears to be increased when the drug is given with meals, but reports are conflicting. Because oral bioav­ ailability can be very poor with noncom­ mercial inlidazole products, caution is recommended with compounded products, and monitoring is recommended if a compounded preparation is used.

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ANTIFUNGALAGENTS

Imidazoles appear to be widely distributed in the body, with detectable concentrations in saliva, milk, and cerumen. CSF penetra­ tion is poor except for fluconazole, which reaches 500/1r-900A, of plasma concentrations. Most imidazoles (except fluconazole) are highly protein bound in the circulation (>95%), most to albumin. The highest concentrations of i.rnidazoles are found in tl1e liver, adrenal glands, lungs, and kidneys. Biotransformation and Excretion:

Hepatic metabolism is the primary route of elimination. Metabolism of ketoconazole and most other in1idazoles by oxidative pathways is extensive. Only -2%-4% of a dose adnunistered PO appears w1changed in the urine. Itraconazole is metabolized to an active metabolite that may contribute significantly to antimicrobial activity. The biliary route is the major excretory pathway (>800A,); -200A, of the metabolites are eliminated in the urine. Fluconazole (in people) is eliminated (;,c9()0A,) unchanged in the urine. The kinetics of voriconazole have not yet been evaluated in anin1als. Pharmacokinetics: The rate of elimina­ tion of ketoconazole appears to be dose dependent-the greater the dose, the longer the elimination half-life. There is also a biphasic elimination pattern, with rapid elimination in the first 1 2- hr, then a slower decline over the next 6-9 hr. Ketoconazole is usually administered bid. The half-life of itraconazole is longer (up to 48 hr in cats), thus allowing treatment once to twice daily. Because of the long half-life and mechanism of action (impaired synthesis of the fungal cell membrane), time to efficacy may take longer than drugs that have more rapid actions (such as an1phofericin B). Therapeutic Indications and Dose Rates

The irnidazoles are used to treat systemic fungal diseases, dem1atophyte infections

IM=iiiii

that have not responded to griseofulvin or topical therapy, Malassezia infection in dogs, aspergillosis, and sporotrichosis in animals that cannot tolerate or do not respond to sodium iodide. For serious infections, combination with amphotericin B is strongly recommended. Among the irnidazoles, tluconazole may be more likely to distribute into tissues that are tough to penetrate. Both itraconazole and tlucona­ zole are generally preferred to other in1idazoles for treatment of systemic fungal infections, including aspergillosis and sporotrichosis. Topically applied in1idazoles (clotrirnazole, miconazole, econazole) are used for local dennatophytosis. Thiabenda­ zole is included in some otic preparations for treatment of yeast infections. Enilconazole is an in1idazole that can be applied topically for treatment of dermato­ phytosis and aspergillosis. It has been used safely in cats, dogs, cattle, horses, and chickens and is prepared as a 0.2% solution for treatment of fungal skin infections. When infused into the nasal turbinates of dogs with aspergillosis, enilconazole treated and prevented the recurrence of fungal disease. When applied topically to dog and cat hairs, enilconazole inhibits fungal growth in 2 rather than 4--8 treatments, as is necessary with other topically administered antifungal agents. General dosages for the antifungal in1idazoles are listed in TABLE 53. The dose rate and frequency should be adjusted as needed for the individual animal. Special Clinical Concerns Adverse Effects and Toxicity: The

imidazoles given PO result in few adverse effects, but nausea, vomiting, and hepatic dysfunction can develop. Ketoconazole in particular is associated with hepatotoxicity, especially in cats. Because irnidazoles also inhibit CYP450 associated with steroid synthesis, as a result, sex steroids, including testosterone and adrenal steroid (cortisol),

DOSAGES OF IMIDAZOLES

Imidazole

Dosage, Route, and Frequency

Enilconazole

10 mg/kg in 5-10 mL, bid for 7-14 days

Fluconazole

5-10 mg/kg, PO, once to twice daily

Itraconazole

5-10 mg/kg, PO, once to twice daily

Ketoconazole

5-20 mg/kg, PO, bid (dogs)

Thiabendazole

44 mg/kg/day, PO, or 22 mg/kg, PO, bid

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ANTI FUNGAL AGENTS

metabolism is inhibited. Adrenal respon­ siveness to adrenoco1ticotropic hom1one (ACTH) will be decreased, pruticularly with ketoconazole. Reproductive disorders related to ketoconazole administration may be seen in dogs. Vmiconazole is associated with a number of adverse effects in people, including vision disturbru1ces. Interactions: Imidazoles, in general, inhibit the metabolism of many drugs. Although ketoconazole has the broadest inhibitory effects, fluconazole followed by itraconazole also inhibit metabolism. Concurrent administration of these drugs with other drugs metabolized by the liver ru1d potentially toxic should be done only with extreme caution. lmidazoles also ru·e substrates for P-glycoprotein trru1sport protein ru1d may compete with other substrates, causing higher concentrations. Many of the substrates for P-glycoprotein ru·e also substrates for CYP450. Rifru11pin, which is a P-glycoprotein substrate, decreases serum ketoconazole because of microsomal enzyme induction. The absorption of the imidazoles, except for that of fluconazole, is inhibited by concurrent administration of cimetidine, ranitidine, ru1ticholinergic agents, or gastric ru1tacids. The risk of hepatotoxic­ ity is increased if ketoconazole ru1d griseofulvin are administered together. Imidazoles might be used concurrently with other ru1tifu.ngals to facilitate synergistic efficacy. Effects on Laboratory Tests: Treat­

ment with imidazoles increases AST, ALT, plasma bilirubin, ru1d plasma cholesterol. Adrenal responsiveness is altered. FLUCYTOSINE

Flucytosine (5-fluorocytosine) is a fluorinated pyrin1idine related to fluoro­ macil that was initially developed as ru1 ru1ti.neoplastic agent. It should be stored in airtight containers protected from light. Solutions for infusion ru·e unstable ru1d should be stored at 15°-20° C. Usually, it is given PO in capsules. Antifungal Activity Mode of Action: Flucytosine is

converted by cytosine derullinase in fungal cells to fluoromacil, which then inte1-feres with RNA ru1d protein synthesis. Fluoroma­ cil is metabolized to 5-fluorodeoxyuridylic acid, ru1 inhibitor of thymldylate synthetase. DNA synthesis is then halted. Mrunmaliru1

2703

cells do not convert large amounts of flucytosine to fluoromacil ru1d, thus, are not affected at usual dosage levels. Fungal Resistance: Resistru1ce to

flucytosine cru1 develop rapidly even during the course of treatment; this precludes its use as the sole treatment for mycotic infections. The mechru1isms of resistance ru·e not completely tmderstood. Antifungal Spectra: The following are

the main orgru1isms usually sensitive to flucytosine: Cryptococcus neof80%). The clearru1ce of flucytosine is approximately equivalent to that of creatini.ne. In renal fail me, elimination of flucytosine is mru·kedly impaired. Pharmacokinetics: With noimal renal function, the plasma half-life of flucytosine is usually 2-4 hr but may be up to 200 hr with oliguria. Serum levels of 50-100 mcg/ mL are usually in the therapeutic rru1ge. Therapeutic Indications and Dose Rates

The more common indications for flucytosine include c1yptococcal meningitis, used together with runphotericin B (-300/o of isolates develop resistru1ce during the com-se of treatment); cru1didiasis (-900/o of isolates ru·e usually sensitive); aspergillosis (some strains are sensitive at 100 mcg/mL). These include GI signs (nausea, vomiting, diarrhea) and reversible hepatic and hematologic effects (increased liver enzymes, anemia, neuti·openia, thrombocytopenia). In dogs, erythernic and alopecic demiatitis may be seen but subsides when the drug is discontinued.

Interactions: There is synergistic antiftmgal activity between an1photericin B and ketoconazole, and the combination may retard the emergence of strains resistant to flucytosine. The renal effects of ampho­ tericin B prolong elimination of flucytosine. If flucytosine is used together with immunosuppressive drugs, severe depression of bone marrow ftmction is possible. Effects on Laboratory 1ests: Treat­ ment with flucytosine increases alkaline phosphatase, AST, ALT, and other liver leakage enzymes, and decreases RBC, WBC, and platelet counts. GRISEOFULVIN

Griseofulvin is a systemic antiftmgal agent effective against the conunon denna.to­ phytes. It is practically insoluble in water and only slightly soluble in most organic solvents. Pa.iticle sizes of g1iseofulvin vary from 2. 7 im1 ( ultra.i11icrosizecl) to 10 pm (microsized). Antifungal Activity Mode of Action: Dermatophytes concenti·ate griseofulvin through an energy-dependent process. Griseofulvin then disrupts the mitotic spindle by interacting with the polyn1erized microtu­ bules in susceptible demiatophytes. This leads to production of multinuclea.te ftmgal

Fungal Resistance: Demiatophytes can be ma.de resistant to griseofulvin in vitro.

active againstMicrosporum, Epidei·mo­ phylon, and Trichophylon spp. It has no effect on bacteria. (incluclingAclinomyces a.i1d Nocardia spp), other fungi, or yeasts. Pharmacokinetic Features

Absorption: Plasma levels peak -4 hr

after administration PO, but absorption from the GI tract continues over a prolonged period. Absorption is highly va.ifable and influenced by a number of factors. The rates of disaggregation and dissolution in the GI tract limit the bioavailability of griseofulvin; thus, microsizecl and ultra.i11icrosizecl pa.iticles are usually used. High-fat meals, ma.i·ga.i·ine, or propylene glycol significa.i1tly enhance GI a.bso1vtion of griseofulvin a.i1d a.re indicated if the microsized particles are used. Distribution: Griseofulvin is deposited in keratin precursor cells within 4-S hr of administration PO. Sweat a.i1cl transde1mal fluid loss appear to play an i.mpo1ta.i1t role in griseofulvin transfer in the stratum comeun1. When tl1ese cells differentiate, griseofulvin remains bound and persists in keratin, ma.king it resistant to fungal invasion. For this reason, new growth of hair, nails, or horn is the first to become free of fungal infection. As the ftmgus-conta.ining keratin is shed, it is replaced by nom1al skin and hair. Only a small fraction of a dose of griseofulvin remains in the body fluids or tissues. Biotransformation and Pharmacoki­ netics: Depending on the species, 100/12 hr). GI safety appears to be greater for rneloxican1 than for nonselective NSAlDs, and meloxica.m has been shown to be chondroneutral in rodent studies. Deracoxib: Deracoxib, the first NSAID of the coxib class approved for use in dogs, is available in a beef-flavored chewable tablet fommlation in the USA. Deracoxib has been shown to inhibit COX-2-rnediated PGE, production. COX-1:COX-2 ratios repmted for deracoxib in in vitro cloned canine ceU assays indicate it is 1,275-fold more selective for COX-2, whereas ln vitro canine whole blood assays indicate it is 12- to 37-fold selective for COX-2. Deracoxib is indicated for the control of postoperative pain and inflammation associated with orthopedic surgery at a dosage of 3-4 mg/kg/day for up to 7 days, PO, and for the control of pain and i.nflanm1ation associated with osteoa.1thritis a.t a dosage of 1-2 mg/kg/day, PO. Once absorbed, protein binding is >90%, and the elimination half-life is 3 hr. Firocoxib: Firocoxib is a coxib-class

NSAID approved in the USA and Europe for the control of pain and inflammation associated with osteoaithritis and for the control of postoperative pain and inflanuna­ tion associated with soft-tissue and orthope­ dic surgery in dogs. In Canada, Australia, and New Zealand it is approved for use in osteoarthritis and soft-tissue and orthope­ dic surgery. It is available in a chewable tablet formulation. After administration PO, firocoxib is rapidly absorbed and then elin1inated by hepatic metabolism and fecal excretion. The elimination half-life is -8 hr,

a!Jowing dosing at 5 mg/kg/day, PO. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 384-fold more selective for COX-2. As with other NSAlDs, protein binding is high, at -96%. GI safety appeai-s to be greater than that of nonspecific NSAlDs. Robenacoxib: Robenacoxib is a

coxib-class highly selective COX-2 inhibitor, structura!Jy related to the human NSAlDs cliclofenac and !W1tiracoxib. Robenacoxib is used for the control of pain and inflamma­ tion associated with osteoarthritis, mthopedic and soft-tissue surge1y in clogs (approved in Europe), and for musculoskel­ etal disorders and soft-tissue surgeries in cats (approved in the USA and Europe). Dosage is 2 mg/kg, PO, initially and then 1-2 mg/kg/day thereafter (for up to 6 days in cats). COX-l :COX-2 ratios from in vitro canine whole blood assays indicate it is 128-folcl more selective for COX-2. As with other NSAlDs, protein binding is high, at -98%. GI safety appeai-s to be greater than that of nonselective NSAIDs. The elimina­ tion half-life is l hr after oral administration. Adn"linistration with food decreases bioavailability of robenacoxib. Mavacoxib: Mavacoxib is a coxib-class COX-2 inhibitor approved in Europe and Australia for the control of pa.in and inflan1mation associated with degenerative joint disease in dogs. Mavacoxib is structura!Jy related to the human NSAlD celecoxib; however, substitution of a meiliyl group with a single fluorine a.torn has conferred great resistance to metabolism, resulting in an elimination half-life of 17 days in yoW1g Beagle dogs. Unlike the major route of elimination of other NSAlDs, that of mavacoxib is biliaiy excretion ofilie parent molecule. In field t1ials conducted in aged dogs wiili osteoarthritis, ilie half-life was foW1d to be even longer at 44 days, and in these older dogs, approxin1ately l in 20 exhibited a half-life of >80 days. These population phannacokinetic studies in target patients were used to optimize ilie close regin1en. The long half-life means mavacoxib has a tmique dose regimen: ilie initial close is 2 mg/kg, PO, repeated 14 clays later; iliereafter, ilie closing interval is l mo, with the total coW"Se not exceeding seven closes (6.5 mo). Food significantly increases bioavailability. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate mavacoxib is 128-fold more selective for COX-2. As with oilier NSAIDs, protein binding is high, at -98%. GI safety appears to be greater ilian that of nonselective NSAIDs.

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ANTI-INFLAMMATORY AGENTS The elimination half-life is 1 hr after oral administration. Tepoxalin: Tepoxalin is a dual inhibitor of both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). From a mechanistic perspective, its LOX activity (reduction of leukotriene production) may reduce components of inflammation not controlled by COX isoenzyme inhibition. It is available for dogs as an oral tablet. The initial dosage is 20 mg/kg, followed by a maintenance dosage of' 10 mg/kg/day. Tepoxalin is rapidly absorbed and reaches peak plasma concentration 2-3 hr after administration. Its plasma half-life is short (2 hr), but it is metabolized to a carboxylic active metabolite (tepoxalin pyrazol acid) that has a long half-life (12-15 hr). The metabolite, tepoxalin pyrazol acid, lacks the LOX activity of the parent molecule. BoU1 tepoxalin and its actiVP metabolite are highly bound to plasma protein (98o/o-9goA,). The most commonly reported adverse effects are GI related (eg, dia.rrhea and vomiting in -20% of dogs treated for 4 wk). Other NSAIDs: A large number of prescription and nonprescription NSAIDs are available for human use. However, because of species dilierences in metabo­ lism, efficacy, and toxicity, many are not recommended for use in animals. For example, in dogs, indomethacin is highly toxic to the GI tract and may result in severe ulceration, hematemesis, and melena at U1erapeutic doses. Piroxicam undergoes extensive enterohepatic recycling in dogs, resulting in a prolonged plasma half-life. GI ulceration and bleeding and renal papillary necrosis have been seen in dogs receiving piroxican1 at dosages of 0.3-1 mg/kg/day. Ibuprofen is an arylpropionic acid derivative used in dogs as an anti-inflamma­ tory agent. However, dogs are much more sensitive to the development of GI adverse effects from ibuprofen administration than are people. At therapeutic doses, adverse effects seen in dogs include vomiting, diarrhea, GI bleeding, and renal in.t'ection. Ibuprofen is not recommended for use in dogs or cats. Naproxen has been used in horses at a dosage of 5-10 mg/kg, once to twice daily. Bioavailability is lower ( -50%) for naproxen than for other NSAIDs, and the elimination half-life is -5 hr in horses. In dogs, the elimination half-life of naproxen is 35---74 hr, preswnably because of extensive enterohe­ patic recirculation. The pharmacokinetics in dogs also appear to be breed dependent. Because of the prolonged half-life of

2721

naproxen, dogs are extremely sensitive to its adverse effects. Coxib class drugs, including celecoxib and valclecoxib, developed for use in hwnan medicine are COX-2 selective. In clinical studies, the incidence of GI ulceration in patients receiving valclecoxib or celecoxib was significantly less than that of those receiving naproxen. The use of these drugs in animals has yet to be fully investigated. One pharmacokinetic study with celecoxib in Beagles demonstrated variability in drug elinlination between clogs. In that study, one subgroup of Beagles metabolized celecoxib much more rapidly tl1an the other, wiU1 elimination hall�lives of -2 and 18 hr, respectively. Until fwther data are available regarding tl1e pharmacokinetics and safety of these drugs in animals, tl1eir use in veterinary medicine is not recommended. CHONDROPROTECTIVE AGENTS Polysulfated Glycosaminoglycan: Polysulfatecl glycosaminoglycan (PSGAG) is a semisynthetic glycosan1inoglycan prepared from bovine tracheal cartilage and composed of a polymeric chain of repeating clisaccha.ricle units. The primary glycosami­ noglycan in PSGAG is chonclroitin sulfate. PSGAG is approved for IM use in dogs and intra-articular and IM use in horses for the control of signs associated wilh noninfec­ tious degenerative or traumatic arthritis. In horses, tl1e recommended dosage is 500 mg, IM, every 4 days for 28 clays, or 250 nig by intra-articular injection once weekly for 5 wk. In clogs, the recommended dosage is 2 mg/lb, IM, twice weekly for up to 4 wk. After IM ir\jection, PSGAG is absorbed into tile systemic circulation and eventually incorporated into both healtlly and damaged cartilage. The exact mechanism of action is unknown, but in vitro studies show that PSGAG inhibits PGE2 and catabolic enzymes such as stromelysin, elastase, the metalloproteases, and otl1ers. PSGAG also increases the synthesis of hyalw·onic acid, proteoglycan, and collagen in vitro. Toxicity associated witll administration of PSGAG has been minimal. Because PSGAG is chemically similar to heparin, overdosage may inhibit coagulation, and conctUTent use of aspirin may prolong bleeding times. The use of PSGAG is contraindicated in septic joints. Pentosan Polysulfate Sodium: Pentosan polysulfate sodium (PPS) is a polysulfate ester of xylan, a polymer prepared semisyntlletically from beech-

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ANTI-INFLAMMATORY AGENTS

wood plant material. PPS is chemically and structurally similar to heparin and glycosarninoglycan. The compound is approved by the FDA for use as an oral capsule for the treatment of interstitial cystitis in people. An injectable product is available for use in people, dogs, and horses in Australia and other countries. The mecha­ nism of action is unknown. PPS stimulates hyaluronic acid and GAG synthesis in damagedjoints, inhibits proteolytic enzymes including metalloproteinases, and scavenges free radicals. PPS may also decrease cytokine activity. In canine models of osteoarthritis, IM administration of PPS significantly decreased overall ca.ttilage damage. Because PPS has a hepa.t'in-like structure, coagulopathies may be seen. PPS is given once a week for 4 consecutive weeks, then once every 6 or 12 mo. Hyaluronan: Hyaluronan (formerly hyaluronic acid), a polydisaccharide of glucuronic acid and glucosa.mine, is a component of synovial fluid and articular cartilage. In the USA, a purified fraction of the sodimn salt of hyaluronic acid extracted from rooster combs is available for treatment of horses with osteoartluitis. Hyaluronan is responsible for the viscosity of the synovial fluid and contributes to its

lubricating function in joint movement. As with other chondroprotective agents, the mode of action is m1cleai·. However, because synovial fluid viscoelasticity is decreased in osteoarthritis, the intra-articu­ lar administration of hyaluronan may improve joint lubrication. Hyaluronan inhibits PGE2 synthesis in vitro and in vivo and may inhibit i.nflan1matory enzymes and reduce pain. Most clinical use has been in horses, in which it appears to have minimal adverse effects. Orgotein: Orgotein is a wate1"soluble metalloprotein containing copper and zinc. Found in low concentrations throughout the body, orgotein has superoxide dismutase activity scavenging free oxygen radicals. Orgotein, available as an injectable fonnulation, has been used for treatment of soft-tissue inflan1mation in horses and of arthritis in dogs. Although it has been used as an IM or SC injection, orgotein is typically administered as an intra-articular injection, because its large molecular size may limit absorption via other routes. Intra-articular administration is effective in cases of acute lameness in horses, altl10ugh the onset of therapeutic response may be slow (2-6 wk). Reports indicate that orgotein apparently has a wide safety margin.

ANTINEOPLASTIC AGENTS Anti.neoplastic chemotherapy is an impo1tant component of small animal practice and is routinely used for selected tumors of horses and cattle. Effective use of antineoplastic chemotherapy depends on an understanding of basic principles of cancer biology, drug actions, toxicities, and drug ha.t1dling safety. Tumor Growth and Response to Chemotherapy: The fundamental

biochemical and genetic differences between cancer cells and healthy cells are areas of intense investigation, because these divergences are not fully understood. None of the empirically developed conventional anti.neoplastic drugs appea.t-s to act on a process entirely LU1ique to cai1cer cells. Newer therapies that specifically target markers or pathways unique to particular cancers are evolving. However, the mainstay of cancer therapy continues to

be traditional chemotherapy. Clinically useful cllugs achieve a degree of selectivity on the basis of certain characteristics of cancer cells that can be used as pharrnaco­ logic targets. These characteristics include rapid rate of division and growth, va.t-iations in the rate of drug uptake or in the sensitivity of different types of cells to pa.tticular drugs, and retention in tl1e malignant cells of hormonal responses characteristic of the cells from which the cancer is derived, eg, estrogen responsive­ ness of certain breast carcinomas. Aspects of normal cell growth and the cell cycle provide the rationale for and are of major importance in successful application of antineoplastic chemotherapy. In the S phase, DNA synthesis occm-s; the M phase begins with mitosis and ends with cytokinesis; and the G0 phase is a dormant or nonproliferative phase of the cell cycle. Tumor doubling time is related to the length

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ANTI NEOPLASTIC AGENTS

of the cell cycle and the growth fraction (the proportion of a population of cells undergoing cell division). Antineoplastic agents can be classified according to a number of schemes relative to effects at different stages of the cell cycle. In the simplest sense, cycle-nonspecific agents are considered to be lethal to cells in all phases of the cell cycle. Cells are killed exponen­ tially with increasing drug levels, and the dose-response curves follow firs t -order kinetics. Phase-specific agents exert their lethal effects exclusively or primarily during one phase of the cell cycle, usually S or M; the greater the rate of cell division, the more effective the drug. The G0 phase of the cell cycle is in1portant, not as a target for chemo­ therapeutic agents, but as a time during which dormant tumor cells can escape or repair the effects of drug therapy. Principles of Antineoplastic Chemo­ therapy: The decision to use antineoplas­

tic chemotherapy depends on the type of tumor to be treated, the stage of malignancy, the condition of the animal, and financial considerations. Chemotherapy can be used as an adjuvant to surgery and irradiation and can be administered immediately after or before the primary treatment. Neoadju­ vant therapy is administered before surgery or irradiation and is intended to improve the effectiveness of the primary therapy by possibly decreasing tumor size, stage of malignancy, or presence of micrometastatic lesions. Responses to cancer chemotherapy can range from palliation (remission of secondary signs, generally without increase in survival time) to complete remission (in which clinically detectable tumor cells and all signs of malignancy are absent). The percentage and duration of complete remissions are criteria for the success of a particular chemotherapeutic protocol. Effective clinical use of antineoplastic drugs depends on the ability to balance the killing of tumor cells against the inherent toxicity of many of these drugs to host cells. Because of the narrow therapeutic indices of antineoplastic agents, dosages are frequently calculated based on body surface area (BSA) rather than body mass. However, evidence suggests that small dogs and cats may best be treated based on body weight to avoid overdosage. This is especially true if the primary toxicity is bone marrow suppression. Evidently, BSA does not correlate well with either stem cell nwnber in the bone marrow or resulting hematopoietic toxicity. Correlation is better between body weight and these toxicities. Antineoplastic agents can be administered

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by PO, IV, SC, IM, topical, intracavitary, intralesional, intravesicular, intrathecal, or intra-arterial routes. The route chosen depends on the individual agent and is detennined by drug toxicity; location, size, and type of twnor; and physical constraints. Antineoplastic agents are commonly administered in various combinations of dosages and timing; the specific regimen is referred to as a protocol. A protocol may use one or as many as five or six different antineoplastic agents. Selection of an appropriate protocol should be based on type of twnor, grade or degree of malig­ nancy, stage of the disease, condition of the animal, and financial considerations. Preferences of individual clinicians for treatment of specific neoplastic conditions may also vary. Regardless of the protocol chosen, a thorough knowledge of the mechanism of action and toxicities of each therapeutic agent is essential. Combination antineoplastic chemo­ therapy offers many advantages. Drugs with different target sites or mechanisms of action are used together to enhance destruction of tumor cells. If the adverse effects of the component agents are different, the combination may be no more toxic than the individual agents given separately. Combinations that include a cycle-nonspecific drug administered first, followed by a phase-specific drug, may offer the advantage that cells surviving treatment with the first drug are provoked into mitosis and, therefore, are more susceptible to the second drug. Another advantage of combination therapy is the decreased possibility of development of drug resistance. Special considerations associated with administration of antineoplastic drugs include evaluation of the animal's quality of life, medical and nutritional support, control of pain, and psychologic comfort for the owner. Many owners who choose to treat neoplasia in their pets have experienced cancer themselves or have been involved with individuals or family members who have had cancer. Discussion of neoplasia in pets should be handled tactfully and should provide the owners with appropriate infonnation for decision-making. Resistance to Antineoplastic Agents:

Failure to respond, or resistance, to antineoplastic agents can be seen for several reasons. Pharmacokinetic resistance is seen when the concentration of a drug in the target cell is below tl1at required to kill the cell. This may be due to altered rates of drug absorption, distribu-

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tion, biotransformation, or excretion. In addition, marginal blood flow to a tumor may not provide sufficient drug, resulting in inadequate therapeutic drug concentrations and the potential for creation of a popula­ tion of quiescent, less susceptible cells. Cytokinetic resistance is seen when the tumor cell population is not completely eradicated; this may be a result of donnant twnor cells, dose-limiting host toxicity associated with drug therapy, or the inability to achieve a 100% kill rate even at therapeutic drug dosages. Resistance can also develop via biochemical mechanisms within the twnor cell itself that block transport mechanisms for drug uptake, alter target receptors or enzymes c1itical to drug action, increase concentrations of healthy metabolites antagonized by the antineoplas­ tic drug, or cause genetic changes that result in protective gene amplification or altered patterns of DNA repair. Acquired muJtidrug resistance can result from amplification and overexpression of a multiclrug resistance gene. This gene encodes a cell transmembrane protein that effectively pwnps a variety of structurally unrelated antineoplastic agents out of the cell. As intra.cellular drug concentrations decline, twnor cell swvi val and resistance to therapy increase. Patterns of Toxicity: Conventional antineoplastic a.gents that a.ct primarily on rapidly dividing and growing cells produce multiple adverse effects or toxicities, including bone marrow or myelosuppres­ sion, GI complications, and imnumosup­ pression. Patterns of toxicity may be either a.cute or delayed. Acute vomiting may develop during administration of an emetogenic drug or within 24 hf after administration of chemotherapy, probably from direct stimulation of the chemorecep­ tor trigger zone. Several drugs are available aimed at preventing these toxicities, including dolasetron, ondansetron, and maropitant citrate. Dolasetron and ondansetron a.ct as serotonin receptor (5HT3) antagonists that work centrally on the brain to prevent emesis. Ma.ropitant citrate is an oral or subcutaneous FDA­ approved meclication for acute nausea/ vomiting in veterinary medicine. It works by inhibiting both central and peripheral vomit­ ing pathways by blocking new-okinin-1 receptors to prevent activation of the emetic center. Administration of oral antiemetics may be indicated for delayed GI toxicities, which can occur 3-5 days after chemotherapy administration. New-okinin-1 receptor

antagonists a.re used in human oncology to treat delayed emesis, and there is evidence they may work synergistically or at least in an additive fashion with 5HT3 inhibitors. ln addition to the NK-1 inhibitor maropitant, conu11on antiemetic therapy in veterinary oncology includes metoclopra.mide, which ftmctions through direct antagonism of central and peripheral dopamine receptors. This drug has the added benefit of stin1ulating motility of the upper GI tract without stimulating gastric, biliary, or pancreatic secretions. This effect cru1 be useful in dogs that develop ileus secondary to vincristine administration. Allergic reactions and anaphylaxis may also be of inunedia.te concern with selected drugs ru1d can be treated with antiliista­ mines or corticosteroids as needed. In more severe cases, epinephrine and IV fluids may be indicated. Other delayed toxicities may develop days to weeks after antineoplastic therapy. Myelosuppression, a common delayed toxicity, cru1 be life-threatening because of the increased risk of infection associated with neutropenia Less commonly, increased risk of hemorrhage associated with thrombocytopenia and anemia may be seen. Other in1portant delayed toxicities include tissue dan1a.ge associated with extra.vasation of selected drugs, and alopecia. ca.used by hair follicle damage, particularly in nonshedding breeds with continuous hair growth. Adverse effects on spenna.togenesis and tera.togenesis may be of concern in breeding animals. Unlike in people, chemotherapy-induced stoma.titis or ulcerative enteritis are rru·e events in dogs and cats. Prevention and management of toxicities are crucial to successful antineoplastic therapy. Collection of an adequate database before treatment can identif-y potential problems so that contra.indicated drugs can be a.voided. Several antineoplastic agents should not be used in the presence of specific organ impainnent. For example, doxorubicin should not be used in dogs with certain cardiac abnormalities that impair left ventricular ftmction, mid cisplatin is contraindicated in animals with impaired renal ftmction. When a drug is chosen, supportive or preventive therapy aimed at ameliorating toxic adverse effects may be required. Potential cardiotoxicity of doxorubicin may ue abrogated wiLh coadrnini!;LraLion of dexra.zoxane, an iron chelator that inhibits fonna.tion of free ra.clica.ls implicated in myocarclial injury. Active diw-esis should

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ANTI NEOPLASTIC AGENTS accompany admillistration of nephrotoxic agents (eg, cisplatin). Administration or availability of appropriate antihistamines may be indicated with L-asparaginase and doxorubicin therapy. The availability of recombinant products is an additional resource to manage myelosuppression and inu11w10suppression induced by antineoplastic chemotherapy. Recombinant hwnan (rhG-CSF) and canine (rcG-CSF) granulocyte colony-stimulating factors have been used effectively to manage cytopenias induced by chemotherapy and radiation therapy. Administration of rcG­ CSF results in a rapid, significant increase in neutrophil nwnbers that is sustainable as long as the factor is administered. Neutrophil counts drop quickly when therapy is discontinued. Neutrophi.l phagocytosis, superoxicle generation, and antibody-dependent cellular cytotoxicity all increase with G-CSF treatment. Until rcG-CSF is commercially available, longtem1 (>2---3 wk) or repeated use of recombinant hwnan products should be avoided in clogs and cats, because it can result in anti-factor antibody formation and a subsequent decline in targeted cell nwnbers. Prophylactic antibiotics have been shown to reduce hospitalization rates and death in hwnan cancer patients receiving chemo­ therapy. These are occasionally used in veterinary medicine to reduce the occurrence or severity of hematologic and nonhematologic complications that can result from administration of particular chemotherapy agents.

Safe Handling of Antineoplastic Chemotherapeutic Agents: Most

antineoplastic chemotherapeutic agents are potentially toxic as mutagens, teratogens, or carcinogens. Handling of these agents can result in hazardous personal or environmen­ tal exposure in several ways. A conunon route of exposure is inhalation due to aerosolization during mixing or administration of cytotoxic drugs. This may occur when a needle is withdrawn from a pressurized drug container or on expulsion of air from a drug-filled syringe. Transferring drugs between containers, opening drug-filled glass ampules, or crushing or splitting oral medications may also aerosolize drug residues. The best way to prepare cytotoxic drugs to avoid aerosolization is in a biologic safety cabinet or hood; a Class II, type A vertical laminar air flow hood exhausted outside the building is recommended. Aerosol exposures can be fw-ther decreased through

2725

use of closed system transfer devices that limit escape of air from drug vials into the environment. Administration of chemo­ therapy should occm in dedicated areas, and meticulous attention to technique should be maintained. Intravenous lines used to administer chemotherapy should be prin1ed with nontoxic solution whenever possible. Disposal of contaminated vials, syringes, needles, and gloves in this area should be anticipated, and the proper puncture-proof chemotherapy waste containers provided. Personal protection equipment should be used for chemotherapy preparation, administration, cleanup, and disposal. This should include powde1°free chemotherapy gloves, nonpermeable gowns, respiratory protection, plastic-backed underpads for the working swface, eye and/or splash protection, shoe covers, and a spill kit. Another potential route of exposure to antineoplastic agents is by absorption of drug through the skil1. This could occur during preparation or administration of drug, cleaning of 01e drug preparation area, or handling of excreta from animals that have received selected cytotoxic drugs. Conscientious wearing of disposable, powde1°free gloves and careful handling of drug-contaminated needles or catheters may avoid most exposures of this type. Re-capping of needles containing drug residues is discouraged to avoid accidental self-inoculation. In addition, use of sprayers and pressw·e washers to clean cages, kennels, or stalls of treated animals should be avoided to minimize aerosolization of' hazardous wastes. Antineoplastic agents can be inadve1° tently ingested if food, drink, or tobacco products are allowed in the vicinity of drug preparation areas, treatment areas, or kennels housing treated animals. Any ingestible materials should be restricted to a separate area that is far enough away to avoid any possible contanlination with these agents. All personnel should handle antineoplas­ tic agents with care. Women of child-bearing age should be particularly cautious, and women who are pregnant or breastfeeding should not handle antineoplastic drugs. A somce of exposure to cytotoxic drugs that is conunonly overlooked is the handling of body fluids and excreta of treated patients. Unifom1 guidelines to handle these potentially dangerous substances have not been published. Nevertheless, sin1ple measures can be taken to help minimize exposure of veterinary personnel and pet owners. Collection of biologic samples,

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such as blood, urine, or tissue, should be performed before chemotherapy adminis­ tration. The duration and type of precau­ tionary measures that should be taken after treatment depend on the half-life and routes of elimination of the drug administered. Pet owners and veterinary hospital personnel should be advised to allow dogs to urinate and defecate in a confined area outdoors, away from spaces where people may congregate or children play. A mask should be worn when cleaning litterboxes, and the contents placed in a sealed plastic bag. The use of low-dust kitty litter should be encouraged. Powder-free, disposable gloves should be used when cleaning up urine, feces, or vomitus. Veterinarians ar·e encouraged to contact their local boar·d of health and other federal, state, and local regulato1y agencies for regulations regarding disposal of hazar·dous waste. Classification of Antineoplastic Chemotherapeutic Agents: Conven­

tional cytotoxic anti.neoplastic agents can be grouped by biochemical mechanism of action into the following general categories: alkylating agents, antimetabolites, mitotic inhibitors, anti.neoplastic antibiotics, hormonal agents, and miscellaneous. The clinically relevant drugs used in veterinary medicine are discussed below, and the indications, mechanism of action, and toxicities of selected agents ar·e summarized in TABLE: 57.

ALKYLATING AGENTS Alkylating agents form highly reactive intern1ediate compounds that ar·e able to transfer alkyl groups to DNA Alkylation can result in miscoding of DNA st.rands, incomplete repair of alkylated segments (which leads to strand breakage or depurination), excessive cross-linking of DNA, and inhibition of st.rand separation at mitosis. Monofunctional alkylating agents transfer a single alkyl group and usually result in miscoding of DNA, strand breakage, or depurination. These reactions can result in cell death, mutagenesis, or carcinogenesis. Polyfunctional alkylating agents typically cause st.rand cross-linking and inhibition of mitosis with consequent cell death. Resistance to one alkylating agent often implies resistance to other drugs in the same class and can be caused by increased production of nucleophilic substances that compete with the target DNA for alkylation. Decreased pern1eation of alkylating agents alld increased activity

of DNA repair systems are also common mechanisms of resistance. Individual alkylating agents are generally cell-cycle nonspecific alld can be sub­ grouped according to chemical structure into nitrogen mustards, ethylenearnines, alkyl sulfonates, nitrosoureas, alld triazene derivatives. Nitrogen Mustards: The most common subgroup of alkylating agents used is the nitrogen mustard group. Mechlorethanli.ne hydrochloride is the prototype of the nitrogen mustards alld is conunonly used in veterinary medicine to treat lymphoma in conjunction with other chemotherapeutics. Because of the highly unstable nature alld extremely short duration of action of mechlorethanli.ne, its use is somewhat linlited in veterinary medicine. Derivatives of meclllorethar11ine conunonly used for various neoplasias include cyclophospha­ mide, chlorarnbucil, alld melphalall. Cyclophosphamide is a cyclic phospha­ mide derivative of mechloretharnine that requires metabolic activation by the cytochrome P450 oxidation system in the liver. Cyclophosphalllide is given PO or IV, alld dose-lin1iting leukopenia associated with bone marTow suppression is the p1irnary toxicity. However, among the alkylating chemotherapy agents, the myelosuppressive effect of cyclophospha­ mide is considered relatively sparing of platelets alld progenitor cells. Sterile hemorrhagic cystitis may result from aseptic chemical in.flan1mation of the bladder urothelium caused by acrolein, a metabolite of cyclophospharnicle. Preven­ tion of this toxicity is key to its manage­ ment. Specifically, concurrent administration of a diuretic, such as furosemicle, may be used when cyclophos­ phanlide is given as a single dose to provide a dilutional effect. In addition, cyclophos­ pharnide may be given in the morning so that patients Call be provided several opportunities to urinate throughout the clay to minimize contact time of acrolein with the bladder lining. In patients with evidence of sterile hemorrhagic cystitis, cyclophos­ pharnide use should be discontinued. Although the signs may be self-limiting, treatment with fluids, NSAIDs, methylsulfo­ nylmethane (MSM), alld int.ravesicular DMSO may be considered. Mesna is a drug that binds and inactivates the urotoxic metabolites of cyclophospharnide within the bladder. Mesna coadnlinistered with fluid diuresis is recommended when ifosfarnide (all analogue of cyclophosphar11ide) or high-close cyclophospharnide is used.

ANTINEOPLASTIC AGENTS

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MECHANISMS OF ACTION, INDICATIONS , AND TOXICI TIES OF SELECTE D ANTINEOPLASTIC AGENTS

Major Indications

Toxicities

Drug

Mechanism of Action

Cyclophospha mide

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Lymphoma, mammary adenocarciQPma, sarcomas, lyrnphocytic leukemia

Nausea, vomiting (infrequent), moderate to severe myelosuppression, sterile hemorrhagic cystitis

Melphalan

Alkylates DNA causing miscoding and cross-linking of DNA strands

Multiple myeloma

Nausea, vomiting, anorexia, moderate myelosuppression (may be more myelosuppressive in cats)

Chlorambucil

Alkylates DNA causing miscoding and cross-linking of DNA strands; slowest-acting alkylating agent

Chronic lymphocytic leukemia, small-cell lymphoma

Nausea, vomiting, mild to moderate myelosuppression

Lomustine (CCNU)

Alkylates DNA causing miscoding and cross-linking of DNA strands; inhibits both DNA and RNA synthesis; not cross-resistant with other alkylating agents

Lymphoma, mast cell tumor, histiocytic sarcoma, CNS neoplasias, multiple myeloma

Nausea, vomiting, moderate to severe myelosuppression (may be delayed for 4-6 wk), hepatotoxicity, nephrotoxicity, pulmonary toxicity

Streptozotocin

Inhibits DNA synthesis; high affinity for pancreatic 13 cells

lnsulinoma

Severe, potentially fatal nephrotoxicit)'. (if given without diuresis) and hepatotoxicity, nausea (inunediate and delayed), vomiting, mild myelosuppression

Dacarbazine (DTIC)

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; inhibits RNA synthesis

Lyn1phoma, sarcomas

Severe acute nausea, vomiting, phlebitis, moderate myelosuppression, hepatotoxicity, anecdotal reports of pleural effusion in cats

lfosfamide

Various sarcomas Analogue of cyclophosphamide; w1dergoes hepatic biotransfo1rnation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

ALKYLATING AGENTS

Nausea, vomiting, myelosuppression, sterile hemorrhagic cystitis, possible nephrotoxicity

(continued)

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MECHANISMS OF ACTION, INDICATIONS, AND TOXICITIES OF SELECTED ANTINEOPLASTIC AGENTS (continued) Drug

Mechanism of Action

Major Indications

Toxicities

ANTIMETABOLITES Methotrexate

Inhibition of dihydroLymphoma folate reductase that is required for formation of tetrahydrofolate, a necessary cofactor in thymidylate synthesis; thyn1idylate essential for DNA synthesis and repair

5-Fluorouracil

Pyrinlidine analogue; interferes with DNA synthesis and may be incorporated into RNA to cause toxic effects

Carcinomas (systemic); cutane­ ous carcinomas (topical)

Systemic: nausea, vomiting, moderate myelosuppression, neurotoxicity, GI ulceration, neurotox­ icity, hepatotoxicity Topical: local irritation, pain, hyperpigmentation Cannot be given to cats (fatal neurotox­ icity)

Cytarabine

Pyrimidine analogue; incorporates into DNA causing steric hindrance and inhibition of DNA synthesis

Lymphoma (including CNS), leukemias; no activity in solid tumors

Nausea, vomiting, moderate myelosup­ pression, nephrotox­ icity, hepatotoxicity

Gemcitabine

Pyrimidine analogue; incorporates into DNA, causing steric hindrance and inhibition of DNA synthesis

Limited efficacy seen in lyn1phoma and various carcinomas

Mild nausea, vomiting, mild to moderate myelosuppression, pulmonary toxicity, nephrotoxicity

Nausea, vomiting, moderate myelosup­ pression, GI ulceration, hepato­ toxicity, pulmonary toxicity

ANTIBIOTIC ANTINEOPLASTICS Doxorubicin

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomer­ ase II-mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, leukemias, multiple myeloma, osteosarcoma, hemangiosarcoma, and various other sarcomas and carcinomas

Nausea, vomiting, moderate rnyelosup­ pression, hemmThagic colitis, severe cutaneous reactions if extravasated; red urine (not hematuria), transient ECG changes and arrhythmias, nephrotoxicity, anaphylactoid reactions Cumulative dose­ related congestive heart failure in dogs; cw11ulative neplu-otox­ icity in cats (cont,i ,wed)

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MECHANISMS OF ACTION, INDICATIONS, AND TOXICITIES OF SELECTED ANTINEOPLASTIC AGENTS (continued)

Major Indications

Drug

Mechanism of Action

Mitoxantrone

Topoisomerase II-mediated chain scission; DNA aggrega­ tion, oxidation, and strand breakage

Bleomycin

Mixture of glycopep­ Carcinomas tides; generates oxygen radicals that cause chain scission and fragmenta­ tion of DNA

Lymphoma, various carcino­ mas

Dactinomycin Intercalates and binds to Lymphoma, (Actinomycin D) DNA, disrupting helical various sarcomas structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomer­ ase II-mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Toxicities Nausea, vomiting, moderate to severe myelosuppression, diarrhea, bluish discoloration to sclera; less severe adverse effects than others in this group Nausea, vomiting, myelosuppression, fever, allergic reactions including anaphylaxis, hyperpigmentation, skin ulceration, pneumonitis, pulmonary fibrosis Nausea, vomiting, moderate to severe myelosuppression, phlebitis; severe tissue reaction if extravasated

MITOTIC INHIBITORS

Vinblastine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, mast cell tumors

Mild nausea, vomiting, severe myelosuppression, neurotoxicity with high doses, inappro­ priate secretion of antidiuretic hormone

Vincristine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, transmissible venereal cell tumors, various sarcomas

Mild to moderate nausea, vomiting, mild to moderate myelosuppression, severe tissue reaction if extravasated, cumulative periph­ eral neuropathy, constipation, paralytic ileus, inappropriate secretion of antidiuretic hormone (continued)

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MECHANISMS OF ACTION, INDICATIONS, AND TOXICITIES OF SELECTED ANTINEOPLASTIC AGENTS (continued) Drug

Mechanism of Action

Major Indications

Vinorelbine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and a1Test of cell cycle

Primary lung tumors, limited efficacy in mast cell tumors

Mild nausea, vomiting, myelosup­ pression

Paclitaxel

Binds to tubulin, stabilizing microtubule polymer and a.ITesting mitosis

Mammary carcinoma, squamous cell carcinoma

Myelosuppression, nausea, vomiting, hypersensitivity (when Cremor EL is used as vehicle)

Toxicities

MISCELLANEOUS Cisplatin

Reacts with proteins and Osteosarcoma, cai·cinomas, and nucleic acids; fom1s mesothelioma cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Intense nausea, vomiting, mild to moderate myelosup­ pression, potentially fatal neplu·otoxicity if not given with diuresis, anaphylaxis, ototoxicity, peripheral neuropa­ thy, hyperuricemia, hyperrnagnesemia Ca.I111ot be given to cats (fulminant pulmonaiy edema)

Carboplatin

Reacts with proteins and Osteosarcoma, carcinomas nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Mild nausea, vomiting, dia.IThea, moderate to severe myelosuppression

L-Asparaginase

Inhibits protein synthesis by hydrolyzing tumor cell supply of asparagine

Acute lymphoid leukemias and lymphoma

Hypersensitivity reactions, anaphy­ laxis especially after repeated .doses, alteration in coagulation paran1eters, hepatotoxicity, pancreatitis (people), potential inhibition of immune responsive­ ness (B and T cells)

Mitotane (o,p'DDD)

Destroys adrenal zona fasciculata and zona reticulaiis

Pituitary hyperadrenocorti­ cism, palliation of adrenal cortical tumors

Nausea, vomiting, anorexia, dia.IThea, adrenal insufficiency, CNS depression, dermatitis (continued)

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MECHANISMS OF ACTION, INDICATIONS, AND TOXICITIES OF SELECTED ANTINEOPLASTIC AGENTS (continued) Major Indications

Toxicities

Drug

Mechanism of Action

Hydroxymea

Inhibits conversion of ribonucleotides to deoxyribonucleotides by destroying ribonucleo­ side diphosphate reductase

Polycythemia vera, granulocytic and basophilic leukemia, thrombocythemia, investigational for meningiomas

Procarbazine

Mechanism is unclear; inhibits DNA, RNA, and protein synthesis, perhaps through alkylation

Lymphoma, as part Nausea, vomiting, ofMOPP myelosuppression, chemotherapy diarrhea protocol; brain tumors

Nausea, vomiting, mild myelosuppres­ sion, alopecia, sloughing of claws, dysuria

HORMONES Prednisone

Lympholytic; inhibits mitosis in lyn1phocytes

Chlorambucil, the slowest-acting nitrogen mustard, achieves effects gradually and often can be used in aninlals with compromised bone marrpw. It can cause bone marrow suppression, which is usually mild; however, periodic monitoring is recommended with longtem1 administra­ tion. This drug is given PO and is most commonly used in treatment oichronic, well-differentiated cancers; it is considered ineffective in rapidly proliferating tumors. Melphalan, an !.,-phenylalanine delivative of mechlorethamine, is given PO or IV and is plima.lily used in vete1ina.ry medicine to treat multiple myeloma.. Other Alkylating Agents: Of the other subgroups of alkyla.ting agents, several have lin1ited but specific uses. Triethylenethio­ phosphora.mide (thiotepa.), an ethylen­ imine, has been reported as an intra.vesi­ cular treatment for transitional cell carcinoma. of the bladder or as an intra.ca.vi­ tary treatment for pletffal and peritoneal effusions. Busulfa.n, an alkyl sulfona.te, is used specifically in treatment of chronic myelocytic leukemia. and polycythemia vera.. Streptozotocin, a natmally occmring

Lymphoma, mast cell tumors, multiple myeloma, palliative treatment of brain tumors

Sodium retention, GI ulceration, protein catabolism, muscle wasting, delayed wound healing, suppression of hypo­ thalamic-pituitary­ adrenal axis, inununosuppression

nitrosourea, is used for palliation of malignant pancreatic islet-cell tumors or insulinomas. Other nitrosomeas, such as carmustine and lomustine, readily cross the blood-brain barlier and have been useful in management of lymphoma. (including epitheliotropic cutaneous lyn1phoma.), mast cell tmnors, histiocytic sarcomas, and CNS neoplasias. Dacarbazine (DTIC), a triazene derivative, has been used either in combination with doxorubicin or as a single-agent treatment for rnia.psed canine lymphoma. and soft-tissue sarcomas. Temozolomide is an oral inliclazotetra­ zine de1iva.tive of da.carbazine and belongs to a class of chemotherapeutic a.gents that enter the CSF and do not require hepatic metabolism for activation. In people, it is used for refractory malignant gliomas and malignant melanomas. There have been reports in the veterina.iy litera.tw·e of its use as a substitute for dacarbazine (DTIC).

ANTI METABOLITES Antimetabolites resemble normal cellular substances and so can subvert nom1al metabolic pathways in a toxic ma.rmer.

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Three subgroups of antirnetabolites are used: folic acid, pyrimidine, and purine analogues. Folic Acid Analogues: The prototype folic acid analogue is methotrexate, an inhibitor of dihydrofolate reductase, the enzyme that catalyzes conversion of folic acid to tetrahydrofolate. Tetrahydrofolate deficiency blocks reactions requiring folate coenzymes, disrupting both DNA and RNA synthesis. Methotrexate is an S phase-spe­ cific drug that must be actively transported across cell membranes. It can be given PO, IV, IM, or intrathecally. Methotrexate is excreted in the urine, and at high doses may precipitate in renal tubules. Folinic acid can be used to bypass the metabolic blockade produced by folic acid analogues and thus result in rescue of treated cells. Because tumor cells appear less efficient at transport of folinic acid, some degree of selectivity is achieved in the rescue. Resistance to metho­ trexate may develop due to impaired transport of the drug into cells, production of altered fom1S, or increased concentra­ tions of dihydrofolate reductase. Pyrimidine Analogues: Two pyrimidine analogues, 5-fluorouracil and cytarabine, are commonly used. 5-Fluorouracil must be converted to an active 5-fluoro-2 '-deoxyuridine-5'phosphate form to bind the enzyn1e thymidylate synthetase and block or inhibit DNA and RNA synthesis. This drug is consid­ ered S phase-specific. It is used IV but is also available for topical use. Metabolism is via the liver, and the drug readily enters CSF. Occasional CNS reactions have been reported in dogs. Severe irreversible neurotoxicity and sudden death have been described in cats. In people, neurotoxicity is related to deficiency in the enzyme dihydropyrinlidine dehydrogenase, but this has not been investigated in veterinary species. Resistance may develop by decreased activation of the drug or acquisition of altered thyn1idylate syn­ thetase that is not inhibited. Cytarabine (cytosine arabinoside) is an analogue of 2'-deoxycytidi.ne and must be activated by conversion to a 5'-monophos­ phate nucleotide. The nucleotide analogue, AraCTP, inhibits DNA synthesis by substi­ tution of arabinose for deoxyribose in the sugar moiety of DNA; cytarabine may also inhibit DNA repair enzymes. This drug is S phase-specific, and its effectiveness in hematopoietic neoplasms is directly proportional to exposure of cells to the drug; continuous infusion or repeated

injections are usually required. Inhibition of conversion to AraCTP or increased degradation of AraCTP can account for development of resistance. Gemcitabine is anotl1er nucleoside analogue of cytidine which, unlike cyta.rabine, has activity against solid tumors. The drug requires active carrier transport into the cytoplasm where it is ternlinally activated via phosphorylation; consequently, serum levels may not predict intracellul:u concentrations. By acting as a counterfeit nucleotide, coupled with the ability to inhibit multiple enzymes needed for pyridine biosynthesis and DNA repair, gemcitabine is capable of self-potentiation and synergism with other agents, particu­ larly alkylators. Gemcitabine has also been used as a radiation sensitizer. Purine Analogues: Two purine analogues, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are rarely used in veterinary medicine. In people, these drugs are occasionally used for acute leukemias or other autoimmune disorders.

MITOTIC INHIBITORS Vinca Alkaloids: The vi.nca alkaloids

are large, complex molecules derived from the periwinkle plant. Binding to tubulin, the major component of cellular microtu­ bules, accounts for the antineoplastic effects of these drugs. Vinca alkaloids inhibit microtubule polymerization and increase microtubule disassembly. The mitotic spindle apparatus is disrupted, and segregation of chromosomes in metaphase is arrested. These effects account for the primary M-phase action of vinca alkaloids, although other antitubulin effects related to cytoskeletal maintenance and protein trafficking may be seen. The two drugs of importance in this class are vincristine and vinblastine. Both are given IV, and both cause severe local vesication if iajected perivascularly. Drug extravasa­ tion may cause severe tissue reactions and promote exacerbation of self-trauma. The vinca alkaloids are metabolized primarily in the liver but may be partially excreted in an unchanged form in the urine. Although vinca alkaloids are related structurally, resistance to one does not imply resist­ ance to all drugs in this category. Vincris­ tine use is limited by neurologic toxicity that may include a slowly reversible sensorimotor peripheral neuropathy and muscle weakness. In comparison, the dose-limiting toxicity associated with vinblastine is related to rnyelosuppression

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and leukopenia; neurologic toxicity develops only at high doses. Vinorelbine is a second-generation sernisynthetic vinca alkaloid that is derived from vinblastine but with broader anti tumor efficacy. According to studies in the veterinary literature, this drug may have efficacy in canine primary lung and cutaneous mast cell tumors. Taxanes: Paclitaxel and docetaxel are antimicrotubule agents extracted from the Pacific and European yew trees, respec­ tively. Taxanes bind to tubulin subunits, enhance microtubule polyme1ization, and inhibit microtubule depolymerization. Formation of stable microtubule bundles disrupts tubulin equilibtium and blocks normal progression through metaphase, and mitosis is arrested. These agents are actively used in human medicine, but hypersensitivity reactions related to the vehicle Cremophor EL have limited the drug's utility in veterinary medicine. A new wate r -soluble, micellar formulation of paclitaxel has received conditional approval by the FDA for treatment of canine mammary carcinoma and squamous cell carcinoma. Myelosuppression and GI effects ( diarrhea, mucosa] ulceration, and emesis) have been repo1ted in dogs treated with paclitaxel.

ANTINEOPLASTIC ANTIBIOTICS The antineoplastic antibiotics are products of Streptomyces. The important drugs in this group include actinomycin D (dactino­ mycin), doxorubicin, mitoxantrone, and bleomycin. Drugs less conunonly used include daunorubicin, mithramycin, and mitomycin. Actinomycin A was the firstStreptomy­ ces antibiotic isolated and was followed by related antibiotics, including actinomycin D. Actinomycin D binds with double­ strancled DNA and blocks the action of RNA polymerase, which prevents DNA transcrip­ tion. Actinomycin D is considered cell-cycle nonspecific and is given IV but does not cross the blood-brain barrier. Resistance may develop because of decreased cellular uptake of the drug. Occasionally, it is used as a substitute for doxorubicin in dogs with questionable cardiac function or for those dogs that have exceeded the cumulative cardiotoxic close of doxorubicin. The anthracycli.ne antibiotics, particu­ larly doxorubicin, have become in1portant antineoplastic antibiotics. These drugs intercalate and bind to DNA between base pairs on adjacent strands. This causes the

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DNA helix to uncoil, which destroys the DNA template and inhibits RNA and DNA polymerases. Scission of DNA is thought to be mediated by either the enzyme topoisomerase II or by generation of free radicals. Intracellular interactions of anthracycline antibiotics result in the formation of semiquinone radical intem1e­ diates capable of generating hydrogen peroxide and hydroxyl radicals. Considered cell-cycle nonspecific because of the damage associated with radical formation, these drugs probably have their maximal effect during the S phase of the cell cycle. The anthracycline antibiotics are given IV; they are severe vesicants if administered perivascula.rly and may cause a severe, delayed phlebitis. Administration of a free radical scavenger, dexrazoxane, may limit the extent of tissue damage seen with extravasation of this clrng. The anthracy­ cline antibiotics are metabolized in the liver to a variety of less active and inactive products. Doxorubicin toxicity can be manifested in a variety of acute and delayed reactions. Acute effects include hypersensitivity reactions (from nonspecific histamine release), extravasation injury, or transient cardiac arrhythmias. Delayed toxicities can be severe, with the major problem in clogs being cumulative, dose-related cardiac toxicity associated with binding of the drug to cardiac DNA and free radical clan1age to myocardial membranes. A nonspecific decrease in cardiac fibrils occurs, which leads to congestive heatt failure illll"espon­ sive to digitalis. Because the cai·diotoxic effects of cloxorubicin are related to the peak plasma concentrations (rather than area under the curve), slow IV administra­ tion over 15--30 min is recommended to help lessen cardiac injury. Myocai·clial damage from cloxorubicin also can be prevented by coadministration of clexrazoxane, at lO times the close of cloxorubicin. In cats, cumulative closes of doxorubicin can result in neph.rotox:icity at1cl should be avoided or used judiciously in cats with preexisting renal insufficiency. Dose-limiting toxicities of cloxorubici.t1 include severe myelosuppression and GI upset. Also, if cloxorubicin is used in conjunction with radiation therapy, damage by radiation may be augmented. This radiation sensitization effect may necessi­ tate reduction i.t1 radiation or drug dosages, or both. Because of the significant toxicity associated with use of cloxorubicin, newer-generation drugs specifically aimed at reduction of cardiac toxicity have been developed aticl are available in hwnat1

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ANTINEOPLASTIC AGENTS

medicine. Two of these, idarubicin and epirubicin, have been stuclied, but neither is in conunon use in veterinary meclicine. A pegylated liposomal encapsulated forrn of doxorubicin, called doxorubicin HCL liposome iI\iection, has been used effectively in both human and veterinary meclicine. The liposomal formulation results in a longer drug circulation time and reduced myelosuppression and carcliotoxic­ ity. ln dogs, the dose-linliting toxicity of liposomal doxorubicin is a cutaneous reaction called palmar-plantar erythro­ dysesthesia. ln cats, a delayed nephrotoxic­ ity is the dose-linliting toxicity of both conventional and liposomal doxorubicin. Mitoxantrone, an antlu·aceneclione related to the anthracycline antibiotics, has shown promise in veterinary medicine for treatment of lymphoma and vaiious carcinomas. The mechanism of action of mitoxantrone is similar to that of the anthracyclines, but most adverse effects are less severe than those of doxorubicin. An exception is myelosuppression, which is more profound with nlitoxantrone than doxorubicin. Bleomycin is actually a mixture of bleomycin glycopeptides that differ only in their ternlinal antine moiety. The cytotoxic action of these glycopeptides depends on their ability to cause chain scission and fragmentation of DNA molecules. Cells accw11ulate in the G2 phase of the cell cycle, which accounts for the classification of bleomycin as a G2 andM phase-specific agent. Bleomycin may also affect DNA repair enzymes. Given IV or SC, bleomycin does not cross the blood-brain barrier; a large portion is excreted via the kidneys. Bleomycin has ntinin1al myelosuppressive and inm1unosuppressive activities but does have an unusual delayed pulmonary toxicity. Pulmonary toxicity, which is cumulative, may begin as a nonspecific pnetu11onitis that progresses to pulmonary fibrosis. Dangers from pulmonaiy complications are especially in1portant in older animals with preexisting pulmonary disease.

HORMONAL AGENTS Hon11onal therapy for neoplasia commonly involves use of glucocorticoids. Direct ai1titumor effects are related to their lympholytic properties; glucoco1ticoids can inhibit mitosis, RNA synthesis, and protein synthesis in sensitive lyn1phocytes. Glucocorticoids are considered cell-cycle nonspecific and are often used in chemo­ therapeutic protocols after induction by

another agent. U.nfo1tunately, resistance to a given glucocorticoid may develop rapidly and typically extends to other glucocorti­ coids. Toxic effects of glucocorticoid therapy can include peptic ulceration, glucose intolerai1ce, polydipsia and polywia, immunosuppression, pancreati­ tis, osteopenia, hypokalemia, cataracts, and muscle wasting. Prednisone and prednisolone are commonly used to treat lymphoreticular neoplasms in combination with other drugs. Because they readily enter the CSF, dexamethasone, prednisone, and prednisolone are especially useful in treatment of leukemias and lymphomas of the CNS. lndirect benefits of glucocorticoid therapy in cancer include symptomatic improvements in appetite and attitude, suppression of norunfectious fevers, management of hypercalcemia of malig­ nancy (after a definitive diagnosis has been made), and relief of edema associated with spinal cord and brain tumors. However, evidence from several sources suggests that treatment of certain lymphomas with predrusone may increase resistance of neoplastic cells to subsequent cycles of antineoplastic chemotherapy through induction ofMDR-1-related P-glycoprotein expression.

MISCELLANEOUS ANTINEOPLASTIC AGENTS Several drugs used as antineoplastics do not fall into any of the categories mentioned thus fai·. These include L-asparaginase, cisplatin, nlitotane (o,p'DDD), hydroxy­ urea, etoposide, ai1d procarbazine. L-Asparaginase is an enzyn1e derived from Escherichia coli that catalyzes hydrolysis of asparagine. Because some tW11or cells have poor expression of asparagine synthe.tase and ai·e tu1able to produce the anlino acid asparagine, treatment with this drug deprives these cells of exogenously supplied asparagine ai1d ultin1ately linlits protein synthesis. Because protein synthesis is active in the G 1 phase of the cell cycle, L a- sparaginase is considered to be a G 1 phase-specific drug. Preferred routes of adntinistration for L-asparaginase include IM and SC. Anaphylaxis on repeated adnlirustration of L-aspai·aginase may occur as a result of host anti-asparaginase antibody production; pretreatment of atlilllals with ai1tihistai11ine helps to prevent this acute toxic reaction. Anti-asparaginase antibody production may also account for development of tumor resistance, as can a decreased tun1or cell requirement for

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ANTI NEOPLASTIC AGENTS

asparagine. A related drug, pegaspargase, is modified from L-asparaginase by covalent modification with monomethoxypolyethyl­ ene glycol. The conjugated drug produces fewer hypersensitivity reactions than does L-asparaginase. Cisplatin (cis-diamine-dichloroplati­ num) functions primarily as a bifunctional alkylator but is included in the miscellane­ ous category because of its unusual structure. It is a platinum ion complexed to two chloride ions and two ammoniwn molecules. Cisplatin causes inter- and intrastrand DNA cross-linking that disrupts DNA helices and prevents DNA synthesis. Cisplatin is cell-cycle nonspecific and has been used both for its direct antitumoral and radiation-sensitizing effects. It is administered by IV drip in combination with aggressive saline diuresis. Excretion is prolonged, with up to 500A, of a dose still present in the body 5 days al'ter administra­ tion. Extreme, dose-limiting, proximal tubular renal necrosis typifies the delayed adverse effects of cisplatin along with other responses that may include ototoxicity, moderate bone marrow suppression, peripheral nemopathy, and renal potassimn and magnesiwn wasting. Cisplatin causes fatal pulmonary edema in cats and must not be used in this species. Because of the extreme toxic adverse effects of cisplatin, newer generation derivatives such as carboplatin and others have been developed. Carboplatin is effective as an acljunct to smgery for treatment of osteosa.rcoma. Nausea and vomiting are less severe than with cisplatin, and carboplatin is not considered neph.ro­ toxic. It is, however, myelosuppressive, with neutropenia being the dose-limiting toxicity. Carboplatin is excreted th.rough the kidneys; consequently, dogs or cats with evidence of compromised renal function require dose acljustments to avoid excessive toxicity. Ca.rboplatin is considered safe for administration to cats. Mitotane ( o,p'DDD ), a derivative of the insecticides DDT and DDD, causes selective destruction of norn1al and neoplastic adrenal cortical cells. Mitotane may act by inhibiting production of steroids induced by ad.renocorticotropic hormone, which causes atrophy of the inner zones of the adrenal cortex. Mitotane is administered PO, and plasma concentrations can be detected for several weeks. Hydroxyurea, a simple hyd.roxylated derivative of mea, is most commonly used in treatment of polycythemia vera. Hyd.roxyu.rea inhibits ribonucleoside diphosphate reductase (RNDR), limits the

2735

conversion of ribonucleotides to deoxyribo­ nucleotides, and blocks DNA synthesis. Cells are arrested in the G,-S interface. Mechanisms of resistance include amplifica­ tion of the RNDR gene or development of RNDR with reduced sensitivity to hydroxy­ mea. Loss of claws has been associated with hyd.roxymea use in anin1als. Epipodophyllotoxins are semisynthetic glycosides of podophyllotoxin derived from the mandrake plant. Although these toxins bind tubulin, their mechanism of action is mu-elated to disruption of mic.rotubules. Instead, they are thought to stinrnlate DNA cleavage mediated by topoisomerase IL Of the two drugs in this class, etoposide and teniposide, the former has been used primarily in treatment of testicular carcinoma. Procarbazine is considered to function as an alkylating agent but is included in the miscellaneous category because tl1e exact mechanism of action is not known. It is typically used as part of the MOPP protocol that includes mechlorethamine, vincristine (tradename Oncovin®), procarbazine, and prednisone for dogs with lyn1phoma. This diug is metabolized and activated in the liver. GI toxicity and myelosuppression are the p1imary concerns associated with tl1e MOPP protocol. Biologic Response Modifiers in Cancer Therapy: In recent years, a nmnber of

alternative modes of cancer therapy have become increasingly available in vete1inary medicine. These novel fonns of therapy work in myriad ways, including enhanced inunune recognition, altered blood vessel fonnation, or by exploitation of specific pathways that are aberrant or overexpressed in neoplastic cells. The widespread use of these newer therapies alone or in combina­ tion with conventional chemotl1erapy has transformed the approach to treatment of many cancer patients. NSAIDs represent one class of biologic response modifiers tl1at work by inhibiting frequently overexpressed COX-2 enzyn1e activity present in many twnor types. Several studies have proposed that tllese drugs may work by reducing cell prolifera­ tion, increasing apoptosis, inhibiting angiogenesis, and modulating immune function. Piroxican1 has been the drug most researched in dogs, but any of the newer NSAIDs with more COX-2 selective inhibition (such as deracoxib or meloxi­ can1) theoretically may yield equal or improved effects. (See also NONSTEllOJDAL ANTI-INFLAMMATORY DRUGS, p 2714.) The clinical usefulness of COX-2 inhibitors has

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ANTINEOPLASTIC AGENTS

been demonstrated in canine transitional cell carcinoma, squamous cell carcinoma, and other tumor types in dogs and cats. NSAIDs are often combined in antiangio­ genic protocols. Metronomic or antiangiogenic dosing of chemotherapy is a novel or nontraditional way to administer chemotl1erapy that consists of the administration of low doses of oral chemotherapy agents at very short intervals, often daily. This treatment approach targets the tumor neovasculature by leveraging the exquisite sensitivity of endotl1elial progenitor cells and ilmnature endothelium to modest doses of alkylating agents. Studies indicate that antiangiogenic factors, such as tlu·ombospondin-1, increase during metronomic chemotherapy. In addition, antitumor immunosuppression mediated tlu·ough T regulatmy cells may be mediated by metronomic protocols. Disease stabilization is considered a successful outcome of low-dose chemotherapy, because direct cytotoxicity to neoplastic cells is not tl1e intent of metronomic chemotl1erapy. Prelirninaiy studies in the veterinaiy literature suggest this is a promising alternative to maxin1ally tolerated doses of conventional chemo­ tl1erapy, paiticularly in a microscopic disease setting, and has the added benefit of linuted adverse effects. Targeting of specific pathways tl1at are aberrant or dysregulated in cancers has yielded novel therapies in a variety of human cancers. An exainple of such a tai·get is tl1e receptor tyrosine kinases (RTKs), wluch mediate processes involved in tun10r growth, progression, and metastasis. These drugs are competitive inhibitors of ATP, ai1d so prevent receptor phosphorylation ai1d subsequent downstream signal transduc­ tion. Mutations in c-kit, an RTK gene involved in mast cell differentiation ai1d proliferation, has been reported in approxin1ately a quarter of caiune mast cell tumors. Toceranib has been approved by the FDA, ai1d biologic response rates of 70%---9091> have been reported in dogs that have mast cell tumors with recognized c-kit mutations. Moreover, toceraiub has activity against other members of the split-kinase fairuly of RTKs, such as vasculai· endothelial growth factor receptor, platelet-de,ived growth factor, and ot11ers. Prelin1inaiy evidence indicates that toceranib has activity against a vaiiety of carcinomas ai1d metastatic osteosarcoma, leading to tumor regression or more often to prolonged disease stabilization. Recent reports indicate that dosages of toceranib rai1ging from 2.4---2.9 mg/kg, PO, every 48 hr (below

the label dosage of 3.25 mg/kg, PO, every 48 hr) result in sufficient target inhibition with substa.J1tially reduced toxicity. Development of a therapeutic vaccine to stimulate active inmmnity against cancer has long been a goal in botl1 human ai1d veterinaiy oncology. This becai11e a reality with introduction of a caiune melanoma vaccine. The vaccine exploits the ilm11w1e response induced by hun1an tyrosinase, ai1 enzyme in the pathway of melanin formation. The vaccine contains a human tyrosinase gene inse,ted into a bacterial plasnud, which is adnunistered trai1sder­ mally. The antibodies ai1d T -cell responses produced by xenogeneic tyrosinase cross-react with the tyrosinase overex­ pressed on cai1ine melai1oma cells. Initial studies reported prolonged survival in dogs with advai1ced stage oral malignai1t melai10ma treated with radiation tl1erapy or surgery of the primaiy trnnor, followed by vaccine administration. Passive inummotl1erapy using monoclo­ nal antibodies has grown substantially in human oncology in recent years. Monoclo­ nal antibodies may attach to specific antigens on cai1cer cells, tl1ereby either marking tl1e cai1cer cells for destruction by tl1e immw1e system or in1pairing functional pathways witlun the neoplastic cells. Furthermore, monoclonal ai1tibodies may be cor\jugated to oilier ai1tineoplastic agents (such as chemotl1erapy agents, radionu­ clides, or other toxins) to allow for more targeted delive1y of cytotoxic therapy to cancer cells while spaiing normal tissues. The introduction of anti-CD20 monoclonal antibodies in humai1 oncology has revolutionized the treatment of B-cell lymphoma with sigruficai1tly in1proved outcomes versus chemotl1erapy alone. In veterinaiy medicine, ai1ti-CD20 ai1d anti-CD52 monoclonal ai1tibodies have received either USDA or conditional approval to treat canine B-cell and T-cell lymphoma, respectively. The mechanisms by which these antibodies work is not fully understood, but several potential mecha­ nisms include antibody-dependent cell-mediated cytotoxicity, cornplement­ dependent cytotoxicity, and direct signaling leading to inhibition of proliferation or to apoptosis. Field studies of each of these antibodies are tmderway. Biologic response modifiers aimed at enhancing innate ai1titumor defense mechanisms of the host has been an area of active investigation. Nonspecific ilnrnu­ nornodulators, including intact bacteria or bacterial cell components, acernaiman, II,.2, ll,.12, inte1feron alpha, levan1isole, ai1d

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ANTINEOPLASTICAGENTS

cimetidine, have been reported with variable efficacy to enhance immune responsiveness and improve outcomes after surgery or antineoplastic chemotherapy. Liposome-encapsulated muran1yl tripeptide phosphatidylethanolamine (L-MTP-PE) is perhaps tl1e best studied nonspecific immunomodulator in veterinary medicine. This synthetic bacterial wall component has been used effectively with chemotilerapy to confer a survival advantage in dogs with splenic hemangiosarcoma and osteosar­ coma. Development of immunomodulators such as lymphokines and cytokines (eg, inter­ leukins, interferon, and tumor necrosis factor) for clinical use in cancer patients has not been fully realized, largely because of toxicity. Consequently, these agents are not commonly used in veterinary medicine. Blocking angiogenesis is an attractive forn1 of anticancer therapy, because tumors must develop their own vascular supply if they are to grow beyond a few millimeters in diameter. Various drugs, such as angiosta­ tin, tlrrombospondin-1, and matrix metalloproteinase in11ibitors, have been investigated with varying results. Specific angiogenesis inhibitors for veterinary patients are not yet conunercially available. At present, metronomic chemotherapy combinations are the most practical approach to antiangiogenic therapy in clinical cases.

ANCILLARY ANTINEOPLASTIC AGENTS Supplementary agents are occasionally used in veterinary oncology to citiler enhance the effect of certain chemotherapy treatments or support the well-being of the patient. Drugs in this category include antiemetic therapy, prophylactic antibiotics, COX-2 inhibitors (NSAIDs), and various pain medications. Bisphosphonates are frequently used in veterinary oncology for a variety of reasons, including to treat bone pain from plimary bone tumors or bone metastasis, and to effectively treat hypercalcemia of malig­ nancy. Bisphosphonates belong to a class of drugs tilat directly inhibit osteoclast activity and the subsequent resorption of bone. In people, these drugs are used for various conditions that are charactelized by bone resorption and bone fragility, such as osteoporosis. In addition to their inhibitory effects on osteoclasts, bisphosphonates are believed to exert direct cytotoxic effects on some cancer cells. These effects include

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induction of apoptosis, inhibition of new blood vessel formation, and reduction of tun1or cell adhesion to bone matrix. Retinoids are a class of compounds structurally related to vitan1iJ1 A. In preclinical studies, all-trans retinoic acid (tretinoin), 13-cis retiJ10ic acid (isotreti­ noin), and the aromatic retinoids etretinate and acitretin have preventive and tilerapeu­ tic effects on carcinogen-induced premalig­ nant and malignant lesions in both human and veterinary medicine. Isotretinoin and etretinate have been used with limited therapeutic success in superficial squamous cell carcinoma and cutaneous lyn1phoma. In people, dran1atic therapeutic effects have been obse1ved in treatment of acute promyelocytic leukemia witil tretinoin. The mechanism of action of retinoids is thought to occur through modulation of cell proliferation and differentiation. Retinoids vary in tileir capacity to induce clifferentia­ tion and to inltlbit proliferation in a variety of hwnan and veterinary cell lines.

TREATMENT OF CANINE LYMPHOMA Lymphoma is tile canine tumor most frequently treated witil chemotherapy. It is the most common hematopoietic neoplasia of dogs (seep 40) and cats and is also among the most responsive to chemotl1erapy. Four antineoplastic agents, vincristine, cyclo­ phosphamicle, doxorubicin, and prednisone, form tl1e basis for many lymphoma treatment protocols. Treatments based on these four drugs are often abbreviated as CHOP (cyclophosphantlcle, hydroxydauno­ rubicin [cloxorubicin], Oncovin® [a trade nan1e of vinclistine], and prednisone) protocols. One commonly used CHOP protocol in veterinary medicine is shown in TABLE 58; nearly 40 protocols for manage­ ment of lymphoma in dogs have been published. The most common recommendation in veterinary oncology is to use a discontinu­ ous chemotherapy protocol, as opposed to maintenance or continual chemotherapy. Discontinuous chemotherapy in dogs appears to have the same or similar remission and survival duration as a traditional maintenance protocol. For this treatment approach, all chemotherapy is discontinued for patients in a complete remission at the encl of the treatment protocol. At the first signs of recurrence of lymphoma, reinduction using tile miginal chemotherapy protocol should be used. Studies have suggested that dogs receiving a

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ANTI NEOPLASTIC AGENTS

CHOP MULTIDRUG CHEMOTHERAPY FOR TREATMENT OF CANINE LYMPHOMA Drug

Dosage

L-Asparaginase

10,000 IU/m , SC

Wk l

Vincristine

O.fHJ.7 mg/m2, IV

Wk 1, 3, 6, 8, 11, 13, 16, and 18

Cyclophosphamide

250 mg/m2, IV or PO

Wk 2, 7, 12, and 17

Doxorubicin

30 mg!m , IV, for dogs > 10 kg; 1 mg/kg for dogs 0.75% hexachlorophene are available only by prescription. Accidental oral ingestion of hexachlorophene results in acute poisoning. Pine tar is a viscid blackish brown liquid, used primarily for antiseptic bandaging of wounds of the hoof and horn. Pine tar contains phenol derivatives that provide antinucrobial properties. Chloroxylenols are broad-spectrum bactericides wiili more activity against gram-positive than gran1-negative bacteria. They are active in alkaline pH; however, contact with organic matter dinunishes their activity. Streptococci are more susceptible than staphylococci. Parachlo­ rometaxylenol (PCMX) and d.ichloro­ metaxylenol (DCMX) are the two most commonly used members of this group. DCMX is more active than PCMX. Strong solutions of these compounds can cause irritation and have a disagreeable odor. A 5% chloroxylenol (eg, PCMX) solution (in a-terpineol, soap, alcohol, and water) is diluted with water (1:4) for skin sterilization and (1:25 to 1:50) for wound cleansing and inigation of the uterus and vagina. PCMX is also combined with hexachlorophene to enhance its antibacterial spectrum and to prevent contamination by gran1-negative organisms.

REDUCING AGENTS Formaldehyde is a gas, whereas glutaral­ dehyde is an oil at room temperature. However, botl1 are readily soluble in water. Their solutions are irritating or caustic to tissues, causing coagulation necrosis and protein precipitation, but have potent germicidal properties against all organisms, including spores. Their solutions do not lose appreciable antinucrobial properties in the presence of organic matter and are

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ANTISEPTICS AND DISINFECTANTS

noncorrosive to metals, paints, and fabric. Both are used as disinfectants. Formalin contains 37% formaldehyde gas in aqueous solution with variable an10unts of methyl alcohol to prevent polymerization. A 1o/er-100/o solution of formaldehyde is commonly used as a disinfectant. Glutaral (glutaraldehyde), a 1o/er-2% alkaline solution (pH 7.5--8.5) in 700/o isopropanol, is a more potent germicide than 4% formaldehyde, effective against all microorganisms, including viruses and spores. It is often used to sterilize surgical and endoscopic i.nstrun1ents and plastic and rubber apparatus. It is a known sensitizer, causing occupational contact dermatitis, as well as bronchial and laryngeal mucous membrane irritation. Orthophthaldehyde (OPA) is an aromatic aldehyde sinli.lar to glutaralde­ hyde but with several potential advantages. Typical 0.55% solutions have excellent stability over a wide pH range (3-9), are less toxic and irritating to eyes and nasal passages, and have a barely perceptible odor. They are compatible with most materials, including flexible endoscopes. OPA solutions are faster acting than glutaraldehyde against mycobacteria but have somewhat less sporicidal activity. A potential disadvantage of OPA is that it stains proteins (including unprotected skin) gray, so it must be handled with caution. Sulfur dioxide, as a gaseous fumigant, is produced by burning sulfur in closed spaces. For maxinlal effect, the surface should be moist, because the gas dissolves in water to fom1 sulfurous acid, which is bactericidal. However, this reducing effect of the acid can also corrode metals, rot fablics, and bleach dyes.

SURFACE-ACTIVE COMPOUNDS Surfactants lower the surface tension of an aqueous solution and are used as wetting agents, detergents, emulsifiers, antiseptics, and disinfectants. As antimicrobials, they alter the energy relationship at interfaces. Based on the position of the hydrophobic moiety in the molecule, surfactants are classified as anionic or cationic.

Anionic Surfactants: Soaps are dipolar

anionic detergents with the general fom1ula RCOONa/K, which dissociate in water into hydrophilic K + or Na+ ions and lipophilic fatty acid ions. Because NaOH and KOH are strong bases (whereas most fatty acids are weak acids), most soap solutions are alkaline (pH 8-10) and may irritate sensitive

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skin and mucous membranes. Soaps emulsify lipoidal secretions of the skin and remove, along with most of the accompany­ ing dirt, desquaniated epithelium and bacteria, which are then 1i.nsed away with the lather. The antibacterial potency of soaps is often enhanced by inclusion of certain antiseptics, eg, hexachlorophene, phenols, carbanilides, or potassium iodide. They are 'incompatible with cationic surfactants.

Cationic Surfactants: Cationic deter­

gents are a group of alkyl- or aryl-substi­ tuted quaternary a.i1unoniw11 compounds (eg, benzalkoniun1 chloride, benzathoniun1 chloride, cetylpylidinium chloride) with an ionizable halogen, such as bromide, iodide, or chloride. The major site of action of these compounds appears to be the cell mem­ brane, where they become adsorbed and cause changes in permeability. The activity of older quaternary animoniw11 compounds is reduced by hard water and by porous or fibrous materials (eg, fabrics, cellulose sponges) that adsorb them. They are also inactivated by anionic substances (eg, soaps, proteins, fatty acids, phosphates). Therefore, they are of limited value in the presence of blood and tissue debris. However, newer dialkyl quaternary animonium compounds (fourth generation, including dodecyl dimethyl a.inmonium bromide, dioctyl dimethyl anunoniun1 bromide, etc) purportedly remain active in hard water and are tolerant of anionic residues. Fifth-generation quaternaries are mixtures of the fourth generation with the second generation and demonstrate greater biocidal activity under conditions of high soil load, making them useful disinfect­ ants in barns and footbaths. Quaternary an1monium compounds are effective against most bacteria, enveloped viruses, some fungi (including yeasts), and protozoa but not against nonenveloped viruses, mycobacteria, and spores. Aqueous solutions of 1: 1,000 to 1:5,000 have good antimicrobial activity, especially at slightly alkaline pH, and are commonly used for disinfection of noncritical instruments and hard surface cleaning. When applied to skin, they may form a film under which microor­ ganisms can survive, which linlits their reliability as antiseptics. Concentrations > 1% are i.njulious to mucous membranes. Octenidine dihydrochloride is a cationic surfactant used increasingly in Europe as an alternative to quaternaries, chlorhexidine, and iodophores for skin, mucous membrane, and wound antisepsis.

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ANTISEPTICS AND DISINFECTANTS

OTHER ANTIBACTERIAL AGENTS

VAPOR-PHASE DISINFECTANTS

The antibacterial activity of dyes was first reported in 1913. Interestingly, the discovery of sulfonamides as chemothera­ peutic agents ensued from the antibacte1ial activity observed in the dye prontosil. Azo dyes (eg, scarlet red and phenazo­ pyridine HCI) are most active in an acidic medium and are effective against gram­ negative organisms. Scarlet red is often used as a 5% ointment on sores, ulcers, and wounds. Pyridium is often incorporated as an analgesic with sulfonamides to treat winary tract infections. Acridine dyes (eg, acriflavine, proflavine, aminacrine) are more active against gram-positive bacteria. Their activity is enhanced in alkaline meditun and antago­ nized by hypochlorites. lmpregnated bandages and gauze and acriflavine jelly have been used extensively for treatment of burns.

Alkylating agents such as formaldehyde, ethylene oxide, and propylene oxide are broad-spectrum biocides active against bacteria, viruses, and fungi, including spores. Ethylene and propylene ox.ides are highly reactive gaseous fwnigants used to sterilize animal feed, human food, surgical equipment that carmot be autoclaved (eg, endoscopes, gloves, syringes, catheters, tubing, implantable devices), laboratory equipment, etc. Both are noncorrosive. However, ethylene oxide has better penetrability than propylene oxide and, therefore, is more conrn1only used. For this application, ethylene oxide is mixed with chlorofluorocarbons or carbon dioxide and sold in gas cylinders. Other gaseous disinfectants (eg, fom1aldehyde, sulfur dioxide, methylbro­ nlide) have been used infrequently because of their toxic or corrosive properties.

ANTIVIRAL AGENTS The conventional approach to control of viral diseases is to develop effective vaccines, but this is not always possible. The objective of antiviral activity is to eraclicate the vims while. minimally impacting the host and to prevent further viral invasion. However, because of their method of replication, viruses present a greater tl1erapeutic challenge than do • bacteria. Viruses comp1ise a core genome of nucleic acid surrounded by a protein shell or capsid. Some viruses are fwther surrounded by a lipoprotein membrane or envelope. Viruses carmot replicate independently and, as such, are obligate intracellular parasites. The host's pathways of energy generation, protein synthesis, and DNA or RNA replication provide the means of viral replication. Viral replication occurs in five sequential steps: host cell penetra­ tion, disassembly, control of host protein and nucleic acid synthesis such that viral components are made, assembly of viral proteins, and release of the virus. Drugs that target viral processes must penetrate host cells; further, because viruses often asswne direction of cell division, drugs that negatively impact a virus are also likely to negatively impact

nom1al pathways of tl1e host. For these reasons, particularly compared with antibacterial drugs, antiviral drugs are characterized by a narrow therapeutic margin. Nephrotoxicity is emerging as an adverse reaction to antiviral drugs in human medicine. Therapy is fwther complicated by viral latency, ie, the ability of the virus to incorporate its genome in tl1e host genome, with cli..tlical infection becoming evident without reexposure to the organism. In vitro susceptibility testing must depend on cell cultures, which are expensiye. More importantly, in vitro inhibitory tests do not necessaiily correlate witl1 tllerapeutic efficacy of antiviral drugs. Pa.rt of tile discrepancy between in vitro and in vivo testing occurs because some drugs requi..t·e activation (metabolism) to be effective. Only a few antivi..t·al drugs ai·e reasonably safe ai1d effective against a lin1ited number of viral diseases, and most of tllese have been developed i..t1 people. Few have been studied in aI1i..t11als, and widespread clinical use of antiviral drugs is not common in veteri..t1ary medicine. The advent of human in1munodeficiency vi..t11s (HIV) and the development of tile cat as a model of HIV infection has somewhat increased tile ani..tnal knowledge base. Only a selection

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ANTIVIRALAGENTS

of the more promising agents and their pmpo1ted attributes are b1iefiy discussed. Most antiviral drugs interfere with viral nucleic acid synthesis or regulation. Such drugs generally are nucleic acid analogues that interfere with RNA and DNA produc­ tion. Other mechanisms of action include interference with viral cell binding or interruption of virus U11coating. Some vi.ruses contain unique metabolic pathways that serve as a target of drug therapy. Drugs that simply inhibit single steps in the viral replication cycle are virustatic and only temporaiily halt viral replication. Thus, optimal activity of some drugs depends on an adequate host immune response. Some antiviral drugs may enhance the inrn1U11e system of the host. TABLE 59 lists the dosage rates for some commonly used ai1tiviral drugs. Pyrimidine Nucleosides: A vaiiety of pyiimidine nucleosides (both halogenated and nonl1alogenated) effectively inhibit the replication of herpes simplex viruses with limited host-cell toxicity. The exact mechanism of action of these compoU11ds appeai-s to reflect substitution of pyiimidine for thyinicli..ne, causing defective DNA molecules. Idoxwicli..ne is effective for treatment of herpesvirus infection of the superficial layers of the cornea (h.erpesvirus keratitis) and of the skin but is toxic when administered systemically. Triflwidine, also an analogue of deoxythymidine, is currently the agent of choice for treatment of herpesvirus keratitis in people. The other antiviral pyrimicli..ne nucleosides have not been used clinically to any notable extent.

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ACYCLOVIR Acyclovir (acycloguanosine) ai1d its L-valyl ester prodrug valacyclovir, represent a new generation of antiviral agents, mainly because of the unique mechanism of action. This purine nucleoside is phosphorylated more efficiently by virus-induced thyn"licline kinase tl1ai1 host thyinidine kinase. Once activated to the t1iphosphate form, it is a better substrate and inhibitor of viral, versus host, DNA polyinerase. Bincling to DNA polyinerase is irreversible. Once acyclovir is incorporated into viral DNA, the DNA chain is tern"linatecl. Acyclovir is relatively safe (probenecid renders the drug safer) and is useful against a vai"iety of infections caused by DNA viruses, especially the herpesvirus family. However, resistance is increasing. Acyclovir is U11able to eli..n1inate latent infections. It is available as an ophthalmic ointment, a topical ointment and creai11, an IV preparation, ai1d vaiious oral formulations. The proclrug deoxyacyclovir is more readily absorbed from the GI tract than acyclovir. Anotl1er similar antiviral pwine nucleoside analogue is ganciclovir, a synthetic guai1ine effective against hwnan cytomegalovirus. Its mechanism of action is similar to that of acyclovir.

PENCICLOVIR AND FAMCICLOVIR

Purine Nucleosides: Ce1tain pwine nucleosides have proved to be effective antivirals ai1d ai·e used as systemic agents.

Fainciclovir is tl1e prodrug fo1111 of penciclovir. Penciclovir is very similar to acyclovir in terms of mechanism of actitm ai1d spectrwn. Although it is much. less potent than acyclovir, penciclovir accwnu­ lates to much 11.igher concentrations inside the cell. Penciclovir has been studied in cats receiving fan1ciclovir at 62.5 mg for 3 clays; it appeared to be well tolerated.

VIDARABINE

RIBAVIRIN

Vidai·abine, or a aA, is used topically for ocular herpesvirus and systemically for h.erpetic encephalitis and neonatal herpesviral infections. This drug is an adenosine derivative tl1at is phosphorylatecl by cellular enzyines to a triphosphate compoU11d that inhibits many viral and hwnan DNA polyinerases and thus DNA synthesis. Herpesviral enzyines are -20-fold more susceptible to t11e drug tl1an host DNA. Vidarabine is administered IV in large volwnes of fluid and is rapicily inactivated. It may produce bone marrow suppression and CNS adverse effects when high blood levels are reached. An ophtl1almic solution also is available.

Ribavirin is a synthetic tria.zole nucleoside (an analogue of guanosine) with a broad speclrwn of activity against many RNA and DNA vi.ruses, both in vitro ai1d in vivo. Susceptible virnses include adenoviruses, herpesviruses, orthomyxoviruses, pai·amyxovi..ruses, poxviruses, picornavi­ ruses, rhabcloviruses, rotavin1ses, a11d retroviruses. Viral resistance to ribavirin is rare. The action ofribavirin involves specific inhibition of viral-associated enzyi.11es, inhibition of the capping of viral mRNA, and inl"libition of viral polypeptide syi.1thesis. It is well absorbed, widely clistributed in the body, eliminated by renal and biliaiy routes as botl1 parent drug and

r

2746

ANTIVIRAL AGENTS

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DOSAGES OF ANTIVIRAL DRUGS Indication

Drug

Preparation

Dose, Route, and Frequency

Idoxuridine

0.1% ophthalmic solution

1 drop, topical, every 5-6 hr

0.5% ophthalmic solution

1drop, topical, every 1-2hr

Trifluridine

1% ophthalmic solution

1drop, topical, every 2hr initially ( 2 days), then 3---8 times daily

Ocular herpesvirus infection

Vidarabine

3% ophthalmic solution

0.4--1cm ointment, topical, every 5-6 hr; 3-6 times daily

Ocular herpesvirus infection

200mg/mL suspension for injection

10-30mg/kg/day,TV, as CRI for 12-24hr

200-mg capsules or tablets

200mg, PO, qid, every 4hr, or 5times daily

5% cutaneous ointment

Cover lesion, topical, every 3 hr, 6 times daily

200mg/ 5mL suspension

80mg/kg/day (mixed with peanut butter), PO, for 7 1-4days

500mg/vial powder

250-500mg/m2, TV, tid, infused over at least 1hr

500mg/vial powder

2-5mg/kg, IV, bid -tid

Acyclovir

Ganciclovir

11mg/kg/day,IV, for 7days

Ribavirin 6 g/ 100mL vial powder

Feline herpesvirus

Pacheco's disease in birds

Susceptible viral infections

Using SPAC- 2nebulizer only, inhalation, 8-18hr period daily

Zidovudine

5-20mg/kg (cats),PO or SC, 10mg/mL syrup; 10mg/mL injection bid-tid

Amantadine

100- and 500-mg capsules

100mg total (human), PO, once to twice daily

Syrup 10mg/mL

100mg/day total Quveniles ),PO

3 x 106 IU/vial

3 x 106 IU/person/day,SC, IM; 0.5-5U/kg/day,PO; 100,000U/kg/ day,SC

FeLV-associated disease

1U/day, PO

FeLV appetite stimulant

15-30U, PO, IM, SC ,once daily on alternate weeks

FIP,FIV

200-300mg/day total (human),PO

Rimantadine Interferon a-2

FIV,FeLV

CR! = constant-rate infusion; FeLV = feline leukemia virus; FIP = feline infectious peritonitis; FFV = feline in11nunocleficiency virus

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ANTIVIRALAGENTS

metabolites, and has a plasma half-life of 24 hr in people. It does not have a wide margin of safety in domestic anin1als. Toxicity is manifest by anorexia, weight loss, bone marrow depression and anemia, and GI disturbances. It has been successfully administered by topical, parenteral, oral, and aerosol routes. Efficacy depends on the site of infection, method of treatment, age of the animal, and infecting dose of virus. Results of human influenza studies with ribavirin have been equivocal.

ZIDOVUDINE Zidovudine (azidothymidine, AZT) is a thyrnidine analogue. Within the virus­ infected cell, the 3' -azido group is used by retroviral reverse transcriptase and incorporated into DNA transcription, preventing viral replication. The shared mechanism of action is inhibition of RNA-dependent DNA polymerase (reverse transcriptase). This enzyme is responsible for conversion of the viral RNA genome into double-stranded DNA before it is integrated into the cell genome. Because these actions occur early in replication, the drugs tend to be effective for acute infections but are relatively ineffective for chronically infected cells. Cellular a-DNA polymerases are inhibited only at concentrations 100-fold greater than those necessary to inhibit reverse transcriptase, thus rendering this drug relatively safe to host cells. Cellular -y-DNA polymerase, however, is inhibited at lower concentrations. AZT is effective against a variety of retroviruses at low concentrations. Resistance to AZT is associated with point mutations resulting in amino acid substitu­ tions in the reverse transcriptase. Prolonged use of AZT can facilitate viral resistance. The risk of resistance also appears to correlate with CD4 cell count and the state of infection. Viral susceptibility to AZT may return after the drug has been discontinued for a period of time. Granulocytopenia and anemia are the major adverse effects of AZT in human patients. The risk of toxicity increases in human patients with low (CD4) lymphocyte counts, high doses, and prolonged therapy. Granulocyte colony-stimulating factor is indicated for management of granulocyto­ penia. CNS adverse effects a.re more likely as therapy is begun. The risk of myelosup­ pression is increased by drugs that inhibit glucuronida.tion or renal excretion and may be increased in ca.ts. After a single dose of AZT at 25 mg/kg in ca.ts, bioa.va.ila.bility is -75%-100%. The

2747

elimination half-life is -1.5 hr, and volume of distribution is 0.82 IJkg. Drug concentra­ tions remain above the effective concentra­ tion 50 (EC50) of 0.19 mcgtmL for feline immw10deficiency virus for at least 24 hr after either IV or PO administration. Although this concentration is higher than that associated with myeloid suppression of human cells, adverse effects in ca.ts are limited to transient restlessness, mild anxiety, and hemolysis. Studies in ca.ts regarding the efficacy of AZT (10--20 mg/kg, bid for 42 days) for feline leukemia. virus infection indicated that AZT prevents retroviral infection if administered immediately after viral exposure and may reduce replication if administered to previously infected animals. Serum-neutral­ izing antibodies developed in some of the infected cats, and the ca.ts became resistant to subsequent viral challenge. There was no altered progression of disease in ca.ts when treatment was withheld until 28 days after infection, although the level of viremia. was much lower than in untreated ca.ts. AZT appeared to be nontoxic in uninfected cats, although 3 of 12 infected kittens becan1e anorectic and icteric and were vomiting after 40 days of treatment. AZT may ca.use Heinz body anemia. CBCs should be performed on ca.ts receiving AZT.

AMANTADINE Amantadine, and its derivative rimanta­ dine, a.re synthetic antiviral agents that appear to a.ct on an early step of viral replication after a.tta.clunent of virus to cell receptors. The effect seems to lead to inhibition or delay of the uncoa.ting process that precedes primary transcrip­ tion. Amanta.dine may also interfere with the early stages of viral mRNA transcrip­ tion. Ama.nta.dine at usual concentrations inhibits replication of different strains of influenza. A virus, influenza. C virus, Sendai virus, and pseudora.bies virus. It is almost completely absorbed from the GI tract, and -90% of a dose administered PO is excreted unchanged in the urine over several days (hwnan data). The main clinical use has been to prevent infection with various strains of influenza. A viruses. However, in people, it also has been found to produce some therapeutic benefit if taken within 48 hr after the onset of illness. Amanta.dine and its derivatives may be given by the PO, intranasal, SC, IP, or aerosol routes. It produces few adverse effects, most of which are related to the CNS; stimulation of the CNS is evident at very high doses.

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ANTIVIRALAGENTS

MISCELLANEOUS ANTIVIRAL AGENTS Several drug classes continue to be investigated mainly because of their in vitro antiviral activities. Their potential clinical usefulness remains obscure in most instances. Included among these agents are thiosemicarbazones, guanidine, benzinuda­ zoles, arildone, phosphonoacetic acid, rifan1ycins and other antibiotics, and several natural products. Oseltamivir is a prodrug that, when hydrolyzed, yields the carboxylated

metabolite that inhibits viral neuramini­ dases of human influenza viruses. Mature influenza viruses bud off from the cell in a sphere of host phospholipid membrane. The virus will adhere to the cell until neuraminidase has been cleaved from the sialic acid residues of the host cell membrane. Neuran1idases allow separation and subsequent release of viral progeny. Hydrolysis, or activation, occurs in the GI tract and liver. The use of oseltanuvir for treatment of viral diseases in dogs (paivovirus and parainfluenza) is Urns fai· anecdotal.

ECTOPARASITICIDES ECTOPARASITICIDES USED IN LARGE ANIMALS Arthropod parasites (ectoparasites) are major causes of livestock production losses throughout the world. In addition, mai1y arthropod species can act as vectors of disease agents for both aninlals and people. Treatment with various parasiti­ cides to reduce or elinunate ectoparasites is often required to maintain health and to prevent economic loss in food aninlals. Some ectopai·asiticides were derived from pesticides used to protect crops. The choice and use of ectoparasiticides depend to a large extent on husbandry and manage­ ment practices, as well as on the type of ectoparasite causing the infestati.OJl. Endectocides are capable of killing both internal and external parasites. Accurate identification of the parasite or correct diagnosis based on clinical signs is necessary for selection of the appropriate parasiticide. The selected agent can be administered or applied directly LO the anin1al, or introduced into the environment to reduce the aithropod population to a level that is no longer of economic or health consequence. Parasites that live pern1anently on the skin, such as lice, keds, and nutes, can be controlled by directly treating the host. Some mange nutes burrow into the skin and are therefore more difficult to control with sprays than are lice and keds, which are found on the surface of the skin. However, once these obligate parasites are eradi­ cated, reinfection occurs only from contact with other infected animals.

Ectoparasites with stages that live off the host (ticks, flies, etc) are less easily controlled. Only a small proportion of the ectoparasite population can be treated on the host at any one time, ai1d other hosts may maintain them. Some tick species stay on the host only long enough to feed, wluch may be as short as 30 nun or as long as 21 days. Biting flies, such as the horn fly, can be found continually on the backs and undersides of cattle, where they suck blood up to 20 times a day; other biting lies (such as stable flies and horse lies) and mosqui­ toes feed to repletion, then leave the ruumal to lay eggs. Nonbiting flies, such as the face fly or house fly, may visit infrequently but can be very armoying and may transmit disease agents. Larvae of certain blowflies live on the skin or in tissues of sheep ru1d other animals and cause cutaneous myiasis. Larvae of other flies spend several months inside anin1als ( eg, nasal bots in..tl1e nasal passages of sheep and goats, bots in the stomach of horses, and cattle grubs or warbles in the back or esophageal tissues). (See a/,so ,LIES, p 885.) Many ectoparasite infestations are seasonal and predictable and can be countered by prophylactic use of ecto­ parasiticides. For exrunple, in temperate cotmtries, lies are seen predominantly from late spring to early autw1m, tick populations often increase in the spring ru1d auttmrn, and lice and mite infestations can be more common during the autwnn and winter months. Treatments can be targeted at anticipated times of peak activity as a way to limit parasite popula­ tions and disease.

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ECTOPARASITICIDES Products are available for parenteral administration or for topical application by various methods, including dips, sprays, pour-ons, spot-ons, dusting powders, and ear tags. The method used depends on the target parasite and host. (See ROUTES OF ADMINISTRATION AND DOSAGE FORMS, p 2508.) Importantly, most topical ectoparasiticides used in the USA are pesticides regulated by the U.S. Environmental Protection Agency (EPA). This is an important distinction from products regulated by the U.S. Food and Drng Administration (FDA), because it is illegal to use an EPA-regulated pesticide product inconsistent with its label directions (www.epa.gov). The regulating agency should be identifiable on the product label. The National Pesticide Information Retrieval System (NPIRS) is a searchable database of EPA-registered products (http://ppis.ceris.purdue.edu/).

Chemotherapeutic Agents Most ectoparasiticides are neurotoxins, exerting their effect on the nervous system of the target parasite. Those used in large animals can be grouped according to strncture and mode of action into the organochlorines, organophosphates and carbarnates, pyrethrins and pyrethroids, macrocyclic lactones (avermectins and rnilbemycins), formarnidines, insect growth regulators, and a number of miscellaneous compatmds, including synergists (eg, piperonyl butoxide ). There are also a number of useful compounds with repellent rather than insecticidal activity, including butoxypolypropylene-glycol and N,N-diethyl-3-methylbenzanlide (DEET, previously called N,N-diethyl-metatolua­ mide).

Organochlorines: Organochlorine compounds have been withdrawn in many parts of the world because of concerns regarding environmental persistence. Organochlorines fall into three main groups: 1) chlorinated ethane derivatives, such as DDT (dichlorodiphenyltrichloroeth­ ane), DDE (dichlorodiphenyldichloroeth­ ane), and DDD (dicofol, methoxychlor); 2) cyclodienes, including chlordane, aldrin, dieldrin, hepatochlor, endrin, and toxa­ phene; and 3) hexachlorocyclohexanes such as benzene hexachloride (BHC), which includes the -y-isomer, lindane. Chlorinated ethanes cause inhibition of sodium conductance along sensory and motor nerve fibers by holding sodium channels open, resulting in delayed repolarization of the axonal membrane.

2749

This state renders the ne1ve vulnerable to repetitive discharge from small stimuli that would nonnally cause an action potential in a fully repolarized neuron. The cyclodienes appear to have at least two component modes of action: inhibition of -y-aminobutyric acid (GABA)-stimulated CJ- flux and interference with Ca2+ flux. The resultant inhibitory postsynaptic potential leads to a state bf partial depolarization of the postsynaptic membrane and vulnerabil­ ity to repeated discharge. A sinlilar mode of action has been reported for lindane, which binds to the picrotoxin side of GABA receptors, resulting in an inhibition of GABA-dependent CJ- ion flux into the neuron. DDT and BHC were used extensively for flystrike control but subsequently replaced in many countries by more effective cyclodiene compounds, such as dieldrin and aldrin. Both the development of resistance and environmental concerns led to their withdrawal. DDT and lindane were widely used in dip formulations to control sheep scab, but they have mostly been replaced by the organophosphates and subsequently the synthetic pyrethroids.

Organophosphates and Carbamates:

The organophosphates comprise a large group of chemicals, many of which are available for topical application and in ear tags as well as for premise control of parasites. There have been many products available worldwide for use in domestic animals, although only a few of the available compounds continue to be used for on-animal treatment. Organophosphates are neutral esters of phosphoric acid or its thio analogue that inhibit the action of acetylcholinesterase (AChE) at cholinergic synapses and at muscle endplates. The compound minlics the strncture of acetylcholine (ACh); when it binds to AChE, it causes transphosphory ­ lation of the enzyn1e. The transphorylated AChE is unable to break down accumulat­ ing ACh at the postsyl'aptic membrane, leading to neuromuscular paralysis. The degree oftransphorylation of the enzyn1e helps to detern1ine the activity of the organophosphate. Eventually, the AChE is metabolized by oxidative and hydrolytic enzyme systems. Organophosphates can be extremely toxic in animals and people, inhibiting AChE and other cholinesterases (see p 3064). Chr011ic toxicity results from inhibition of an enzyn1e known as neuropa­ thy target esterase (NTE) or neurotoxic esterase and is associated with particular

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ECTOPARASITICIDES

compounds. NTE hydrolyzes the fatty acids from the membrane lipid, phosphotidylcho­ line, and inhibition ofNTE appears to cause structural changes in neuronal membranes and a reduction in conduction velocity, which may be manifest as posterior paralysis in some animals. Cases of organophosphate toxicity are treated with oximes or atropine. Organophosphates used topically include coumaphos, diazinon, dichlorvos, malathion, tetrachlorvinphos, trichlorfon, phosmet, and pirimiphos. Ear tags containing chlorpyrifos, coumaphos, diazinon, or pirimiphos are available. These compounds are generally active against fly larvae, flies, lice, ticks, and mites on domestic livestock, although activity varies between compounds and differing fonnulations. Chlorpyrifos can be used in microencapsulated form for residual activity and improved safety. Diazinon and propetamphos have been available in dip fonnulations to control psoroptic mange in sheep. Both eliminate mites and protect in a single application when correctly applied. Diazinon provides longer residual protection than propetamphos. In cattle, a number of compounds have been used for systemic control of warble fly grubs and lice as pour-on applications or in hand sprays, spray races, or dips for tick control. Carbamate insecticides are closely related to organophosphates and are anticholinesterases. Unlike organophos­ phates, they appear to cause a spontane­ ously reversible block on AChE without changing it. The main carban1ate compound used in veterinary medicine is propoxur. CarbaryI, anotller carban1ate previously used in veterinary medicine, has been withdrawn from the veterinary market. Pyrethrins and Synthetic Pyrethroids:

A number of pyrethroids are available in many countries as pour-on, spot-on, spray, and dip formulations with activity against biting and nuisance flies, lice, and ticks on domestic livestock. Flun1ethrin and high cis-cypennetlui.n are also active against mites and have been used to treat psoroptic mange of sheep. Natural pyrethrins are derived from pyretllrum, a mixture of alkaloids from tile Chrysanthemum plant. Pyrethrum extract, prepared from the pyrethrum flower head, contains several molecules collectively known as pyretlui.ns (pyretlui.n I and II, cinerin I and II, and jasmolin I and II). Pyrethrins are lipophilic molecules tllat generally undergo rapid absorption, distJ.i.bution, and excretion. They provide

excellent knockdown (rapid kill) but have poor residual activity because of instability. Pyrethrin I is tile most active ingredient for kill, and pyrethrin II for rapid insect knockdown. Pyrethroids are syntllesized chemicals modeled on the natural pyrethrin molecule. They are more stable, thus have longer residual activity, and have a higher potency than natural pyretllrins. The mode of action of pyrethrins and synthetic pyrethroids appears to be interference witll sodium channels of the parasite nerve axons, resulting in delayed repolarization and eventual paralysis. Synthetic pyrethroids can be divided into two groups (types I and II, depending on the presence or absence of an o:-cyano moiety). Type I compounds have a mode of action similar to that of DDT, involving interfer­ ence with tile axonalNa+ gate leading to delayed repolarization and repetitive discharge of the nerve. Type II compounds also act on theNa+ gate but do so without causing repetitive discharge. The letllal activity of pyrethroids seems to involve action on botll peripheral and central neurons, while peripheral neuronal effects alone probably produce tile knockdown effect. Some preparations contain a synergist (eg, piperonyl butoxide), which inhibits breakdown of pesticides by microsomal mixed-function oxidase ( cytochrome P450) systems in insects. Pyrethroids are generally safe in mammals and birds but are highly toxic to fish and aquatic invertebrates. Concerns have been expressed over tlleir environ­ mental effects, particularly in relation to the aquatic environment, leading to tlleir witlldrawal as sheep dips in some countries. Some of the more common pyrethroids used include 13-cyfluthrin, bioallethrin, cyfluthrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, lambda cyhalothrin, phenothrin, permethrin, prallethrin, and tetramethrin. The content of some syntlletic pyrethroids is also expressed in terms of tile drug isomers, eg, cypermethrin prepar a ­ tions may contain varying proportions of their cis and trans isomers. Thus, cyperme­ thrin (cis:trans 60:40) 2.5% is equivalent to cypermethrin (cis:trans 80:20) 1.25%. In general, cis isomers are more active than tile corresponding trans isomers. Macrocyclic Lactones (Avermectins and Milbemycins): Avermectins and the

structurally related rnilbemycins, collec­ tively referred to as macrocyclic lactones, are fermentation products of Streptomyces avermitilis and S cyanogriseus, respec-

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ECTOPARASITICIDES

tively. Avem1ectins differ from each other chemically in side chain substitutions on the lactone ring, whereas milbemycins differ from the avem1ectins through the absence of a sugar moiety from the lactone skeleton. A number of macrocyclic lactone com­ pounds are available for use in anin1als and include the avern1ectins abamectin, doramectin, eprinomectin, ivennectin, and selamectin, and the milbemycins moxidec­ tin and milbemycin oxime. These com­ pounds are active against a wide range of nematodes and arthropods and are often refen-ed to as endectocides. Endectocidal activity, particularly against ectoparasites, is variable and depends on the active molecule, the product formula­ tion, and the method of application. Macrocyclic lactones can be given PO, parenterally, or topically (as pour-ons and spot-ons). The method of application depends on the host and, to some degree, on the target parasites. In cattle, for example, available endectocide products can be given PO, by injection, or topically using pour-on fomrnlations. The latter are generally more effective against lice (Linognathus, Haematopinus, and to some extent Bovicola) and headfly (Haematobial Lyperosia) infestations than equivalent compounds administered parenterally. In sheep, PO administration of some endectocides has little effect against psoroptic mite infestations (Psoroptes ovis), but parenteral administration increases activity, providing both protection and control depending on the product used. The route of administration and product formulation influence the rates of absorp­ tion, metabolism, excretion, and subsequent bioavailability and pharmacokinetics of individual compounds. Avennectins and milbemycins are highly lipophilic, a property that varies with only minor modifications in molecular structure or configuration. After administration, these compounds are stored in fat, from which they are slowly released, metabolized, and excreted. Ivermectin is absorbed systemi­ cally after PO, SC, or dermal administration; it is absorbed to a greater degree and has a longer hal f -life when given SC or dermally. Excretion of the unaltered molecule is mainly via the feces, with 0.25 kg/day. Zeranol, estradiol, and TBA can be used in male castrates. Dairy heifer replacements carmot be given steroid implants as weanlings. Greater and more consistent responses are obtained in yearling and older cattle than in calves or weanlings, due pruparily to greater intake and to the higher plane of nutrition. In the case of pellet-type implants with effectiveness of90-120 days, consideration can be given to rein1planting cattle midway through the grazing season, provided gains >0.5 kg/clay are maintained. Silastic implants of estradiol are effective for 200-400 clays, depending on dose used. Daily gains in feedlot cattle fed a high-energy diet may be increased 200/o-3()0A, after implantation with an estrogen and an androgen; daily gain in pasture cattle is typically improved by l OO/o-15%. Responses to growth promotion are good when animals are on a high plane of nutrition. Feed conversion efficiency is improved, and lean meat content of the carcass is generally increased. Although less clear, conforma­ tion of implanted cattle tends to improve. Negative impacts of implants on marbling content of the loin muscle can be minimized by finishing cattle to a fat-constant endpoint.

In steers and heifers in the feedlot and provided a high-energy diet, use of an androgen plus an estrogen horn1one combina­ tion is common. Pellet-type implants are effective for as long as 150 days; rein1planting cattle after 70-100 days should be considered because of decreasing response from the pellet-type implants over time. Results from large-pen studies (>25 animals/pen) show that heifers benefit from a combination of estracliol, TBA, and MGA. In small-pen research, however, when fed in combination with growth-promoting implants, MGA use results in reduced gain, feed efficiency, and ribeye area, as well as increased fatness. These contrary findings suggest that although progesterone may have an "anti-growth promoting" effect, the growth-promotion benefit realized from suppression of estrus overcomes the minor negative physiologic impact of progester­ one in conventional large feedlot pens. In some studies in which bulls were treated with estrogens, growth rate increased by 2"/o-lOOA,, and testicular growth was suppressed with a subsequent reduction in moW1ting and aggression. This should make the bulls easier to manage on the fa.n11 and less subject to "dark cutting" after slaughter. The mechanism involved appears to be the reduction of the gonadotropic hormones LH and follicle-stin1ulating hormone (FSH) from the pituitary gland by estrogen, which has a strong negative feedback effect on LH and FSH secretion. This reduction in LH and FSH results in decreased testicular size and lower testoster­ one levels, with a consequent reduction in aggressive behavior. However, there appears to be suffident testosterone secreted to maintain an anabolic effect. Therefore, the repeated use of estrogens in bulls beginning at 1-3 mo of age may lead to a honnonal castration effect with increased growth rate. Use in Horses The use of anabolic agents in horses is not recommended because of adverse effects on the reproductive system. Administration of a steroid ho1111onal androgen analogue decreases testicular size in stallions. Decreased hormonal concentrations, especially LH, testosterone, and inhibin, adversely affect testicular histology and spem1atogenesis and transiently decrease spem1 output and quality. One of the most commonly used compoW1ds is 19-nortestos­ terone for therapy in debilitated and anemic horses. However, use of these compoW1ds is contraindicated, and longterm treatment or large closes have serious adverse effects on reproductive tract flli1ction.

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GROWTH PROMOTANTS AND PRODUCTION ENHANCERS

Use in Other Species In pigs, the growth responses from the use of estradiol, progesterone, and zeranol are variable but generally low. TBA seems to increase lean meat content of pig carcasses. In sheep, the responses to anabolic agents parallel those obtailled in cattle. The most consistent responses have been obtained in lambs finished on high-concen­ trate diets; a 1()%--15% increase in daily gaill can be expected. Anabolic steroids should not be used in lambs to be retained for breeding. Also, in1plantation with zeranol reduces testicular development in ran1 lambs and delays the onset of puberty and reduces the ovulation rate in female sheep. Moreover, the short finishing period and the extensive nature of some production systems militate agaillst widespread practical use of growth promotants in sheep on economic grow1ds. In poultry, responses to estrogens include increased fat deposition. Andro­ gens, however, have given conflicting responses. Hence, their use is of no practical significance at this tin1e. In fish, methyl testosterone can induce sex reversal in raillbow trout, thereby promoting growth and improved feed conversion efficiency. Possible Complications Any hormonal implant has a negative feedback effect on pituitary gonadotropins, thereby reducing LH and FSH secretion. TI1erefore, they can affect the onset of puberty and the regularity of estrous cycles, as well as reduce conception rate in females and testicular development (and thus spenn output) in males. Hormonal growth promo­ tants should never be used in animals that are or may be used for breeding purposes, nor should they be used before puberty to increase growth in yearling thoroughbreds or young pedigree bulls for show purposes. lf given to pregnant heifers, TBA results in increased incidence of severe dystocia, masculin.ization of female genitalia of the fetus, increased calf mortality, and reduced milk yield in the subsequent lactation. The major problem thought to be associated with estrogenic implant use in the feedyard has been a transient increase in mounting behavior and aggression, commonly referred to as buller syndrome (seep 1552). However, it is also believed that the estrogen in the implant alone is not sufficient to cause bulle1-s. TI1e "buller" is the animal being pursued by one or more pen mates that repeatedly attempt to mount the buller throughout the day and several days.

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Buller syndrome generally affects 2"/o--3"/o of the feedyard steer population, but this rate can double or triple during the late swnmer and early fall months. An increase in yearling steers off native grass pastme (which are usually given a high-dose implant immedi­ ately on arrival), ditunal temperatw-e fluctua­ tions Q1ot days and cool nights that shift social activity to early evening hours), dusty pen conditions (exacerbated by evening social activity), feeding com or hay that may be moldy, and incomplete fem1entation on freshly harvested silage can also contribute to increases in buller syndrome. Feedlot pens with a greater nw11ber of animals experience a greater incidence of bull er activity, and the incidence of hullers increases linearly with increasing mtmber of animals within a pen above 80--100 animals per pen. Til.is suggests the agonistic behavior is a population phenomenon, requiting a ctitical mass of both the dontinant, mounting animals and the animals they are attempting to mount. Bullers have been shown to have greater circulating concentrations of monoanl.ine oxidase and reduced circulating concentrations of progesterone than non-buller pen mates. These effects generally last for 1--10 days after inlplanta­ tion and then subside. However, there have been a few reports of undesirable behavior in steers that lasted for 4--1() wk. The cause of this unpredictable adverse behavior is not clear; it may be a function of rearing and socialization climate. It is generally more severe in dairy cattle used for beef produc­ tion. If the problem is severe, the buller steers should be identified and removed; if very severe, removal of the in1plants or administration of 50--100 mg of progesterone in oil for a nun1ber of days to suppress behav­ ior should be considered. In addition to buller syndrome, estrogenic implants may increase the size of rudimen­ tary teats. Factors Affecting Response A nun1ber of factors affect the response to growth-promoting in1plants, including genetic makeup, plane of nutrition, and the sex and age of the animal. Animals should be gaining a minimum of 0.25 kg/day before an economic response is obtailled. Implants are best used in animals on a high plane of nutrition and under good husbandry conditions. They are an aid to, but not a substitute for, good husbandry. Consequently, there is little economic incentive in implanting cattle destined for a 3- to 4-mo "store period," during which time animals are fed to gaill

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GROWTH PROMOTANTS AND PRODUCTION ENHANCERS

little or no weight. Responses are reduced in calves (based on health condition and diet), and responses are good in yearlings. Prior implantation does not affect the response to the next implantation. Also, once the implant effect has ceased, the rate of gain reverts to the rate that would be expected in nonimplanted animals, assuming the level of feeding is the same. Also, extra weight induced by implants in early life is transferred through to extra carcass weight at slaughter.

GROWTH HORMONE The peptide most commonly used to enhance growth and production is growth hom1one (GH). Its chemical structure is species-spe­ cific, and it has a short half-life (20-30 min). It is not orally active and is rapidly digested and cleared by the gut, liver, and kidney; thus, it must be administered via a parenteral route. Sustained-release (14-28 days) fom1ulations have been developed for use in cattle to obviate the need for daily injections. When administered to cattle, GH increases growth rate (5%--lOOAi), feed conversion efficiency, and the carcass lean:fat ratio. Gender has little effect on response in cattle. Response to GH is lower in older cattle with greater fat deposition. There is an interaction between magnitude of response and nutritional level; protein content and specific amino acid composition may be important to achieve maximal responses. The effects of GH are largely additive to those obtained from steroid implants. GH improves growth and feed efficiency in sheep but not in poultJy. Recombinant GH in pigs has dramatic effects, resulting in an increase in daily gain (200Ai), decrease in feed intake (5%), and a decrease in the feed:gain ratio (20%). A lOOAi increase in Jean content and a 35% decrease in adipose tissue may be realized in swine. AdministJ·a.tion of bovine GH at 25 mg/day to lactating cattle increases milk yields of dairy cows by as much as 200A,. GH has been approved for commercial use in some countries to increase milk production.

13-ADRENERGIC AGONISTS As of 2015, there are two [3-adrenergic agonists (f3AAs) approved for use as growth promotants in feedlot cattle in the USA: ractopamine and zilpaterol. Phenetha.nola.­ mine f3AAs are chemically sinlilar in structure to epinephrine and norepineph­ rine and have paracrine, neurotransmitter, and endocrine (ho1111onal) effects. There is a range of f3AA compounds resulting from structural modifications and aromatic ring

substitution. The f3AAs bind to [3-a.drenergic receptors, which have been classified into [31, [32, and [33 subtypes based on the physiologic response obtained. [31 receptors are located prin1arily in cardiac muscle but also can be found in skeletal muscle, [32 receptors in tracheal and skeletal muscle, and [33 receptors in brown adipose tissue. In general, f3AAs have specificity for receptor subtypes, thereby providing specificity regarding their physiologic actions. However, there are multiple receptor subclasses in most tissues, and the relative concentJ·a.tions of [31 and [32 receptors in a tissue detennine the physiologic response. Muscle and adipose cells have predominantly [32 receptors. f3AA use leads to an increase in muscle mass caused by upregulation of mRNA transcrip­ tion, resulting in increased protein synthesis, and a decrease in carcass fat due to decreased rates of lipid accretion. The exact proportion of receptor subtypes varies between tissues and also across species, resulting in species-specific responses to select f3AAs. For example, swine a.re believed to have more [31 than [32 receptors in their skeletal muscle; ruminants are believed to have more [32 than [31 receptors. The physiologic activity of f3AAs depends on the close, receptor bind­ ing specificity, mode of administration, rate of absorption, and metabolic clearance rate in treated animals. Also, because tissue becomes refractory to exogenous f3AA administration, f3AAs are fed only during the final days of the finishing phase; extended feeding ultimately results in a complete loss of tissue response to f3AAs. The major use of f3AAs in food animal production is to increase carcass leanness and lean tissue produced per animal. ln cattle and sheep, weight gain, gain:feecl ratio, and meat content are increased by 1()0,.(,...2()0A, and lipid content is decreased by 7%-200Ai. ln swine and chickens, respons"es are much lower, with pigs responding better than chickens. Weight gain is increased by ZOAi-4%, and gain:feed ratio is slightly improved in chickens but not in pigs. Meat content is increased by ZO/o-4% and lipid content decreased by 7o/o--8% in chickens and pigs. Adverse effects depend on compound administered, close used, and species treated, but those selected for commercial use have minimal adverse effects. They are orally active. Dosage level of tl1e compound used affects the response obtained; tl1e optimal dose often varies for different production variables measured. The most consistent effects are increased proportion of lean meat, but tl1e effects on meat quality

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GROWTH PROMOTANTS AND PRODUCTION ENHANCERS

vaiy with compound used, dosage given, duration of treatment, and species treated. Cettain compounds have been reported to decrease tenderness of meat in cattle. The use of 13-agonists as growth promoters is banned in the EU. Illegal use of clenbuterol in cattle and certain l3AAs in poultry is a threat in some countries, requiring vigilance by regulato1y authorities. The longtenn accumulation of these compounds in hair and ocular tissue has been used to screen for their presence in some countries.

ANTIMICROBIAL FEED ADDITIVES Maintenance of healthy animals requires prevention of infection by pathogenic organisms. In addition, specific alteration of a host's microflora may have beneficial effects on aimnal production by alteration of n.m1inal flora, resulting in changes in the proportions of volatile fatty acids produced during n.m1inal digestion. Thus, antimicro­ bial compounds may improve production efficiency of healthy animals fed optimal nutritional regimens. Production-enhancing antimicrobial compounds cat1 be classified as ionophore or nonionophore antibiotics. This distinction is in1portant, because ionophores have no use in hwnan medicine and do not have any link or possible effect on antimicrobial resistance to therapeutic antibiotics in either people or food animals; to group all antin1icrobials together for debate about the risk to tl1erapeutic antibiotics is ill advised and overly

2765

simplistic. Antimicrobial compounds ai·e administered in tl1e feed at low dose rates relative to high doses required for therapeu­ tic effects. Feed additives can be given once the n.m1en is fw1ctioning, although some antibiotic compounds can be fed to calves before this point. Antimicrobial growth promotants commonly used in livestock are detailed in TABLE 62. Anliimicrobials ai·e used in male and female animals without adverse effects on ovarian and testiculai· development or function because they are poorly absorbed. Unlike at1abolic steroids, they do not affect carcass composition. Antimicrobials are conunonly used in conjunction with estradiol, zeranol, or TBA, and generally their combined effects are additive. lonophore Antibiotics Ionophores (eg, monensin and lasalocid) modify the movement of monovalent (sodium and potassium) and divalent (calcium) ions a.cross biologic membranes, modify the n.unen microflora, decrease acetate and methane production, increase propionate, may improve nitrogen utilization, at1d cat1 increase dry matter digestibility in n.m1inants. Their main effect is to increase feed efficiency, but they may also in1prove growth rates of run1inants on high-roughage diets. Administration of monensin to cattle results in 2%-1 (JOA, improvement in liveweight gain (in animals on a high-roughage diet), 3o/2 wk old. Breeding flocks should be revaccinated annually. The vaccine can be used in an outbreak, because it elicits rapid protection after vaccination. It is not approved for use in wild ducks. An inactivated vaccine, which appears to be as efficacious as the modified-live vaccine, has not been tested on a large scale and is not currently licensed.

HEXAMITIASIS Hexarnitiasis is an acute, infectious, catarThal ente1itis of turkeys, pheasants, quail, chukar· partridges, ar1d peafowl. The highest mortality occurs in birds 1-9 wk old. Natural infection has not been observed in chickens. Pigeons are susceptible to another species of Sp'ironucleus (S columbae). Hexarnitiasis is rare in North America. Etiology: The causative protozoan parasite in turkeys, S meleagridis (fom1erly He.xamita meleagridis) is spindle-shaped; averages 8 x 3 µm; and has four anterior, two anterolateral, and two posterior flagella. It has not yet been cultured in experimental media, although it has been grown in the allantoic cavity of developing chicken and turkey embryos. It is transmitted directly by ingestion of contaminated feces and water. Encysted hexarnitids are resistant to

environmental conditions outside tl1e bird and, therefore, may be more in1portant in the transmission of tl1e disease. Up to \/3 of the recove1ing birds become car·1iers and shed parasites in their droppings. Clinical Findings and Lesions:

Signs of hexarnitiasis are nonspecific and include watery diarrhea that may be yellowish later in the disease, dry unkempt feathers, listlessness, and rapid weight loss despite the fact the birds continue to eat. Birds may die in coma or convulsions. Bulbous dilatations of the small intestine (especially duodenum and upper jejunum) filled with watery contents are characteristic. The crypts of Lieberkiihn contrun myriad S meleagridis, which attach to the epithelial cells by their posterior flagella.

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2802

HEXAMITIASIS

Diagnosis: Diagnosis of hexamitiasis depends on finding the flagellates by microscopic examination of scrapings of the duodenal and jejuna! mucosa. Spirnnucleus spp move with a rapid, darting motion (in contrast to the jerky motion of trichomonads). To avoid contamination of instruments with other cecal protozoa, the duodenum should be opened first. Spironucleus spp may be demonstrated in poults that have been dead for several hours if the scrapings are placed in a drop of warm (104 ° F [40° C]), isotonic saline solution on the slide. Presence of a few Spironucleus in birds >10 wk old may be unimportant in terms of the disease but still act as a reservoir of infection.

Prevention and Treatment: Because many birds remain carriers of Sp'ironiicleus, breeder turkeys and young poults should be raised on separate premises if possible, preferably with separate attendants. Wire platforms should be used under feeders and waterers. Pheasants and quail may also be carriers and should not be raised in the same location as poults. Indirect transmis­ sion can occur if affected fecal material is transferred to another location by contanlinated equipment or clothing. There is no effective treatment or vaccine for hexamitiasis, although oxytetracycline (0.22% in the feed for 2 wk) or chlortetracy­ cline (0.022%--0.044% in the feed for 2 wk) may be of some benefit to control secondary infections.

NECROTIC ENTERITIS Necrotic enteritis is an acute enterotoxemia The clinical illness is usually very short, and often the only signs are a severe depression followed quickly by a sudden increase in flock mortality. The disease primarily affects broiler chickens (2--5 wk old) and turkeys (7--12 wk old) raised on litter but ca.n also affect conunercial layer pullets raised in cages. Early mortality is often related to coccidiosis vaccination programs, with Eimeria cycling in these flocks.

Etiology and Pathogenesis: The causative agent is the gram-pqsitive, obligate, anaerobic bacteria Closl1'idium pmjhngens. It is usually isolated on blood agar, incubated anaerobically at 37° C (98.6° F), on which it produces a double zone of hemolysis. There are two primary C pmfringens types, A and C, associated with necrotic enteritis in poultry. Toxins produced by the bacteria cause damage to the small intestine, liver lesions, and mortality. C pe1:fringens is a nearly ubiquitous bacteria readily found in soil, dust, feces, feed, and used poultry litter. It is also a normal inhabitant of the intestines of healthy chickens and turkeys. The enterotoxemia that results in clinical disease most often occurs either after a change in the intestinal microflora or from a condition that results in damage to the intes­ tinal mucosa (eg, coccidiosis, mycotoxico­ sis, salrnonellosis, ascarid larvae). High dietary levels of animal byproducts (eg,

fishmeal), wheat, barley, oats, or rye predispose birds to the disease. Anything that promotes excessive bacterial growth and toxin production or slows feed passage rate in the small intestine could promote the occU1Tence of necrotic enteritis. In many cases, concurrent coccidiosis (especially Eimmia maxima, and E acervulina to a lesser extent) is associated with outbreaks in conunercial broilers, although recent investigations with NetB-positive isolates have reportedly caused disease without predisposition from Eimm·ia infections.

Clinical Findings and Lesions: Most

often the only sign of necrotic enteritis in a flock is a sudden increase in mortality. However, birds with depression, ruffled feathers, and diarrhea may also be seen. The gross lesions are primarily found in the small intestine Qejumun/ileum), which may be ballooned, friable, and contain a foul-smelling, brown fluid. The mucosa is usually covered with a tan to yellow pseudomembrane often referred to as a "Turkish towel" in appearance. This pseu­ domembrane may extend throughout the small intestine or be localized. The disease usually persists in a flock for 5--10 days, and mortality is 2%--500,1,.

Diagnosis: A presumptive diagnosis is based on gross lesions and a gran1-stained smear of a mucosa! scraping that exhibits large, gram-positive rods. Histologic

ROTAVIRAL INFECTIONS IN CHICKENS, TURKEYS, AND PHEASANTS

2803

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Prevention, Control, and Treatment:

Mucosa I surface of small intestine of a broiler chicken infected with Clostridium perfringens (necrotic enteritis). Courtesy of Dr. Billy Hargis.

findings consist of coagulative necrosis of one-third to one-half the thiclmess of the intestinal mucosa and masses of short, thick bacte1ial rods in the fibrinonecrotic debris. Isolation of large numbers of C per:fringens, from intestinal contents that produce the double zone of hemolysis as described above, can confirm the diagnosis. Double zone hemolysis should not be used as the sole criterion for identification of C pe1frin­ gens, because some strains do not produce both toxins responsible for the hemolysis characteristics. Differential media specifically designed for isolation of C pe1:fringens is available and may be useful for diagnosis. Necrotic enteritis must be differentiated from lesions produced by Eime1ia brunetti and also from ulcerative enteritis. Uncom­ plicated coccidiosis rarely produces lesions as acute or severe as those seen with necrotic enteritis. Ulcerative enteritis caused by C colinum usually produces focal lesions from the distal portion of the small intestine (ileum) to the ceca and is almost always accompanied by hepatic necrosis.

Because C peifringens is nearly ubiquitous, it is important to prevent coccidiosis, especially E acervulina and E maxima infections, as well as changes in the intestinal microflora that would promote its growth. This has traditionally been accomplished by adding antibiotics in the feed such as virginiamycin (20 g/ton feed), bacitracin (50 g/ton feed), and lincomycin (2 g/ton feed), as well as ionophore-class anticoccidial treatments. The move to antibiotic-free feeds has also been associated with markedly increased use of coccidiosis vaccines, resulting in early circulation of mixed Eimeria infections that are associated with the resurgence in incidence of necrotic enteritis. Avoiding drastic changes in feed and minimizing the level of fishmeal, wheat, barley, or rye in the diet can also help prevent necrotic enteritis. When higher amounts of wheat, barley, or rye are necessary, use of enzymes for nonstarch polysaccharides in the feed has reduced the level of necrotic enteritis in flocks fed these cereals. A dministration of selected probiotics or competitive exclusion cultures has been used successfully to both prevent and treat clinical necrotic enteritis (pre­ sumably by preventing proliferation of C perfringens). Treatment for necrotic enteritis is most commonly administered in the drinking water, with bacitracin (200-400 mg/gal for 5-7 days), penicillin ( 1,500,000 u/gal. for 5 days), and lincomycin (64 mg/gal. for 7 days) most often used. In each case, the medicated drinking water should be the sole source of water. Moribund birds should be removed promptly, because they can serve as a source of toxicosis or infection due to cannibalism.

ROTAVIRAL INFECTIONS IN CHICKENS, TURKEYS, AND PHEASANTS Rotaviral infections are characterized by enteritis and diarrhea in young birds, but chickens have been infected without showing clinical signs. Avian rotaviruses consist of four distinct serotypes (A-D). Group A rotaviruses

share a common group antigen with mammalian rotaviruses. Group D rota­ viruses have been identified only in avian species. The relationships of the other two avian serotypes to mammalian serotypes have not been established. Transmission

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ROTAVIRAL INFECTIONS IN CHICKENS, TURKEYS, AND PHEASANTS

is horizontally by the oral route. Egg transmission has not been reported. Early signs of diarrhea (wet litter), depression, and poor or abnormal appe­ tite can be seen 2-5 days after infection. Dehydration occurs rapidly, and mortality can be as high as 30%-50% in pheasants but is lower in turkeys and chickens. The survivors appear healthy but smaller than nonnal. Lesions consist of dilated intestines filled with yellowish, frothy, watery contents. Often, the carcass is dehydrated. Mortality is variable and is usually due to dehydration and emaciation or secondary bacterial infections. Early diarrhea and inappetence that sometimes end with death are indicative but not pathognomonic of rota.viral infection. Fecal samples or intestinal contents can be examined by electron microscopy with negative staining, either

directly or after ultracentrifugation. Numerous rota.viral particles -70 nm in diameter, with double-shelled capsids, can be seen and are distinguishable from reovirus by their more sharply defined outer edges. For viral isolation in chicken-embryo liver cells or chick kidney cells, fecal material must be treated with trypsin. Isolated rota.viruses belong mostly to serotype A and, in general, do not cause cytopathic effects on primary isolation. The presence of virus can be demonstrated 2-3 days after inoculation by immunofluorescent staining. Reverse transcriptase PCR is currently used to detect the virus in gut contents. No commercial vaccines are available. Thorough cleaning and disinfection of infected houses is advisable to limit infection. There is no specific treatment.

TRICHOMONOSIS Ttichomonosis in domestic fowl, pigeons, doves, songbirds, and hawks is character­ ized, in most cases, by caseous accumula­ tions in the throat and usually by weight loss. It has been te1med "canker," "roup," and, in hawks, "frounce." Etiology: Both Trichomonas gallinae and a newly recognized species, T stablei'i, are the causative organisms of tJichomono­ sis. These flagellated protozoa live in the sinuses, mouth, throat, esophagus, liver, and other organs. Ttichomonosis is more prevalent among domestic pigeons and wild doves than among domestic fowl, although severe outbreaks have been reported in chickens and turkeys. Some trichomonad strains ca.use high mortality in pigeons and doves. Hawks may become diseased after ea.ting infected birds and conunonly show liver lesions, with or without throat involvement. Pigeons and doves transmit the infection to their offspring in contami­ nated pigeon milk. Contaminated water is probably the most important source of infection for chickens, turkeys, and songbirds, and the parasite has been shown to survive at least 20 min in distilled water. Clinical Findings: The disease course of trichomonosis is rapid. The first lesions

appear as small, yellowish areas on the oral mucosa. They grow rapidly and coalesce to fonn masses that frequently completely block the esophagus and may prevent the bird from closing its mouth. Much fluid may a.ccun1ulate in the mouth. There is a watery ocular discharge and, in more advanced stages, exudate about the eyes that may result in blindness. Birds lose weight rapidly, become weak and listless, and sometimes die within 8---10 days. In chronic infections, birds appear healthy, although trichomona.ds can usually be demonstrated in scrapings from the mucous membranes of the throat. Lesions: The bird may be riddled with caseous, necrotic foci. The mouth and esoph­ agus contain a mass of necrotic material that may extend into the skull and sometimes through the surrounding tissues of the neck to involve the skin. In the esophagus and crop, the lesions may be yellow, rounded, raised areas, with a central conical caseous spur, often referred to as "yellow buttons." The crop may be covered by a yellowish, diphthelitic membrane that may extend to the proventriculus. The gizzard and intestine a.re not involved. Lesions of internal organs a.re most frequent in the liver; they vary from a few small, yellow areas of necrosis to almost complete replacement of liver tissue by caseous necrotic deb1is. Adhesions

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ULCERATIVE ENTERITIS and involvement of other internal organs appear to be contact extensions of the liver lesions. Diagnosis: Lesions of trichomonosis are characteristic but not pathognomonic; those of pox, fungal disease, Salmonella., and other infections can be similar. 'Ihchomonosis has sometimes been confused with histomoniasis (seep 2835) because of the similarity in liver lesions. Diagnosis should be confirmed by microscopic examination of a smear of mucus or fluid from the throat to demonstrate the presence of trichomonads. Trichomonads can be cultured easily in various artificial media such as Dian1ond's media, 0.2% Loeffler's dried blood serum in Ringer's solution, or a 2% solution of pigeon serum in isotonic salt solution. Good growth is obtained at 98.6 ° F (37° C). Antibiotics may be used to reduce bacterial contamination.

2805

Control: Because trichomonads in pigeons are so readily transmitted from parent to offspring in the nmmal feeding process, chronically infected birds should be separated from breeding birds. In pigeons, recovery from infection with a less vimlent trichornonacl str·ain appears to provide some protection against subsequent attack by a more virulent strain. Successful treatments include carnidazole (10 mg/kg body wt), metronidazole (60 mg/kg body wt), and dirnetridazole (50 mg/kg body wt, PO; or in the drinking water at 0.05% for 5-6 clays). None of these drngs is approved for use in birds in the USA, but they could be used in non-food-producing birds by veterinary prescription. Bi.rd feeders and waterers should be cleaned regularly and if an outbreak of trichornonosis is docu­ mented or suspected, feeders and waterers should be removed for -2 wk and cleaned with a 10% bleach solution.

ULCERATIVE ENTERITIS (Quail disease) Ulcerative enteritis was first diagnosed in bobwhite quail (Colinus virginianus). It also affects chickens, turkeys, pheasants, grouse, and other galli.naceous birds. The disease has also been reported in pigeons and psittacine birds. In Japanese quail (Cotuinix coturnixjaponica), only experimentally induced cases have been reported in highly inbred populations. An ulcerative enteritis-like disease is caused by Clostridium peifringens in Coturnix quail. Ulcerative enteritis occurs worldwide and may be acute or chronic. Etiology, Epidemiology, and Patho­ genesis: Clostridium colinum is the etiologic agent. It is an anaerobic, fastidious to culture, gram-positive, spore-fom1ing, slightly curved rod, -1 x 3-4 µrn wide, witl1 subtem1inal, oval spores. In chickens, the disease is a complex that is linked to stress, coccidiosis, infectious bursal disease, and other predisposing factors. To induce experimental disease in bobwhite quail, > 106 viable bacterial cells rnust be administered PO; chickens inoculated at tl1e san1e levels are not affected. Birds that develop chronic ulcerative enteritis or that have recovered fromilie disease remain can-iers. Infection can be

introduced by flies feeding on contan1inated fecal material or by recovered carrier birds. Wected birds shed the bacterium in their droppings. Bobwhite quail are the most susceptible to this highly contagious disease. Most cases are reported in captive populations of bobwhite quail, suggesting that management plays a role in t11e incidence. C colinum spores can survive in ilie premises for monilis. Clostridium spp have been isolated from water samples obtained from &inker pipes in which biofilm and mineral deposits were present. After oral infection, tl1e bacte1iurn adheres to the intestinal villi, producing enteritis and ulcers in portions ofilie small intestine and upper large intestine. Bacilli migrate toilie liver via portal circulation, producing necrotic foci tl1at later coalesce into extensive hepatic necrosis. Infarcts of ilie spleen are common. Stained smears of the lesions reveal the rod-shaped C colinum microorganism. Aliliough toxigeni.city tests in mice have been negative, the role of an in situ-produced toxin in the pathogenesis has been suggested but not demonstrated. Clinical Findings: In susceptible bobwhite quail, sudden death occurs without signs or weight loss and with up

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2806

ULCERATIVE ENTERITIS

to 100% mortality in just 2--3 days. Acute lesions include hemorrhagic enteritis of the duodenum. In chickens and other game birds, the course of the disease is less severe and is accompanied by anorexia. Signs are sinillar to those seen in coccidiosis: depressed, listless birds with humped backs, ruffled feathers, diarrhea, and sometimes bloody or watery white droppings, especially in quail in the prolonged course. Chickens recover within 2--3 wk, and mortality rarely exceeds 100/o. Lesions: In early disease stages, tl1e most common lesions include small, round ulcers surrounded by hemoIThages in the small intestine, ceca, and upper large intestine. Small ulcers later coalesce to form larger, sometimes perforating ulcers, producing local or diffuse peritonitis. The presence of blood in the gut resembles coccidiosis. Characteristic yellow to gray necrotic foci are the predominant lesions in the hepatic parenchyrna. Splenomegaly with hemor­ rhages and necrotic areas may be present. Diagnosis: Gross postmortem lesions, including intestinal ulcerations and yellow to gray necrotizing lesions in the liver, assist in diagnosis. C colinum can be seen in grarn­ stained smears of the liver and intestinal lesions. In bacteremic birds, the microor­ ganism can also be found in blood and spleen smears. In chickens, differentiating ulcerative

enteritis from coccidiosis (seep 2791) may be difficult, because both diseases may be present simultaneously. Necrotic enteritis (see p 2802) and histomoniasis (seep 2835) may also present a diagnostic problem, but the hepatic lesions of ulcerative enteritis help differentiate it from tl1ese diseases. C colinum can be isolated from liver samples cultured in strict anaerobic conditions in prereduced blood glucose­ yeast horse plasma medium. A fluorescent antibody test has been used to accurately diagnose ulcerative enteritis. PCR assay has also been reported as an effective diagnostic test. Prevention, Treatment, and Control:

Bacitra.cin in the feed at 200 g/ton is used for prevention in quail. Streptomycin (0.006%) and furazolidone (0.02%) in ilie feed are effective to treat ilie disease. Prevention must start wiili good management practices (eg, a.voiding the introduction of new birds into existing flocks). High population density is a predisposing factor. The use of cages is recommended in quail breeding. Sick and dead birds should be removed promptly. Total cleanup between flocks, pest control in and around the premises, and periodic treatment of watering systems with irmocuous chemicals that dissolve mineral and or biofilm build-up a.re good preventive measures.

AVIAN CAMPYLOBACTER INFECTION Can1pylobacteriosis is a significant enterocolitis of people frequently acquired tlrrough consumption of undercooked poultry meat contan1ina.ted with Campylo­ bacter jejuni. It is the lea.ding bacterial cause of sporadic enteritis in developed countries. It can also be acquired from handling backyard poultry as well as diarrheic companion anin1als and from contan1inated water. The organism colonizes the intestine of chickens, turkeys, and waterfowl but is generally nonpa.tho­ genic in birds. Some strains of C jejuni have been reported to ca.use enteritis and death in newly hatched chicks and poults; however, it has not been possible to satisfy Koch's postulates and reproduce ilie syndrome previously tenned "avian

vibrionic hepatitis" by administering isolates of C jejuni to chickens. Commercial poultry and free-living birds are natural reservoirs of the them1ophilic ca.rnpyloba.cters ( C jejuni, C coli, and Clari) and other poorly defined species. It is estimated that more than ha.If of all commercial broiler and turkey flocks harbor C jejuni, although the prevalence can vary from 0% tol00% depending on season (lowest in fall and winter and highest in swnmer). The organism has been isolated from numerous birds, including Columbae and domestic and free-living Gallifonnes and Anserifom1es. C jejuni has been found in all areas of commercial poultry production. Isolation of the organism is a function of swveillance

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AVIAN CAMPYLOBACTER INFECTION

and ability of laboratory personnel to culture and identify Campylobacter spp. Etiology and Epidemiology: C jejuni is the predominant species associated with foodborne infection derived from poultry. C coli and C lari can also be recovered from the intestinal tract of poultry and have also been implicated in foodborne infection. Environn1ental contanlination is probably the most conu11on source of infection for poults, chicks, and ducklings. Litter can remain infective for long periods, subject to at least a l()OA, moisture level and neutral pH. Exposed chicks and poults become colonized and can continue to excrete C jejuni for their lifetimes. Contanlinated water may introduce infection into poultry flocks, and nonchlorinated water derived from a dan1, river, or shallow well should be regarded as a possible source. Rats, mice, wild birds, darkling beetles, and houseflies can infect flocks; equipment and footwear contanlinated with feces from an infected source may also serve as a vehicle of transmission. Once C jejuni has been introduced into the environment, rapid transmission within the flock occurs, with subsequent colonization of a high proportion of exposed breeders, commercial-meat, or laying-strain poultry. Some strains of Campylobacter can be transmitted vertically, either on tlle surface of eggs or by transovar­ ial transmission. It has been isolated from the reproductive tracts of hens and roosters. Clinical Findings and Lesions: Many chicks are colonized with Campylobacter spp early in life with no associated clinical signs or pathology. Most chicks display no lesions associated with Campylobacterinfection. Some studies have reported that challenged chicks may exhibit distention of the jejunum, disseminated hemorrhagic enteritis, and in some cases, focal hepatic necrosis. Microscopic lesions of infected chicks include edema of the mucosa of the ileum and cecum with C jejuni in tlle brnsh border of enterocytes. Mononuclear infiltration of the submucosa and villous atrophy occur, with intraluminal accumula­ tion of mucus, erythrocytes, and mononu­ clear and polymorphonuclear cells. However, infected flocks seldom exhibit increased mortality rates or decreased feed conversion. It is unclear whetller tllese findings represent a true clinical syncl.rome in chicks, because challenge studies frequently result in no lesions.

2807

Diagnosis: Fecal specin1ens should be collected using swabs, tllen placed in Cary-Blair transport medium. Alternatively, cecal droppings can be collected into sterile laboratory san1pling bags and packed on ice. Eruiclu11ent culture of specimens in semisolid motility medium facilitates isolation when small numbers of C jejuni are present. Campylobacter can be cultured on many different selective media, but commonly available formulations contain Brucella, agar base and bovine blood with as many as seven antibiotics that inhibit overgrowtll of Enterobacteriaceae. They also can be cultured on blood agar by selective filtration; bacteria in a 1/10 diluted fecal sample are allowed to penetrate a filter (0.45 µm pores) placed on the surface of a blood agar plate. After the liquid is absorbed into the plate, the filter is removed. Thermophilic Campylobacter spp shoulcl. be cultured at 42 ° C under humid, micro­ aerophilic conditions (85% nitrogen, l()OA, carbon dioxide, and 5% oxygen) for 48 Ju·. Some strains require a hydrogen-enriched atmosphere (5%). Campylobacler spp of significance in poultry are oxidase- and catalase-positive, indole-negative, and reduce selenite. The thern1ophilic species may be characte1ized on the basis of hippurate hydrolysis; nalidixic acid sensitivity is no longer reliable because of the increasing prevalence of fluoroquino­ lone-resistant C jejuni. The Penner or Lior serotyping schemes can be used to classify C jejmii 1ibotyp.i.ng, or pulsed-field gel analysis can distinguish among various C jejuni isolates. Control and Prevention: Because

C jejuni is not found as a specific pathogen

under commercial conditions, treatment of poultry flocks is not a consideration. If C jejuni is considered a problem in compan­ ion bird aviaries or in exotic species, antibiotics such as erythromycin can be administered in drinking water. Galliforn1es should receive a dosage of 10-30 mg/kg for 4 consecutive days, and Psittaciformes ancl. exotics should be medicatecl. at 3�0 mg/kg. Because of the zoonotic risk associated with C jejuni and its ability to rapidly develop antibiotic resistance, antibiotics should be used with caution in companion birds. Fluoroquinolones and erythromycins are tlle classes of antimicrobials used to treat people for campylobacteriosis. Preharvest prevention of Campylobacter infection in conm1ercial species is based on strict biosecurity, decontanlination of housing between successive flocks,

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AVIAN CAMPYLOBACTER INFECTION

exclusion of rodents and wild birds, and insect eradication. Chlorination of drinking water to 2 ppm and operation of farms on a stlict "all-in/all-out" basis occasionally reduces the prevalence of infection. In the context of commercial production in the USA where earth-floored housing is used and litter is recycled, preharvest control of C jejuni is impractical. Innovative methods of prevention, such as competitive exclusion, bacteriophage therapy, bacterio­ cins, and the use of vaccines, are under intensive investigation. Withholding feed from broilers and turkeys for at least 12 hr before slaughter and thorough decontamina­ tion of transport coops and modules reduce fecal contanunation and lower U1e level of C jejuni introduced into processing plants.

Zoonotic Risk: C jejuni is a major source of foodborne enteritis in people; contan1i­ nated, undercooked poultry is responsible for >50% of cases investigated. The condition was recognized in the mid-1970s, and the signiiicance of the organism has become apparent with in1proved methods of isolation and identification. Nonchlorin­ ated grotmd water, unpasteurized milk, young diarrheic pets, and contanunated beef and pork products are also responsible for infection of people. Improved washing of carcasses, use of counter-flow scalding, elin1ination of

immersion chillers, and reduction in manual handling by installation of advanced automated equipment can reduce C jejuni contamination on poultry meat. Chemical disinfectants, such as chlorine, peracetic acid with hydrogen peroxide, and trisodiw11 phosphate, glutaraldehyde and succinic acid, and organic compounds, such as lactic and acetic acids, may effectively reduce C jejuni on poultry carcasses in the processing plant. Some research indicates that bacteriophages and bacteriocins may also be useful. However, the regulations regarding chemical or biological sanitizers that can be used in processing plants and the performance standards for Campylo­ ba.cter in the plant are currently in flux. Gan1ma irradiation at levels of 1-3 kGy effectively elin1inates Cjejuni from poultry carcasses and prorlucts. Irradia­ tion has been endorsed by a number of international health agencies, but irradiated foods are not widely available in the USA because of consumer concerns. The risk of foodborne C jejuni infection can be reduced through cooking of poultry to achieve a core temperature of74°C for l min. Concurrent hygienic storage, handling, and preparation are necessary to prevent contamination of prepared foods, work surfaces, and utensils by raw poultry and other meats.

AVIAN CHLAMYDIOSIS (Psittacosis, Ornithosis, Parrot fever) Avian chlamydiosis can be an inapparent subclinical infection or acute, subacute, or chronic disease of wild and domestic birds characterized by respiratory, digestive, or systemic infection. Infections occw· worldwide and have been identified in at least 460 avian species, particularly caged birds (primarily psittacines), colonial nesting birds (eg, egrets, herons), ratites, raptors, and poultry. Among poultry, turkeys, ducks, and pigeons are most often affected. The disease is a significant cause of economic loss and hun1an exposure in many parts of the world.

Etiology and Epidemiology:

Chlamydia psittaci, fonnerly renamed Chlamydophila psittaci, is an obligate intracellular bacteriwn. All strains of

chlan1ydia share an identical genus-specific antigen in their lipopolysaccharide but often differ in the composition of other cell-wall antigens, thus providing a basis for serotypic identification. Eight serotypes are recognized; of these, six (A-F) infect avian species and are distinct from mammalian Chlamydia serotypes. More recently, strains of C psittaci have been classified using genetic differences in the ompl gene into nine genotypes. Seven of these (A, B, C, D, E, F, and E/B) are found in avian species and usually correspond to the equivalent serotype. Each avian serotype/ genotype tends to be associated with certain types of birds (see TABLE 4). The same serotype/genotype may cause mild disease or asymptomatic infection in one species but severe or fatal disease in

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AVIAN CHLAMYDIOSIS

another species. Serotype A and Dare highly virulent for turkeys and can cause mortality of �30%. Serotypes Band E are most frequently recovered from wild birds. Avian serotypes are capable of infecting people and other manunals. Transmission is by the fecal-oral route or by inhalation. Respirato1y discharge or feces from infected birds contain elementary bodies that are resistant to drying and can remain infective for several months when protected by organic deb1is (eg, litter and feces). Airborne particles and dust spread the organism. After inhalation or ingestion, elementary bodies attach to mucosa! epithelial cells and are internalized by endocytosis. Elementary bodies within endosomes in the cell cytoplasm inhibit phagolysosome formation and differentiate into metabolically active, noninfectious reticulate bodies that divide and multiply by binaiy fission, eventually fo1ming nwnerous infectious, metabolically inactive elementaty bodies. Newly formed elementary bodies are released from the host cell by lysis. The incubation pe1iod is typically 3-10 clays but may be up to several months in older birds or after low exposure. Host and microbial factors, route at1cl intensity of exposure, and treatment detemune clinical course. Possible sources of C psillaci include infected birds, asymptomatic caiTiers, vertical transmission from infected hens, infected mammals, and contat11inated environments. Stressors (eg, trai1sp01t, crowding, breeding, cold or wet weather, dietary changes, or reduced food availabil­ ity) and concwTent infections, especially

2809

those causing in1munosuppression, can initiate shedding in latently infected birds and cause recurrence of clinical disease. Carders often shed the organism intennit­ tently for extended peliocls. Persistence of C psillaci in the nasal glands of chronically infected birds may be an importat1t source of organisms. Longtenh inapparent infections lasting for months to years are common and are considered the normal Ch/.am . ydia-host relationship. The prevalence of infection vai·ies considerably between species and by geographic location. Infection is endemic in commercial turkey flocks; no clinical signs or mild respiratory signs and low mortality ai·e the corru11on presentations. Outbreaks are rare. Although chickens are relatively resistant to clinical disease, asymptomatic infection is frequent. Epidemiologic studies report prevalence varying from l()OA, to >900A, using serology, culture, or PCR detection; 3o/cr-500A, of surveyed wild avian populations may be seropositive. Clinical Findings and Lesions: Severity of clinical signs and lesions depends on the virulence of tl1e orgai1ism, infectious close, stress factors, and susceptibility of the bird species; asymptomatic infections are common. Nasal and ocular clischai·ge, conjW1ctivitis, sinusitis, green to yellow­ green droppings, fever, inactivity, ruffled feathers, weakness, inappetence, and weight loss can be seen in clinically affected birds. Clinical pathology test results vaiy with the organs most affected and severity of the disease. Hematologic changes most

ASSOCIATIONS BE TWEEN AVIAN GENOTYPES OF CHLAMYDIA PSITTACI AND TYPES OF BIRDS

c

A

B

Pigeons, doves

++

+

+

+

++

++

+

Wateifowl

+

+

++

+

++

Turkeys

+

+

+

++

+

+

++

+

++

+

+

Psittacines

Chicken Passe1ines

+

D

++

Ratites Wild birds

E

++ ++

++ ; Genotype most commonly associated with this bird species or group. + ; Genotype less commonly associated with this bird species or group.

++

E/B

F +

+

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2810

AVIAN CHLAMYDIOSIS

often present are anemia and Jeukocytosis with heterophilia and monocytosis. Plasma bile acids, AST, LDH, and uric acid may be increased. A radiograph or a laparoscopy may reveal an enlarged liver and spleen and thickened airsacs. Necropsy findings in acute infections include serofibrinous polyserositis (airsacculitis, pericarditis, perihepatitis, peritonitis), pneumonia, hepatomegaly, and splenomegaly. Multiple tan to white to yellow foci and/or petechial hemorrhages can be seen in the liver and spleen. Similar lesions are seen in other systemic bacterial infections and are not specific for avian chlamydiosis. Multifocal necrosis in the liver and spleen is associated with small granular, basophilic intracyto­ plasmic bacterial inclusions in multiple cell types; occasional heterophils; and increased mononuclear cells (macrophages, lymphocytes, plasma cells) in hepatic sinusoids and splenic sinuses. Necrosis results from direct cell lysis or vascular damage. The latter is also the source of the generalized serofib1inous exudate. In chronic infections, enlargement and discoloration of the spleen or liver may be noted. Necrosis and bacte1ial inclusions are not seen, but the mononuclear cell response is present in these birds. Lesions are usually absent in latently infected birds, even though C psillaci is often being shed. Diagnosis: Because of the variety of clinical presentations and common occurrence of latently infected carriers, no single diagnostic test can reliably detemline infection. Procedures to detect the organism or antibodies are used. In general, tl1e more acute the disease, the greater the nwnber of infective organisms .md the easier it is to make a diagnosis. When birds are acutely ill, clinical findings, including hematology, clinical chemistries, and

Marked hepatomegaly in an ornate lorikeet

(Trichoglossus ornatus) with chlamydiosis. Courtesy of Dr. A J. Van Wettere.

radiology or typical gross lesions are adequate for a tentative diagnosis. The combination of a serologic and an antigen detection test, especially PCR, or culture, is a practical diagnostic scheme to confiml chlamydiosis. In live birds, the preferred sample for bacterial culture or PCR is a single conjunctiva!, choanal, or cloaca! swab. Multiple samples collected throughout 3-5 days are recommended for detection of intermittent shedding by asymptomatic birds. Antibodies may or may not be detectable depending on the test used and on the level and stage of infection. Interpretation of titers from single serum san1ples is difficult. A 4-fold increase in titers between paired acute and convalescent san1ples is diagnostic, and high titers in a majority of samples from several birds in a population are sufficient for a presumptive diagnosis. Serologic methods include direct and modified direct complement fixation, elementary body agglutination, antibody ELISA, and indirect immunofluorescence. The elementary body agglutination test detects IgM and is useful to dete1mine recent infection. The complement fixation metl10ds are more sensitive than agglutina­ tion methods. High antibody titers may persist after treatment and complicate evaluation of subsequent tests. Antigen detection methods include in1rnunohistochemistry (eg, inununofluores­ cence, inununoperoxidase), ELISA, and PCR. ELISA kits developed for detection of Chlamydia trachomatis in people are available commercially and are relatively inexpensive. Their exact specificity and sensitivity for detection of C psillaci is most often unknown; they appear to have good specificity but somewhat low sensitivity. These kits are most useful when birds are clinically ill. PCR is the most sensitive and specific test, btit results may differ between laboratories because of the Jack of standardized PCR prin1ers and laboratory method variations. False-positive results are a.concern witl1 PCR, because cross-contanlination can occur relatively easily. The organism can also be identified in inlpression smears of affected tissues (eg, liver, spleen, and Jung). Chlamydiae stain purple with Giemsa and red witl1 Macchia­ vello and Gimenez stains. Immunohistochemistry is usually more sensitive than the histochemical stains mentioned above for detecting bacteria in tissue. Confimlation requires isolation and identification of C psittaci in chick embryo or cell cultures (BGM, L929, Vero) at a

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AVIAN CHLAMYDIOSIS

qualified laboratory. Cloaca!, choanal, oropharyngeal, conjunctiva!, or fecal swabs (in a special Chlamydia transport media) from live birds, or tissues (liver and spleen preferred) from dead birds should be refrigerated and submitted promptly to the laboratory. Freezing, drying, improper handling, and improper transport media can affect viability. The laboratory should be contacted for directions to submit samples. Concurrent infections with other, more easily diagnosed diseases (eg, colibacillosis, pasteurellosis, herpesvirus infections, mycotic diseases) may mask chlan1ydial infection. Laboratory and clinical findings should be correlated. Chlamydiosis must be distinguished from other respiratory and systemic diseases of birds. Prevention and Treatment: Human and avian chlamydiosis is a reportable disease; state and local governmental regulations should be followed wherever applicable. No effective vaccine for use in birds is available. Treatment prevents mortality and shedding but cannot be relied on to eliminate latent infection; shedding may recur. Tetracyclines ( chlortetracycline, oxytetracycline, doxycycline) are the antibiotics of choice. Drug resistance to tetracyclines is rare, but reduced sensitivity requiring higher dosages is becoming more common. Tetracyclines are bacteriostatic and effective only against actively multiplying organisms, making extended treatment times (from2-S wk, during which minin1un1-inhibitory concentrations in blood must be consistently maintained) necessary. When tetracyclines are administered orally, additional sources of dietary calciun1 (eg, mineral block, supplement, cuttle bone) should be reduced to mininlize inte1ference with drug absorption. Outbreaks of clinical disease in poultry flocks are not common. Treating infected flocks with chlortetracycline at 400-750 g/ton of feed for a minimum of2 wk has effectively decreased potential risk of infection for plant employees. The medicated feed must be replaced by nonmedicated feed for2 days before slaughter and processing. Calcium supplementation must be withheld during treatment with chlortetracycline, with calcium concentration in the feed reduced to s0.7%. Medicated feed should be provided for 45 days if elimination of the organism is attempted. Use of some tetracycline antibiotics and doxycycline in poultry is prohibited, and state regulations should be followed. Persistence of

2811

oxytetracycline residues in eggs of laying hens is 9 days, and persistance of doxycy­ cline residues is26 days after administra­ tion at 0.5 g/L for 7 days. In pigeons and companion birds, use of chlortetracycline-medicated feeds for 45 days was historically a standard recom­ mendation for imported birds (seep 1897). Difficulties in palatability of the feed itself or the high level of antibiotic necessary for adequate blood levels have limited its use. Doxycycline is the current drug of choice, because it is better absorbed, has less affinity for calcium, better tissue distribu­ tion, and a longer half-life than other tetracyclines. Doxycycline added to feed or water can also result in adequate blood levels and has less effect on normal intestinal flora than does chlortetracycline. The dosage and duration of the treatment varies between species. Protocols derived from controlled studies performed in the particular species treated should be used when available (seep 1897). See also information in the Compendium of Measures To Control Chlamydophila psillaci lnfection Among Humans (Psittacosis) and Pet Birds (Avian Chlamydiosis), 2010, National Association of State Public Health Veterinarians (NASPHV). When specific information is lacking, an empiric starting dosage of 400 mg/L of water, or25-50 mg/kg/day, PO, has been suggested. Appropriate biosecurity practices are necessary to control the introduction and spread of chlamydiae in an avian popula­ tion. Minimal standards include quarantine and examination of all new birds, prevention of exposure to wild birds, traffic control to minimize cross-contan1ination, isolation and treatment of affected and contact birds, thorough cleaning and disinfection of premises and equipment (preferably with small units managed on an all-in/all-out basis), provision of uncontaminated feed, maintenance of records on all bird movements, and continual monitoring for presence of chlamydia! infection. The organism is susceptible to heat (it may be destroyed in 1,500 infective parasites have been recovered from a single slug.

Pathogenesis and Clinical Findings:

Ascaridia, Heterakis, and Capillaria spp

are widely distributed and cause such nonspecific signs as general unthriftiness, inactivity, depressed appetite, and retarded growth; in severe cases, death may result. A mere few ascaiids may depress weight, and larger nun1bers may block the intestinal tract. Ascaiids may migrate up the oviduct (via the cloaca) to become enshelled later within the egg (an aesthetic, but not a public health, problem, avoidable by careful egg-candling before the release of eggs to market). A dissimilis (turkey rom1dworn1) may also migrate out of the intestine, through the portal system, and into the liver, causing hepatic granulomas. H gallina1um, a mild pathogen, in large nmnbers may cause thickening, inflamma­ tion, or nodulation in the cecal walls. lnfection with H gallinarom has been associated with cecal and hepatic granulo­ mas. H eterakis isolonche, highly patho­ genic in pheasants, may cause 500Ai mortality. H gallina1um carries Histo­ monas meleag1idis, the protozoan that causes histomoniasis (seep 2835). C contorta in the mucosae of the crop and esophagus, and C obsignata in the wall of the small intestine, cause marked thickening and inflammation of the organs. Birds harboring large nmnbers of these threadlike worms become weak ai1d emaciated and may die. Young birds are the most severely affected by gapeworn1s. Sudden death and vern1inous pnemnonia characterize early outbreaks. Signs of gasping, choking, shaking of the head, inanition, emaciation, and suffocation may follow. Necropsy reveals adult gapeworms obstructing the lunlina of the trachea, bronchi, and lungs. Respiratory inflammation may be present. The blood-red, female gapeworm is usually found in copulation with a much smaller, paler male with its head embedded deep in the host tissue. The joined pair have a "¥"-shaped or forked appeai·ance.

2831

Oxyspirura mansoni is a slender nematode, 12-18 nun long, found beneath the nictitating membrane of chickens and other fowl in tropical and subtropical regions. The parasite causes various degrees of inf1all1mation, lacrimation, corneal opacity, and disturbed vision. Among other nematodes, Amidostomum anseris attacks the gizzard lining of ducks and geese alld causes dark discoloration, necrosis, alld sloughing at the parasitic loci. Dispharynx nasuta causes ulceration, thickening, and maceration of the proven­ triculus; heavily infected birds may die. Tetrameres americana, a b1ight red wonn discernible tllrough the proventricular wall, causes diaiThea, emaciation, alld wiili heavy infection, death. Trichostrongylus tenuis causes inflan1ed ceca, weight loss, anemia, alld death, especially in young birds. Ornithostmngylus quadriradiatus, a blood-sucking parasite, causes pigeons to regmgitate bile-stained fluid mixed with food; greenish mucoid diarrhea from hemorrhagic intestines, emaciation, alld death follow. Most pathogenic tapewonns ai·e found in the small intestine; the scolex, usually buried in the mucosa, generally causes mild lesions. Davainea proglottina may cause weight loss. Raillietina tetragona causes weight loss and decreased egg production; R echinobothrida produces granulomas at its attachment sites ("nodular disease").

Diagnosis: A reliable diagnosis Call be made only by accurate identification of the individually recovered parasites; careful and complete necropsy techniques are essential. Only by specific recognition of the parasite can meallingful recommendations for flock therapy and mallagement be made. Treatment and Control: Improvement

of mallagement alld sanitation in confined operations will generally lower the parasite levels in tl1e birds. In range birds, the only option is to move to new pastures, although the benefit that may result will be of short duration. Application of approved insecticides to soil alld litter when premises are unoccupied may interrupt the life cycle of tl1e parasite by destroying its intermedi­ ate host. When the premises are restocked, groups of birds of different species or ages should be widely separated to avoid spread of parasites. Migration of litter beetles or other insects may infect new or widely separated housing. Approved compounds are very limited in the USA Because of frequently changing regulations, the status of ally medication

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2832

HELMINTHIASIS

should be checked before its administra­ tion. Approved drugs for the USA are listed online in the FDA's Green Book and in the commercially available Feed Compendiwn. Only approved drugs may be used in birds producing eggs or meat for the commercial market. Label directions and recommended doses should be followed precisely, with scrupulous adherence to withdrawal times. Piperazine compounds are relatively nontoxic and have been widely used against ascariasis. Because of this, drug resistance is widespread in many regions of the world. Several piperazine salts are available internationally. Because only the piperazine moiety is efficacious, doses should be calculated based on mg of active piperazine/ bird. Piperazine should be completely conswned by birds within a few hours, because only relatively high concentrations of the drug elin1inate worn1s. It may be given to chickens as a single dose, 50 mg/bird ( 909'o. Since the advent of vaccination, losses from Marek's disease have been reduced dramatically in broiler and layer flocks. However, disease may become a serious problem in individual flocks or in selected geographic areas (eg, the Delmruva broiler industry). Of the many causes proposed for tl1ese excessive losses, early exposure to very virulent virus strains appears to be among the most important.

LYMPHOID LEUKOSIS (Avian leukosis)

Under natural conditions, lymphoid leukosis has been the most common fom1 of tl1e leukosis/sarcoma group of diseases seen in chicken flocks, although in the 1990s myeloid leukosis become prevalent in meat-type chickens. The International Conm1ittee on Taxonomy of Viruses placed viruses of the avian leukosis/sarcoma group in the Alpharetrovirus genus of the fan1ily Retrovi1idae.

2851

Members of this RNA group of viruses have sinillar physical and molecular characteristics and share a common group-specific antigen. Detection of the major antigen (p27) present in the core of leukosis/sarcoma viruses fonns the basis of several diagnostic tests. Lymphoid leukosis occurs naturally only in chickens. Experi­ mentally, some of the viruses of tl1e leukosis/ sru·coma group can infect and produce tumors in otl1er species of birds or even man11nals. The infection is known to exist in viltually all chicken flocks except for some SPF flocks from which it has been eradi­ cated. Tumor mortality commonly accounts for -lo/o-2"A, of birds, with occasional losses of ,c20%. Subclinical infection, to which most flocks are subject, decreases several important performance traits, including egg production and quality. The frequency of infection has been reduced substantially in the primary breeding stocks of several commercial poultry breeding companies, particularly egg-type breeders. In recent years this control program has expanded, and infection has become infrequent or absent in certain commercial flocks. The frequency of lymphoid leukosis twnors even in heavily infected flocks is typically low ( 22 days old. In the proximal femur, the condition is also refen-ed to as femoral head necrosis, which is reported to be the most common cause of lameness in broiler chickens. The etiology appears to be ve1tically transmitted staphylococci, often in combination with infection by immunosuppressive viruses (eg, INFECTIOUS BURSAL DISEASE, seep 2837). Floor eggs have been shown to be common can-iers of staphylococci, so their use should be avoided. A high standard of hatch­ ery hygiene can reduce this risk. Formalde­ hyde funligation within the hatchers is also likely to help. In addition, hatchery fluff samples (ie, hatching deb1is such as down

Osteomyelitis of the tibiotarsus in a 43-day­ old broiler. Courtesy of Dr. H.J. Barnes.

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MYOPATHIES

with infection of the free thoracic and adjacent vertebrae, resulting in chronic osteomyelitis and spinal cord compression. Clinical signs of leg paresis often develop in broilers >35 days old. Other sporadic causes of osteomyelitis and/or arthritis in poultry include Pastew0 ella mullocida, Ornithobacteiium rhinotracheale, Truepei·ella (Arcanobacte­ rium) pyogenes, Entei-ococcus spp, Stre ptococcus spp, Salmonella spp, Streptobacillus moniliformis, and Aspergillus spp. Osteomyelitis and arthritis are detected on gross examination by examination of articular surfaces and bone physes. Detection of subtle lesions requires histopathology. Affected joints are often swollen with fibrinous or caseous exudate. Bones have areas of lysis and/or replace­ ment by caseous exudate, most often within the physcal region. Response to treatment with antibiotics cmrently approved for use in poultry is often poor for bacterial bone and joint infections. Antibiotics may be used to control tl1e bacteremia contributing to new cases and to modify the bacterial flora within a flock. When individual birds a.re of high value, long-term antibiotic therapy may improve some less severe cases. Control requires minimizing sources of infection and stock susceptibility.

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Viral Arthritis: Seep 2886. Osteopetrosis: Osteopetrosis in chickens is due to infection with specific strains of avian leukosis virus (seep 2851). Growth and differentiation of osteoblasts is altered by the virus, resulting in diaphyseal and/or metaphyseal, periosteal, and circmnferential accumulation of woven and lamellar bone. Osteopetrosis is bilaterally symmetrical and involves the long bones, especially the tibiotarsus and tarsometatar­ sus. Birds 8--12 wk old are most commonly affected. Lymphoid leukosis often occurs in chickens with osteopetrosis. Avian osteopetrosis differs from man1ma.lian osteopetrosis in which a defect in osteo­ clast function results in abnorrnal bone resorption and accumulation of primary spongiosa in the marrow cavity. Amyloid Arthropathy: Extensive amyloid arthropathy is primarily caused by Enlei 12 wk old are most commonly affected, and flock incidence may be as high as 20%. Rupture of the Peroneus (Fibularis) Longus Muscle The peroneus muscle originates on the proximal end of tl1e tibiotarsus and patelJar tissue, with attachments to other muscles in that area. In turkeys, the insertion appears to be in three places. A small band of tissue from the medial side of the muscle runs to the lateral tibial condyle. The main muscle tendon crosses the lateral side of the hock and joins other tendons that extend the hock and may affect foot and toe move­ ment. The muscle is thin and wide, covering the anterior and lateral surface of the leg,

2885

and is covered by a heavy aponeurosis in which the tendon is embedded. Rupture of the aponeurosis and muscle occurs as a 1-2 cm horizontal wound on the anterior and/or lateral surface of the muscle. It occurs above the middle of the tibiotarsus at the top of the ossifying tendon where the tendon attaches to the muscle. Rupture usually occurs at 10-14 wk, the age at which turkey leg tendons become ossified, reducing the elasticity of the tissue in that location. Rupture of the peroneus longus muscle is an uncommon muscle lesion. It is most frequent in females and may affect as much as 5% of the flock. The separation of tl1e muscle likely occurs slowly, caused by activity such as repeated springing, in turkeys that are becoming heavier and maturing earlier. Affected birds are not lan1e, but the resulting hem01Thage causes a red, blue, or green discoloration under the skin around and ventral to the rupture site (drun1stick). This results in dowi1grading of the carcass at processing. The affected portion can be trimmed. NUTRITIONAL MYOPATHY Nutritional myopathy in chickens, turkeys, waterfowl, and ostriches is attributed to vitan1i.n E/selenium deficiency. However, as in rnanunals, seleniwn deficiency is most often the main cause of the myopatl1y. Vitamin E deficiency, when accompanied by a sulfur amino acid deficiency, causes nutritional myopathy in chicks b.Y. -4 wk of age. Lesions of vitamin E/selenium deficiency have been reported in skeletal (especially breast muscle), heait, and smooth muscle (gizzai·d and intestine) of clucks, turkeys, and chickens. Arsenic, zinc, copper, and otl1er metals are antagonistic to selenium, and exposure to these other metals may precipitate outbreaks. Gross lesions, with pale foci or streaking, are similai· to those of nutritional myopathies in manm1als. Microscopic chai1ges include focal or widespread myofiber swelling, edema, hyalinization, mineralization, degeneration, and lysis with infiltration of macrophages and heterophils. Hypercellu­ larity from proliferation of satellite cells may be prominent if regeneration is occun-ing. Poultry feeds in many parts of the world contain added selenium at 0.1-0.4 ppm to prevent this myopathy. TOXIC MYOPATHY Ionophores ai·e toxic at increased doses. Ionophore toxicity causes muscle damage

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2886

MYOPATHIES

with incoordination, leg wealrness, dian-hea, dyspnea, and reduced feed intake and weight. Stw1ting may also occur. Type I ("red muscle" or oxidative) fibers are most susceptible, and lesions are most prominent in the leg musculature. Lesions may also be found in heart and gizzard muscle. Adult birds (chickens, turkeys, ratites) and birds with no previous exposure are more sensitive to ionophore coccidiostats. Gross and histologic changes are similar to those of nutritional myopathy (see above). Ionophores promote movement of cations across the cell membrane, causing disruption of the ionic equilibrium, increased intracytoplasmic concentration of Ca2+ , and cell death. The toxic dose of ionophores is decreased if they are used in cor\junction with tiamulin, erytJiromycin, or chloramphenicol. Salinomycin at the dose reconm1ended for chickens (60 g/ton) is toxic for turkeys; doses> 15 g/ton are toxic in turkeys. Monensin (100 g/ton) and lasalocid (100 g/ton) at the dose recom­ mended for chickens are not toxic to turkeys. Coffee senna (Senna occidentali s) toxicity can produce clinical signs and gross and histologic changes in muscles sin1ilar to those seen in ionophore toxicity.

INJECTION SITE INJURY lr\jection of antibiotics and vaccines in any location can result in focal inflammatory myositis. Cellulitis and myositis in the neck region causing post1.1ral and/or neurologic signs can be seen in poultry after improper administration of vaccines. It is most commonly seen in broiler chicks. Affected birds may show ataxia, twisting of the neck, leg paralysis, and rec"umbency. Swell­ ing of the subcutaneous and muscle tissue in the neck region at the ir\jection site is seen grossly. Microscopically, a lympho-

cytic and/or granulomatous inflan1matory infiltrate is present within the muscle and subcutis. The inflammatory infiltrate can extend to the epidural spaces. With oil-emulsion vaccines, empty spaces representing lipid droplets surrounded by a granulomatous inflanunatory reaction can be seen.

MINIMAL MYOPATHY A minimal myopathy is seen in otherwise nonnal meat-type poultry. Affected birds show no clinical signs, and their muscles are grossly nonnal, but microscopically there is mild myofiber degeneration and fat accumulation between myofibers. Focal or multi.focal scattered myofibers are hyalinized and mineralized. More severe examples of this lesion contain individual myofiber necrosis, increased fat, and fibroplasia between fibers. No specific cause has been detennined for these minin1al changes, which have been obse,ved by avian pathologists but are not described in the literature. Minimal myopathy is not an established name for this condition.

GENETIC MYOPATHY Type II glycogen storage disease (acid maltase deficiency, Pompe disease) has been reported in Japanese quail. Symptoms start between 4 and 6 wk of age, and affected quail show progressive myopathy with reduced ability or inability to lift their wings, fly, or get back on their feet after being placed on their back (flip test). Glycogen deposition occurs in skeletal muscle, cardiac muscle, and smooth muscle, as well as in the brain and spinal cord. Both red and white muscle is affected, but lesions are more pronounced in the pectoralis superficialis (white muscle).

VIRAL ARTHRITIS (Tenosynovitis, Reoviral arthritis) Reovirus infections are ubiquitous in commercial poultry flocks. They are global in distribution, although the virulence of viruses appears to differ between regions. Most strains are nonpathogenic and appear to survive hannlessly in the intestine, whereas others have been associated with several disease conditions, including malabsorption and other ente1ic disorders,

hydropericardium, and occasionally respiratory disease. In many instances, the association of the reovirus with disease is uncertain. An exception to this is viral arthritis, or tenosynovitis, because it can be reproduced experimentally by infecting birds with reovirus alone. Viral arthritis results in severe lameness in heavy broiler breeds of chickens and

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VIRALARTHRITIS occasionally in laying breeds. Although lameness in turkeys has sometin1es been reported to be associated with avian reoviruses, experin1ental evidence in the past has been unable to confinn that turkeys are as susceptible to these viruses as chickens. However, recent field evidence from the USA indicates the presence of novel reoviruses causing arthritis and tendon rupture clinically identical to that in chickens. Reoviruses have been isolated from a range of other avian (including wild) species, and it is possible that cross-infection occurs, although ducks and geese have reoviruses that differ genetically from those of chickens. Etiology and Pathogenesis: Viral arthritis is caused by avian reoviruses, which are RNA viruses related to but distinct from manunalian reoviruses. Strains differ in virulence, ranging from those causing arthritis and sometin1es death to those that exist harmlessly in the gut. The mechanisms that determine whether a reovirus is pathogenic or harmless are poorly understood. Several antigenic types a.re known, and although some cross-protection occurs between types, it is rarely complete. Most infections are acquired by ingestion. After intestinal replication, the virus spreads via the bloodstrean1 to all parts of the body. Pathogenic viruses localize in the hock joint, where they cause arthritis. Other organs, such as the liver, may be affected. Transmission and Epidemiology:

Avian reoviruses can be egg transmitted, so infected breeder hens pass virus to chicks. Transmission is short-lived, and only a small nucleus of chicks can-y virus. Infection is spread locally to hatchmates by the fecal-oral route. The virus is quite resistant to inactivation and can persist on farm materials for many days or weeks. Fomites are important. Serious outbreaks of viral arthritis are followed by a decreased incidence in later hatch groups of birds from the same parent flock and may be related to decreased egg transmission and development of maternal immunity. Day-old chicks a.re more sus­ ceptible than older birds when exposed by natural means. The younger the chick when infected, the more likely it is that disease will develop. Clinical Findings: Viral arthritis usually is seen in broilers 4-8 wk old as unilateral or bilateral swellings of the tendons of the shank and above the hock. It can also be found in much older chickens, usually at

2887

peak of production or beyond, probably because of reactivation of persistent virus at sexual maturity. Affected birds walk with a sWted gait or prefer not to move. In the most severe fom1, mpture of the gastrocne­ mius tendon is conrn1on, although digital flexor tendons are sometimes affected and many cull birds are seen around the feeders and waterers. The most severely affected birds do not recover; less severely affected birds may recover in 4-{j wk. Infection is asymptomatic in many birds. Feed efficiency and rate of weight gain are decreased. Mortality is 2%-10% and morbidity 5%-500Ai. Lesions: An acute, fulminating infection is occasionally seen in young chicks and embryos with cardiomegaly, hepatomegaly, and splenomegaly with necrotic foci. Edema around the tendons of the leg is marked, petechial hemoIThages develop in the synovial membranes above the hock, and fusion and calcification of the tendon bundles are common. Blood clots and hemoIThages are seen accompanying mpture of the gastrocnemius tendon. In the most severe cases, pitted erosions of the cartilage of the distal tibiotarsus ar·e seen with flattening of the condyles. Histologi­ cally, the synovial cells are hypertrophied, hyperplastic, and infiltrated by lymphocytes and macrophages. The synovia contain lyn1phoid aggregates with heterophils and macrophages. In the heart, infiltration of heterophils or lymphocytes between myocardial fibers is a consistent finding. Diagnosis: A presumptive diagnosis can be based on unilateral or bilateral swelling of the tendons of the shank ar1d tendon bundle above the hock and on the inflan1111a.tory changes in the tendons and synovia. described above. However, other ca.uses of lan1eness such as Mycoplasma synoviae or Escherichia coli should be considered. Reovirus can be isolated from affected joints in primar-y chick embryo kidney, liver, or lung cell cultures, or via the yolk sac or cho1ioal­ lantoic membrane of embryona.ted chicken eggs. In view of the widespread nature of reovirus infections without disease, isolation from the gut is not significant. In many laboratories, PCR is used for vims identifica­ tion and is more rapid and sensitive than isolation. Avian reoviruses ar·e now classified according to their sigma surface proteins, and the indications ar·e that the novel USA turkey and European chicken viruses ar·e different from the conunon ones associated with viral arthritis. The turkey isolates are genetically related to the turkey enteric reoviruses, but further molecular analysis

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2888

VIRAL ARTHRITIS

is awaited. In view of the ability of avian reoviruses to recombine, it is possible these new arthritogenic variants in both species have evolved by this means. ELlSA is the serologic test of choice, and most birds are positive early in infection. Virus neutraliza­ tion tests and challenge of immunized chickens can be used to identify the specific serotype. However, serologic results can be difficult to interpret in view of the ubiquity of reovirus infections. Culture procedures should be used to differentiate mycoplasmal and other bacterial infections. Treatment and Control: There is no treatment. Live and killed vaccines are available. Maternal antibodies prevent early infection in chicks and minimize or

prevent egg transmission. In view of egg transmission and the greater susceptibil­ ity of baby chicks, the main objective of vaccination is to ensure good immunity in the parent flock. Vaccination programs should be directed to the serotype(s) present in local flocks. Adult birds are less susceptible to clinical disease if exposed by natural routes. Currently available commercial vaccines against viral arthritis are not effective against the newly encountered chicken viruses described in Europe or against those causing arthritis in turkeys. Zoonotic Risk: There have been no reported zoonotic risks associated with avian reovirus infections.

AVIAN ENCEPHALOMYELITIS (Epidemic tremor) Avian encephalomyelitis (AE) is a viral disease of young chickens, turkeys, Japanese quail, pheasants, and pigeons. Turkeys are less susceptible to natural infection and generally develop a milder clinical disease than chickens. Ducklings and guinea fowl are susceptible to experimental infection. AE is characterized by neurologic signs that result from infection of the CNS with an RNA virus in the family Picomaviridae. Infection occurs via vertical and horizontal transmission. If a breeder flock becomes infected during egg production, the virus is verti..cally transmit­ ted to the offspring and a major outbreak occurs. The disease often appears in a series of flocks hatched from the infected breeder flock. Field strains of the virus are enterotropic and multiply in the intestine. Infected birds shed the virus in their feces for a few clays to a few weeks, which se1ves to spread the infection to hatchmates. There is no convincing evidence that the virus persists in infected birds. AE virus is resistant to envirorunental conditions and may remain infectious for long periods. Clinical Findings: Vertically infected chicks conm10nly show clinical signs during the first week after hatching, although signs may be present in a few birds at hatching. Clinical signs appear later in hatchmates that are horizontally infected by the fecal-oral route. Vertical infection followed by horizontal infection causes a characteristic

biphasic mortality pattern. The main clinical signs are ataxia and leg weakness that varies from sitting on hocks to paresis that progresses to paralysis and recumbency. Fine tremors of the head and neck are evident in some birds and a.re characteristic of the disease. They are responsible for the common name, epidemic tremors. Tremors vary in frequency and severity and are best seen after birds are disturbed or excited. This can easily be done by placing the bird on its back and letting it right itself. Cupping the bird in one's hands often results in a buzz­ ing feeling because of rapid, fine tremors. Severely affected birds lay on their side and exhibit intermittent fine tremors of the head, neck, and legs. Horizontally infected chicks usually show clinical signs at 2-4 wk of age; thus, clinical disease progresses through the flock for the first few weeks, and the episode is usually over by the time the flock is -4 wk old. Morbidity and mortality rates vary and depend on the level of egg transmission and degree of immunity in the flock. In severe outbreaks, both morbidity and mortality may exceed 500Ai. After 4 wk of age, chickens are resistant to disease but not infection. An exception occtll'S occasionally in older chickens after vaccination with egg-embryo-adapted conunercial vaccines. Affected birds exhibit typical CNS signs like those seen in younger chicks. In laying chickens, there is a.sudden, 5%--l()OA, drop in egg production, which

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BOTULISM usually lasts for 8 billion/mL. In chickens, volun1e is 1-2 times that of turkeys, but the concentration is about one-half. Collected semen is usually pooled and diluted with an extender before use. Chicken and turkey semen begins to lose fertilizing ability when stored>1 hr. Liquid cold (4°C) storage of turkey and chicken semen can be used to transport semen and maintain spermatozoa! viability for -6--12 hr. This short-term storage of semen is conunon in turkeys, while not as common in chickens. When using liquid cold storage for>1 hr, turkey semen must be diluted with a semen extender at least 1: 1 and then agitated slowly (150 rpm) to facilitate oxygenation; chicken semen should be diluted and then cooled-agitation is not necessary. Chicken and turkey semen may

be frozen, but reduced fertility linlits usage to special breeding projects. Under experinlental conditions, fertility levels of 900/o have been obtained in hens inseminated at 3-day intervals with 400-500 million frozen-thawed chicken spermatozoa. Several commercial semen extenders are available and are routinely used, paiticu­ lai·ly for turkeys. Extenders enable more precise control over inseminating dose and facilitate filling of tubes. Results may be comparable to those using undiluted semen when product directions ai·e followed. Dilution should result in an insemination dose containing -300 million viable spe1matozoa for turkeys. However, the nun1ber of spermatozoa inseminated will rai1ge from 150-300 million viable cells depending on the age of the turkey hens inseminated. In chickens, the nwnber of diluted semen inseminated will range from -100-200 million spetm cells per insemina­ tion. Producers usually determine the spermatozoa concentration 3.11d dilute the semen to obtain the approptiate spem1 cell concentration for either the turkey or chicken. For insemination, when holding the hen upright, pressure is applied to the abdomen ai·ound the vent, particularly on the left side. This causes the cloaca to eve1t 3.11d tl1e oviduct to protrude, so that a syringe or plastic straw can be inserted -1 in. (2.5 cm) into the oviduct 3.lld tl1e appropriate amount of semen delivered. As the semen is expelled by the inseminator, pressure around the vent is released, which assists the hen in retaining spem1 in the vagina or oviduct. When inseminating undiluted turkey semen, the high sperm cell concen­ tration allows for 0.025 mL ( -2 billion spem1atozoa) to be inseminated at regulai· intervals of 7-10 days, yielding optinlal fertility. In chickens, because of the lower spermatozoon concentration 3.11d shotter duration of fertility, 0.05 mL ofw1diluted pooled semen, at intervals of 7 days, is required. The hen's squatting behavior indicates receptivity and the time for the first insemination. For maxinrnl fertility, inseminations may be started before tl1e initial oviposition in turkeys, whereas this is not necessary in chickens. Fertility tends to decrease later in tl1e season; therefore, it may be justified to inseminate more frequently or use more cells per insemina­ tion dose as hens age.

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2896

DISORDERS OF THE REPRODUCTIVE SYSTEM

DISORDERS OF THE REPRODUCTIVE SYSTEM CYSTIC RIGHT OVIDUCT Fluid accwnulation in the vestigial right oviduct is a conui1on fmding in hens. The abdominal cyst is filled with clear fluid and is attached to the right side of the cloaca! wall. The cyst may vary in size from barely perceptible to 15-20 cm in diameter. An increased incidence has been seen in flocks after infectious bronchitis virus outbreaks. Oviductal cysts are a necropsy fmding that rarely, if ever, affect flock perfo1mance.

DEFECTIVE OR ABNORMAL EGGS Most "ridged," "sunbw·st," "slab-sided," soft-shelled, or double-shelled eggs are the result of eggs colliding in the shell gland region of the oviduct when an ovwn (yolk) is released too soon after the previous one. Necropsy examinations have demonstrated that two full-sized eggs can be found in the shell gland pouch. As the second egg comes in contact with the first, pressw·e is exerted, disrupting the pattern of mineralization. The first egg acquires a white band and chalky appearance, while the second egg is flattened on its contiguous surface (ie, slab-sided). Pimpled or rough eggs may have been retained too long in the shell gland. Blood spots result when a follicle vessel along the stigma ruptures as the ovw11 is being released. Meat spots occur when a piece of follicle membrane or residual albwnen from the previous day is incorporated into the developing egg. Many abnom1alities appear to have no specific cause, but the incidence is much higher in hens subjected to stressful management conditions, rough handling, or vaccination during production. A significant increase in the number of soft-shelled eggs is also common as a result of viral diseases such as infectious bronchitis, egg drop syndrome, and Newcastle disease. Small eggs with no yolk form a.round a nidus of material (residual albun1en) in the rna.gnwn of the oviduct. Small eggs with reduced albwnen and eggs with defective shells may be the result of damage to the epitheliwn of tl1e magnw11 or shell gland. Very rarely, foreign material that enters the oviduct through the vagina (eg, a roundworm) may be incorporated into an egg.

EGG-BOUND OR IMPACTED OVIDUCTS A fully fonned egg may lodge in the shell gland or vagina because the egg is too big (eg, double-yolked) or because of hypocal­ cernia, calcium tetany, or previous tra.wna (usually pecking) to the vent and/or vagina that obstructs oviposition. This condition may be more prevalent in young hens that are brought into production before body development is adequate or in hens that are overweight or obese. It occurs more often during spring and swnmer months because of overstimulation of birds by increasing light intensity and day length, which can be compOLmded by rapid increases in the amount of feed and/or excessive protein Qysine). This is a medical emergency in pet birds but is usually recognized only during necropsy in commercial poultry. When impaction occurs, eggs that continue to form create layers of albwnen and yolk material, and the oviduct becomes very large. Some eggs are refluxed to the abdomi­ nal cavity (abdominal laying), and affected hens assume a penguin-like posture.

EGG PERITONITIS (Egg yolk peritonitis)

Egg peritonitis is characterized by fibrin or albwnen-like material with a cooked appearance among the abdominal viscera. It is a common cause of sporadic death in layers or breeder hens, but in some flocks may become the major cause of death before or after reaching peak production and give the appearance of a contagious disease. It is diagnosed at necropsy. Peritonitis follows reverse movement of albwnen and Escherichia coli bacteria. from the oviduct into the abdomen. If the incidence is high, culture should be done to differentiate betweenPasteurella (fowl cholera) or Salmonella infection. Antibiotic treatment of peritonitis caused by E coli infections is usually ineffective. Manage­ ment of body weight and tuillormity, reproductive development (ovary follicle growth and maturation), and drinking water sanitation are the best preventive strategies. When hens have too many large ovarian follicles, a problem described as erratic

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DISORDERS OF THE REPRODUCTIVE SYSTEM

oviposition and defective egg syndrome (EOOES) is seen in broiler breeders. This condition is accompanied by a high incidence of double-yolked eggs, prolapses of the oviduct, internal ovulation, and/or internal laying that often results in egg peritonitis and mortality. EOOES is prevented by avoiding light stimulation of underweight pullets too early and by following guidelines for body weight and unifonnity, and lighting recommendations for each breeder strain. Overweight hens may also have a higher incidence of erratic ovulations and mortality associated with egg peritonitis.

FALSE LAYER These hens ovulate normally, but the yolk is dropped into the abdominal cavity rather than being collected by the oviduct because of inflammation and resulting obstruction of the oviduct after infection with Escheri­ chia coli or Mycoplasma gaUise'J)licum. The yolk is absorbed from the abdominal cavity. The hen looks like a normal layer but does not produce eggs. Hypoplasia of the ovary and oviduct has been associated with infectious bronchitis vims infections (see p2909) at an early age (1-2 wk). Atresia or even atrophy of the ovary are caused by severe stress, chronic infections, insuffi­ cient feed intake, inadequate feeder space, and feed refusal due to mycotoxins in the feed.

HYPOCALCEMIA, SUDDEN DEATH, OSTEOPOROSIS, OR CAGE LAYER FATIGUE Pullets or hens with insufficient dietary calcium, phosphorns, or vitan1in 03 may die suddenly or be found paralyzed from hypocalcemia while shelling an egg. This may be associated with high production and withdrawal of calcium from bones for egg shell production, in which case the main lesion may be osteoporosis. At necropsy, there is an egg in the shell gland and the ova are active and fully developed. There are no other lesions, although medullary bone may be lacking. Paralyzed hens respond to calcium IV, and this response may be useful in diagnosis. Osteoporosis is a major cause of death in high-production flocks. Hens with osteoporosis may show similar signs at necropsy, or the ova may be regressing with no egg in the oviduct. The femur is always fragile, and medullary bone is always absent in osteoporosis. These hens may also

2897

respond to calcium IV if there are no fractures of the legs or vertebrae. The use of large particle size calcium (limestone, oyster shell) in the diet may be beneficial. High rates of mortality due to fractures are common in birds affected with osteoporo­ sis. This situation is more common in broiler breeder hens in slatted houses due to the trauma caused by jumping on and off the slats. Ru{>tured egg follicles indicating trawna can be found during necropsy examination of these birds. A condition known as hypocalcemia or calciun1 tetany (paralysis) has been seen in modern or high-yielding broiler breeder hens. Signs such as panting, spread wings, and prostration may be seen in the early morning hours preceding paralysis and death by asphyxia. Careful postmortem examination reveals a fully active ovary and the presence of a partially or fully fanned egg in the shell gland in the absence of other lesions. This indicates that the hen used all available calcium from the bloodstream in an effort to complete the egg shell. The condition is common in flocks with poor body weight uniformity that are fed high-calciun1 diets in the weeks before the onset of lay and brought into production by drastic increases in day length and feed allocation. Hypocalcemia can be prevented by management practices that promote body weight uniformity and avoid excessive/premature allocation of high-calcimn diets and light stimulation. Mortality can be reduced by the administra­ tion ("topping of the feed") of 5 g of oyster shell per hen for 3 consecutive days, and · addition of vitamin 03 to the drinking water. This treatment should be suspended for 3 days and then repeated. Severe cases will require continual treatment for2-3 wk (3 days of treatment followed by 3 days without). Feeding of recomrnended levels of calciwn, using large-particle-size calciwn, and providing adequate ventilation and cooling are helpful to prevent or reduce the incidence of this condition. Mortality and the presence of an egg in the shell gland also can be caused by a condition referred to as sudden death syndrome, first reported in Australia This is believed to be caused by marginal levels of potassium and phosphorns in the diet, resulting in cardiomyopathy.

INTERNAL LAYER In these hens, partially or fully fanned eggs are found in the abdominal cavity. Such eggs reach the cavity by reverse peristalsis of the oviduct. If they have no shell, they are often

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2898

DISORDERS OF THE REPRODUCTIVE SYSTEM

misshapen because of partial or complete absorption of the contents. Frequently, only empty shell membranes are present. No control or treatment is known. This condition is related to en-atic ovulation and defective egg syndrome (seep 2896).

INFERTILITY Infertility caused by male management problems is common. Problems may be caused by an inadequate nwnber of healthy males or because males have reduced sperm production resulting from chronic disease, inadequate feed intake, or starvation (harsh feed restriction). However, obese females may be less efficient in transporting sperm to the infundibulwn, resulting in reduced fe1tilization of the ovum as it is released from the ovary. The male must be dominant to the females, or mating will not occur. Commercial turkey hens are inseminated artificially with semen collected from the toms and used the same day (seep 2895). Parthenogenesis is responsible for some infertility in turkeys. There are host sperm glands in the oviduct of females, and live sperm can be retained for 3-4 wk. Water­ fowl have a rudimentary penis, and prolapse of the penis is occasionally repmted in drakes. There is no treatment.

NEOPLASIA The most frequent tumor of the reproduc­ tive system is adenocarcinoma of the oviduct. Neoplastic cells are shed from tumors in the oviduct into the abdominal cavity. They implant on the ovary, pancreas, and other viscera and produce multiple, hard, yellow nodules. Tkey may block lymph return and result in ascites. The incidence increases with age, and this twnor may be a frequent cause of death after 2 yr. Affected hens are condemned at processing. Leiomyoma of the broad ligament is an estrogen-induced hypertrophy of the smooth muscle of the broad ligan1ent. It is benign and is an incidental finding at necropsy or processing. A variety of ovarian and testicular tumors has been described. Marek's disease (see p 2849) is a common cause of tw110rs of the ovary.

OOPHORITIS AND OVARY REGRESSION Regression of the ovary may result in leakage of free yolk into the abdomen (yolk peritonitis); this rarely causes death

except when yolk material migrates through the air sacs to the lung and causes foreign body pneumonia. Free yolk is seen in many cases of acute illness, injury, or forced molt. Regression of the ovary is frequently caused by low body weight, deliberate reduction of feed, overcrowd­ ing, or lack of feeder space. Infectious diseases such as Newcastle disease, fowl cholera, pullornm disease, and avian influenza are known to cause this condition. It can also result from severe stress, which is often accompanied by feather molt, emaciation, and dehydration.

PROLAPSE OF THE OVIDUCT When an egg is laid, the vagina everts through the cloaca to deliver the egg. U there has been injury to the vagina, such as from a large or double-yolk egg, or if the hen is fat, the vagina may not retract immediately, leaving it exposed for a short time. This may result in cannibalism (see p 2873). When the protruding organ is pecked by other hens, the complete oviduct and parts of the adjacent intestinal tract may be pulled from the abdominal cavity ("peckout"). Bleeding from the vent is obse1ved as a result of pecking. Alternatively, the vagina swells, carmot retract, and remains prolapsed ("blow­ out"). The hen dies from shock. Prolapse has been associated with excessive/ premature photostimulation, poor body weight uniformity, early laying (inadequate body size), large eggs, double-yolked eggs, and obesity. Cannibalism may be prevented by beak trimming, managing light intensity, maintaining appropriate stocking density, and avoiding nutritional deficiencies.

SALPINGITIS Salpingitis is an inflammation of the oviduct, which may contain liquid or caseous exudate. In young pullets, it is often clue to Mycoplasma gallisepticiim, Escherichia coli, Salmonella spp, or Pasteurella multocida (fowl cholera) infection and can result in reduced egg production. It is a frequent lesion in female broilers and ducks at processing. On gross examination, salpingitis may be difficult to differentiate from impacted oviduct in adults. As the oviduct becomes nonfunctional, the ovaries a.re usually atrophied. Unless associated with an infectious problem, this condition tends to be found sporadically during necropsy of cull hens.

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SEX REVERSAL If the normal left ovary of a hen is destroyed by infection, the vestigial right organ may develop as a testicle and the hen may develop male characteristics.

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Neoplasia in the adrenal glands or ovary that result in the production of testosterone could also cause the development of male secondary sexual characteristics (comb and wattles) in affected females.

EGG DROP SYNDROME '76 Egg drop syndrome '76 (EDS '76) is an atadenovirus-induced disease characterized by Lhe production of pale, soft-shelled, and shell-less eggs by apparently healthy laying hens. The disease in laying hens has conunonly been called "egg drop syn­ drome," but the full name (egg drop syndrome '76 [EDS '76]) should be used to distinguish it from the recently recognized flaviviral disease of ducks, which has been called "egg drop syndrome in ducks," and "duck egg drop syndrome," creating potential for confusion. Etiology: EDS '76 is caused by a double-stranded DNA virus, duck adenovi­ rus l (also known as EDSV), which belongs to the genus Aladenovirus. The virus commonly infects both wild and domestic ducks and geese, but evidence of infection has also been found in coots, grebes, herring gulls, owls, storks, swans, and quail. The adenovirus group antigen cannot be demonstrated by conventional means, and EDSV differs from other avian adenoviruses by strongly agglutinating avian RBCs, a fact that allows use of a hemagglutination­ inhibition test for detection of antibodies to the virus. The virus grows to high titers in embryonated duck and goose eggs and in cell cultures of duck or goose 01igin. It replicates well in chick-embryo liver cells, less well in chick kidney cells, and comparatively poorly in chick-embryo fibroblasts. It does not grow in embryonated chicken eggs or in manunalian cells. The virus is resistant to pH range 3-10 and to heating for 3 hr at 56°C (132.8 °F). Infectivity is lost after treatment with 0.5% formalde­ hyde or 0.5% glutaraldehyde. Only one serotype of EDSV has been recognized to date. Epidemiology and Pathogenesis: The natural hosts for EDSV are ducks and geese. It is thought tl1at the virus was introduced to chickens through a vaccine that had been

grown in contaminated duck-embryo fibroblasts. The virus became established in chickens, causing substantial problems with egg shell quality and loss of eggs. All ages and breeds of chickens are susceptible to infection. Disease tends to be most severe in heavy broiler-breeders and hens producing brown eggs. Japanese quail (Coturnix colurnixjaponica) also develop disease. There are rare reports that the egg drop syndrome virus (EDSV) has caused either a drop in egg production or respira­ to1y tract disease in other species, eg, turkeys, ducks, geese, and quail. Three patterns of disease are recog­ nized in chickens: 1) Classical EDS '76 occurs when primary breeding stock are infected and the virus is transmitted vertically through the egg. The virus often remains latent until the progeny chick reaches sexual maturity, at which time the virus is excreted in the eggs and droppings, infecting susceptible contacts. 2) Endemic EDS is the result of horizontal infection of the flock during lay. It is usually seen in commercial egg layers. Contaminated egg collection trays are one of the main vehicles of horizontal transmission between flocks, and outbreaks are often associated with a common egg-packing station. 3) Sporadic EDS '76 has been recognized occasionally in flocks. This is due either to direct contact with domestic ducks or geese or, more often, to use of a water supply contan1inated with wildfowl droppings. Although infection by this route is uncommon, there is always a risk that these introductions of the virus could form a starting point for endemic disease. The main method of hmizontal spread is through contanlinated eggs or equipment such as trays, crates, trucks, or personnel. Droppings are also infective. The virus can be transmitted by bleeding or vaccination needles. Insect transmission may be possible but has not been proved.

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After horizontal infection, the virus grows to low titers in the nasal mucosa. This is followed by viremia, vi.ms replication in lymphoid tissue, and then massive replication for -5 days in the pouch shell gland. Changes in the egg shell coincide wi.th vi.ral replication in the shell gland. Both the exterior and interior of eggs produced between 8 and -18 days after infection contain virus. Exudate and secretions from the oviduct are rich in virus and pass into the droppings, which may become mildly to moderately watery for 2-3 days. Unlike other fowl adenoviruses, there is little, if any, virus growth in the epithelial cells of the intestine. lnterestingly, the massive vi.ral replication in the pouch shell gland occurs after seroconversion, a fact that is useful diagnostically. Chicks hatched from infected eggs may excrete vi.rus and develop antibody. More often, the virus remains latent, and antibody does not develop until the bird starts to lay, at which time the vi.ms reactivates and grows in the oviduct, repeating the cycle. Clinical Findings: ln flocks without antibody, the first sign of the disease is the production of pale-shelled eggs, quickly followed by production of soft-shelled and shell-less eggs. lntemal quality of eggs is w1affected in experimentally induced disease. Transient dullness may be seen in the days before the shell changes are noticed. The thin-shelled and shell-less eggs are fragile, and the birds tend to eat them; these eggs also may get trampled into litter and may be ove'rlooked unless a careful examination is made. Although it has been shown experimentally that eggs usually continue to be produced at a nonnal rate

Eggs produced by hens in a flock with EDS'76. One normal egg is present (center, back row). Affected eggs include pale and thin-shelled eggs and shell-less eggs. The contents of the egg at the bottom right have been lost, leaving a thick, collapsed shell membrane. Courtesy of Dr. Joan Smyth.

(so the disease name may be a misnomer), the number of useable eggs produced falls by 10%--400/o. Egg production by the flock usually returns to normal. In flocks in which there has been some spread of vi..rus and some of the birds have antibody (usu­ ally 100/er-200/o), the condition is seen as a failure to achieve predicted production tar­ gets; careful exan1ination shows that these flocks experience a series of small group episodes of infection and disease. Birds wi.th antibody slow the spread of vi.ms. There is no effect on fertility or hatchabil­ ity of those eggs wi.th a shell quality that is satisfactory for setting. Diagnosis: Production of pale, thin­ shelled and shell-less eggs by a flock that appears otherwise healthy should raise strong suspicion of EDS '76. Transient mild depression and/or mild watery droppings may be noted. Ridged eggs and poor internal quality are not features of EDS '76. Poor egg shell quality at peak production in healthy hens should also raise strong suspicion of classical EDS '76. With endemic or sporadic EDS '76, disease can develop in laying hens of any age. In cage units, spread can be slow, and the signs may be overlooked or perceived as a small depression (2%--4%) of egg yi.eld. Clinically, EDS '76 can be distinguished from Newcastle disease (seep 2856) and influenza vi.rus infections (seep 2902) by the absence of illness, and from infectious bronchitis (see p 2909) by the absence of respiratory signs, the absence of ridged and malformed eggs, and the absence of poor internal egg quality. Coniirmatory labora­ tory testing is needed for definitive diagnosis. Searching for evidence of seroconversion is the easiest diagnostic approach for nonvaccinated flocks. When selecting birds for diagnosis, especially in cage units, it is important to target hens that have produced affected eggs, because if the problem is due to EDSV infection, these hens will already have seroconverted. A hemagglutination-inhibition test using fowl RBCs, and ELISA, are the serologic tests of choice. In addition, the serun1 neutralization test can be used for coniinnation. The double immunodiffusion test also has been used. PCR-based tests and antigen capture ELISA tests have been used to detect EDSV DNA and antigen, respectively. Again, appropriate selection of the hens to be examined is very important. EDSV can be isolated by inoculating cmbryonated duck or goose eggs or duck- or chick-embryo liver cell cultures. It is important to select recently infected birds for testing, but these

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ASPERGILLOSIS can be difficult to identify, especially if the birds are on litter. An easier method is to feed affected eggs to antibody-free hens. These hens can then be tested for serocon­ version after the first abnormal eggs are produced, or tested for evidence of EDSV DNA or antigen by PCR or antigen capture ELISA, respectively, or virus isolation can be attempted from the pouch shell gland of these hens.

Control: There is no treatment for EDS '76. The classic form has been eradicated from primary breeders. Use of dedicated equipment and egg trays for each fann, and/or washing and disinfecting plastic egg trays before use, can help to control the endemic fonn. The sporadic fom1 can be

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prevented by separating chickens from other birds, especially waterfowl. General sanitary precautions are indicated, and potentially contaminated water should be chlorinated before use. Inactivated vaccines with oil adjuvant are available and, if properly administered, successfully prevent the disease. They reduce but do not prevent vims shedding. The�e vaccines are given during the growing period, usually at 14-18 wk of age, and can be combined with other vaccines, such as those for Newcastle disease. Sentinel chickens may be placed along with vaccinated chickens and periodically checked for antibodies, which would allow detection of the presence of virus in the flock.

AIR SAC MITE Cytodites nudus is a small cosmopolitan mite occasionally noticed as white spots on the bronchi, lungs, air sacs, and abdominal organs of chickens, turkeys, pheasants, pigeons, canaries, and mallards. (See also p 1906.) These mites are readily transmis­ sible between birds through coughing. They are rarely found in commercial industries. The 14- to 21-day life cycle involves a larval

and two nymphal stages. Infestation densities vary, and clinical signs range from none to weakness, weight loss, pneumonia, peritonitis, pulmonary edema, and death. Recommended treatments include ivermectin, a nearby dichlorvos pest strip (placed out of reach of the birds), topical moxidectin, or a pyrethrin/piperonyl butoxide spray.

ASPERGILLOSIS (Brooder pneumonia, Mycotic pneumonia, Pneumomycosis) Aspergillosis is a disease, usually of the respiratory system, of chickens, turkeys, and less frequently ducklings, pigeons, canaries, geese, and many other wild and pet birds. In chickens and turkeys, the disease may be endemic on some farms; in wild birds, it appears to be sporadic, frequently affecting only an individual bird. Severe outbreaks usually occur in birds 7-40 days old. (See also ASPERGILLOSIS in mammals, p 633, and in PET BIRDS, p 1899.)

Etiology and Epidemiology: Aspergil­ lusfumiga,tus is a common cause of the disease. However, several other Aspergillus spp may be incrinlinated. High mortality rates are seen in chicks and poults that inhale large nun1bers of

spores during hatching in contan1inated incubators or when placed on mold-bearing litter. In older birds, infection is caused primaiily by inhalation of spore-laden dust from containinated litter or feed or dusty rai1gc areas. Morbidity can be underesti­ mated in finishing flocks until slaughter inspection reveals pulmonaiy lesions.

Clinical Findings and Lesions: Dyspnea, hyperpnea, somllolence at1d other signs of nervous system involvement, inappetence, emaciation, at1d increased thirst may be seen. In chicks or poults up to 6 wk old, the lungs are most frequently involved. Airsaccu­ litis is a cause of postmmtem condemllation in young mature turkeys intended for food supply. Pulmonary lesions are characterized

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by white to yellow plaques and nodules a few mm to several cm in diameter; occasionally, mycelial masses may be seen within the air passages on gross examination. The plaques and nodules also may be found in the syrinx, air sacs, liver, intestines, and occasionally the brain. The encephalitic form is most common in turkeys. An ocular fonn is seen in chickens and turkeys as mycotic keratitis, in which large plaques may be expressed from the medial canthus. Diagnosis: The fungus can be clemon­ strated by culture or by microscopic exan1ination of fresh preparations. One of the plaques is teased apart and placed on a suitable mediun1, usually resulting in a pure culture of the organism. Histopathologic examination using a special fungus stain reveals granulomas containing mycelia. Differential diagnoses include infectious bronchitis, Newcastle disease, infectious laryngotracheitis, mycobacteriosis, colibacillosis, other mycoses (eg, ochro-

conosis, zygomycosis), and nutritional encephalomalacia. Treatment and Control: Treatment of affected birds is generally ineffective. Spontaneous recovery from pulmonary aspergillosis can occur if reexposure to the mold is prevented. Strict adherence to sanitation procedures in the hatchery minimizes early outbreaks. Grossly contan1inated or cracked eggs should not be set for incubation, because they enable bacterial and fungal growth and may explode and disseminate spores through­ out the hatching machine. Contaminated hatchers should be thoroughly cleaned and fumigated with enilconazole or formaldehyde. Avoiding moldy litter or ranges serves to prevent outbreaks in older birds. Cleaned pens should be sprayed or fumigated with enilconazole following label directions, and all equipment should be cleaned and disinfected.

AVIAN INFLUENZA Avian influenza (Al) viruses infect domestic poultry as well as pet, zoo, and wild birds. In domestic poultry, Al viruses are typically of low pathogenicity (LP), causing subclinical infections, respiratory disease, or drops in egg production. However, a few Al viruses cause severe systemic infections with high mortality. This highly pathogenic (HP) fom1 of the disease has historically been called fowl plague. In most wild birds, Al viral infections are subclinical except for the recent H5N1 HP Al viruses of Eurasian lineage. Etiology: Al viruses are type A ortho­ myxoviruses characterized by antigenically homologous nucleoprotein and matrix internal proteins, which are identified by serology in agar gel immunodiffusion (AGID) tests. Al viruses are fmther divided into 16 hemagglutinin (Hl -16) and 9 neuraminidase (N 1-9) subtypes based on hemagglutinin inhibition and neuran1ini­ dase inhibition tests, respectively. Most Al viruses (Hl-16 subtypes) are of low pathogenicity, but some of the H5 and H7 Al viruses are highly pathogenic for chickens, turkeys, and related gallinaceous domestic poultry.

Epidemiology and Transmission: LP Al viruses are distributed worldwide and are recovered frequently from clinically normal shorebirds and migrating waterfowl. Occasionally, LP viruses are recovered from imported pet birds and ratites. The viruses may be present in village or backyard flocks and other birds sold through live-poultry markets, but most commercially raised poultry in developed countJ.ies are free of Al viruses. The HP viruses arise from mutation of some H5 and H7 LP viruses and cause devastating epidemics. Stan)ping-out programs are used to quickly eliminate the HP viruses in developed countries, but some developing counb.ies may use vaccines to control HP viruses. The incubation period is highly variable and ranges from a few days in individual birds to 2 wk in t11e flock. Transmission between individual birds is by ingestion or inhalation. Naturally and experimentally, cats and dogs have been infected witl1 one stJ.·ain of H5N1 Eurasian HP Al virus. Experi­ mental infections occurred after respiratory exposure, ingestion of infected chickens, or contact exposw·e, but cats were more susceptible than dogs. Potentially, domestic pets could serve as a transmission vector between farms, but the ability of other Al

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AVIAN INFLUENZA

vimses, including other H5N l strains, to infect pets is unknown. Other manm1als that have been experimentally infected include pigs, ferrets, rats, rabbits, guinea pigs, mice, mink, and nonhw11an p1imates. Transmis­ sion between farn1s is the result of breaches in biosecwity practices, principally by movement of infected poultry or contami­ nated feces and respiratory secretions on fomites such as equipment or clothing. Airborne dissemination between farms may be important over limited distances. Limited spread by wild birds of the Eurasian H5Nl HP Al virus has been suggested but is not typical of other HP Al viruses. OU1er HP Al and all LP Al have minimal potential to infect dogs and cats. Clinical Findings and Lesions: Clinical signs, severity of disease, and mmtality rates vary depending on Al virus strain and host species.

Low Pathogenicity Avian Influenza Viruses: LP Al viruses typically produce respiratory signs such as sneezing, coughing, ocular and nasal discharge, and swollen infraorbital sinu es in poultry. Sinusitis is conm1on in domestic ducks, quail, and tmkeys. Lesions in the respiratory tract typically include congestion and inflanima­ tion of the trachea and lungs. In layers and breeders, there may be decreased egg production or fertility, ova ruptme (evident as yolk in the abdominal cavity) or involution, or mucosa! edema and inflanuna­ tory exudates in the lwnen of the oviduct. A few layer and breeder chickens may have acute renal failure and visceral urate deposition (visceral gout). The morbidity and mortality is usually low unless accompanied by secondary bactelial or viral infections or aggravated by environmental stressors. Sporadic infections by any subtype of LP Al viruses can occur, but H9N2 LP Al is common in poultry in Asia, the Middle East, and North Aflica. High Pathogenicity Avian Influenza Viruses: Even in the absence of secondary pathogens, HP Al viruses cause severe, systemic disease wi.U1 high mortality in chickens, turkeys, and other gallinaceous poultry; mo1tality can be as high as 1000;6 in a few days. In peracute cases, clinical signs or gross lesions may be lackitlg before death. However, in acute cases, lesions may include cyanosis and edema of the head, comb, wattle, and snood (tmkey); edema and red discoloration of the shanks and feet due to subcutaneous ecchyrnotic hemor­ rhages; petechial hemorrhages on visceral organs and in muscles; and blood-tinged

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oral and nasal discharges. In severely affected bit·ds, greenish diarrhea is conm1on. Birds that survive the peracute infection may develop CNS involvement evident as torticollis, opisthotonos, incoordination, paralysis, and drooping wings. The location and severity of microscopic lesions are highly variable and may consist of edema, hemorrhage, and necrosis in parenchymal cells of multiple visceral organs, skitl, and CNS. Diagnosis: LP and HP AT viruses can be readily isolated from oropharyngeal and cloaca! swabs, and HP Al viruses from many internal organs. Al viruses grow well in the allantoic sac of9- to 11-day-old embryonat­ ing chicken eggs, and U1ey agglutit1ate RBCs. The hemagglutmation is not inhibited by ewcastle disease or other paramyxovi­ ral antiserw11. Al viruses are identified by demonstrating the presence of 1) influenza A matrix or nucleoprotein antigens using AGID or other suitable immunoassays, or 2) viral RNA using an influenza A-specific reverse transcriptase-PCR test. LP Al must be differentiated from other respit·ato1y diseases or causes of decreased egg production, mcludmg I) acute to subacute vit·al diseases such as infectious bronchitis, infectious laryngotracheitis, low virulent Newcastle disease, and infections by other paramyxovimses; 2) bacterial diseases such as mycoplasmosis, infectious co1yza, ornithobacteriosis, turkey coryza, and the respit·atory forn1 of fowl cholera; and 3) fungal diseases such as aspergillosis. HP Al must be differentiated from other causes of high mortality such as virulent Newcastle disease, peracute septicemic fowl cholera, heat exhaustion, and severe water deprivation. Prevention and Treatment: Vaccines can prevent clinical signs and death. Furthe1�

Hemorrhagic skin visible on the feet of a chicken with avian influenza. Courtesy of Dr. David E. Swayne.

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more, viral replication and shedding from the respiratory and GI tracts may be reduced in vaccinated birds. Specific protection is achieved through autogenous virus vaccines or from vaccines prepared from AI virns of the same hemagglutinin subtype. Antibodies to the homologous viral neura.minidase antigens may provide pa.ttial protection. Cun·ently, only inactivated whole AI virus, recombinant fowlpox-AI-H5, and recombi­ nant herpesvir·us-turkey-AI-H5 (rHVf-AI-H5) vaccines a.re licensed in the USA. The use of any licensed AI vaccine requires approval of the State Veterinarian. In addition, use of H5 and H7 AI vaccines in the USA requires USDA approval. Treating LP-affected flocks with broad-spect.1un1 antibiotics to control seconda.iy pathogens and increasing house temperatures may reduce morbidity and mortality. Treatlnent with a.i1tivira.l com­ pounds is not approved or recommended. Suspected outbreaks should be reported to appropriate regulatory authorities.

Zoonotic Risk: AI viruses exhibit host adaptation to birds. Hwnan infections have

occurred, usually as isolated, rare, individual cases. Most htm1an cases have originated from infection with Eurasian H5N1 HP AI vims and, most recently, Chinese H7N9 LP AI virus. The total accumulated hwnan cases of H5Nl HP AI virus in Asia and Africa from 2003-2013 is 648, of which 384 were fatal. The prima.iy risk factor for human infection has been direct contact with live or dead infected poultry, but a few cases have resulted from consw11ption of uncooked poultry products, defeathering of infected wild swans, or close contact with hun1an cases. Respira­ tory infection has been the most frequent presentation of human H5Nl cases. For H7N9 LP AI, total accw1rnlated hwna.i1 cases in China for 2013 is 137, of which 45 were fatal. Most cases had exposure risk to live-poult1y markets. Conjunctivitis was the most frequent symptom in hun1an cases of H7N7 HP AI virus infection in the Nethet' lands during 2003, with 89 confinned cases and 1 fatality. Other HP AI virnses and all LP AI vimses have produced very rare or no hwnan infections.

AVIAN METAPNEUMOVIRUS (Turkey rhinotracheitis, Avian pneumovirus, Swollen head syndrome) Avian metapneun10vitus (a.MPV) causes turkey rhinotraclJeitis, an a.cute respira­ tory tract infection of turkeys. It is also associated with swollen head syndrome in broilers and broiler breeders, as well as egg production losses in layers. The virus was first detected in turkeys in South Africa in the late 1970s and has spread to a.II the major poultry-producing areas in the world except for Australia. a.MPV has been detected not only in chickens and turkeys but also in pheasants, Muscovy ducks, and guinea fowl. Geese, most other duck species, and possibly pigeons a.re suggested to be refractory to disease. Epidemiologic studies provide evidence for the circulation of a.MPV in wild birds, especially water­ associated species. Some outbreaks have been attributed to vaccine-derived viruses, which may persist for several months in the environment. Wection with aMPV is often complicated by seconda.iy bacteria.I infections, leading to high economic losses. In 2001 the first human metapnewnovirus OlMPV) was isolated and classified as a member of the genusMetapneumoviius, which causes respiratory infections in

people. Experimental studies suggest that turkeys also may be susceptible to llMPV. Complete genome sequencing confirmed that the genomic organization of hMPV is sin1ila.r to tl1at of a.MPV. Overall, little is known about the cross-species pathogenic­ ity of these two vituses.

Etiology: aMPV is.a member of the fa.t11ily Pa.ranwxoviridae and of subfamily Pneumovirinae, which consists of the genus Pneumovirus (including the human and bovine respiratory syncytia.l viruses) and the genus Metapneumovirus. Currently the genus Metapneumoviius comprises a.MPV and hMPV. Isolates of a.MPV a.i·e grouped in subtypes A to D. The sequence of the attachment glycoprotein (G protein) can be used to subtype different strains. Based on the phylogenetic a.t1alysis of F protein sequences, it was suggested that the European subtypes A, B, and D a.re all more closely related to each other than to subtype C. More recently, a.MPV subtype C isolates were also identified in pheasants in Korea

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and water-associated bird species in Europe. The latter was shown to be of a different genetic lineage than the USA subtype C isolates. Irrespective of the differences within subtype C, isolates of this subtype display a hlgher amino acid sequence homology to hMPV than to European aMPV subtypes A, B, and D. Transmission and Epidemiology: The spread of aMPV appears to depend on the poultry population density, standard of hygiene, and biosecurity. Within or between poultry flocks, aMPV may spread rapidly horizontally by direct contact or by contact with contanlinated material. aMPV is assumed to be highly contagious. The enveloped virus is rapidly destroyed after release from the host to the environment. Because aMPV affects mainly ciliated epithelial cells of the upper respiratory tract, transmission is most likely to be airborne, especially by aerosol. But ciliated cells of the reproductive tract and possibly macro­ phages also may be target cells of aMPV. Metapneumovi.rus subtype C was isolated from eggs of experimentally infected SPF turkeys, but it was suggested that the ve1tical route may be sho1t-lived and may play only a minor role in viral transmission. Birds appear to shed aMPV for only a few days after infection. This short period of shedding suggests that there is no latency or carrier status under experimental condi­ tions. There is evidence that on farms aMPV may persist for longer periods. Reconvales­ cent flocks may be repeatedly reinfected with aMPV within one fattening pe1iod. Clinical Findings: aMPV induces an acute, highly contagious infection of the upper respiratory tract of turkeys and chickens. The disease affects all age groups, although younger birds seem to be more susceptible. In fattening turkeys the upper respiratory tract is predominantly affected, while in laying hens only a mild respiratory infection with a drop in egg production and egg quality has been seen. Coughing associated with lower respiratory tract involvement may lead to prolapses of the uterus in laying turkeys. Typical respiratory signs in young turkeys include serous, watery nasal and ocular discharge; frothy eyes; and conjunctivitis. At later stages, signs include mucopurulent, turbid nasal discharge; plugged nostrils; swollen infraorbital sinuses; and snicking, sneezing, coughing, or tracheal rales. These respiratory signs are accompanied by depression, anorexia, and ruffled feathers.

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The incubation period is 3-7 clays, and morbidity in birds of all ages may reach 100%. Mortality may be lo/o--30A,depending on age and constitution of the flock as well as secondary infections. Birds without secondary infections with good constitution may recover within 7 1-0 days. However, in birds with secondary infections and under poo.r management, the disease may be prolonged and exacerbated by ai..rsacculitis, pericar·ditis, pnew11onia, and peri..hepatitis. Infection in chlckens and pheasants is less clearly defined and may not always be associated with clinical signs. aMPV is associated with swollen head syndrome in chickens. This condition is characte1ized by swelling of the peri- and infraorbital sinuses, frothy eyes, nasal dischar·ge, to1ticollis, and opisthotonos due to ear infection. Typically, 2%. 1n broiler breeders and commercial layers, egg production and quality are frequently affected. Lesions: Macroscopic lesions depend on the cowse of infection, especially on secondary bacterial infections, and ar·e most prominent on days 4-10 after infection. Gross lesions induced after experin1ental infection are due to rhlnitis, tracheitis, sinusitis, and ai..rsacculitis. Infected birds may be free of gross lesions. Serous to turbid mucus may be observed in tl1e nasal cavity, nasal turbinates, trachea, and in infraorbital sinuses. Dming the course of infection, the secreted mucus turns from clear and serous to turbid and purulent. Nonspecific signs of inflarnmation, such as swelling and hyperemia of t11e mucosa and excessive mucus, can be seen in the upper respirato1y tract and in the air sacs. If secondary bacterial infections are present, copious inflarnmatory exuclates are found in the respirato1y tract. 1n addition, pneumo­ nia, pericarditis, perihepatitis, spleno­ megaly, and hepatomegaly are seen. 1n the reproductive tract of laying turkeys, lesions car1 include egg peritonitis, ovary and oviduct regression, folded shell mem­ branes in the oviduct, and misshapen eggs. Microscopic exan1ination of the upper respiratory tract, including the secondary bronchi during the first 2 clays after aMPV infection, reveals loss of cilia, increased glandular activity, congestion, and mild mononuclear infiltration of t11e submucosa. The most pronounced microscopic lesions ar·e found in the mucosa or the nasal turbinates, whlch may be the most suitable tissue for microscopic evaluation and diagnosis of aMPV infection. Harclerian

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AVIAN METAPNEUMOVIRUS

glands and lacrimal glands may also show infiltration of lymphocytes and fonnulation of lymphoid follicle-like structures in the interstitial tissue and around the secondary collecting ducts. Diagnosis: Obtaining samples from the upper respiratory tract of birds in the early stages of the disease is extremely important when attempting virus isolation. Especially in broiler-type chickens, samples should be taken before the sixth day after infection. Once clinical signs are obvious, the isolation of replicating aMPV may not be successful. The most suitable san1ples for aMPV detection are tracheal and choanal swabs. Tracheal organ cultures prepared from turkey or chicken embryos, or 1- to 2-day-old chicks, are the most sensitive for primary isolation of aMPV. Ciliostasis may occur within 7 days of aMPV A and B but not subtype C inoculation or after passages. The virus has also been isolated after the inoculation of6- to 8-day-old embryonated chicken or turkey eggs via the yolk sac route and identified by electron microscopy, virus neutralization test, or molecular techniques. Cell cultures have not proved successful for the primary isolation of the virus. However, once the virus has been isolated and adapted in the systems above, it will grow in a variety of avian and manm1alian cultures. Reverse transcriptase PCR (RT-PCR), as well as real-time RT-PCR, tests targeting the F, N, or G gene of aMPV have been developed and are widely used to detect the virus in clinical-material, particularly respirato1y swabs. Some nested RT-PCR tests have been constructed so that the subtype as well as the identity of virus can be determined from the clinical san1ple. Based on tl1e growing amount of genome sequence data and access to sequencing techniques, detailed characterization and molecular differentiation of isolated aMPV strains is commonly done. Antigen detection tests have also been developed, including inununofluorescence and inununoperoxidase assays on botl1 fixed and unfixed tissues. Because of difficulties in isolation and identification of aMPV, serologic assays have been developed to confirm infection in commercial chickens and turkeys. A number of commercial ELlSA kits are available and are conrn1only used, but other techniques, including virus neutralization and indirect immunofluorescence tests, have also been used. Both acute and convalescent serum san1ples should be submitted for analysis. Although ELlSA systems that use either subgroup A or B strains as antigens detect

antibodies to both of these subgroups because of some cross-reactivity, the homologous antigen should be used for tl1e efficient detection of subgroup C. The subtype specificity of the applied test may result in limited or no detection of other subtypes or new emerging aMPV strains that do not cross-react. Paran1yxoviruses (particularly Newcastle disease and paramyxovirus 3 (seep 2856), infectious bronchitis virus (seep 2909), and influenza viruses (seep 2902) may cause respiratory disease and egg production problems in chickens and tw·keys that closely resemble aMPV infection. These viruses can be differentiated on the basis of morphology, hemagglutinating and neuran1inidase activity, and molecular characteristics. A wide range of bacteria and Mycoplasma spp can cause signs very similar to those of aMPV. These agents are frequently present as secondai.y oppo1tu.nis­ tic pathogens and may mask tl1e presence of the aMPV. Prevention and Treatment: Good management practices can significantly reduce the severity of infection, especially in turkeys; in particular, optimal ventilation, stocking densities, temperature control, litter quality, and biosecw·ity have a positive influence on the outcome of the disease. Some success in reducing disease severity by controlling secondary bacterial infections with antibiotics has also been reported. Both live and inactivated vaccines are available for inunu.nization of chickens and turkeys and are widely used in countries where the disease is endemic. Maternal antibodies do not provide sufficient protection against aMPV infection and do not interfere significantly with vaccination. Thus, a vaccination prograi.n should plan for the first immunization as soon as possible after hatching. It is crucial to achieve a homogenous state of inunu.nization per flock and farm by application of an adequate vaccine dose to all birds. Live vaccines, which may be applied by spray or drinking water in the field, stimulate both local respiratory and systemic inununity, and cross-protection between subtypes may occur. But live vaccines may induce only short-lived protection, especially for grow-out of toms, because of the fast decline of local immu.nity. Thus, repeated revaccination of tw·keys is common practice. There is, however, a risk of reversion of the live vaccine stains to more virulent variants. Inactivated aMPV vaccines are often used

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BORDETELLOSIS for booster immunization of layer and breeder flocks after priming with live vaccines. While inactivated vaccines alone induce only partial protection against aMPV infection, the most efficient and long-lasting protection is achieved by a combined prime-boost vaccination progran1. This program comprises repeated prin1ing with live attenuated vaccines and booster immunization with inactivated adjuvanted

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vaccines. As experimentally shown, in ovo vaccination may also be a promising strategy for effective, early induction of an immune response. Besides live attenuated and classical inactivated vaccines, some genetically engineered viruses, including recombinant vectored vaccines, have been designed and tested under experin1ental conditions. These have induced partial protection and need further development.

BORDETELLOSIS (Turkey coryza, Bordetella avium rhinotracheitis) Avian bordetellosis is a highly infectious, acute upper respirato1y tract disease of turkeys characterized by high morbidity and usually low mortality. Other synonyms previously used for the disease include A/cali­ genes rhinotracheitis, adenovirus-associated respiratory disease, acute respiratory disease syndrome, and turkey rhinotracheitis. Although the disease primarily affects turkeys, quail a.re also susceptible, and it is an opportunistic infection in chickens. Damage to the upper respiratory tract from prior exposure to an upper respiratory disease agent or vaccine such as infectious bronchitis virus or Newcastle disease vims, or from an environmental irritant such as anunonia, is necessary to induce signs in chickens. Bordetellosis has been identified in almost every area of the world where turkeys are intensively reared. Historically, it has been severe in focal areas and rare or nonapparent in other locations. The reasons for these epidemiologic differences are not known.

Etiology and Pathogenesis: The causative agent is Bordetella avium, a gran1-negative, nonfermentative, motile, aerobic bacillus. It can be grown using many different media, including Mac­ Conkey agar, Bordet-Gengou agar, veal infusion broth, trypticase soy broth, blood agar, and brain-heart infusion broth. Strains of B avium typically produce small (0.2-1 nun diameter after 24 hr incubation), compact, translucent, glistening pearl-like colonies with smooth edges. After serial passage in the laboratory, a rough colony type with a dry appearance and a serrated, irregular edge can be observed for some isolates. Rough colonies represent a global suppression of virulence factors inB avium termed antigenic variation and are

nonpathogenic. When the bacillus is grown in broth media high in nutrients, filamen­ tous fonns can be observed. The mechanism of pathogenesis involves the ability of B avium to destroy ciliated epithelial cells in the trachea. Ce1tain strains of the bacteria adhere to the ciliated pseudostrati.fied columnar epithelium and produce toxins, some of which appear to be similar to those from other Bordetella spp. Toxins associated with pathogenic strains of B avium include a heat-labile toxin, tracheal cytotoxin, dem10necrotic toxin, and osteotoxin. Adherence factors associated with the bacterium include the hemagglutinin Baal autotransporter protein and possibly pill and componeuts associ­ ated with lipopolysaccharide. Damage to the tracheal cartilage with distortion and discoloration of the tracheal rings is often observed and thought to be caused by the cytotoxin and/or the osteotoxin. Some mortality is due to suffocation from

Scanning electron microscopy of a trachea from a poult 3 days after Bordetella avium infection; note numerous B avium cells attached to ciliated columnar epithelial cells. Courtesy of Dr. Mark W. Jackwood.

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BORDETELLOSIS

increased mucus production in the trachea and tracheal collapse. As with many bacterial infections, iron acquisition is necessary for colonization and spread of Bavium in the host. Virulence factor expression is globally controlled by a virulence gene locus in response to environmental conditions that favor antigenic variation an10ngB a:uium isolates. Damage to the upper respiratory tract can lead to secondaiy infections with Escheri­ chia coli or other agents, which can significantly increase the severity of the disease. In many cases, tuxkeys infected solely with Bavium recover within 4---6 wk without serious consequences. Epidemiology and Transmission: Mor­ bidity is usually 80%--lOO"A, in young turkeys. Mortality can range from (JOA, in birds with uncomplicated disease to >400,1, if secondaiy invaders ai·e present. Mortality can increase and signs can become severe if young turkeys infected with Bavium also become infected with other agents ( eg, E coli, Newcastle disease virus) or when environ­ mental conditions in turkey barns are less than optimal. Bordetellosis is a major initiator of colibacillosis in turkeys. There is an age-related resistance to the disease. 'furkeys >4--5 wk old are most often refractory to the disease but not infection, and thus can be a factor in spread of the bacterium. B avium is highly contagious and easily transmitted from infected turkeys to susceptible birds by direct contact. It can also be transmitted tlu·ough contaminated drinking water, feed, and litter, which can remain infectious for 1--6 mo. Clinical Findings: Signs of the disease

usually occur 7--10 days after infection and include sinusitis with a clear nasal discharge that can be observed when pressure is applied to the nai·es. Foainy­ watery eyes, a snick or cough, mouth breathing, dyspnea, tracheal rales, and altered vocalization are also characteristic. Complicated disease can result in more exaggerated signs including airsacculitis.

Lesions: Lesions are primarily found in the upper respiratory tract and consist of nasal and tracheal exudates, collapse of cartilaginous rings, and progressive loss of ciliated epithelium. In uncomplicated disease, the tracheal epithelium can return to nom1al 4---6 wk after the onset of signs. At necropsy, turkeys with characteristic bordetellosis have watery eyes and extensive mucus in the sinuses and trachea, which rarely extends below the tracheal

bifurcation. The lining of the trachea may have extremely mild hemorrhage in some cases, and softening of the tracheal rings is usually felt. In addition, a dorsal/ventral flattening of the trachea can sometimes be observed. Pnew11onia and airsacculitis ai·e observed only when the disease is complicated by another disease agent. Diagnosis: Diagnosis of infection is confirmed by isolation of B avium on MacConkey agar and identification using standard biochemical assays. Nonferment­ ing, small, slow-growing colonies from specin1ens from the anterior trachea are typical. The bacteriwn is best isolated from the anterior trachea; cultures ta.ken from the sinuses frequently become overgrown with other, fasteHeplicating bacteria such as Proteus spp. Serology is also important, and both microagglutination ( detects IgM) and ELISA (detects IgG) tests ai·e available. The microagglutination test can detect specific antiboclies --1 wk after infection. The ELISA test generally detects specific ai1tibodies >2 wk after infection and has the added benefit of detecting maternal antibody. Monoclonal antibody-based agglutination and indirect in1munofluorescent tests as well as PCR tests have also been used to identify

Bavium.

Other nonfennenters, Bbronchiseptica and B hinzii, which ai·e for tl1e most part nonpathogenic, can sometimes be isolated from the trachea and must be differentiated from Bavium. Patl1ogenic Bavium can be clifferentiated by growth and colony morphol­ ogy on MacConkey agar, no growth on minin1al essential mediwn, a negative urease reaction, and hemagglutination of guinea pig erythrocytes. B a:uium also agglutinates chicken and turkey erytlu·ocytes. Treatment: Treatment witl1 antin1icrobial

agents by aerosol, injection, or in the water has not been effective, even tl1ough Bavium may be highly sensitive. The tracheal epitl1elium of the turkey is a clifficult location to medicate even though blood levels of tl1e antimicrobial appeai· to be adequate. Resistance to streptomycin, sulfonamides, and tetracycline cai1 be carried on plasmids and has been observed for some strains of Bauium. Antimicrobial therapy may be helpful for secondaiy colibacillosis. Control and Prevention: Vaccination

with bacterins ai1d a live temperature­ sensitive mutant vaccine have given mixed results depending on the age of the turkey and the method of administration.

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INFECTIOUS BRONCHITIS

Typically, turkeys >3 wk old respond positively to vaccination with the live temperature-sensitive vaccine. Vaccina­ tion is not widely practiced by turkey breeders, and the immunity that is passed to progeny generally comes from natural infections. B avium is easily carried between farms. Thus, prevention should include a good biosecw·ity program. Rigorous cleanup

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and disinfection after field outbreaks is essential. Most of the commonly used disinfectants are effective. Zoonotic Risk: B avium may be a rare opportunistic pathogen in people. In ad­ dition, a closely related organism, B hinzii, also isolated from poultry, has been associated with septicemia and bacteremia in older or immunocompromised people.

INFECTIOUS BRONCHITIS Infectious bronchitis is an acute, highly contagious disease of major economic impo1tance in commercial chicken flocks throughout the world. It is usually characterized by respiratory signs, although decreased egg production and poor egg quality are sometimes seen in breeders and layers. Some strains of the etiologic agent, infectious bronchitis virus (IBV), are nephropathogenic, causing interstitial nephritis, particularly in chicks. Associa­ tions with myopathy and proventriculitis have also been reported. Etiology and Epidemiology: IBV is a coronavirus that only causes disease in chickens, although some other birds may be subclinically infected. Some serotypes are geographically restricted, but multiple serotypes commonly cocirculate in one geographic region. In recent years, a novel IBV genotype, the QX sti·ain, has become increasingly common in Asia and Europe. IBV is shed by infected chickens in respira­ tory discharges and feces, and it can be spread by aerosol, ingestion of contaminated feed and water, and contact with contami­ nated equipment and clothing. Naturally infected chickens and those vaccinated with live IBV may shed vims inte1mittently for up to 20 wk after infection. The incubation period is generally 24-48 hr, witl1 the peak in excretion of virus from tl1e respiratory tract lasting� days after infection. The severity of disease and the body systems involved are influenced by the strain of tl1e virus; the age, strain, in1lllune status, and diet of the chickens; and cold sti·ess. In addition, coinfection with Mycoplasma gallisepticum,

Mycoplasma synoviae, Esche richia coli, and/or Avibacterium paragallinaium can exacerbate disease.

Clinical Findings: Morbidity is commonly close to lOOOA,. Chicks may cough, sneeze, and

have tracheal rales for 10-14 days. Con­ jW1ctivitis and dyspnea may be seen, and sometimes facial swelling, particularly with concurrent bacterial infection of the sinuses. Chicks may appear depressed and huddle under heat lamps. Feed conswnption and weight gain are reduced. Infection with nephropathogenic strains can cause initial respiratory signs, then later depression, ruffled feathers, wet droppings, greater water intake, and death. In layers, egg production may drop by as much as 700Ai, and eggs are often misshapen, with thin, soft, rough, and/ or pale shells, and can be smaller and have watery albW11en. In most cases, egg production and egg quality return to 1101° ma!, but this may take up to 8 wk In most outbreaks mortality is 5%, although mortality rates are higher when disease is compli-cated by concurrent bacterial infection. Nephro­ pathogenic strains can induce interstitial nephritis with high mortality (up to 600A,) in young chicks. Infection of young chicks may cause pennanent damage to the oviduct, resulting in layers or breeders that never reach normal levels of production. Lesions: In the respiratory tract, the trachea, sinuses, and nasal passages may contain serous, catarrhal, or caseous exudates, and the air sacs a foamy exudate initially, progressing to cloudy thickening. If complicated by infection with E coli, tl1ere may be caseous airsacculitis, perihepatitis, and pericarditis. Birds infected when very young may have cystic oviducts, whereas those infected while in lay have an oviduct of reduced weight and length and regres­ sion of the ovaries. Infection with nephro­ pathogenic strains results in swollen, pale kidneys, with the tubules and ureters distended with w·ates; in birds with urolithiasis, the ureters may be distended with urates and contain uroliths, and the kidneys may be atrophied.

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INFECTIOUS BRONCHITIS

Diagnosis: L aboratory confirmation is required for diagnosis of respiratory fonns because of similarities to mild fonns of disease caused by agents such as Newcastle disease virus, avian metapneumovirus, infectious laryngotracheitis virus, mycoplas­ mas, A paragallinarum, and Ornithobacte­ rium rhinotracheale. Demonstration of seroconversion or a rise in antibody titer against IBV by ELISA, or hemagglutination inhibition or virus neutralization tests can be used for diagnosis when there is a history of respiratory disease or reduced egg production. Definitive diagnosis is generally based on virus detection and identification. Virus can be isolated by inoculation of homogenates of tracheal, cecal tonsil, and/or kidney tissue into 9- to 11-day--old SPF chicken embryos, with growth ofIBV indicated by embryo stunting and curling, and deposition of urates in the mesonephros, with variable mortality. Alternatively,IBV may be isolated in tracheal organ cultures, with growth of virus indicated by cessation of cilial motility. Several blind passages of the virus may be necessary for isolation of some field strains. More rapid diagnosis may be achieved using reverse transcriptase-polymerase chain reaction (RT-PCR) assays to detect viral RNA in nucleic acid extracts of tracheal, cecal tonsil, or kidney tissue. Typing viruses can help distinguish vaccine and field strains and may help diagnose outbreaks caused by serotypes distinct from those of the vaccines used in a flock. Serotypes have been identified using sera from SPF chickens inoculated with known serotypes in virus neutralization tests. However, because this is expensive and time consuming, it is not Ieadily available. A restricted range of serotype­ specific monoclonal antibodies (MAb) have been developed for serotyping, but direct detection viral antigen using these MAbs to inununohistochemically stain tissue sections from diseased birds is of limited value because of the low concentration of antigen in tissues. The MAbs have been best used after propagation in chicken embryos, to detect viral antigen in the chorioallantoic membranes by inununofluorescence or inununoperoxidase staining, or in the allantoic fluid by ELISA. Analyses of the products ofRT-PCR assays are now conunonly used to identify the virus serotype and to identify individual strains within serotypes. The S l region of the spike glycoprotein gene determines the serotype, andR T -PCR products derived from this region can be subjected to restriction fragment length polymorphism analysis,

analyzed by nucleotide sequencing, or compared with reference strains using high-resolution melting curve analysis. Genotype detem1ination based on the S l region can be complemented by analyzing other regions of the viral genome, including the nucleocapsid gene and the 5' untrans­ lated region. These analyses can also aid in rapid detection of novel recombinantIBVs. Control: No medication alters the course ofIBV infection, although antimicrobial therapy may reduce mortalities caused by complicating bacterial infections. In cold weather, increasing the ambient tempera­ ture may reduce mortalities, and reducing the protein concentrations in feed and providing electrolytes in drinking water may assist in outbreaks caused by nephropathogenic strains. The attenuated vaccines used for inununization may produce mild respiratory signs. These vaccines are initially given to 1- to 14-day-old chicks by spray, d1inking water, or eye drop, and birds are commonly revaccinated.Revaccination with a virus from a distinct serotype can induce broader protection. Attenuated or adjuvanted inactivated vaccines can be used in breeders and layers to prevent egg production losses. There are many distinct serotypes ofIBV, and new or variant serotypes, which are not fully controlled by existing vaccines, are identified relatively frequently. Some variants may be derived from recombination between existing field strains and vaccine strains, whereas others result from point mutations in existing strains. Selection of vaccines should be based on knowledge of the most prevalent serotype(s) on the premises. The correlation between serotype and protection is imperfect, and definition of the most approp1iate vaccine, or combina­ tion of vaccines, may require experin1ental assessment of several combinations of vaccines to identify the most effective regimen. The most conunonly used live vaccines in the USA contain derivatives of the Massachusetts, C onnecticut, and Arkansas strains, whereas in Australia, where the most prevalent serotypes are distinct from most other countries, vaccines are based on derivatives of the VicS and Armidale strains. In Europe, vaccines incorporating derivatives of the 4/91 strain and those derived from QX-like viruses are available. Vaccination with selected variant serotypes may be of use when these variants are the dominant strain in flocks, although regulatory authorities in some countries only pennit use of vaccines derived from the Massachusetts strain.

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INFECTIOUS CORY2A

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INFECTIOUS CORYZA Infectious coryza is an acute respiratory disease of chickens characterized by nasal discharge, sneezing, and swelling of the face under the eyes. It is found worldwide. The disease is seen only in chickens; reports of the disease in quail and pheasants probably describe a similar disease that is caused by a different etiologic agent. In developed countries such as the USA, the disease is seen primarily in pullets and layers and occasionally in broilers. In the USA, it is most prevalent in commercial flocks in California and the southeast, although the northeastern USA has experienced significant outbreaks. In developing countries, the disease often is seen in very young chicks, even as young as 3 wk old. Poor biosecurity, poor environ­ ment, and the stress of other diseases are likely reasons why infectious coryza is more of a problem there. The disease has no public health significance. Etiology: The causative bacterium is Avibacleriiim paragallinarum, a gram-negative, pleomorphic, nonmotile, catalase-negative, microaerophilic rod that requires nicotinamide adenine dinucleotide CV-factor) for in vitro growth. When grown on blood agar with a staphylococcal nurse colony that excretes the V-factor, the satellite colonies appear as dewdrops, growing adjacent to the nurse colony. V fa - ctor-independentAv pa.ragallinarum have been recovered in South Africa and Mexico. The most commonly used serotyping scheme is the Page scheme, which groups Av paragallinarum isolates into three serovars (A, B, and C) that COJTelate with inununotype specificity. Epidemiology and Transmission: Chronically ill or healthy carrier birds are the reservoir of infection. Chickens of all ages are susceptible, but susceptibility increases with age. The incubation period is 1-3 days, and the disease duration is usually 2-3 wk Under field conditions, the duration may be longer in the presence of concurrent diseases, eg, mycoplasmosis. Infected flocks are a constant threat to uninfected flocks. Transmission is by direct contact, airborne droplets, and contamina­ tion of drinking water. "All-in/all-out" management has essentially eradicated infectious coryza from many commercial poultry establishments in the USA.

Commercial fam1s that have multiple-age flocks tend to perpetuate the disease. Egg transmission does not occur. Molecular techniques such as restriction endonuclease analysis �d ribotyping have been used to trace outbreaks of infectious coryza. Clinical Findings: In the mildest fom1 of the disease, the only signs may be depres­ sion, a serous nasal discharge, and occasion­ ally slight facial swelling. In the more severe forn1, there is severe swelling of one or both infraorbital sinuses with edema of the surrounding tissue, which may close one or both eyes. In adult birds, especially males, the edema may extend to the intermandibu­ lar space and wattles. The swelling usually abates in 10-14 days; however, if secondary infection occurs, swelling can persist for months. There may be varying degrees of rales depending on the extent of infection. In Argentina, a septicemic fom1 of the disease has been reported, probably due to concun-ent infections. Egg production may be delayed in young pullets and severely reduced in producing hens. Birds may have diarrhea, and feed and water consumption usually is decreased during acute stages of the disease. Lesions: In acute cases, lesions may be limited to the infraorbital sinuses. There is a copious, tenacious, grayish, semifluid exudate. As the disease becomes chronic or other pathogens become involved, the sinus exudate may become consolidated and turn yellowish. Other lesions may include conjunctivitis, tracheitis, bronchitis, and airsacculitis, particularly if other pathogens are involved. The histopathologic response of respiratory organs consists of disintegra­ tion and hyperplasia of mucosa! and glandu­ lar epithelia and edema with infiltration of heterophils, macrophages, and mast cells. Diagnosis: Isolation of a gram-negative, satellitic, catalase-negative organism from chickens in a flock with a history of a rapidly spreading coryza is diagnostic. The catalase test is essential, because nonpathogenic hemophilic organisms, which are catalase­ positive, are present in both healthy and disea5ed chickens. A PCR test that can be used on the live chicken and that has proved superior to culture, even in developing countries, has been developed. A real-time version of the PCR is also available.

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INFECTIOUS CORYZA

Production of typical signs after inoculation with nasal exudate from infected into suscep­ tible chickens is also reliable diagnostically. No suitable serologic test exists; a hemagglu­ tination-inhibition test is the best of those available. Swelling of the face and wattles must be differentiated from that seen in fowl cholera (seep 2822). Other diseases that must be considered are mycoplasmosis, laryngotracheitis, Newcastle disease, infectious bronchitis, avian influenza, swollen head syndrome ( ornithobacterosis), and vitamin A deficiency. While currently found only in South Afiica and Mexico, the presence of a V-factor-independentAv paragallinarum must also be considered. The Av paragal­ linarum PCR is an ideal diagnostic tool in this situation. Control and Treatment: Prevention is the only sound metl10d of control. "All-in/ all-out" faim programs with sound manage­ ment and isolation methods are the best way to avoid infectious coryza Replacements should be raised on the same farm or obtained from clean flocks. If replacement pullets are to be placed on a fann that has a history of infectious coryza, bacterins ai·e available to help prevent and control tl1e disease. USDA-licensed bacterins are available, and bactetins also ai·e produced within states for intrastate use. Bacterins also are produced in many other countries.

Because serovai-s A, B, and C ai·e not cross-protective, it is essential that bacterins contain the serovai-s present in the target population. Vaccination should be completed -4 wk before infectious coryza usually breaks out on the individual faim. Antibodies detected by the hemagglutination-inhibition test after bactetin administration do not necessarily c01Telate with protective immunity. Cont.rolled exposure to live organisms also has been used to immunize layers in endemic areas. Because early treatment is important, water medication is recorrunended immediately until medicated feed is available. Erythromycin and oxytetra­ cycline are usually beneficial. Several new-generation antibiotics ( eg, fluoroquin­ olones, macrolides) are active against infectious coryza Vaiious sulfonamides, sulfonainide-tri.rnethoprim, and other combinations have been successful. Antibiotic use in chickens is subject to national regulations that vary from country to country, and use and efficacy of the various antibiotics must be reviewed in the light of the relevant national regulations. In more severe outbreaks, although treatment may result in in1provement, the disease may recur when medication is discontinued. Preventive medication may be combined witl1 a vaccination prograin if started pullets are to be reared or housed on infected premises.

INFECTIOUS LARYNGOTRACHEITIS Infectious laryngotracheitis (ILT) is an acute, highly contagious, herpesvirus infection of chickens and pheasants characterized by severe dyspnea, coughing, and rales. It can also be a subacute disease with nasal and oculai· discharge, tracheitis, conjunctivitis, and mild rales. The disease is caused by Gallid herpesvirus I, commonly known as infectious lai-yn.gotracheitis virus (ILTV). It has been reported from most areas of the USA in which poultry are intensively reared, as well as from many other countries. Clinical Findings: In the acute form,

gasping, coughing, rattling, and extension of the neck during inspiration are seen 5--12 days after natural exposure. Reduced productivity is a varying factor in laying flocks. Affected birds are anorectic and

inactive. The moutl1 and beak may be bloodstained from the tracheal exudate. Mortality vaiies but may reach 50% in adults and is usually due to occlusion of the trachea by hemotThage or exudate. Signs usually subside after -2 wk, although some birds may show signs for longer petiods. Strains of low virulence produce little or no mortality with mild respiratory signs and a slight decrease in egg production. After recovery, birds remain can·iers for life ai1d become a source of infection for susceptible birds. The latent virus can be reactivated under stressful conditions. Infection also may be spread mechanically. Several epidemics have been traced to the transport of birds in containinated crates, and the practice of litter spread in pastures is believed to be related to epidemics of the disease.

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QUAIL BRONCHITIS Diagnosis: The acute disease is charac­ te1ized by the presence of blood, mucus, yellow caseous exudates, or a hollow caseous cast in the trachea. Microscopi­ cally, a desquamative, necrotizing tracheitis is characteiistic of acute disease. In the subacute fonn, punctifonn hemorrhagic areas in the trachea and larynx and mild conjunctivitis with lacrirnation may be detected. A rapid diagnosis can be achieved by detection of intranuclear inclusion bodies in the tracheal epithelium early in the cow·se of the disease; results of the microscopic examination can be rapidly confinned by detection of viral DNA using virus-speciilc PCR assays. Isolation and identification of the virus is done in chicken embryos or tissue culture from embryo liver or kidney cells or from kidney cells from adult chickens. Chicken embryos are preferred for virus isolation. Chorioallan­ toic membrane of developing chicken embryos (9-12 days old) is inoculated with the specimen. Microscopic examination of the chorioaliantoic membrane lesion shows intranuclear inclusions. On microscopic exan1ination of the trachea, intranuclear inclusion lesions produced by ILTV infection must be differentiated from the

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diphtheiitic form of fowlpox infection that produces intracytoplasmic inclusions. Field isolates and vaccine strains of ILTV are routinely differentiated by PCR an1plification of single or multiple ILTV genome areas, followed by sequencing of the PCR products and comparative analysis of the sequences obtained. More recently, field isolates and vaccines strains have been differentiated more accurately by full gen\:ime sequencing analysis. Control: In endemic areas and on fanns where a specific diagnosis is made, fue disease is controlled by implementation of biosecuiity measmes and vaccination. Vaccination is done with live attenuated vaccines and viral vector recombinant vaccines. Live vaccines oiiginated from virulent isolates tl1at were attenuated by consecutive passages in embryos or tissue culture. These are applied via eye drop or through mass vaccination by water or spray. Viral vector recombinant vaccines in fowlpox and herpesvirns of turkeys have been designed to express ILTV immunogenic proteins and are administered to individual birds by in ovo, SC, or wing-web vaccination.

QUAIL BRONCHITIS Quail bronchitis is a naturally occurring, highly contagious, often fatal respiratory disease of bobwhite quail, seen both in the wild and in captivity. The disease is of major economic significance to gamebird breeders and has a worldwide distribution. It is a se1ious disease on certain farms where quail are pen-raised, and particularly when quail of different ages are maintained on the san1e premises. The causative agent, quail bronchitis vims, is a Group I serotype 1 avian adenovirus that can be readily isolated from the respiratory tract of acutely affected birds. The virus is also easily isolated from fecal samples, intestine, liver, and occasion­ ally the bursa ofFabricius. lt is highly contagious and spreads rapidly furough multiple-age w1its. Other avian species, particularly chickens, may be carrie1s. Clinical signs include respiratory distress, coughing, sneezing, rales, and na.sal or ocular discharge. Loose, watery droppings are common in some acutely affected older

birds. Conjunctivitis, mild to severe tracheitis (the trachea may be completely filled with mucus), airsacculitis, hepatitis, and gaseous distention of the intestines may be seen. Multiple pale, pinpoint (3 mm) foci of necrosis in the liver and mottling and enlargement of tl1e spleen are common lesions in infected birds. Mortality may reach 1000/o in birds 30 species of cyanobacteria that can be associated with toxic waterblooms. Neurotoxic alkaloids (called anatoxins) can be produced by

Anabaena, Aphanizomenon, and Planlctothrix, while saxitoxins (also

called paralytic shellfish toxins) can be produced by Anabaena, Aphanizomenon, and Lyngbya. Hepatotoxic heptapeptides called microcystins can be produced by Anabaena, Microcystis, Nostoe, and Planklolhrix. The brackish water genus Nodularia produces a hepatotoxic pentapeptide related, in both structure and function, to microcystins. Cylindro­

spermopsis, Anabaena, Aphanizomenon, Raphidiopsis, and Umezakia can produce

a potent hepatotoxic alkaloid called cylindrospermopsin. Some genera, especially Anabaena, can produce both neuro- and hepatotoxins. If a toxic waterbloom contains both types of toxins, the neurotoxin signs are seen first, because their effects occur much sooner (minutes) than those of the hepatotoxins (1 to a few hours). Other noncyclic peptides and amino acids produced by cyanobacteria can also have biological activity. One recent amino acid with neurologic deg­ enerative activity is BMAA (15-methylamino alanine). BMAA has been implicated as the causative agent of amyotrophic lateral sclerosis or parkinsonism dementia. Poisoning usually does not occw· unless there is a heavy waterbloom that forms a dense surface scum. Factors that contribute to heavy waterblooms are nutrient-rich

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eutrophic to hypereutrophic water and wann, sunny weather. Evidence supports the observation that global climate change causes earlier, more intense, and longer­ lasting warm weather that leads to more extensive waterblooms of cyanobacteria. Agriculture practices (eg, runoff of fertilizers and animal wastes) that promote nut1ient emichment also contribute to and intensify waterbloom formation. The problem is augmented by light winds or wind conditions that lead to areas of very high (scum) concentrations of cyanobacte­ ria, especially leeward shoreline locations where livestock drink. Experiments with both toxin groups have revealed a steep dose-response curve, with as much as 900/o of the lethal dose being ingested without measurable effect. Animal size and species sensitivity influence the degree of intoxica­ tion. Monogastric anin1als are less sensitive than ruminants and birds. Depencling on waterbloom densities and toxin content, animals may need to ingest only a few ounces to be affected. However, if the waterbloom is less dense or cyanotoxin content is low, as much as several gallons may be needed to cause acute o.r lethal toxicity. Among domestic animals, dogs are most susceptible to a toxic waterbloom. This is due to their preference for swinuning and drinking in dense waterblooms and a greater species sensitivity to the cyanotox­ ins, especially the neurotoxins. Although the species sensitivity and signs of poisoning can vary depending on the type of exposure, the gross and histopathologic lesions are quite similar among species poisoned by the hepatotoxic peptides and neurotoxic alkaloids. Death from hepato­ toxicosis induced by cyclic peptides is generally accepted as being the result of intrallepatic hemorrhage and hypovolemic shock. This conclusion is based on large increases in liver weight as well as in hepatic hemoglobin and iron content that account for blood loss sufficient to induce ilTevers­ ible shock. In animals that live more than a few hours, hyperkalemia or hypoglycemia, or both, may lead to death from liver failure within a few days to a few weeks. Neurotoxicosis, with death occurring in minutes to a few hours from respiratory arrest, may result from ingestion of the cyanobacteria that produce neurotoxic alkaloids. Species and strains of Anabaena, Aphanizomenon, Oscillal01ia, and Planklolhrix can produce a potent, postsynaptic cholinergic (nicotinic) agonist called anatoxin-a that causes a depolarizi..11g neuromuscular blockade. Strains of Anabaena can produce an irreversible

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organophosphate anticholinesterase called anatoxin-a(s). Anabaena, Aphan'izomenon, Cylinclrospe,mopsis, and Lyngbya can produce the potent, presynaptic sodium channel blockers called saxitoxi..11s. Clinical Findings and Lesions: One of

the earliest effects (15-30 min) of microcys­ tin poisoning is increased serum concentra­ tions of bile acids, alkaline phosphatase, -y-glutan1yltransferase, and AST. The WBC count and clotting times increase. Death may occur within a few hours (usually within 4-24 hr), up to a few days. Death may be preceded by coma, muscle tremors, paddling, and dyspnea. Watery or bloody dian·hea may also be seen. Gross lesions include hepatomegaly due mostly to intrallepatic hemorrhage. Intact clumps of greenish cyanobacteria can be found i..11 the stomach and GI tract, and there is a greenish stain on the mouth, nose, legs, and feet. Hepatic necrosis begins centri­ lobularly and proceeds to the periportal regions. Hepatocytes are disassociated and rounded. After death, debris from disas­ sociated hepatocytes can be found in the pulmonary vessels and kidneys. Clinical signs of neurotoxicosis progress from muscle fasciculations to decreased movement, abdominal breathing, cyanosis, convulsions, and death. Signs in bi..l·ds are similar but include opisthotonos. In smaller ani.nlals, death is often preceded by leaping movements. Cattle and horses that survive acute poisoni..11g may have signs of photosensitization in areas exposed t0 light (nose, ears, and back), followed by hair loss and sloughing of the skin. Diagnosis: Diagnosis is based prin1aiily on history (recent contact with cyanobacte­ ria waterbloom), signs of poisoning, and necropsy findings. Samples of the water­ bloom should be taken as soon as possible for microscopic exainination to confirm the presence of the toxigenic cyanobacteria and for cyanotoxin analysis. Although there are nontoxic and toxic strains of all the known toxic species, it is not possible to identify a toxic strain by visual exanli.na­ tion. Cyanobacteria are detected by light microscopy, identified using morphologic chai·acte1istics, and counted per standard volume of water. Stai1dai·d protocols to san1ple and monitor cyanobactelia as well as practical keys for the identification of toxic species are available. Some laboratories cai1 analyze for the cyanotoxilis either by chemical or biologic assay. Animal bioassays (mouse tests) have traditionally been used to detect the

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presence of the entire range of cyanotoxins based on survival times and signs of poisoning. These tests provide a definitive indication of toxicity, although they cannot be used for precise quantification of compow1ds in water or to determine compliance with standards for environmen­ tal levels. A nwnber of analytic techniques are available to detem1ine microcystins in water. These techniques must provide for quantitative comparison to the guideline or regulatory value in tem1S of toxicity equivalents. The method most suitable in this regard is high-performance liquid chromatography (HPLC) or HPLC coupled with mass spectrometry. These methods still involve estimation of the concentration and therefore provide only an estin1ate of toxicity. This is largely due to the limited availability of certified reference standards for the cyanotoxins. Commercial reference materials, purified from laboratory cultures or waterbloom material, for some microcyst­ ins, nodularin, cylindrospennopsin, and saxi­ toxins are available. A synthetic reference material for anatoxin-a is also available. No known conrn1ercial reference material is available for anatoxin-a(s). Newer methods of inunw10assay, for quantification purposes, are also available. These include conunercial ELISA kits in hoth laboratory and field fom1a.ts for microcystins/nodula.rin, cylindrospennopsin, and saxitoxins. Also available is a receptor-binding assay colorin1etric plate kit for ana.toxin-a Treatment:. After removal from the contaminated water supply, affected anin1als should be placed in a protected area out of direct swilight. Ample quantities of water and good quality feed should be ma.de available. Because the toxins.have a steep dose­ response curve, surviving animals have a good chance for recovery. Although therapies for cyanoba.cterial poisonings have not been investigated in detail, activated charcoal slurry is likely to be of benefit. In laboratory studies, an ion-exchange resin such as cholestyramine has proved useful to absorb the toxins from the GI tract, and certain bile acid transport blockers such as cyclosporin A, rifampin, and silyma.rin injected before dosing of microcystin have effectively prevented hepa.totoxicity. No therapeutic antagonist has been foW1d effective against ana.toxin-a, cylindrospermopsin, or the saxitoxins, but atropine and activated charcoal reduce the muscarinic effects of the anticholinesterase ana.toxin-a.(s). Prevention: Removal of animals from the affected water supply is essential. If no

other water supply is available, anin1als should be allowed to drink only from shore areas kept free (by prevailing winds) of dense surface scwns of cyanobacteria.. Some efforts have been made to erect surface barriers (logs or floating plastic booms) to keep shore a.r·eas free of surface sewn, but these a.r·e not very successful. Cyanoba.cteria.can be controlled by adding copper sulfate (CuS04) or other copper­ based algicidal treatments to the water. The usual treatment for CuS04 is 0.2-0.4 ppm, equivalent to 0.65-1.3 oz/10,000 gal. of water or 1.4-2.8 lb/a.cre-foot of water. Livestock (especially sheep) should not be watered for at least 5 days after the last visible evidence of the cyanoba.cteria. waterbloom. CuS04 is best used to prevent wa.terbloom fo1ma.tion, and care should be taken to avoid water that has dead cyanoba.cteria. cells, either from treatment with algicide or natural aging of the bloom, because most toxin is released in the water only after breakdown of the intact cyanoba.cteria cells. A chemical control method receiving attention are comp0tmds to bind and remove phosphorus from eutrophic waters. This has the potential to minimize one of the more in1portant nutrients responsible for cya.noba.cteria wa.terblooms. Common phosphorus treatments include lime, aluminwn sulfate, ferric chloride, and some types of clay particles. These treatments also act as flocculating a.gents and fonn particulates with algae cells and other debris that settle out and remove the bloom from the water colwnn. For example, when alwn (potassiwn alW11inum sulfate) is used in a water supply, a precipitate (floe) forms that carries algae cells, dirt, and bacteria. to the bottom, but charged items such as phosphate and colloids are botmd by the same precipitate through their charges. A newer, effective phosphorus-binding compoW1d product available in the USA since 2010 uses a pa.tented phosphorus­ locking technology containing lanthanW11 (5%), a naturally occurring earth element, embedded inside a clay matrix (-95%). Source water management techniques for control of cyanoba.cterial growth include flow maintenance in regulated rivers, water mixing techniques both to eliminate stratification and reduce nut1ient release from sedin1ents in reservoirs, and the use of algicides in dedicated water supply storages. Algicides disrupt cells and liberate intra.cellular toxins. Algicide use should be in accordance with local environment and chemical registration regulations. In situations where multiple offtakes a.re available, the selective withdrawal of water

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from different depths can minimize the intake of high surface accumulations of cyanobacterial cells. Water treatment techniques can be hlghly effective to remove both cyanobacterial cells and cyanotoxins ( especially microcyst­ ins) with the appropriate technology. Most cyanotoxins remain intracellular, unless the cells are lysed or damaged from age or stress from water conditions or chemical treatment. The one exception is cylindro­ spermopsin, which is actively secreted from even healthy cells. This makes it possible to remove cells and cyanotoxins (especially microcystins) by coagulation and filtration in a conventional treatment plant. Treatment of water containing cyanobacte­ rial cells with oxidants such as chlorine or

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ozone, while killing cells, will result in the release of free cyanotoxin. Therefore, the practice of prechlorination or preozonation is not recommended without a subsequent step to remove dissolved cyanotoxins. Microcystins are readily oxidized by a range of oxidants, including ozone and chlorine. Adequate contact time and pH control are needed to achieve optimal removal of these compounds, whlch is more difficult in the presence of whole cells. Microcystins, anatoxin-a, cylindrospermop­ sin, and some saxitoxins are also adsorbed from solution by both granular activated carbon and, less efficiently, by powdered activated carbon. The effectiveness of the process should be determined by monitor­ ing cyanotoxin in the product water.

CYANIDE POISONING In acute cyanide poisoning, cyanide ions (CN-) bind to, and inhibit, the ferric (Fe3+) heme moeity fom1 of mitochondrial cytochrome c oxidase (synonyms: Ma, complex IV, cytochrome A3, EC 1.9.3.1). This blocks the fourth step in the rnitochon­ d!ial electron transport chain (reduction of 02 to H20). resulting in the arrest of aerobic metabolism and death from histotoxic a.noxia. Tissues that heavily depend on aerobic metabolism such as the heart and brain are particularly susceptible to these effects. Cyanide also binds to other heme-containing enzymes, such as members of the cytochrome p450 family, and to myoglobin. However, these tissue cyanide "sinks" do not provide sufficient protection from histotoxic anoxia The acute lethal dosage of hydrogen cyanide (HCN) in most anin1al species is -2 mg/kg. Plant materials containing �200 ppm of cyanogenic glycosides are dangerous. There are at least two fom1s of chronic cyanide poisoning in domestic aninlals: 1) hypothyroidism due to disruption of iodide uptake by the follicular thyroid cell sodium-iodide syn1porter by thiocy­ anate, a metabolite in the detoxification of cyanide, and 2) chronic cyanide and plant cyanide metabolite (eg, various glutamyl [3-cyanoalanines)-associated neuropathy toxidromes (eg, equine sorghum cystitis ataxia syndrome, cystitis ataxia syndromes in cattle, sheep, and goats).

Etiology: Various chemical forms of cyanides are found in plants, fumigants, soil sterilizers, fertilizers (eg, cyanan1ide), pesticides/rodenticides (eg, calcium cyanomide) and salts used in industrial processes, such as gold mining, metal cleaning and electroplating, photographic processes, and others. Hydrogen cyanide is also known as prussic acid, and cyanide salts liberate cyanide gas in the presence of acids (eg, in the stomach). Cyanide prepa­ rations are still used as vertebrate pest control agents for control of feral pigs, fox, Australian brush-tailed possums, and other pest or predator species in a .nun1ber of countries. Cyanide salts are still used as killing agents in entomology and (illegally) as a method of fishing and/or collection of aquarium fish species (ie, cyanide fishing). Combustion of common polyacrylonitriles (plastics), wool, silk, keratin, polyurethane (insulation/upholstery), melamine resins (household goods), and synthetic rubber results in the release of cyanide gas. Car fires are notorious sources of cyanide exposure, and cyanide is also a notable component of internal combustion engine exhaust and tobacco smoke. Carbon monoxide poisoning with cyanide gas is thus an extremely common component of smoke inhalation toxidromes. Toxicity can result from accidental, improper, or malicious use or exposure. However, in livestock species, the most

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frequent cause of acute and chronic cyanide poisoning is ingestion of plants that either constitutively contain cyano­ genic glycosides or are induced to produce cyanogenic glycosides and cyanolipids as a protective response to environmental conditions (plant cyanogenesis). Plant cyanogenesis is a common process and has been documented in >3,000 different plant species distributed over -110 different families of fems, gymnosperms, and angiosperms. Of these plants, -300 species are potential causes of acute and chronic cyanogenic glycoside poisoning, and there are -75 different cyanogenic glycosides (all of which are 0-!3-glycosidic derivatives of o.-hydroxynitriles). Plant species of notable veterinary in1portance include Sorghum spp (Johnson grass, Sudan grass, and S bicolor, the common cereal grain crop referred to as "sorghum" or the synonyms durra, jowari, milo), Acacia grnggii (guajillo), Amelanchier alnifolia (western service berry), Linum spp (linseeds and flaxes), Smnbucus nigra (elderberry), Buckley suckleyana (poison suckleya), Triglochin maritima and T palustris (marsh arrow grasses), Manni/wt esculenlum (cassava), all members of the Prunus genus until proved otherwise (apricot, peach, chokecherry, pincheny, wild black cherry, ornamental cheny, peaches, nectarines, apricots, almonds, bird cherries, black thorn, cherry law·els [ conunercial orchard species are often specifically bred for low cyanide content; however, ornamental members of this genus are often highly poisonous]), Nandina domestica (heavenly or sacred bamboo), Phaseolus lunatus (lima beans), members of the Vi,cia genus until proved otherwise (vetches; often, pasture species have-been bred for low cyanogenesis), Lotus spp (bird's-foot treefoils; often, pasture species have been bred for low cyanogenesis), Trifolium sp (clovers; often, pasture species have been bred for low cyanide content), Zea mays (corn), Eucalyptus spp (gum trees), Hydrangea spp (hydrangeas), Pte1idimn aquilinum (bracken fem), Bahia oppositifolia (bal1ia), and Chaenom­ ales spp (flowering quince) (See also SORGHUM POISONJNG, p 3155). A munber of insect species are also able to synthesize hydrogen cyanide and/or sequester hydrogen cyanide that is derived from the cyanogenic glycosides of their plant hosts (notably the USA eastern tent caterpillar Malacosoma ame,icanum that is associated with mare reproductive loss syndrome (see also MARE REPRODUCTIVE LOSS SYNDROME, p 1343); however, cyanide is not the cause of ma.re reproductive loss

syndrome. Invertebrates such as Burnet moths (Zygaena spp) that feed on bird's­ foot trefoils), as well as certain centipede and millipedes, are potentially hazardous food sources for exotic pet species. Plant cyanogenesis in response to environmental stressors is an important part of the etiology and risk of acute cyanogenic glycoside poisoning. Within plants, amino acids that are not used for protein synthesis can be metabolized to o.-hydroxynitriles and then to cyanogenic glycosides. Plants are protected from the potential adverse effects of cyanogenic glycosides by two features: cyanogenic glycosides are largely found within cell vacuoles, and the presence of the detoxify­ ing enzyme !3-cyanoalanine synthase ( which is responsible for production of some of the cyanide derivatives putatively involved in the chronic cyanide-associated neurologic toxidromes). Even so-called "acyanogenic" plants can become toxic under appropriate environmental circumstances. Environmen­ tal conditions that danrnge relevant plant species, reduce protein synthesis, enhance the conversion of nitrate to an1ino acids in the presence of reduced protein synthesis, and/or inhibit !3-cyanoalanine synthase potentially increase the risk of cyanogen­ esis. Relevant envirorunental factors include crushing, wilting, freezing, high environmental temperatures, herbicide treatment, water stress, cool moist growing conditions, nitrate fertilization, high soil nitrogen:phosphorus ratios, soil phospho­ rus deficiency, low soil sulfur ( decreases detoxification of cyanogenic glycosides to thiocyanates within plants), insect attack, and various plant diseases. Herbicide treatment of plants is important in that it may also increase plant palatability. Crushing and/or mastication of potentially cyanogenic plants is in1portant in develop­ ment of the acute toxidrome, because this releases cyanogenic glycosides from plant cell vacuoles and exposes them to catabolism by 13-glucosidase and hyclroxyni­ trile lyase present in the plant cell cytosol. Yotmg, rapidly growing areas of plants and areas of regrowth after cutting often have high cyanogenic glycoside content. As a rough approximation, rapidly growing Sorghum spp are often hazardous until they reach -60 cm in height; however, this is no guarantee of safety, and if there is any doubt regarding cyanogenic potential, samples of potential forage should be tested. Plant seeds and leaves typically have higher cyanogenic potential, while the fleshy parts of fruits generally have low levels. Drying often increases the cyanogenic potential of

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plants, whereas ensiling may reduce cyanide content by -50%. [3-glucosidase and hydroxynitrile lyase are also present in the rumen rnicroflora, and a rumen pH of -6.5-7 favors conversion of cyanogenic glycosides to cyanide. Rwninants on high-energy grain rations are somewhat less susceptible, because their lower rwnen pH ( -4--6) reduces the fom1ation of cyanide. Consw11ption of water before grazing on cyanogenic pastures appears to increase the risk. Monogastiic animals with low stomach pH are also somewhat less susceptible to cyanogenic glycoside poisoning. However, these factors do not guarantee immunity from poisoning. Under conditions of low-level exposure, mammals detoxify -80% of ingested cyanide to thiocyanate via mitochondrial rhodanese. Thiocyanate is then largely excreted in urine. Often, the rate of the rhodanese pathway is limited by the availability of thiosulfate; also notably, dogs have lower overall rho­ danese activity than other species. Minor, but toxicologically important, pathways of detoxification in mammals include the combination of cyanide with hydroxyco­ bala.min (vitamin B,2.,) to yield cyanoco­ balamin (vitamin B,2), and the nonenzymatic combination of cyanide with cysteine to form [3 t- hiocyanoalanine, which is conve1ted to 2-ilninothiazolidine-4-ca.rboxylic acid and subsequently excreted. Small a.mounts of [3-thiocyanoalanine are also excreted in saliva Dietary levels of sulfur an1ino acids (L-cysteine and L-methionine) strongly influence the rate of detoxification of cyanide, and low dietary intakes are associated with higher blood cyanide levels, partiCLLiarly under conditions of chronic, low level exposure. Dietary sulfur and sulfur amino acid intake are known to sti·ongly affect the neurologic toxidromes associated with chronic cyanide/cyanogenic glycoside exposure in people. Chronic low-level cyanide/cyanogenic glycoside exposure is associated with increased exposure to the cyanide met a ­ bolite thiocyanate. Under conditions of thiocyanate overload, thiocyanate acts as a competitive inhibitor of thyroid follicular cell iodine uptake by the sodium/iodide symporter. This results in reduced iodi­ nation of tyrosine, reduced T3 synthesis, increased blood TSH, goiter, and hypothy­ roidism. Similar effects occur with some plant glucosinolates (goitrogenic glyco­ sides). Seleniwn deficiency appears to enhance these effects. Chronic, low-level cyanide/cyanogenic glycoside exposure (often in combination with low dietary sulfur and/or sulfur a.n1ino

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acid intake) is associated with neuropathy syndromes in horses and ruminants. Sorghun1 cystitis ataxia syndrome of horses is associated with diffuse nerve fiber degeneration in the lateral and ventral funiculi of the spinal cord and brain stem. Similar syndromes have been described in rwninants. Comparisons between these syndromes as chronic cyanogenic glycoside--associated hw11an myeloneu­ ropathies such as Konzo and tropical ataxic neuropathy have been made; however, the precise toxins and modes of action are yet to be fully defined. All of these toxidromes appear to be related to a combination of chronic cyanide/cyanogenic glycoside exposure combined with low dietary sulfur and/or sulfur amino acid intake and possibly other nutritional deficiencies. Lathyro­ genic plant cyanide metabolites such as [3--cyanoalanine have been implicated as causative or at least contiibutory agents. Chronic, low-level cyanogenic glycoside exposure (notably from Sorghum spp) has been associated with musculoskeletal teratogenesis (ankyloses or aitlu·ogryposes) and abortion.

Clinical Findings: Acute cyanide poisoning: Signs generally occur within

15-20 n1in to a few hours after animals consun1e toxic forage, and survival after onset of clinical signs is rarely >2 hr. Excitement can be displayed initially, accompanied by rapid respiration rate. Dyspnea follows sho1tly, with tachycai·dia. The classic "bitter almond" breatl1 smell may be present; however, the ability to detect this smell is genetically detem1ined in people, and anosrnic people ( a significant prop01tion of the population) carmot detect it. Salivation, excess lacril11ation, and voiding of urine and feces may occur. Vomiting may occur, especially in pigs. Muscle fasciculation is common and progresses to generalized spasms and coma before death. Animals may stagger and struggle before collapse. In other cases, sudden unexpected death may ensue. Mucous membranes are bright red but may become cyanotic tem1inally. Venous blood is classically described as "cherry red" because of the presence of high venous blood p02; however, this color rapidly changes after death. Serw11 a.nu11onia and neutral ai1d aromatic ai11ino acids are typically increased. Cardiac arrhythmias are common due to myocai·dial histotoxic hypoxia. Death occurs during severe asphyxial convulsions. The heart may continue to beat for several minutes after struggling, and breathing stops. The

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elimination half-life of cyanide in dogs is reported to be 19 hr, so prognosis of recove1y without therapeutic intervention is grave: it would take more than 4 days to eliminate >95% of the cyanide present. Chronic cyanide poisoning: Chronic cyanogenic glycoside hypothyroidism will present as hypothyroidism with or without goiter. Cystitis ataxia toxidromes are typically associated with posterior ataxia or incoordination that may progress to in-eversible flaccid paralysis, cystitis secondary to urinaiy incontinence, and hindlimb wine scalding and alopecia. Death, although uncommon, is often associated with pyelonephritis. Late-term abortion and musculoskeletal teratogenesis may also occur. Lesions: Acute cyanide poisoning: Necropsy personnel may require appropriate personal protective equipment, including respirators with suitable cartridges. Venous blood is classically described as being "bright cheny red"; however, this color rapidly fades after death or if the blood is exposed to the atmosphere. Whole blood clotting may be slow or not occur. Mucous membranes may also be pink initially, then become cyanotic after respiration ceases. The run1en may be distended witl1 gas; in some cases the odor of"bitter almonds" may be detected after opening. Rw11en contents may provide a positive sodium picrate paper test (or positive results on other rapid cyanide test strip systems). RWllen gases may provide positive results in cyanide Draeger tube rapid test systems. Agonal hemorrhages of the heart may be seen. Liver, serosal surfaces, tracheal mucosa, and ltmgs may be congested or hemorrhagic; so111e froth may be seen in respiratory passages. Cyanide also binds to iron (both Fe2+ and Fe3+ ) present in myoglobin (although this occurs more slowly than the binding to cytochrome c ox:idase and, hence, is not protective); this may result in a generalized dark coloration of skeletal muscle. Neither gross nor histologic lesions are consistently seen. Multiple foci of degeneration or necrosis may be seen in the CNS of dogs chronically exposed to sublethal an10unts of cyanide. These lesions have not been reported in livestock. Chronic cyan·ide poisoning: Goiter may be present. Cystitis ataxia toxidromes are characterized by opportunistic bacterial cystitis with or without pyelonephritis and diffuse nerve fiber degeneration in the lateral and ventral funiculi of the spinal cord and brain stem.Hindlimb urine scalding and alopecia may be present.

Diagnosis: Appropriate history, clinical signs, postmortem findings, and demonstra­ tion ofHCN in J"UI1len (stomach) contents or other diagnostic specinlens support a diagnosis of cyanide poisoning. Vete1inar­ ians should be aware of the possible need to use approp1;ate personal protective equipment, including a respirator, when collecting sainples that may liberate cyanide gas (eg, =en contents and J"UI1len gas cap). A rapid qualitative and presumptive diagnosis can be made by testing represen­ tative plant samples or stomach contents using the picric acid paper test or by collecting mmen gas cap sainples by trocarization and testing with a Draeger cyanide gas detection tube or other cyanide gas detection system. Negative results with such rapid presumptive tests do not completely exclude the possibility of cyanide poisoning. Suitable specinlens for more sophisticated testing include the suspected food source, mmen/stomach contents, sai11ples of the mmen gas cap, heparinized whole blood, liver, and muscle. Antemortem whole blood is preferred; other specimens should be collected as soon as possible after death, preferably within 4 hr. Specinlens should be sealed in an airtight container, refrigerated or frozen, and submitted to the laboratory without delay. When cold storage is unavailable, inlmer­ sion of specinlens in l %---3% mercuric chloride has been satisfacto1y. The rationale for using liver as a diagnostic sample is that cyanide binds to the Fe3+ form of cytochrome p450 and other heme-containing metabolic enzymes. The rationale for using skeletal muscle is that cyanide will bind to the iron moiety in myoglobin. Where available, measurement of the urinary metabolite of cyanide, thiocyanate, may reveal increased concentrations after cyanide poisoning. Hay, green chop, silage, or growing plants containing >220 ppm cyanide asHCN on a wet-weight (as is) basis are very dangerous as aninlal feed. Forage containing 750 ppmHCN is hazardous, 500----750 ppmHCN is doubtful, and 60 cm tall or have been proved by testing to

have acceptable cyruude levels, to reduce danger from prnssic acid poisoning. Animals should be fed before first ttuning out to pastw·e; hung1y ruumals may conswne forage too rapidly to detoxify HCN released in tl1e run1en. Animals should be turned out to new pasttu·e later in the day; potential for prnssic acid release is reported to be hlghest dw'Lng early morning hours. Free-choice salt and mineral with added sulfur may help protect against prnssic acid toxicity. Grazing should be monitored closely during periods of environmental stress, eg, drought or frost. Abundant regrowtl1 of sorghun1 can be dangerous; tl1ese shoots should be frozen ru1d wilted before grazing. Green chop forces livestock to eat both stems aJ1d leaves, thereby reducing problems caused by selective grazing. Cutting height can be raised to minin1ize inclusion of regrowth. Sorghum hay ru1d silage usually lose ;;,5()% of prussic acid content during cw'ing aJ1d ensiling processes. Free cyanide is released by enzyme activity and escapes as a gas. Although a rru·e occurrence, hazardous concentrations of prnssic acid may still remain in tile final product, especially if the forage had an extremely !ugh cyanide content before cutting. Hay has been dried at oven temperatures for up to 4 days with no significaJ1t loss of cyanide potential. These feeds should be aJ1alyzed before use whenever high prussic acid concentra­ tions ru·e suspected. Potentially toxic feed should be diluted or mixed with grain or forage t11at is low in prussic acid content to achieve safe concentrations in tile final product. At least in theory, the risk of chronic cyruude poisoning syndromes may be reduced by iodine supplementation in the case of hypotllyroiilism and by sulfur-contai1ung an1ino acids in the case of chronic neurologic toxidromes. Great care must be taken when providing supplemen­ tal elemental sulfur sources in run1inru1ts because of tl1e possible risk of polioen­ cephalomalacia (seep 1281).

FOOD HAZARDS AVOCADO Ingestion of avocado (Persea americana) has been associated witll myocardial necrosis in matnmals and birds and with sterile mastitis in lactating mammals. Cattle,

goats, horses, nuce, rabbits, guinea pigs, rats, sheep, budgerigms, caJ1aries, cockatiels, ostriches, chlckens, turkeys, and fish ru·e susceptible. Caged birds appear more sensitive to the effects of avocado, while chlckens and turkeys apperu· more

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resistant. Although an old case report exists of two dogs developing myocardial dan1age after avocado ingestion, dogs appear to be relatively resistanl compared with other species. Etiology: Ingestion of fruit, leaves, stems, and seeds of avocado has been associated with toxicosis in animals; leaves are the most toxic patt. The Guatemalan vai·ieties of avocado have been most conunonly associated with toxicosis. When purified, the toxic p1inciple in avocado, persin, causes mastitis in lactating mice at 60-100 mg/kg, and dosages > 100 mg/kg result in myocai·dial necrosis. Goats develop severe mastitis when ingesting 20 g of leaves/kg, whereas 30 g of leaves/kg results in cai·diac ir\ju1y. Acute cai·diac failure developed in sheep fed avocado leaves at 25 g/kg for 5 days; 5.5 g/kg of leaves fed for 21 days or 2.5 g/kg for 32 days caused chronic cardiac insufficiency. Budgerigars fed 1 g of avocado fruit developed agitation at1d feather pulling, while 8. 7 g of mashed avocado fruit resulted in death within 48 hr. Myocardial ir\jury, mastitis, and colic have been reported in horses ingesting avocado fruit at1d/or leaves. Pathogenesis: Avocado causes necrosis

and hemorrhage of mammary gland epithelium of lactating mammals ai1d myo­ cai·dial necrosis in birds and mammals. Persin isolated from avocado leaves has caused lesions similar to those rep01ted in natural cases. Clinical Findings: In lactating anin1als,

sterile mas ti tis occurs within 24 hr of exposure to avocado, accompanied by a 75%decrease in milk production. Affected matnmary glands are firm, swollen, and produce watery, curdled milk. Lactation may provide a degree of protection against myocardial ir\jury when avocado is ingested at lower doses. In nonlactating manunals, or at higher doses, myocai·dial insufficiency may develop within 24-48 hr of ingestion and is characterized by lethai·gy, respiratory distress, subcutaneous edema, cyanosis, cough, exercise intolerance, and death. Horses may develop edema of the head, tongue, and brisket. Birds develop lethargy, dyspnea, anorexia, subcutaneous edema of the neck and pectoral regions, and may die. Lesions: Mai1m1ary glat1ds are edematous and reddened, with wa.te1y, curdled milk. In animals with cardiac insufficiency, there is congestion of lungs at1d liver, often with dependent subcutaneous edema. There may be pulmonaiy edema and free fluid within

2965

the abdominal cavity, pericardial sac, and thoracic cavity. The heait may contain pale streaks. Histopa.thologic lesions in the ma.mmaiy gland include degeneration and necrosis of secret01y epitheliwn, with interstitial edema at1d hemoITha.ge. Myocai·dial lesions include degeneration at1d necrosis of myocai·dial fibers, which are most pronounced in ventricular walls and septtun; interstitial hemorrhage at1d/or edema may be present. In horses, symmet1ic ischemic myopa.thy of the head muscles and tongue, as well as ischemic myelomala­ cia. of the lwnbar spinal cord, have been described. Diagnosis: Diagnosis of avocado toxicosis relies on history of exposure and clinical signs. There ai·e no readily available specific tests that will confi.nn diagnosis. Differential diagnoses include other causes of mastitis (eg, infectious) and other myocai·dial disorders, including ionophore toxicosis, yew toxicosis, vitai11in E/seleniwn deficiency, gossypol, cai·diac glycoside toxicosis (eg, oleander), cai·diomyopathy, and infectious myocai·ditis. Treatment: NSAIDs and analgesics may

benefit animals with mastitis. Treatment for congestive heart failure (eg, diuretics, antiatThytlunic drugs) may be of benefit but may not be economically feasible in livestock.

BREAD DOUGH Raw bread dough ma.de with yeast poses mechanical and biochemical hazards when ingested, including gastric distention, metabolic acidosis, and CNS depression. Although any species is susceptible, dogs ai·e most conunonly involved because of their indiscriminate ea.ting habits. Pathogenesis: The watm, moist environment of the stoma.ch serves as an efficient incubator for the replication of yeast within the dough. The expanding dough mass ca.uses the stoma.ch to distend, resulting in vascular compromise to the gastric wall similar to that seen in gast1ic dila.tation/volvulus. With sufficient gastric distention, respiratory compromise occw'S. Yeast fem1entation products include ethanol, which is absorbed into the bloodstream, resulting in inebriation and metabolic acidosis. Clinical Findings: Early clinical signs may include unproductive attempts at emesis, abdominal distention, and

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depression. As ethanol intoxication develops, the anin1al becomes ataxic and diso1iented. Eventually, profound CNS depression, wealrness, recumbency, coma, hypothem1ia, or seizures may be seen. Death is usually due to the effects of the alcohol rather than from gastric distention; however, the potential for dough to trigger gastric dilatation/volvulus in susceptible dog breeds should not be overlooked. Diagnosis: A presumptive diagnosis can be based on history of exposure and clinical signs. Blood ethanol levels are consistently increased in cases of bread dough toxicosis. Differential diagnoses include gastric dilatation/volvulus, foreign body obstruc­ tion, ethylene glycol toxicosis, and ingestion of other CNS depressants (eg, benzodiaz­ epines). Treatment: With recent ingestions in asymptomatic aninlals, emesis may be attempted, although the glutinous nature of bread dough may make removal via emesis difficult. In anin1als in which emesis (whether induced or spontaneous) has been unsuccessful, gastric lavage may be attempted. Cold water introduced into the stomach may slow the rate of yeast fennentation and aid in dough removal. In rare cases, surgical removal of the dough mass may be required. Animals presenting with signs of alcohol toxicosis should be stabilized and any life-threatening condi­ tions corrected before attempts to remove the dough are made. Alcohol toxicosis is managed by correcting acid-base abnor­ malities, managing cardiac arrhythmias as needed, and maintaining nom1al body temperature. Providing fluid diuresis to enhance alcohol elin1ination may be helpful Anecdotally, yohimbine (0.1 mg/kg, IV) has been used to stimulate severely comatose dogs with alcohol toxicosis.

CHOCOLATE Chocolate toxicosis may result in poten­ tially life-threatening cardiac arrhythmias and CNS dysfunction. Chocolate poisoning occurs most commonly in dogs, although many species are susceptible. ContJ.ibuting factors include indiscriminate eating habits and readily available sources of chocolate. Deaths have also been reported in livestock fed cocoa by-products and in animals consuming mulch from cocoa-bean hulls. Etiology: Chocolate is derived from the roasted seeds of Theobroma cacao. The primary toxic principles in chocolate are the

methylxanthines theobromine (3, 7-climeth­ ylxanthine) and caffeine (1,3,7-tJ.imethyl­ xanthine). Although the concentration of theobromine in chocolate is 3-10 times that of caffeine, both constituents contribute to the clinical syndrome seen in chocolate toxicosis. The exact amount of methylxan­ thines in chocolate varies because of the natural variation of cocoa beans and variation within brands of chocolate products. However, in general, the total methylxanthine concentration of d1y cocoa powder is -800 mg/oz (28.5 mg/g), unsweetened (baker's) chocolate is -450 mg/oz (16 mg/g), semisweet chocolate and sweet dark chocolate is -150-160 mg/oz (5.4-5.7 mg/g), and milk chocolate is -64 mg/oz (2.3 mg/g). Chocolate bars labeled as a percentage of cocoa/cacao are based on unsweetened chocolate, ie, a 65% cacao bar would contain -293 mg (450 mg x 0.65) of methylxanthines per oz (10.4 mg/g). White chocolate is an insignificant source of methylxanthines. Cocoa bean hulls contain -255 mg/oz (9.1 mg/g) methyl.xanthines. The LD,,o of both caffeine and theobro­ mine is reportedly 100-200 mg/kg, but severe signs and deaths may occur at much lower dosages, and individual sensitivity to methyl.xanthines vruies. ln general, mild signs (vomiting, dirui:hea, polydipsia) may be seen in dogs ingesting 20 mg/kg, cardiotoxic effects may be seen at 40-50 mg/kg, and seizures may occur at dosages �60 mg/kg. One ounce of milk chocolate per pound of body weight is a potentially lethal dose in dogs. Pathogenesis: Theobromine and caffeine are readily absorbed from the GI tJ.·act and widely distributed throughout the body. They are metabolized in the liver and m1dergo enterohepatic recycling. Methyl­ xanthines ru·e excreted in the m·ine as both metabolites and unchanged parent compounds. The half-lives of theobromine and caffeine in dogs ru·e 17.5 hr and 4.5 hr, respectively. Theobromine ruid caffeine competitively inhibit cellular adenosine receptors, resulting in CNS stimulation, diuresis, ruid tachycru·dia. Methylxanthines al o increase intracellular calcimn levels by increasing cellular calcium entry ruid inhibiting intracellular sequestration of calcium by the sarcoplasmic reticulum of striated muscle. The net effect is increased strength and contractility of skeletal ruid cardiac muscle. Methylxanthines may also compete for benzodiazepine receptors within the CNS ruid inhibit phosphodiester­ ase, resulting in increased cyclic AMP

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levels. Methylxanthines may also increase circulating levels of epinephrine and norepinephrine. Clinical Findings: Clinical signs of chocolate toxicosis usually occur within 6--12 hr of ingestion. Initial signs may include polydipsia, vomiting, dian·hea, abdominal distention, and restlessness. Signs may progress to hyperactivity, polyuria, ataxia, rigidity, tremors, and seizures. Tachycardia, premature ventricu­ lar contractions, tachypnea, cyanosis, hypertension, hyperthermia, bradycardia, hypotension, or coma may occur. Hypoka­ lemia may occur late in the course of the toxicosis, contributing to cardiac dysfunc­ tion. Death is generally due to cardiac arrhythmias, hyperthem1ia, or respiratory failure. The high fat content of chocolate products may tiigger pancreatitis in susceptible animals. Lesions: No specific lesions may be found in animals succumbing to chocolate toxicosis. Hyperemia, hemorrhages, or congestion of multiple organs may occur as agonal changes. Severe arrhythmias may result in pulmonary edema or congestion. Chocolate or cocoa bean hulls may be present in the GI tract at necropsy. Diagnosis: Diagnosis is based on history of exposure, along with clinical signs. Amphetamine toxicosis, ma huang/guarana (ephedra/caffeine) toxicosis, pseudoephed­ rine toxicosis, cocaine toxicosis, and ingestion of antihistamines, antidepres­ sants, or other CNS stimulants should be considered in the differential diagnosis. Treatment: Stabilization of sympto­ matic animals is a priority in treating chocolate toxicosis. Methocarbamol (50-220 mg/kg, slow IV; no more than 330 mg/kg/day) or diazepam (0.5-2 mg/kg, slow IV) may be used for tremors and/or mild seizures; barbiturates may be required for severe seizures. Arrhythmias should be treated as needed: propranolol (0.02-0.06 mg/kg, slow IV) or metoprolol (0.2-0.4 mg/kg, slow IV) for tachyarrhyth­ mias, atropine (0.01-0.02 mg/kg) for bradyarrhythmias, and lidocaine (1-2 mg/kg, IV, followed by 25-80 mg/kg/min infusion) for refractory ventricular tach­ yarrhythmias. Fluid diuresis may assist in stabilizing cardiovascular function and hastening urinary excretion of methylxanthines. Once animals have stabilized, or in animals presenting before clinical signs have developed (eg, within 1 hr of inges-

2967

tion), decontamination should be per­ formed. Induction of emesis using apomorphine or hydrogen peroxide should be initiated; in aninlals that have been sedated because of seizure activity, gastric lavage may be considered. Activated charcoal (1-4 g/kg, PO) should be adminis­ tered; because of the enterohepatic recirculation of methylxanthines, repeated doses should be ad.ministered. every 12 hr in symptomatic animals for as long as signs are present (control vomiting with metoclopramide, 0.2-0.4 mg/kg, SC or IM, qid. as needed). Other treatment for symptomatic animals includes maintaining thermoregulation, correcting acid-base and electrolyte abnormalities, monitoring cardiac status via electrocardiography, and placing a urinary catheter (methylxanthines and their metabolites can be reabsorbed. across the bladder wall). Clinical signs may persist up to 72 hr in severe cases. MACADAMIA NUTS Ingestion of macadamia nuts by dogs has been associated. with a nonfatal syndrome characterized. by vomiting, ataxia, weak­ ness, hypertherrnia, and depression. Dogs are the only species in which signs have been repo1ted. Etiology: Macadamia nuts are cultivated. from Macadamia inlegrifolia in the conti­ nental USA and M tetraphylla in Hawaii and Australia. The mechanism of toxicity is not known. Dogs have shown signs after ingesting 2.4 g of nuts/kg body weight. Dogs experin1entally dosed with commercially prepared. macad.an1ia nuts at 20 g/kg developed clinical signs within 12 hr and were clinically nom1al without treatment within 48 hr. Clinical Findings: Within 12 hr of ingestion, dogs develop weakness, depression, vomiting, ataxia, tremors, and/or hyperther1nia. 'Iremors may be secondary to muscle weakness. Macadamia nuts may be identified. in vomitus or feces. Mild transient increases in sefUill triglycerides, lipases, and alkaline phosphatase were reported. in some dogs experin1entally dosed with macad.arnia nuts; these values quickly returned to baseline. Signs generally resolve within 12-48 hr. Diagnosis: Diagnosis is based on history of exposure and clinical signs. Differential diagnoses include ethylene glycol toxicosis, ingestion of hypotensive agents, and infectious diseases (eg, viral enteritis).

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Treatment: For asymptomatic dogs with recent ingestion of more than 1-2 g/kg, emesis should be induced; activated charcoal may be of benefit with large ingestions. Fortunately, most symptomatic dogs recover without any specific treatment. Severely affected dogs may be given supportive treatment such as fluids, analgesics, or antipyretics.

RAISINS AND GRAPES Ingestion of grapes or raisins has resulted in development of anuric renal failure in some dogs. Cases reported to date have been in dogs; anecdotal reports exist of renal failure in cats and ferrets after ingestion of grapes or raisins. It is not known why many dogs can ingest grapes or raisins with impunity while others develop renal failw·e after ingestion. The condition has not been reproduced experimentally, although raisin extracts have been shown to cause damage to canine kidney cells in vitro. Pathogenesis: The exact mechanism of toxicity is unknown, although the primary injwy appears to be in the proximal renal tubular epitheliwn. Affected dogs develop anuric renal failure within 72 hr of ingestion of grapes or raisins. A clear dose-response relationship has not been determined, but as few as 4-5 grapes were implicated in the death of an lS-lb (8.2-kg) dog. Clinical Finding:;: Most affected dogs develop vomiting and/or diarrhea within 6-12 hr of ingestion of grapes or raisins. Other signs include lethargy, anorexia, abdominal pain, weakness, dehydration, polydipsia, and tremors lShivering). Serwn creatinine levels tend to 1ise early and disproportionately compared with serwn urea nitrogen levels. Oliguric or anuric renal failure develops within 24-72 luof exposure; once anwic renal failure develops, most dogs die or are euthanized. Transient increases in serum glucose, liver enzymes, pancreatic enzymes, serum calcium, or serw11 phosphorus develop in some dogs. Diagnosis: Diagnosis is based on history of exposure, along with clinical signs. Other causes of renal failure (eg, ethylene glycol, cholecalciferol) should be considered in the differential diagnosis. Treatment: Prompt decontamination of significant ingestion of grapes or raisins is recommended. Emesis may be induced

with 3% hydrogen peroxide (2 rnUkg; no more than 45 mL), followed by activated charcoal. With large ingestions or in cases in which vomiting and/or diarrhea has spontaneously developed within 12 hr of ingestion of grapes or raisins, aggressive fluid diuresis for a minimum of 48 hr is recommended. Renal function and fluid balance should be monitored during fluid administration. For oliguric dogs, urine production may be stimulated by using dopamine (0.5-3 mcg/kg/min, IV) and/or furosemide (2 mg/kg, IV). Anuric dogs are unlikely to swvive unless peritoneal dialysis or hemodialysis is performed; even then, the prognosis is guarded.

XYLITOL Xylitol is a sugar alcohol used to sweeten sugar-free products such as gwns, candies, and baked goods. Ingestion of xylitol or xylitol-containing products by dogs has resulted in development of hypoglycemia and, less commonly, hepatic injwy and/or failure. Dogs are the only species in which xylitol toxicosis has been reported. Pathogenesis: In most manm1als, xylitol has no significant effect on insulin levels, but in dogs, xylitol stinlulates a rapid, dose-dependent insulin release that can result in profound hypoglycemia. Dosages of xylitol over -75-100 mg/kg (34--45 mg/lb) have been associated with hypoglycemia in dogs. Some dogs ingesting xylitol at dosages >500 mg/kg (227 mg/lb) may develop severe hepatic insufficiency or failure, the mechanism of which is unknown. Clinical Findings: Signs of hypoglycemia can develop within 30 min of ingestion or may be delayed up to 12-18 hr if the xylitol is in a substrate that slows its absorption (eg, some gum products). Clinical signs of hypoglycemia include vomiting, weakness, ataxia, depression, hypokalemia, seizures, and coma. Signs of liver injwy may not occur until �24-48 hr after ingestion of xylitol, although increases in liver enzymes are often detectable within 8-12 hr of ingestion. Clinical signs of liver injwy include depression, vomiting, icterus, and coagulopathy; other findings include hyperbilirubinemia, tlu·ombocytopenia, and hyperphosphatemia. Hyperphosphatemia is considered a poor prognostic indicator, because it was present in 4 of 5 dogs that died of liver failure after xylitol ingestion (phosphorus was not measured in tl1e fifth dog). Not all dogs that develop xylitol­ induced liver injwy develop hypoglycemia.

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Diagnosis: Diagnosis is based on clinical findings and history of exposure. Other causes of hypoglycemia include hypoglyce­ mic drugs, juvenile hypoglycemia, hunting dog hypoglycemia, insulinoma, and parenteral insulin overdose. Differential diagnoses for liver insufficiency include infectious (eg, leptospirosis, viral hepatitis), enviromnental (eg, heat stroke, trauma), and toxic (eg, iron, acetan1inophen, mushroom, blue-green algae, cycad palms) causes. Lesions of dogs succumbing to liver injury have included hepatic necrosis with loss of normal hepatic architecture. Treatment: Because of the potential for rapid onset of clinical signs of hypoglyce­ mia, emesis should ideally be attempted only under veterinary supervision and in asymptomatic aninlals. Activated charcoal does not appreciably bind xylitol and is not reconunended. If>75-100 mg/kg (227 mg/lb) of xylitol has been ingested, a.ninlals should be hospitalized and baseline blood glucose values measured; dogs ingesting>500 mg/kg (227 mg/lb) of xylitol should have baseline liver values measured. Blood glucose

2969

should be monitored every 1-2 hr for at least 12 hr, while liver values should be evaluated every 24 hr for at least 72 hr. If hypoglycemia develops, it should be managed with dextrose IV boluses and/or constant-rate infusions. Hypoglycemia may persist as long as 24 hr or more, so treatment should be continued until the dog can maintain a nonnal blood glucose level without supplemental dextrose. Dextrose should be administered to dogs ingesting xylitol at>500 mg/kg (227 mg/lb), even though normoglycemic, and hepatoprotec­ tants such as N -acetylcysteine, S-adenosyl­ methionine, and silymarin should be considered. Treatment of coagulopathy or other manifestations of liver insufficiency should be performed as needed. The prognosis for uncomplicated hypoglycemia is good, if prompt treatment is obtained. Mild increases in liver enzyme usually resolve within a few days. Severe increases in liver enzymes and/or signs of liver insufficiency indicate a more guarded prognosis; in one study, 62.5% of dogs with signs of liver injtu)' died or were euthanized despite aggressive veterinat)' intervention.

HERBICIDE POISONING Herbicides are used routinely to control noxious plants. Most of these chemicals, par-ticularly the more recently developed synthetic organic herbicides, are quite selective for specific plants and have low toxicity for man1mals; other, less-selective compounds (eg, sodium arsenite, arsenic trioxide, sodium chlorate, anm10nium sulfan1ate, borax, and many others) were fonnerly used on a large scale and are more toxic to animals. Vegetation treated with herbicides at proper rates normally will not be hazardous to animals, including people. Particularly after the herbicides have dried on the vegetation, only small amounts can be dislodged. When herbicide applications have been excessive, dan1age to lawns, crops, or other foliage is often evident. The residue potential for most of these agents is low. However, runoff from agricultmal applications and entrance into drinking water carmot be excluded. The possibility of residues should be explored if significar1t exposure of food-producing

animals occurs. The tinle recommended before treated vegetation is grazed or used as animal feed is available for a nwnber of products. Most health problems in animals result from exposme to excessive quantities of herbicides because of improper or careless use or disposal of containers. When herbicides are used properly, poisoning problems in veterinary practice are rare. With few exceptions, it is only when animals gain direct access to the product that acute poisoning occurs. Acute signs usually will not lead to a diagnosis, although acute GI signs are frequent. All common differential diagnoses should be excluded in animals showing signs of a sudden onset of disease or sudden death. The case history is critical. Sickness after feeding, spraying of pastures or crops adjacent to pastures, a change in housing, or direct exposme may lead to a tentative diagnosis of herbicide poisoning. Generally, the nature of exposure is har·d to identify because of storage of herbicides in mis- or unlabeled containers. Unidentified

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spillage of liquid from containers or powder from tom or damaged bags near a feed source,or visual confusion with a dietary ingredient or supplement,may cause the exposure. Once a putative chemical source has been identified,an anin1al poison control center should be contacted for information on treatments,laboratory tests, and likely outcome. Chronic disease caused by herbicides is even more difficult to diagnose.It may include a history of herbicide use in proximity to the animals or animal feed or water source, or a gradual change in the animals' perfonnance or behavior over a period of weeks,months,or even years. Occasionally,it involves manufacture or storage of herbicides nearby.San1ples of possible sources (ie,contanunated feed and water) for residue analysis,as well as tissues from exposed animals taken at necropsy,are essential. Months or even years may be required to successfully identify a problem of chronic exposure. To recognize whether an animal has been exposed to herbicides or accidental poisoning,standardized analytical proce­ dures for diagnostic investigation of biologic mate1ials have become established and are

•ttN•i•

subsumed under the term "biomonitoring." Accurate biomonitoring is an in1portant tool to evaluate htunan or animal exposure to such herbicides by measuring the levels of these chemicals,their metabolites,or altered biologic structures or functions in biologic materials such as urine,blood or blood components,exhaled air,hair or nails,and tissues. The use of urine is advantageous because of ready availability. As such,urine has been used for biomonitoring of several herbicides,including 2,4-D, 2,4,5-T,MCPA (2-methyl- 4-chlorophenoxyacetic acid) , atrazine,diuron,alachlor,metolachlor, paraquat, diquat,in1azapyr,imazapic, in1azethapyr,imazan1ox,in1azaquin,and irnazamethabenz-methyl herbicides,with the objective to assess exposure and health risk to exposed anin1als. If pois011ing is suspected,the first step in management is to halt further exposure. Anin1als should be separated from any possible source before attempting to stabilize and support them. If there are life-threatening signs,efforts to stabilize animals by general mitigation methods should be started. Specific antidotal treatments,when available,may help to confirm the diagnosis.As time pennits,a

HERBICIDE POISONING

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Acetochlor

2,148--2,950mg/kg

Dog , lyr 12 mg/kg/day

Rabbit 4,1 66mg/kg

Acifluorfen

1,300mg/kg (F)

Rat, 2yr 18 0ppm

Rabbit >2,000mg/kg

Acrolein

2 9mg/kg

Rat, 13wk 150mg/Lin drinking water

Rabbit 231mg/kg

Alachlor

930-1,200mg/kg

Dog, 90days 200 active ingredients used as herbicides; however, some of them are believed to be obsolete or no longer in use. Of these, several have been evaluated for their toxic potential and are discussed below. More specific information is available on the label and from the manufacturer, cooperative extension service, or poison control center. Selected information on herbicides, such as the acute oral toxic dose (LD50) in rats, the amount an animal can be exposed to without being affected (no adverse effect level), the likelihood of problems caused by dem1al contact in rabbits (dermal LD50, eye and skin irritation), deleterious effects on avian species, and toxicity to fish in water, is included for some commonly used

•4H•!•

2971

herbicides (see TABLE 1). Comparative toxic doses (TD) and lethal doses (LD) of selected herbicides in domesticated species, such as monkeys, cattle, sheep, pigs, cats, dogs, and chickens, is also summarized (see TABLE 2). The infom1ation is only a guideline, because the toxicity of herbicides may be altered by the presence of other ingredients (eg, impurities, surfactan'ts, stabilizers, emulsifiers) present in the compound. With a few exceptions, most of the newly developed chemicals have a low order of toxicity to mammals. However, some herbicides, such as atrazine, buturon, butiphos, chloridazon, chlorpropham, cynazine, 2,4-D and 2,4,5-T alone or in combination, dichlorprop, dinoseb, dinoterb, linuron, mecoprop, monolinuron, MCPA ( 2-methyl-4-chloro­ phenoxyacetic acid), prometryn, propa­ chlor, nitrofen, silvex, TCDD (a common contaminant during manufacturing process of some herbicides such as 2,4-D and 2,4,5-T), and tridiphane, are known to have adverse effects on development of embryos and reproduction abnonnalities in experin1ental anin1als. A list of such chemicals is sun1rnarized in TABLE 3.

HERBICIDE POISONING (continued)

Toxicity to Fish in Water

Skin and Eye Irritation

LC50 5 day Bobwhite quail and Mallard duck 5,620 mg/kg

LC50 96hr Rainbow trout 0.45 mg/L

Skin-mild Eye-mild

LC50 8day Mallard duck > 10,000 mg/kg

LC50 96hr Rainbow trout 31 mg/L

Skin-moderate Eye-severe

LD50 (oral) Bobwhite quail 19 mg/kg Mallard duck 9. 1 mg/kg

LC50 24 hr Bluegill and Rainbow trout 0.0 24 mg/L

Skin-severe Eye-severe

Avian Toxicity/NOAECb

Skin-mild Skin-irritation Guinea pig-dem1al sensitization Eye-mild

LD50 (oral) Birds >2, 250 mg/kg LC50 5 day Birds >5,620 ppm LC50 8day Bobwhite quail and Mallard duck >10,000 ppm

LC50 96hr Bluegill and Rainbow trout 3.9-lOppm

Skin-slight Eye-mild Ccontinued)

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lrtNIII

HERBICIDE POISONING (cont'inued)

Compound

Acute Oral LD 50-Rat

NOAELa (oral)

Atrazine

2,000-3,080 mg/kg

Dog, l yr 150 ppm Rat, 2 yr IO ppm

Rabbit 7,500 mglkg

Amitrole

4,080 mglkg (M)

Rat, 13wk 2 mg/kg/day

Rat>5,000 mglkg

Ammonium sulfarnate

3,900 mglkg

Rat, 105days 10,000 mglkg/day

Bensulfron methyl

>5,000 mglkg

Rat,dog, 2 yr 750 ppm indiet

Rat>2,000 mglkg

Bensulidec

271-770 mglkg

Dog,90days 12.5 mglkg/day

Rabbit 3,950 mg/kg

Bentazon

l,lOO mglkg ( cat 500 mglkg)

Rat, 90days 3.5 mglkg/day Dog, 90days 7.5 mglkg/day

Rat>2,500 mglkg

Bispyribac sodium

Acute Dermal LD50

Rat, 2 yr 1.1 mglkg/day (M) 1.4 mg/kg/day (F)

Borax

2,000-6,000 mglkg

Bromacil

5,200 mglkg

Rat, clog, 2 yr 250 mglkg/day

Rabbit>5,000 mglkg

Bromoxynil

190-779 mglkg

Rat, 90days 50 mglkg/day

Rabbit>2,000 mglkg

Butachlor"

2,000-3,300 mglkg

Rabbits maternal and fetal effects, 50 mglkg/day

Rat>13.3 glkg

Butylatec

>5,431 mglkg (M) 4,659 mglkg (F)

Rat, 2 yr 20 mglkg/day Dog, 1 yr 25 mglkg/day

Rabbit>4,640 mglkg

Rat, 2 yr 9 mg/kg/day (M) 3 mglkg/clay (F)

Rat>5,000 mglkg

Carfentrazone ethyl >5,000 mglkg

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2973

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb LC60 8day Mallard duck >10,000ppm in diet

Toxicity to Fish in Water LC6096hr Rainbow trout 8.8 mg/L

Skin and Eye Irritation Skin-slight

Skin-mild Eye-mild

LD60 Mallard duck 2,000 mg/kg LC60 48hr Crucian carp 1,000- 2,000 mg/L

Skin-none

LC6096hr Bluegill and Rainbow trout >150ppm

Skin-none Eye-serious

LD50 Bobwhite quail 3wk 50 mg/kg, poor hatchability

LC6096hr Bluegill 1.4mg/L Rainbow trout 0. 7 mg/L

Eye-none

LD60 Japanese quail 720mg/kg Mallard duck 2,000mg/kg

LC6096hr Bluegill 616mg/L Rainbow trout 1,060mg/L

Slight iITitant

LC60 Bobwhite quail and Mallard duck >5,620ppm

LC5096hr Bluegill and Rainbow trout >100ppm

Skin-minor Eye-minor

LC60 8day Bobwhite quail and Mallard duck >10,000mg/kg

LC60 48hr Bluegill 71mg/L Rainbow trout 56mg/L

Skin-irritating Eye-irritating

Acute LD60 Bobwhite quail 100mg/kg Mallard duck 200mg/kg

LC6096hr Rainbow trout 0.05mg/L

Skin-none Eye-none

LD,;o Bobwhite quail 3,000mg/kg

Skin-none Eye-moderate Guinea pig-dermal sensitization LC50 8day Bobwhite quail 40,000 mg/kg Mallard duck 46,400ppm in diet

LC6096hr Bluegill 6.9mg/L Rainbow trout 4.2mg/L

Skin-moderate Eye-mild

LC60 Bobwhite quail and Mallard duck >5,620ppm

LC6096hr Bluegill 2 ppm Rainbow trout 16ppm

Skin-none to slight Eye-minimum

(continued)

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lr�=IIII

HERBICIDE POISONING (continued) NOAELa (oral)

Compound

Acute Oral LD50-Rat

Chloramben

5,620mg/kg

Chlorotoluron

>10,000mg/kg

Chlorpropham

4,100-7,000 mg/kg

Rat ,dog, 2yr 100-350mg/kg/day

Chlorsulfuron

5,545mg/kg (M) 6,293mg/kg (F)

Rat,2yr 100ppm in diet

Rabbit >3,400mg/kg

Chlorthal dimethyl

3,000-12,000mg/kg

Rat , 2yr 2,000mg/kg

Clethodim

1,630mg/kg (M) 1,360mg/kg (F)

Dog, lyr >l mg/kg/day

Rabbit >5,000mg/kg

Clodinafoppropargyl

1,392mg/kg (M) 2,271mg/kg (F)

Rabbit >2,000mg/kg Dog, 90days 0.346mg/kg/day (M) 1.89mg/kg/day (F)

Clomazone

2,077mg/kg (M) 1,369mg/kg (F)

Dog, 1yr 2,000mg/kg

Clopyralid

>4,300mg/kg

Rat , 2yr 50mg/kg/day

Rabbit >2,000mg/kg

Cloransulam-methyl

>5,000mg/kg

Dog, lyr 10mg/kg/day

Rabbit >2,000mg/kg

Copper chelate

498mgfkg

Rabbit >2,000mg/kg

Copper sulfate

470mgfkg

Rabbit >8,000mg/kg

Cyanazine d

182-334mg/kg

Dog, 2yr 2,000mg/kg

Cycloate

2,000--3,190mg/kg

Dog, 240mg/kg/day

Rabbit >4,640mg/kg

Acute Dermal LD50 Rabbit >3,160mg/kg

VetBooks.ir

HERBICIDE POISONING

•tM•f•

2975

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb LC50 8day Mallard duck> 4,640 mg/kg

Toxicity to Fish in Water Not toxic to fish

Skin and Eye Irritation Skin-mild Eye-mild

LC50 96hr Rainbow trout> 100 mg/L LD50 8day Mallard duck>2,000 mg/kg

LC50 48 hr Bluegill 6.3-6.8mg/L Rainbow trout3-6mg/L

Skin-moderate Eye-moderate

LC50 8day Mallard duck>5,000 mg/kg

LC50 96hr Rainbow trout>250 mg/L

Skin-none Eye-mild

LD50 young Bobwhite quail 5,500 mg/kg

Not toxic to fish

Skin-none Eye-mild

LC50 8day Bobwhite quail 4,270 ppm Mallard duck 3,978ppm in diet

LC50 Bluegill 13 ppm Rainbow trout 18ppm

Skin-none Eye-moderate

LC50 Birds>5,000 ppm

LC50 Freshwater fish 0.3 ppm

Skin-none Eye-slight to severe

LD50 8day Bobwhite quail and Mallard duck 5,620 ppm in diet

LC50 96hr Bluegill 3 4 mg/L Rainbow trout 19 mg/L

Skin-mild Eye-moderate

LCso Bobwhite quail and Mallard duck> 4,640 ppm in diet

LC50 96hr Bluegill 125 mg/L Rainbow trout 103.5 mg/L

Skin-mild Eye-severe

LC50 5 day Bobwhite quail and Mallard duck>5,620 ppm

LC50 96hr Bluegill>15 4 ppm Rainbow trout>86ppm

Skin-none Eye-slight

LC50 8day Mallard duck>1,000 ppm in diet

LC50 96hr Bluegill 1.2- 7.5 mg/L Rainbow trout 2,000 mg/kg

LC50 96hr Bluegill 23 mg/L Rainbow trout 9 mg/L

Skin-none Eye-mild

LC50 7 day Bobwhite quail>56,000 mg/kg

LC50 96hr Rainbow trout 5.6mg/L

Skin-none Eye-none ( ,..,..-1,; ...... ,,,,..,,.1\

VetBooks.ir

2976

HERBICIDE POISONING

l�·HIII

HERBICIDE POISONING (continued)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Cyhalofopbutyl

>5,000mg/kg

Dog 46.7mg/kg/day (M) 45.9mg/kg/day (F)

Rat >5,000mg/kg

Dalapon

6,600-9,330mg/kg

Di -allate ci

340-460mg/kg

2,4-D

370-700mg/kg

Rat, 2yr 50mg/kg/day

Rabbit >2,000mg/kg

2,4-D dimethylamin e

949-4,650mg/kg

Dog, lyr 1 mg/kg/day

Rabbit >2,000mg/kg

2,4-D isooctyl ester

500-700mg/kg

Dog, lyr 1mg/kg/day

Rabbit >2,000mg/kg

Dazomet

551-646mg/kg (M) 335-562mg/kg (F)

Rat, 2yr 1.6mg/kg/day

Rabbit >2,000 mg/kg

Dicamba

l,707mg/kg

Rat, 2y r 125mg/kg/day Dog, 2yr 50mg/kgday

Rabbit >2,000mg/kg

Dichlob enil

>3,160mg/kg

Rat, 2y r >20ppmin di et Pig, 6mo >50ppmin di et

Rabbit >1,350mg/kg

Dichlorprop or 2,4-DP

700mg/kg (M) 500mg/kg (F)

Rat, 4mg/kg

Diclosulam

>5,000mg/kg

Rat, 0.05mg/kg

Rabbit >2,000mg/kg

Difenzoquat (methylsulfate)

617mg/kg (M) 373mg/kg (F)

Dog, lyr 20mg/kg/day

Rabbit >2,000mg/kg

Diflu fenzopyr

1,600to >5,000mg/kg

Dog, lyr 28 mg/kg/day (M) 26 mg/kg/day (F)

Rabbit >5,000mg/kg

Acute Dermal LD50

. Mous e 1,400mg/kg

VetBooks.ir

HERBICIDE POISONING

•i·N•f•

2977

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb

Toxicity to Fish in Water LC 50 96hr Bluegill >99.2mg!L Rainbow trout >l.65mg!L

Skin and Eye Irritation Skin-none Eye-minimal

LC 50 96hr Fish 210- 340mg!L LC 50 96hr Fish 8.2mg!L LC 50 8day Mallard duck >4,640mg/kg

LC 50 96hr Bluegill >300mg!L Rainbow trout 800mg!L

Skin-none Eye-moderate

LC 50 8day Mallard duck >5,600ppm

LC 50 96hr Bluegill 524mg!L Rainbow trout 250mg!L

Skin-minimal Eye-severe

As for 2,4-D (above)

Skin-none Eye-severe

LD50 Bobwhite quail 415ppm in diet

LC so Rainbow trout 2.4- 16.2mg!L

Skin-mild Eye-severe

LC 50 8day Bobwhite quail and Mallard duck >4,600mg/kg

LC 50 96hr Bluegill and Rainbow trout >1,000mg!L

Skin-moderate Eye-extreme

LC 50 8day Mallard duck >5,200ppm in diet

LC 50 96hr Bluegill and Rainbow trout 7 mg!L

Skin-none Eye-mild to moderate

LCw Upland birds ,waterfowl >10,000ppm in diet

LC 50 Bluegill 1.1mg!L Rainbow trout 100-200mg!L

Skin-none Eye-none

LC 50 Most sensitive aquatic species 10-100mg!L

Skin-moderate Eye-moderate

LCw8day Bobwhite quail and Mallard duck 4,640ppm in diet

LC 50 96hr Bluegill 696mg!L Rainbow trout 711mg!L

Skin-mild Eye-mild

LC 50 Mallard duck >5,620ppm

LC so Bluegill 135ppm Rainbow trout 106ppm

Skin-very slight Eye-mild to slight (conl'inued)

2978

HERBICIDE POISONING

VetBooks.ir

lr�:1111

HERBICIDE POISONING (contimied)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Dirnethenamid

429-1,293mg/kg

Dog, lyr 50-250ppm in diet

Rabbit >2,000mg/kg

Dinoterb

25mg/kg

Diquat

231-440mg/kg

Rat reproduction , l mg/kg/day

Rabbit >400mg/kg

Dithiopyr

>5,000mg/kg

Dog, lyr 5,000mg/kg

Diuron

3,400mg/kg

Dog, 2yr 25mg/kg

Rat >2,000mg/kg

DNOC

25-85mg/kg

Rat , 2yr 0.59mg/kg/day

Rat 600-2,000mg/kg Rabbit 1,000mg/kg

EPTC (s-ethyldipropylthiocarbamate)

1,630mg/kg

Dog, 90days 20mg/kg

Rabbit 2,7505,000mg/kg

Ethalfluralin

Rat >5,000mg/kg (dog,cat >200mg/kg)

Rat ,mouse , 90days 68mg/kg

Rabbit >2,000mg/kg

Ethephon

1,600-4,229mg/kg

Rat , 2yr 375 mg/kg/day Mouse , 78 wk 4.5mg/kg/day

Rabbit >5,000mg/kg

Fenoxaprop d

2,357mg/kg (M) 2,500mg/kg (F)

Dog, 2yr 0.375mg/kg/day

Rabbit >1,000mg/kg

Fenoxaprop-ethyl"

4,430mg/kg

Dog, 2yr 0.9mg/kg/day

Rat >5,000mg/kg

Flamprop-methyl

1,210mg/kg

Dog, 2yr 10mg/kg/day

Rat >294mg/kg

Acute Dermal LD50

HERBICIDE POISONING

VetBooks.ir

•M=i!f•

2979

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb

Toxicity to Fish in Water

LCso Bobwhite quail and Mallard duck >5,620 ppm in diet

LC 50 Bluegill 6.4 mg/L Rainbow trout 2.6 mg/L

LC50 Partridges 3-5 ppm in diet

Toxic to fish

LC50 Paitridges 270-300 ppm in diet

LC50 Fish 80-210 mg/L

Skin-none Eye-mild

LC50 Bobwhite quail and Ma!lai·d duck >5,260 ppm in diet

LC50 Bluegill 0.7 mg/L Rainbow trout 0.5 mg/L

Skin-slight Eye-moderate

LC50 Bobwhite quail 1,730 ppm Mallard duck >5,000 ppm in diet

LC50 Bluegill 7.4 mg/L Rainbow trout 4.3 mg/L

Skin-none Eye-mild

LD50 Japanese quail 10-25 mg/kg

LC50 Fish 0.2-13 mg/L

Skin-erythema and edema Eyes-corrosive Guinea pig--dennal sensitization

LC50 7 day Bobwhite quail 20,000 ppm in diet

LC50 Bluegill 27 mg/L Rainbow trout 19 mg/L

Skin-mild Eye-severe

LC50 8day Bobwhite quail and Mallard duck >5,000 ppm

LC50 Bluegill 0.03-0.1 mg/L Rainbow trout 0.0370.136 mg/L

Skin-slight to moderate Eye-slight

LC508day Mallard duck >10,000 ppm

LC50 96 hr Bluegill 222-300 mg/L Rainbow trout 254-350 mg/L

Skin-corrosive Eye-corrosive

LD50 Japanese quail >5,000 mg/kg

LC50 Bluegill 3.3 mg/L Rainbow trout 3.4 mg/L

Skin-slight Eye-serious nonreversible corneal opacity

LC50 8day Bobwhite quail ai1d Mallard duck 5,620 ppm

LC50 Bluegill 0.31 mg/L Rainbow trout 0.46 mg/L

Skin-slight Eye-moderate

LD50 Bobwhite quail 4,640 mg/kg Mallard duck >1,000 mg/kg

LC50 96 hr Rainbow trout 4.7 mg/L

Skin-none Eye-none

Skin and Eye Irritation Skin-mild Eye-moderate

(continued)

VetBooks.ir

2980

HERBICIDE POISONING

lrl:1111

HERBICIDE POISONING (conl'inued)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Florasulam

>6,000 mg/kg

Dog, lyr 5 mg/kg/day

Rabbit>2,000 mg/kg

Fluazifop-p-butyl

3,6804,096 mg/kg (M) 2,4512,721 mg/kg (F)"

Rat, 90days > 10 mg/kg/day

Rabbit>2,400 mg/kg

Flucarbazonesodium

>5,000 mg/kg

Dog, l yr 35.9 mg/kg/day

Rat>5,000 mg/kg

Flufenacet

1,617 mg/kg (M) 589 mg/kg (F)

Dog, 1 yr 1.29 mg/kg/day

Rat>2,000 mg/kg

Flumetsulam

>5,000 mg/kg

Flumiclorac

3,200 to >5,000 mg/kg

Dog, 1 yr 100 mg/kg/day

Rat>2,000 mg/kg

Fluometuron

>8,000 mg/kg

Rat, 103wk 125 mg/kg/day

Rat>2 g/kg Rabbit 10 g/kg

Fluroxypyr

.>5,000 mg/kg

Dog, 1 yr 150 mg/kg/day

Rat>2,000 mg/kg

Fluthiacet

>5,000 mg/kg

Dog, lyr 57.6 mg/kg/day (M) 30.3 mg/kg/day (F)

Rat>2,000 mg/kg

Foramsulfuron

>3,881 mg/kg

Rat, 2 yr 849 mg/kg/day (M) 1,135 mg/kg/day (F)

Rat>5,000 mg/kg

Fosamine ammonium

24,000 mg/kg

Rat, 90days 1,000 mg/kg

Rabbit> 1,683 mg/kg

Glufosinate (ammonium salt)

1,510-2,030 mg/kg

Dog, lyr 5 mg/kg/day

Rat>1,390 mg/kg

Glyphosate

4,230-5,600 mg/kg

Dog, 2 yr >500 mg/kg/day

Rabbit>5,000 mg/kg

Acute Dermal LD50

Rat>2,000 mg/kg

VetBooks.ir

HERBICIDE POISONING

•M:i!j• HERBICIDE POISONING

2981

(continued)

Avian Toxicity/NOAECb

Toxicity to Fish in Water

Skin and Eye Irritation

LD50 14day Japanese quail 175mg/kg

LC50 96hr Rainbow trout>100mg/L

Skin-none Eye-none

LD50 5day Bobwhite quail>4,659ppm Mallard duck>4,321ppm

LC50 96hr Bluegill 0.5mg/L Rainbow trout 1.4mg/L

Skin-slight Eye-mild

NOAEC (reproduction) NOAEL (chronic) Mallard duck 233mg/kg/day Rainbow trout 2.75mg/L

Skin-none Eye-minimal

LC50 5day Bobwhite quail>5,317ppm Mallard duck>4,970ppm

LC50 Bluegill 2.26- 2.4ppm Rainbow trout 3.49- 5.84ppm

Skin-none Eye-minimal

LC50 Mallard duck>5,620ppm

LC,,o Bluegill>300ppm Rainbow trout>293ppm

Skin-none Eye-slight

LC50 Mallard duck>5,620ppm

LC50 96hr Bluegill 17.4mg/L Rainbow trout 1.1mg/L

Skin-severe Eye-moderate

LC50 96hr Bluegill 96mg/L Rainbow trout 47mg/L Crucian carp 17mg/L LC50 5day Mallard duck>5,000ppm

LC50 96hr Bluegill 14.3mg/L Rainbow trout 13.4-100mg/L

Skin-none Eye-slight

LC50 5day Bobwhite quail and Mallard duck>5,620ppm

LC50 96hr Bluegi\1140mcg/L Rainbow trout 43rncg/L

Skin-none Eye-minimal

LC50 Bobwhite quail and Mallard duck>5,000ppm

Skin-moderate Eye-mild

1050 Mallard duck >10,000ppm in diet

LC50 Bluegill 670mg/L Rainbow trout 1,000rng/L

Skin-none Eye-moderate to severe

LC50 5day Japanese quail >5,000mg/kg

LC50 96hr Bluegill 56-75mg/L Rainbow trout>26.7mg/L

Skin-slight Eye-moderate to severe

LC50 8day Bobwhite quail and Mallard duck 4,500ppm in diet

LC50 96hr Bluegill 120mg/L Rainbow trout 86mg/L

Skin-none Eye-slight to moderate (continued)

VetBooks.ir

2982

HERBICIDE POISONING

lfd:1111

HERBICIDE POISONING (contim,ed)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Hal osulfuron

l,287mg/kg

Dog, 13wk 10mg/kg/day

Rat >5,000mg/kg

Hexazin one

l,690mg/kg

Rat, 2yr 250mg/kgin diet

Rabbit >5,278mg/kg

lmazamethabenzmethyl

>5,000mg/kg

Dog, 1yr l,OOOppm

Rabbit >2,000mg/kg

lmazaquin

>5,000mg/kg

Dog, 1yr l,OOOppm

Rabbit >2,000mg/kg

Imazamox

>5,000mg/kg

Dog, 1yr 40,000ppm

Rat >4,000mg/kg

Imazapic

>5,000mg/kg

Dog, 1yr 5,000ppm

Rabbit >2,000mg/kg

Imazapyr

>5,000mg/kg

Dog, 1yrfeeding l,OOOppm Rat 300mg/kg/day (teratol ogy)

Rabbit >2,000mg/kg

lmazethapyr

>5,000mg/kg

Dog, lyr 25mg/kg/day

Rabbit >2,000mg/kg

Is oproturon

1,800-2,400mg/kg

Dog, 90days Rat, 2yr 3mg/kg/day

Rat >3.2g/kg

Is oxaflutole

>5,000mg/kg

Dog, lyr l,200ppm

Rat >2,000mg/kg

Linuron

1,200-4,000mg/kg

Dog, 2yr 6.25mg/kg/day ( observed anemia)

Rabbit >5,000mg/kg

Maleic hydrazide

>5,000mg/kg (acid) >6,950 mg/kg (Na + salt) >3,900mg/kg (K+ salt)

Dog, 1yr 25mg/kg

Rabbit >20,000mg/kg

MCPA

700-1,160mg/kg

Rat, 7m o 100mg/kg/day (l owers wt gain)

Rabbit 3,4004,800mg/kg

Acute Dermal LD50

VetBooks.ir

HERBICIDE POISONING

2983

•M=i!j• HERBICIDE POISONING (continued) Avian Toxicity/NOAECb

Toxicity to Fish in Water

LC50 5 day Bobwhite quail and Mallard duck>5,620 ppm

LC5() 96hr Bluegill> 118 mg/L Rainbow trout>131 mg/L

LC50 5-8day Bobwhite quail and Mallard duck>10,000 ppm in diet

LC5() 96hr Bluegill 370-420 mg/L Rainbow trout 320-420 mg/L

Skin and Eye Irritation Skin-slight Eye-slight 'Skin-none Eye-severe but reversible

Skin-none Eye-slight Skin-slight LC50 Mallard duck>5,672 ppm

LC5() 96hr Bluegill>119 ppm Rainbow trout>122 ppm

Skin-none Eye-none Skin-slight Eye-moderate

LC50 8day LC5() 96hr Bobwhite quail and Mallard Bluegill and Rainbow trout duck>5,000 ppm in diet >100 mg/L

Skin-mild Eye-more severe

LD5() Bobwhite quail and Mallard duck>2,150 ppm in diet

LC5() 96hr Bluegill 420 mg/L Rainbow trout 340 mg/L

Skin-mild Eye-irritation reversible

LC50 96hr Crucian carp 193 mg/L Rainbow trout 240 mg/L

Skin-none Eye-none

LC5() 5 day Bobwhite quail and Mallard duck>4,255 ppm

LC5() 96hr Bluegill>4.5 mg/L Rainbow trout>1. 7 mg/L

Skin-minimal Eye-minimal

LC5() 5-8day Japanese quail>5,000 ppm Mallard duck 3,083 ppm in diet

LC00 96hr Bluegill and Rainbow trout 16mg/L

Skin-mild Eye-moderate

LD50 Bobwhite quail and Mallard duck>10,000 mg/kg

LC5() 96hr Bluegill 1,608mg/L Rainbow trout 1,435 mg/L

Skin-slight Eye-severe

LD50 Bobwhite quail 377 mg/kg

LC50 96hr Bluegill and Rainbow trout 90 mg/L

Skin-slight Eye-moderate

(continued)

VetBooks.ir

2984

HERBICIDE POISONING

•pj:j•j•

HERBICIDE POISONING (continued)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

MCPB

4,700mg/kg

Rat , 6mo 1.6mg/kg/day

Rat >2,000mg/kg

Mecoprop

930-1,2 10 mg/kg

Rat , 90days 3.8mg/kg/day Dog , 90days 15 mg/kg/day

Rabbit 900mg/kg

Mesotrione

>5,050 mg/kg

Metam(sodium and isothiocyanate)

1,800mg/kg(M) 1,700mg/kg(F) 97mg/kg (isothiocyanate)

Rat, 65days (inhalation, in inspired air) 6hr/day for 5days/ wk at 0.045mg/L

Methyl bromide

Acute LC50 (inhalation) 4.5mg/Lair

Safe threshold for people 0.065rng/L air

Acute Dermal LD50

Rat >5,050mg/kg

Rabbit 10,000 mg/kg

Methyl isothiocyanate

82 mg/kg(M)

Dog, 2 yr 10mg/Lin drinking water

Rabbit 2 02 mg/kg(F) 145mg/kg(M)

Metobromuron

2,450-2,500 mg/kg

Rat, 2 yr 2 50mg/kg/day Dog, 100mg/kg/day

Rabbit >2,000 mg/kg

Metolachlor"

800--2,780mg/kg

Rat, 90days 1,000mg/kg Dog , 90days 500mg/kg

Rabbit >5,000mg/kg Rat >10g/kg

Metosulam

>5,000mg/kg

Dog, lyr 10mg/kg/day

Rabbit >2,000 mg/kg

Metribuzin

1,090--2,300 mg/kg

Rat, 2 yr 5mg/kg Dog, 2 yr 2 .5mg/kg

Rat ,rabbit >2 0,000mg/kg

Napropamide

>5,000mg/kg

Dog , 13wk 4,640mg/kg

HERBICIDE POISONING

VetBooks.ir

IHNIII

2985

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb

Toxicity to Fish in Water

LC50 8day Bobwhite quail and Mallard duck>5,000ppm in diet

LC50 96 hr Bluegill 14mg/L Rainbow trout 4.3mg/L

Skin -moderate Eye-moderate

LC50 Bobwhite quail and Mallard duck 5,000- 5,500ppm in diet

LC50 96hr Bluegill>100 mg/L Rainbow trout 124mg/L

Skin-slight Eye-intense

1050 Bobwhite quail >2,000mg/kg Mallard duck >5,200mg/kg

LC50 96hr Bluegill and Rainbow trout>120 mg/L

Skin-slight Eye-moderate

LC50 Bobwhite quail>10,000 Mallard duck>5,000ppm in diet

LC50 96hr Bluegill 0.047mg/L Rainbow trout 0.029mg/L

Skin-corrosive Eye-corrosive

Acute toxicity Bluegill 11mg/L

Skin-severe Eye-severe

LC50 5day Mallard duck 10,936mg/kg

LC50 96hr Bluegill 0.13mg/L Rainbow trout 0.37mg/L

Skin-corrosive Eye-severe

LC50 8day Bobwhite quail >20,000ppm Mallard duck >4,640ppm in diet

LC 50 96hr Bluegill 4mg/L Rainbow trout 3mg/L

Skin-moderate Eye-moderate

LC50 5day Bobwhite quail and Mallard duck>10,000ppm in diet

LC50 96hr Bluegill 15mg/L Rainbow trout 3mg/L

Skin-none Eye-none

Skin and Eye Irritation

Skin-none Eye-slight LC50 Bobwhite quail and Mallard duck >4,000ppm in diet

LC50 96hr Bluegill SO mg/L Rainbow trout 64- 76 mg/L

Skin-none Eye-none

LC50 5day Bobwhite quail >5,600ppm Mallard duck 7,200ppm in diet

LC50 96hr Bluegill 20- 30 mg/L Rainbow trout 9- 16mg/L

Skin-none Eye-none

(continued)

2986

HERBICIDE POISONING

VetBooks.ir

lttHIII

HERBICIDE POISONING (continued) Acute Oral LD50-Rat

NOAELR (oral)

Naptalam

>5,000mg/kg l ,770mg/kg (Na + salt)

Rat ,dog, 90days l,OOOmg/kg (Na + salt)

Nicosulfuron

Mouse >5,000mg/kg Dog, 1 yr >5,000ppm in diet(M)

Oxadiazon

>5,000mg/kg

Rat ,dog, 2yr lOOmg/kg

Rabbit >2,000mg/kg

Oxyfluorfen

Rat,dog >5,000mg/kg

Rat, 2yr 2mg/kg Dog, 2.5mg/kg

Rabbit >5,000mg/kg

Paraquat (dichloride)

150-283mg/kg

Rat, 2yr l.25mg/kg Dog, 1yr 0.45mg/kg

Pebulate

l,120mg/kg

Rat , 2yr 15ppm in diet (eye lesions)

Rabbit 4,640mg/kg

Pendimethalin

1,050 to >5,000mg/kg

Dog, 2yr 12.5mg/kg/day

Rabbit >5,000mg/kg

Phenmedipham

8,000mg/kg

Dog, 2yr >1,000ppm in diet

Rat >2,000mg/kg Rabbit>10,000mg/ kg

Picloram

5,000-8,200mg/kg

Rat, 2yr 150mg/kg/day

Rabbit>4,000mg/kg

Prometlyn

3,750--5,235mg/kg

Dog, 90days 2,000mg/kg

Propanil

1,080 to >2,500mg/kg

Dog, 2yr 5,000mg/kg

Propoxycarbazone

>5,000mg/kg

Dog, lyr 258mg/kg(M) 55.7mg/kg(F)

Rat>5,000mg/kg

Compound

Acute Dermal LD50 Rabbit >20,000mg/kg

Rat,rabbit >2,000mg/kg

Rat>2,000mg/kg (finished product)

VetBooks.ir

HERBICIDE POISONING

•H=i!f•

2987

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECh LC50 8day Bobwhite quail 5,600ppm Mallard duck>10,000ppm in diet

Toxicity to Fish in Water LC50 96hr Bluegill 354mg/L Rainbow trout 76mg/L

Skin and Eye Irritation Skin-mild Eye-moderate

'

LC50 LC50 96hr Bobwhite quail and Mallard Bluegill and Rainbow trout duck>5,620ppm in diet >l,OOOmg/L

Skin-none Eye-moderate

LC50 Bobwhite quail and Mallard duck>5,620ppm in diet

LC50 96hr Bluegill 12.5 mg/L Rainbow trout 2 mg/L

Skin-moderate Eye-mild

LC50 Bobwhite quail>5,000 Mallard duck>4,000ppm in diet

LC50 96hr Bluegill 0.2mg/L Rainbow trout 0.41mg/L

Skin-none Eye-moderate

LC50 5day Bobwhite quail 981ppm Mallard duck 4,048ppm in diet

LC50 96hr Rainbow trout 26mg/L

Skin-slight Eye-moderate

LC50 Bobwhite quail and Mallard duck>2,400ppm in diet

LC50 96hr Bluegill and Rainbow trout 7.4mg/L

Skin-slight Eye-mild

LC 50 8day Bobwhite quail 3,149ppm Mallard duck 10,900ppm in diet

LC50 96hr Bluegill 0.199 mg/L Rainbow trout 0.138mg/L

Skin-none Eye-mild

LC50 4day Bobwhite quail>2,480ppm in diet

LC 50 96hr Bluegill 760mg/L LC 50 21day Rainbow trout>210mg/L

Skin-moderate Eye-severe

LD50 8day Bobwhite quail>2,500 Mallard duck>5,000mg/kg

LC50 96hr Bluegill 14.5mg/L Rainbow trout 19.3mg/L

Skin-mild Eye-moderate

LC50 5-- 7day Bobwhite quail and Mallard duck>10,000ppm in diet

LC50 96hr Bluegill 10mg/kg Rainbow trout 2.5--2.9mg/L

Skin-none Eye-slight

LC50 8day Bobwhite quail 2,861ppm Mallard duck 5,627ppm in diet

LC50 96hr Bluegill 2.3mg/L Rainbow trout 4.6mg/L

Skin-moderate Eye-serious

Skin-slight Eye-minimal (continued)

2988

HERBICIDE POISONING

VetBooks.ir

IHNIII

HERBICIDE POISONING (continued)

Compound

Acute Oral 1050-Rat

NOAELa (oral)

Propyzamide

5,620-8,350 mg/kg

Dog, 2 yr >7.5 ppm in diet

Rabbit 3,160 mg/kg

Pyrazon

3,030-3,600 mg/kg

Dog, 2 yr 1,500 ppm in diet

Rat >2,000 mg/kg

Pyridate

1,285-1,412 mg/kg

Dog, lyr 30 mg/kg/day

Rabbit >2,000 mg/kg

Pyrithiobac-sodium

4,000 mg/kg

Rat (longterm), 59 mg/kg

Rat >2,000 mg/kg

Quinclorac

3,060 mg/kg (M) 2,190 mg/kg (F)

Dog, 1 yr 142 mg/kg/day (M) 140 mg/kg/day (F)

Rat >2,000 mg/kg

Quizalofop-p-ethyl

1,2101,670 mg/kg (M) 1,1821,480 mg/kg (F)

Dog, lyr 10,000 mg/kg

Rimsulfuron

>5,000 mg/kg

Dog, lyr 50 ppm in diet

Rabbit >2,000 mg/kg

Sethoxydim

3,200 mg/kg (M) 2,676 mg/kg (F)

Dog, lyr >8.86 mg/kg (M) >9.41 mg/kg (F)

Rat, mouse >5,000 mg/kg

Siduron

>7,500 m�g

Rat,2 yr 500 ppm in diet

Rabbit >5,500 mg/kg

Simazine

>5,000 mg/kg

Rat, 2 yr >5 mg/kg/day

Rabbit >10,200 mg/kg

Sodium chlorate

1,200-7,000 mg/kg

Rabbit 500 mg/kg

Sulfentrazone

2,416-3,297 mg/kg

Rat, 10 mg/kg/day Rat >5,000 mg/kg (oral developmental studies)

Sulfosulfuron

>5,000 mg/kg

Mouse, 90 days 7,000 mg/kg of diet

Acute Dermal 1050

Rat >5,000 mg/kg

HERBICIDE POISONING

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2989

HERBICIDE POISONING (continued)

Avian Toxicity/NOAECb

Toxicity to Fish in Water

LC50 8day Bobwhite quail and Mallard duck>10,000ppm in diet

LC50 96hr Bluegill 100mg/L Rainbow trout 72mg/L

Skin-slight Eye-moderate

LC50 Bluegill 40mg/L

Skin-slight Eye-slight

LC50 8day Bobwhite quail>5,000ppm in diet

LC50 96hr Rainbow trout>l.2mg/L

Skin-none Eye-slight

LC5() Bobwhite quail and Mallard duck>6,300ppm

LC50 96hr Bluegill 5.8mg/L Rainbow trout 8.2mg/L

Skin-mild Eye-moderate

Skin and Eye Irritation

1050 LC50 96hr Bobwhite quail and Mallard Bluegill and Rainbow trout duck>5,000mg/kg >100mg/L

Skin-irritating Eye-moderate

LC50 8day Bobwhite quail and Mallard duck>5,000ppm in diet

LC50 96 hr Bluegill 0.46-2.8mg/L Rainbow trout 10.7mg/L

Skin-none Eye-slight

LC5() 8day Bobwhite quail >5,620ppm Mallard duck>2,510ppm in diet

LC50 96hr Bluegill 100mg/L Rainbow trout 32mg/L

Skin-mild Eye-mild

LC50 8day LC50 96 hr Bobwhite quail and Mallard Bluegill and Rainbow trout duck>5,600ppm in diet >1,000mg/L

Skin-none Eye-moderate

LC50 Bobwhite quail and Mallard duck>10,000mg/kg

Skin-slight Eye-slight

LC50 48hr Crucian carp 18mg/L

LC50 8day LC50 96 hr Bobwhite quail>5,260ppm Bluegill and Rainbow trout Mallard duck 10,000ppm in >100mg/L diet

Skin-none Eye-none

LC50 48hr Fish 10,000mg/L

Skin-moderate Eye-moderate

LD50 Bobwhite quail and Mallard duck>5,620ppm

LC50 96hr Bluegill 93.8mg/L Rainbow trout>130mg/L

Skin-mild Eye-moderate

1050 Bobwhite quail and Mallard duck 5,620ppm

LC50 96hr Rainbow trout>97mg/L

Skin-slight Eye-slight (continued)

2990

HERBICIDE POISONING

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IH=IIII

HERBICIDE POISONING (continued)

Compound

Acute Oral LD50-Rat

NOAELa (oral)

Tebuthiuron

644mg/kg

Dog, 1yr >25mg/kg/day

Rabbit >200mg/kg

Thiazopyr

>5,000mg/kg

Dog, 1yr 0.8mg/kg/day

Rat >5,000mg/kg

Thifensulfuronmethyl

>5,000mg/kg

Rat , 2yr 25ppm in diet

Rabbit >2,000mg/kg

Tralkoxydim

1,258mg/kg CM:) 934mg/kg (F)

Rat (teratogen), 30mg/kg

Rat >2,000mg/kg

Triallate

800-2,165 mg/kg

Dog, 2yr 15mg/kg/day (highest tested)

Rabbit 8,200mg/kg

Triasulfuron

>5,000mg/kg

Dog, 1yr 129mg/kg/day

Rat >2,000mg/kg

Tribenuron-methyl

>5,000mg/kg

Dog, lyr 875ppm in diet

Rabbit >2,000mg/kg

Trichloracetic acid

3,200-5,000mg/kg

Triclopyr

630-729mg/k�

Rat , 2yr 3mg/kg/day

Rabbit >2,000mg/kg

Tri.fluralin

>5,000mg/kg

Dog, 2yr 18.75mg/kg/day

Rabbit >?,000mg/kg

Vernolate

1,200-1,900mg/kg

Dog, 90days >38mg/kg/day

Rabbit >1,955mg/kg

Acute Dermal LD50

Rat >2,000mg/kg

• NOAEL = No obse1vable adverse effect l2,500mg/kg

LC 50 96hr Bluegill 112mg!L Rainbow trout 144mg/L

Skin-slight Eye-slight

LD50 Bobwhite quail and Mallard duck 5,328mg/kg

LC50 Bluegill and Rainbow trout 3.5mg/L

Skin-slight Eye-slight

LC50 8day Bobwhite quail and Mallard duck>5,620mg/kg

LC50 96hr Bluegill and Rainbow trout 100mg!L

Skin-none Eye-moderate

LD 50 Mallard duck>3,020mg/kg

LC50 96hr Bluegill>6.1mg!L Rainbow trout>7.2mg!L

Skin-mild Eye-mild

LC50 8day Bobwhite quail and Mallard duck>5,000mg/kg

LC50 96hr Bluegill 1.3mg/L Rainbow trout 1.2mg!L

Skin-moderate Eye-slight

LC50 8day Bobwhite quail and Mallard duck>5,000ppm

LC50 96hr Bluegill and Rainbow trout>100ppm

Skin-none Eye-none

LC50 Bobwhite quail and Mallard duck>5,620ppm

LCw96hr Bluegill 760mg/L Rainbow trout 730mg!L

Skin-none Eye-mild to moderate

LDw Chicken 4,280mg/kg

Not toxic to fish

Skin-severe Eye-severe

LCw8day Bobwhite quail 2,935ppm Mallard duck>5,401ppm in diet

LCw96hr Bluegill 148mg/L Rainbow trout 117mg/L

Skin-none Eye-slight

LCw8day Bobwhite quail and Mallard duck>5,000ppm in diet

LCw96hr Bluegill 0.05--0.07mg!L Rainbow trout 0.02- 0.06mg/L

Skin-none Eye-moderate

LCw 7day Bobwhite quail 12,000ppm in diet

LC50 96hr Bluegill 8.4mg/L Rainbow trout 9.6mg!L

Skin-none Eye-none

Skin and Eye Irritation

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2992

HERBICIDE POISONING ORAL TOXIC DOSES (TD) AND LETHAL DOSES (LD) OF HERBICIDES IN DOMESTIC SPECIES

Compound

TD/LD

Species

Dosage (mg/kg)

LD50

Chickens

547

Dogs

100-800

Pigs

500

Hens

380-765

Pigs

100

Calves

200

Cattle

250 for 3 days

Sheep

250 for 2 days

Cattle

250 for 10 days

Sheep

250 for 10 clays

Phenoxy acid derivatives Phenoxy acid and its sodium salt

LD

TD Butyl glycol ester

Amine salts

TD TD

or 500 for 7 days Bipyridyl compounds or quaternary ammonium Paraquat

LD

Diquat

Dogs

25-50

Cats

35

Monkeys

50-70

Cattle

35-50

Chickens

110-360

Sheep

8-10

Pigs

75

Dogs

100-200

Cats

35-50

Cattle

20--40

Chickens

200--400

Cattle

100 for 10 days

Sheep

250 or 100 for 2 clays

Chickens

50 for 10 days

Dogs

100-200

Cats

35-50

Ureas and thioureas Diuron

Linuron

TD

TD

(continued)

HERBICIDE POISONING

2993

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ORAL TOXIC DOSES (TD) AND LETHAL DOSES (LD) OF HERBICIDES IN DOMESTIC SPECIES (continued) Compound

Tebuthiuron

TD/LD

Species

Dosage (mg/kg)

Cattle

20-40

Chickens

200-400

LD50

Cats

>200

TD

Cats

200

Dogs

>500

TD

Dogs

50 /clay for 3 mo8

Chickens, No deaths were reported at a quail, or clucks dosage of500 mg/kg body wt. Protoporphyrinogen oxidase inhibitors Cats

>500

Propanil

Dogs

1 ,217

Propyzamicle

Dogs

>10 ,000

Hens

26

Dogs

50

Pigs

50

Goats

100

Cattle

2-50

Sheep

20-50

LD

Sheep

25 for5 days

LD50

Hens

26

TD

Cattle

25 for8 clays

Sheep

25 for 10 clays

Dogs

>2 ,000

Cattle

250

Chickens

500 for10 days

Metribuzin Anilide, acetamides, or amide compounds

Dinitrophenolic compounds DNOC

LD50

TD

Dinoseb

Dinitroaniline Trifluralin

Bromacil TD

(continued)

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2994

HERBICIDE POISONING ORAL TOXIC DOSES (TD) AND LETHAL DOSES (LD) OF HERBICIDES IN DOMESTIC SPECIES (continued)

Compound

TD/LD

Species

Dosage (mg/kg)

Sheep

50 for 10 days or 250 for 8 days

Rabbits

>2,000

Chickens

>2,000

Dogs

>5,000

LD50

Dogs

510

TD

Chickens

150 for 10 days or 250 for 7 days

Cattle

25 for 5 days or 50 for 3 days

Sheep

25 for 5 days or 50 for 3 days

LD50

Dogs

>4,000

LD50

Chickens

>3,000

LD50

Cattle

>750

Sheep

>l,000

Carbamates and thiocarbamate compounds Asulan1

Di-allate

Phenrnediphan1

LD50

Picrolinic acid de1ivative Picloran1

a Anorexfa and weight loss reported. No deaths were repoited in dogs at a tebuthiuron dosage of 500 mgtkg body wt.

INORGANIC HERBICIDES AND ORGANIC ARSENICALS Substances such as inorganic arsenicals (sodium arsenite, arsenic trioxide), organic arsenicals (methyl arsonate, methyl arsonic acid), sodium chlorate, an1monium sulfamate, borax, and many others were fonnerly used on a large scale. These older herbicides are nonselective, generally cheaper, more toxic, and more likely to cause problems than newer compounds. Their use has been mostly curtailed in developed countries.

Arsenicals: The use of inorganic

arsenicals as herbicides has been reduced greatly because of livestock losses, environmental persistence, and their carcinogenic potential. These compounds can be hazardous to anin1als when used as

recommended. Rwninants (including deer) are apparently attracted to and lick plants poisoned with arsenite. The highly soluble organic arsenicals can concentrate in pools in toxic quantities after a rain has washed them from recently treated plants. Arsenicals are used as desiccants or defoliants on cotton, and residues of cotton harvest fed to cattle may contain toxic amounts of arsenic. Signs and lesions caused by organic arsenical herbicides resemble tl10se of inorganic arsenical poisoning. Single toxic oral doses for cattle and sheep are 22-55 mg/kg. Poisoning may be expected from smaller doses if consumed on successive days. Dimercaprol (3 mg/kg for large animals, and 2.5-5 mg/kg for small animals, IM, every 4-6 tu') is the reconunended therapy. Sodiwn thiosulfate also has been used (20-30 g, PO, in -300 mL of water for cattle; one-fourth this dose for sheep); however, a

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HERBICIDE POISONING

2995

HERBICIDES WITH POTENTIAL TO CAUSE DEVELOP MENTAL TOXICITY IN EX PERIMENTAL ANIM AL S

Compound

Effects

Atrizine

Disruption of ovarian cycle and induced repetitive pseudopregnancy (rats, at high doses)

Buturon

Cleft palate, increased fet;aJ mortality (mice)

Butiphos

Teratogenic (rabbit)

Chloridazon

Malfmmations

Chlorpropham

Malformations or other developmental toxicity (mice)

Cynazine

Malformations such as cyclopia and diaphragmatic hernia (rabbits); skeletal variations in rats

2,4-D• or 2,4,5-T• alone or in combination

Malfmmations such as cleft palate, hydronephrosis; teratogenic (mice, rats)

Dichlorprop

Teratogenic (mice); affect postnatal behavior (rats)

Dinosebb

Multiple defects (mice, rabbits)

Dinoterb

Skeletal malformations (rats); skeletal,jaw, head, and visceral (rabbits)

Linuron

Malformations (rats)

Mecoprop

Malformations (mice only)

Monolinuron

Cleft palate (mice)

MCPN

Teratogenic and embryotoxic (rats), teratogenic (mice)

Prometryn

Head, limbs, and tail defects (rat)

Propachlor

Slightly teratogenic (rats)

Nitrofen

Malformations (mice, rats, hamsters)

b

Silvex

Teratogenic (mice)

TCDD•

Malformations/teratogenic (fetotoxicity in chickens, rats, mice, rabbits, guinea pigs, hamsters, and monkeys)

Tridiphane

Malformations such as cleft palate (mice); skeletal varia­ tions (rats)

"TCDD is a common contaminant during the manufacturing process of some herbicides such as 2,4-D and 2,4,5-T. b Obsolete c 2-methyl-4-chlorophenoxyacetic acid

rationale for its use is not established, and it may be unrewarding. (See also ARSENIC POISONING, p 3071.) Ammonium Sulfamate: Ruminants

apparently can metabolize anunonium

sulfamate to some extent and, in some studies, exposed animals made better gains than did control animals. However, sudden deaths have occurred in cattle and deer that consumed treated plants. Large doses (> 1.5 g/kg) induce ammonia poisoning in

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2996

HERBICIDE POISONING

ruminants. Treatment is designed to lower rumen pH by dilution with copious amounts of water to which weak acetic acid (vinegar) has been added. Borax: Borax is toxic to animals if

consumed in moderate to large doses (>0.5 g/kg). Poisoning has not been reported when borax was used properly but has occurred when it was accidentally added to livestock feed and when borax powder was scattered in the open for cockroach control. Principal signs of acute poisoning are diarrhea, rapid prostration, and perhaps convulsions. An effective antidote is not known. Balanced electrolyte fluid therapy with supportive care is indicated. Sodium Chlorate: Many cases of chlorate

poisoning of livestock have occurred both from ingestion of treated plants and from accidental consun1ption of feed to which it was mistakenly added as salt. Cattle some­ times are attracted to foliage treated with sodium chlorate. Considerable quantities must be consumed before signs of toxicity appear. The minin1un1 lethal dose is 1.1 g/kg for cattle, 1.54-2.86 g/kg for sheep, and 5.06 g/kg for poultry. Ingestion results in hemolysis of RBCs and conversion of Hgb to methemoglobin. Treatment with methylene blue (10 mg/kg) must be repeated frequently because, unlike the nitrites, the chlorate ion is not inactivated during conversion ofHgb to methemoglobin and is capable of producing an unlimited quantity of methemoglobin as long as it is present in tl1e body. Blood transfusions may reduce some of the tissue anoxia caused by methemoglobin; IV isotonic saline can hasten elimination of the chlorate ion. Mineral oil containing 1% sodium thiosulfate will inhibit further absorption of chlorate in monogastric anin1als.

ORGANIC HERBICIDES Anilide, Acetamides, or Amide Compounds: These herbicides (propanil,

cypromid, clomiprop, bensulide, dimethe­ narnid) are plant growth regulators, and some members of this group are more toxic than others. Hemolysis, methemoglobine­ mia, and immunotoxicity have occurred after experimental exposure to propanil. (For discussion of bensulide, see p 2997.)

Bipyridyl Compounds or Quaternary Ammonium Herbicides: The bipyridyl

compounds (diquat, paraquat) produce toxic effects in the tissues of exposed animals by development of free radicals.

Tissues can be irritated after contact. For example, mouth lesions have been seen after contact with recently sprayed pastures. Skin irritation and corneal opacity occur on external exposure to these chemicals, and inhalation is dangerous. Animals, including people, have died as a result of drinking from contaminated containers. Paraquat and diquat have somewhat different mechanisms of action. Diquat exerts most of its hamtful effects in the GI tract. Animals drinking from an old diquat container showed anorexia, gastritis, GI distention, and severe loss of water into the lumen of the GI tract. Signs of renal impaim1ent, CNS excitement, and convulsions occur in severely affected individuals. Lung lesions are uncommon. Paraquat has a biphasic toxic action after ingestion. Immediate effects include excitement, convulsions or depression and incoordination, gastroenteritis with anorexia, and possibly renal involvement and respiratory difficulty. Eye, nasal, and skin irritation can be caused by direct contact, followed within days to 2 wk by pulmonary lesions as a result of lipid­ membrane peroxidation and thus destruc­ tion of the type I alveolar pneumocytes. This is reflected in progressive respiratory distress and is evident on necropsy as pulmonary edema, hyaline membrane deposition, and alveolar fibrosis. There is no specific treatment. Because these chemicals are absorbed slowly, intensive oral administration of adsorbents in large quantities and cathartics is advised. Bentonite or Fuller's earth is preferred, but activated charcoal will suffice. Toxicity of paraquat is enhanced by deficiency of vitamin E or selenium, oxygen, and low tissue activity of glutathione peroxidase. Therefore, vitamin E and selenium with supportive therapy may be useful in early stages of intoxication. Excretion may be accelerated by forced diuresis induced by mannitol and furosemide. Oxygen therapy and fluid therapy are contraindicated. Carbamate and Thiocarbamate Compounds: These herbicides (terbu­

carb, asulam, carboxazole, EPTC, pebulate, triallate, vernolate, butylate, thiobencarb) are moderately toxic; however, they are used at low concentrations, and poisoning problems would not be expected from normal use. Massive overdosage, as seen witl1 accidental exposure, produces signs similar to those induced by the insecticide carbamates, with lack of appetite, depression, respiratory difficulty, mouth

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HERBICIDE POISONING

watering, diarrhea, weakness, and seizures. Thiobencarb has induced toxic neuropa­ thies in neonatal and adult laboratory rats. It appears to increase pem1eability of the blood-brain barrier. There is no suitable antidote. Supportive and symptomatic treatment is recommended. Aromatic/Benzoic Acid Compounds:

The herbicides in this group (chloramben, dicamba, and naptalam) have a low order of toxicity to domestic anin1als, and poisoning after nmmal use has not been reported. Environmental persistence and toxicity to wildlife is also low. The signs and lesions are similar to those described for the phenoxy acid derivatives (see below). There is no suitable antidote. Supportive and sympto­ matic treatment is recommended. Phenoxy Acid Derivatives: These acids and their salts and esters (2,4-D [2-4-dichlorophenoxyacetic acid], dalapon, dichlorprop [2,4-DPJ, 2,4,5-T [2,4,5-trichlorophenoxyacetic acid], 2,4-DB, MCPA, MCPB, mecoprop, and silvex) are commonly used to control undesirable plants. As a group, they are essentially nontoxic to animals, except silvex which is unusually very toxic. When large doses are fed experimentally, general depression, anorexia, weight loss, tenseness, and muscular weakness (particularly of the hindquarters) are noted. Large doses in cattle may interfere with rumen function. Dogs may develop myotonia, ataxia, posterior weakness, vomiting, diarrhea, and metabolic acidosis. The oral LD50 for 2,4-D and 2,4,5-T in dogs is 100--800 mg/kg. Even large doses, up to 2 g/kg, have not been shown to leave residues in the fat of animals. These compounds are plant growth regulators, and treatment may result in increased palatability of some poisonous plants as well as increased nitrate and cyanide content. The use of 2,4,5-T was curtailed because extremely toxic contaminants, collectively called dioxins (TCDD and HCDD), were found in technical grade material (see p 3056). TCDD is considered carcinogenic, mutagenic, teratogenic, and fetotoxic, and is able to cause reproductive damage and other toxic effects. Although manufacturing methods have reduced the level of the contaminants, use of this herbicide is very limited worldwide. Treatment is usually symptomatic and supportive. IV fluids should be given to promote diuresis. Adsorbents and drugs

2997

that aid in restoration of liver function are recorrunended. Dinitrophenolic Compounds: Several

substituted dinitrophenols alone or as salts such as dinitrophenol, dinitrocresol, dinoseb, and binapacryl are highly toxic to all classes of animals (LD50 20-100 mg/kg body wt). Poisoning can occur if animals are sprayed accidentally or have immedi­ ate access to forage that has been sprayed, because these compounds are readily absorbed through skin or lungs. Dinitro­ phenolic herbicides markedly increase oxygen consumption and deplete glycogen reserves. Clinical signs include fever, dysp­ nea, acidosis, tachycardia, and convul­ sions, followed by coma and death with a rapid onset of rigor mortis. Cataracts can occur in animals with chronic dinitrophe­ nol intoxication. In cattle and other ruminants, methemoglobinemia, intravascular hemolysis, and hemopro­ teinemia have been seen. Exposure to these compounds may cause yellow staining of the skin, conjunctiva, or hair. An effective antidote for dinitrophenol compounds is not known. Affected animals should be cooled and sedated to help control hyperthermia. Use of physical cooling measures (eg, cool baths or sponging and keeping the animal in a shaded area) are recommended. Atropine sulfate, aspirin, and antipyretics should not be used. Dextrose-saline infusions in combination with diuretics and tranquiliz­ ers such as diazepan1 (not barbiturates) are very useful. Phenothiazine tranquilizers are contraindicated. IV administration of large doses of sodiwn bicarbonate (in carni­ vores), parenteral vitamin A, and oxygen therapy may be useful. If the toxin was ingested and the anin1al is alert, emetics should be administered; if the anin1al is depressed, gastric lavage and treatment with activated charcoal should be performed. In ruminants with methemoglobinemia, methylene blue solution (2o/o-4%, 10 mg/kg, IV, tid, during the first 24--48 hr) and ascorbic acid (5-10 mg/kg, IV) are useful. Organophosphate Compounds:

Organophosphate compounds such as glyphosate, glufosinate, and bensulide are broad-spectrun1, nonselective systemic herbicides. Glyphosate and glufosinate exist as free acids, but because of their slow solubility they are marketed as the isopropyl amine or trimethylsulfonium salts of glyphosate and the ammonium salt of

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2998

HERBICIDE POISONING

glufosinate. These are widely used herbicides with low toxicity. However, they are toxic to fish. Sprayed forage appears to be preferred by cattle for 5-7 days after application, but this causes little or no problem. Dogs and cats show eye, skin, and upper respiratory tract signs when exposed during or subsequent to an application to weeds or grass. Nausea, vomiting, staggering, and hindleg weakness have been seen in dogs and cats exposed to fresh chemical on treated foliage. The signs usually disappear when exposure ceases, and minimal symptomatic treatment is needed. However, formulations of these compounds may lead to hemolysis and GI, cardiovascular, and CNS effects due to presence of the surfactant polyoxyethyleneamine. Treatment should include washing the chemical off the skin, evacuating the stomach, and tranquilizing the anin1al. Massive exposure with acute signs due to accidental poisoning should be handled as an organophosphate poisoning (seep 3064). Bensulide, listed as a plant growth regulator, has an oral LDii() in rats of 271-770 mg/kg; in dogs, the lethal dose is >200 mg/kg. The most prominent clinical sign is anorexia, but other signs are sinillar to those caused by 2,4-D poisoning. Triazolopyrimidine Compounds:

Triazolopyrinlidine herbicides include cloransularn-methyl, diclosulan1, florasu­ larn-methyl, flumetsularn, and metosularn. The acute oral toxicity is very low. There is no suitable antidote. Supportive and symptomatic treatment is recommended. Ureas and Thiourea Compounds:

The ureas and thioureas (polyureas) are available under different names such as diuron, fluometuron, isoproturon, linuron, buturon, chlorbromuron, chlortoluron, chloroxuron, difenoxuron, fenuron, methiuron, metobromuron, metoxuron, monuron, neburon, parafluron, siduron, tebuthiuron, tetrafluron, and thidiazuron. Of these, diw·on and fluometuron are the most commonly used in the USA, whereas isoproturon is mostly used in other countries. In general, these compounds have low acute toxicity and are unlikely to present any hazard in normal use, except tebuthiuron, which may be slightly hazardous. Cattle are more sensitive to poly­ urea herbicides than sheep, cats, and dogs. Signs and lesions are sinillar to those described for the phenoxyacetic herbicides (see above). The substituted urea herbicides induce hepatic microsomal enzymes and may alter metabolism of other xenobiotic

agents. Altered calcium metabolism and bone morphology have been seen in laboratory anin1als. Recovery from diuron intoxication is quick (withi11 72 hr), and no signs of skin iITitation or dermal sensitiza­ tion have been reported in guinea pigs. After repeated administration, hemoglobin levels and RBC counts are significantly reduced, while methemoglobin concentration and WBC counts are increased. Increased pigmentation (hemosiderin) in the spleen is seen histopathologically. LiJluron in sheep causes erytllrocytosis and leukocytosis with hypohemoglobinemia and hypoproteinemia, hematuria, ataxia, enteritis, degeneration of the liver, and muscular dystrophy. In chickens, it leads to weight loss, dyspnea, cyanosis, and diarrhea. It is nontoxic to fish. Fluometuron is less toxic t11an diuron. In sheep, depression, salivation, g1inding of teeth, chewing movements of the jaws, mydriasis, dyspnea, incoordination of movements, and drowsiI1ess are conunonly seen. On histopathology, severe congestion of the red pulp witil corresponding atrophy of the white pulp of the spleen and depletion of the lymphocyte elements have been reported. The acute LDii() of isoproturon in rats is sinillar to that of diuron. Polyurea herbicides have been suspected to have some mutagenic effects but do not have carcinogenic potential. In general, these compounds do not cause develop­ mental and reproductive toxicity, except for monolinuron, linuron, and buturon, which are known to cause some teratogenic abnor­ malities in experimental animals. There is no suitable antidote. Supportive and symptomatic treatment is recommended. Polycyclic Alkanoic Acids or Aryloxy­ phenoxypropionic Compounds: Mem­

bers of tlus group (diclofop, fenoxaprop, fenthiaprop, fluazifop, haloxyfop) have moderately low toxicity (acute oral LDii() in rats 950 mg/kg to >4,000 m�g), except for haloxyfop-methyl (LDii() -400 mg/kg). These compounds are more toxic if exposure is dermal. The dem1al LD50 of diclofop in rabbits is only 180 mg/kg. There is no suitable antidote. Supportive and sympto­ matic treatment is reconunended. Triazinylsulfonylurea or Sulfonylurea Compounds: Toxicity of this group of

herbicides ( chlorsulfuron, sulfometuron, etharnetsulfuron, chloremuron) appears to be quite low. The oral acute LDii() in rats is in the range of 4,000-5,000 m�g. The dem1al acute LD50 in rabbits is -2,000 mg/kg. There is no suitable antidote. Supportive and symptomatic treatment is reconunended.

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HERBICIDE POISONING

Triazines and Triazoles: Triazines and triazoles have been used extensively as selective herbicides. These herbicides are inhibitors of photosynthesis and include both the asymmetric and synunetlic triazines. Exan1ples of symmetric triazines are chlorostriazines (sinlazine, atrazine, propazine, and cyanazine), the thiomethyl­ s-triazines (ametryn, prometryn, terbutryn), and methoxy-s-triazine (prometon). The commonly used asyn1rnetric triazine is metribuzin. These herbicides have low oral toxicity and are unlikely to pose acute hazards in normal use, except arnetryn and metribu­ zin, which may be slightly to moderately hazardous. They do not irritate the skin or eyes and are not skin sensitizers. The exceptions are atrazine, which is a skin sensitizer, and cyanazine, which is toxic by the oral route. Sensitivity of sheep and cattle to these herbicides is appreciably high. The main signs are anorexia, hemotoxia, hypothermia, locomotor disturbances, irritability, tachypnea, and hypersensitivity. Simazine is excreted in milk, so it is of public health concern. Atrazine is more toxic to rats but comparatively less toxic to sheep and cattle than simazine. When cultured human cells are exposed to atrazine, splenocytes are damaged; bone marrow cells are not affected. Atrazine induces liver microsomal enzymes and is converted to N-dealkylated derivatives. In contrast to simazine, it is not excreted in milk. There is no suitable antitlote. Supportive and symptomatic treatment is recommended. Protoporphyrinogen Oxidase Inhibitors: Protox inhibitors may be

diphenyl ether (OPE) or non-diphenyl ether (non-OPE) such as nitrofen and oxadiazon. In the past few years, numerous other non-oxygen-bridged compounds (non-OPE protox inhibitors) with the same site of action (carfentra­ zone, JV 485, and oxadiargyl) have been marketed. Protox inhibitors have little acute toxicity and are unlikely to pose an acute hazard in normal use. These compounds increase porphyrin levels in animals when administered orally; the porphyrin levels return to normal within a few days. There is no suitable antidote. Supportive and symptomatic treatment is recommended. Substituted Anilines: The most com­ monly used herbicides of tllis group are alachlor, acetochlor, butachlor, metolachlor,

2999

and propachlor. Low doses in rats and dogs do not produce any adverse effects, but longtern1 exposure in dogs causes liver toxicity and affects the spleen. Ocular lesions produced by alachlor are considered to be unique to the Long-Evans rat, because the response has not been seen in other strains of rats or in mice or dogs. Compared with other substituted anilines, propachlor is severely irritating to the eye and slightly irritating to the skin. Propachlor produces skin sensitization in guinea pigs. High doses of propachlor produce erosion, ulceration, and hyperpla­ sia of the mucosa and herniated mucosa! glands in the pylo1ic region of stomach and hyperti·ophy and necrosis of the liver in rats. In dogs, there is poor diet palatability, which results in poor feed consw11ption and weight loss. There is no suitable antidote. Supportive and symptomatic ti·eatment is recommended. lmidazolinones: Imidazolinone herbicides include imazapyr, inlazameth­ abenz-methyl, imazapic, imazethapyr, irnazamox, and imazaquin. These are selective broad-spectrum herbicides. Imidazolinone herbicides caused slight to moderate skeletal myopathy and/or slight anemia in dogs during 1-yr dietary toxicity studies with three structurally similar intidazolinones (imazapic, imazaquin, and imazethapyr). There is no evidence of any adverse effect on reproductive perfor­ mance or of fetal abnormalities in rats or rabbits. There is no suitable antidote. Supportive and symptomatic treatlnent is reconm1ended. Other Herbicides: Bromacil and terbacil are commonly used metl1yluracil com­ pounds. Toxic doses of bromacil can be hazardous, especially for sheep, but no field case of toxicity has been reported. The nitrile herbicides, ioxynil and bromoxynil, may uncouple and/or inhibit oxidative phosphorylation. Ioxynil, presumably because of its iodine content, causes enlargement of the thyroid gland in rats. A number of substances are used as defoliants in agriculture. For example, sulfuric acid is used to destroy potato haulms and two closely related trialkylphos­ phorothioates (DEF and merphos) to defoliate cotton. A notable feature of the latter is that it produces organophosphate­ induced delayed neuropathy in hens. Chlomequat is used as a growth regulator on fruit trees. The signs of toxicity in experimental animals indicate that it is a partial cholinergic agonist.

HOUSEHOLD HAZARDS

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HOUSEHOLD HAZARDS See also RODENT!CIDE POISONING, p 3165; TOXICITIES FROM HUMAN DRUGS, p 3024; POISONOUS PLANTS, p 3103; and FOOD HAZARDS, p 2964. Household chemicals (eg, products containing alcohols, bleaches, or corro­ sives) found in the home represent a risk of toxicosis if companion animals are exposed to concentrates or undiluted products, but casual exposure to areas in which these compounds have been used appropriately rarely causes any serious problems.

ALCOHOLS Alcohol toxicosis results in metabolic acido­ sis, hypothermia, and CNS depression. All species are susceptible. Etiology: Ethanol, methanol, and

isopropanol are the alcohols most frequently associated with toxicosis in companion animals. Ethanol is present in a variety of alcoholic beverages, some rubbing alcohols, drug elixirs, and fermenting bread dough (seep 2965). Methanol is most commonly found in windshield washer fluids (windshield "antifreeze"). The lethal oral dose of methanol in dogs is 4-8 ml/kg, although significant clinical signs may be seen at lower dosages. Isopropanol is twice as toxic as ethanol and is found in rubbing alcohols and in alcohol-based flea sprays for pets. Oral dosages of isopropanol �0.5 ml/kg may result in significar1t clinical signs in dogs. Pathogenesis: All alcohols are rapidly

absorbed via the GI tract and most are well absorbed dermally; toxicosis from overspraying pets with alcohol-based flea sprays is not uncommon. Alcohols reach peak plasma levels within 1.5--2 hr and are widely distributed throughout the body. They are metabolized in the liver to acetaldehyde (ethanol), formaldehyde (methanol), and acetone (isopropanol); these intermediate metabolites are then further converted to acetic acid, formic acid, and/or carbon dioxide. (In people and some other primates, accumulation of formic acid after methanol ingestion results in retinal and neuronal damage; nonpri­ mates are efficient at eliminating fonnic acid and therefore do not develop the blindness and cerebral necrosis seen in

primates.) Alcohols are eliminated via the urine as parent compound as well as metabolites. In dogs, up to 5()0A, of a dose of methanol may be eliminated unchanged via the lungs. Alcohols are GI irritants, and ingestion may result in vomiting and hypersaliva­ tion. Alcohols and their metabolites are potent CNS depressants, affecting a variety of neurotransmitters within the nervous system. Metabolites such as acetaldehyde may stimulate the release of catecholamines, which can affect myocardial function. Metabolic acidosis results from the formation of acidic intermediates, and both parent com­ pounds and metabolites contribute to increases in osmolal gap. Hypothermia may develop due to peripheral vasodila­ tion, CNS depression, and interference with thermoregulatory mechanisms. Hypoglycemia develops secondary to alcohol-induced depletion of pyruvate, resulting in inhibition of gluconeogenesis. Clinical Findings and Diagnosis:

Signs generally begin within 30-60 min of ingestion and include vomiting, diarrhea, ataxia, disorientation (inebriation), depre­ ssion, tremors, and dyspnea. Severe cases may progress to coma, hypothennia, seizures, bradycardia, and respiratory depression. Death is generally due to respiratory failure, hypothermia, hypoglycemia, and/or meta­ bolic acidosis. Pneumonia secondary to aspiration of vomitus is possible. The determination of blood alcohol levels may help to confirm the diagnosis of alcohol intoxication. Treatment: Stabilization of severely

symptomatic animals is a priority. Adequate ventilation should be main­ tained, and cardiovascular and acidbase abnormalities should be corrected. Seizures can be controlled with diazepam (0.5-2 mg/kg, IV) as needed. For asympto­ matic animals, induction of emesis may be of benefit in the first 20-40 min after ingestion. Activated charcoal is not thought to appreciably bind small-chain alcohols and is not often recommended. Bathing with mild shampoo is recommended for significant dermal exposures. Supportive care, including thermoregulation and fluid diuresis to enhance alcohol elimination,

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HOUSEHOLD HAZARDS

should be administered. Anecdotally, yohimbine(0.1 mg/kg, IV) has been used to stimulate respiration in severely comatose dogs with alcohol toxicosis.

CHLORINE BLEACHES Exposure to undiluted chlorine bleaches may result in GI, dermal, and ocular irritation or ulceration as well as significant; respiratory irritation. All species are susceptible. Because of the countercurrent anatomy and physiology of the avian lung, caged birds are at increased risk of succumbing to fumes from bleaches and other cleaning agents.

Etiology: Chlorine bleaches are primarily

used as household cleaners and pool sanitizers. Household bleaches tend to contain sodium hypochlorite at 3%---1 OOA., and pH of these products may range from 9( mildly irritating) to>11 ( corrosive). Pool treatments may contain lithium, calcium, oc sodium hypochlorites at concentrations up to 700/o-80%, with pH that may range from acidic to alkaline. Pets may be exposed by chewing on containers of undiluted product, drinking from buckets containing product diluted in water, or swimming in recently treated pools.

Pathogenesis: The relative hazard of a particular bleach product depends on the concentration of hypochlorite, pH, and dilution of the product. In general, levels of hypochlorite 11 or 10%) bleach products or products with pH>11 may cause significant GI corrosive injury. Ingestion or inhalation of significant amounts of chlorine bleach occasionally results in hyp ernatremia, hyperchloremia, and/or metabolic acidosis. Acute inhalation may result in

3001

immediate coughing, gagging, sneezing, or retching. In addition to the immediate respiratory signs, animals exposed to concentrated chlorine fumes may develop pulmonary edema12---24 hr after exposure. Ocular exposures may result in epiphora, blepharospasm, eyelid edema, and/or corneal ulceration. Dermal exposure may result in mild dermal irritation and bleaching of ti'le hair coat. Oral, dermal, and ocular irritation or ulceration are possible. Respiratory lesions may include tracheitis, bronchitis, alveolitis, and pulmonary edema.

Treatment: For oral exposures, emesis

and activated charcoal are contraindi­ cated; instead, dilution with milk or water is recommended. Any spontaneous vomiting should be managed, and animals should be monitored for development of GI irritation/ulceration (see below). In cases when protracted vomiting causes electrolyte or hydration abnormalities, fluid therapy may be of benefit. For respiratory exposures, the animal should be moved to an area with fresh air and monitored for dyspnea. Stabilization of severely dyspneic animals is a must; pulmonary edema should be treated as needed. Bathing with mild shampoo and thorough rinsing is recommended for significant dermal exposures. Ocular exposures should be treated with10---20 min of ocular inigation with physiologic saline, followed by fluorescein staining of the cornea to detect corneal injury.

CORROSIVES Acid or alkaline corrosives produce significant local tissue injury that can result in full-thickness burns of skin, cornea, and the mucosa of the oral cavity, esophagus, and stomach. All species are susceptible. Heavy coats may provide some protection from dermal exposure.

Etiology: Corrosives are divided into

acid and alkaline corrosives. Acidic household products include anti-rust compounds, toilet bowl cleaners, gun-cleaning fluids, automotive batteries, swimming pool cleaning agents, and etching compounds. Alkaline corrosive agents include drain openers, automatic dishwasher detergents, toilet bowl cleaners, radiator cleaning agents, and swimming pool algicides and "shock" agents. In general, alkaline products with pH>11 pose risk of significant corrosive injury.

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HOUSEHOLD HAZARDS

Pathogenesis: Acids produce immedi­ ate coagulative necrosis of tissue and impart significant pain on contact, which may limit exposure. Alkaline agents produce immediate, penetrating liquefac­ tive necrosis of tissue; the lack of significant discomfort on contact with alkaline products may result in prolonged exposure. For these reasons, burns from alkaline products tend to be deeper and more extensive than burns from acidic agents. Burns from alkaline agents may take up to 12 hr after exposure to become fully apparent, whereas the extent of acid burns is usually evident shortly after contact. Esophageal burns are more common with alkaline agents, and the absence of significant oral burns does not necessarily indicate that no esophageal damage has developed. Full-thickness ulceration of the esophagus may result in pleuritis or peritonitis due to leakage of ingesta into body cavities. Esophageal burns may result in stricture formation during healing, resulting in dysphagia, megaesophagus, and aspiration pneumo­ nia. Additionally, although the contents of the stomach may serve to buffer and dilute corrosive agents, gastric ulceration and possibly perforation may occur with significant exposures. Respiratory exposure to corrosives (especially acids) may result in respiratory distress, tracheo­ bronchitis, or pneumonitis. Dermal or ocular exposures may result in severe ulceration of dermis or cornea. Clinical Findings and Lesions: Clinical

signs that may occur after ingestion of corrosive agents include vocalization, hypersalivation, lethargy, polydipsia, vomiting (with or without blood), abdominal pain, dysphagia, pharyngeal edema, dyspnea, and oral, esophageal, and/or gastric ulceration. In severe cases, shock may develop rapidly after exposure. Lesions are initially milky white to gray but gradually tum black as eschar formation occurs. Necrotic tissue may slough within days of exposure. Dyspnea, cyanosis, and pulmonary edema may occur secondary to inhaled corrosive agents. Dermal exposure may result in significant burns, with local pain, erythema, and tissue sloughing. Ocular exposure may cause blepharospasm, epiphora, eyelid edema, conjunctivitis, or corneal ulceration. Burns of skin, cornea, and GI mucosa range from mild ulceration to full-thickness necrosis with extensive tissue sloughing. Peritonitis or pleuritis

may develop secondary to perforating ulcers of esophagus or stomach. Respira­ tory lesions may include tracheitis, bronchitis, pneumonitis, pulmonary edema, or aspiration pneumonia. Treatment: Because of the rapid action of corrosive agents, much of the damage from exposure occurs before treatment can be started. Stabilization of animals presenting as dyspneic, in shock, or witl1 severe electrolyte abnormalities is always a priority. For recent oral exposures, immediate dilution witl1 water or milk should be done. Under no circumstances should emesis be attempted because of the risk of further mucosal exposure to corrosive material. Likewise, gastric lavage is contraindicated because of the risk of perforation of weakened esopha­ geal/gastric walls and the risk of further exposure of mucosa to the corrosive material as it is removed. Attempts to chemically neutralize an acid with weak alkali (or alkali with weak acid) are also contraindicated because of the production of exothermic reactions that can result in thermal burns. Activated charcoal is ineffective in cases involving ingestion of corrosives, and tl1e presence of charcoal on damaged mucosa may impede wound healing. After dilution, general supportive care should be instituted, including monitoring for respiratory difficulty, pain manage­ ment, antibiotics (if ulcers are present), and anti-inflammatories as needed. Endoscopic evaluation of the esophagus and stomach for ulceration should be performed -12 hr after exposure; this time fran1e will allow the full extent of tissue injury to become apparent. The use of corticosteroids in cases witl1 significant esophageal mucosal injury is controver­ sial. Corticosteroids decrease inflanuna­ tion and may aid in minimizing stricture formation, but t11ey also suppress the immune system and may enhance susceptibility to secondary infection. In animals with significant oral and/or esophageal burns, gastrostomy tubes may be necessary to provide nutrition while affected tissues heal. Dermal or ocular exposures should be managed by flushing with copious amounts of water or physiologic saline; eyes should be flushed for a minimum of 20 min, followed by fluorescein staining. Standard topical treatments for dermal or ocular burns should be instituted as needed.

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HOUSEHOLD HAZARDS

Alkaline Batteries Ingestion of alkaline batteries poses. a risk of GI tract corrosive injury and foreign body obstruction. Dogs are most commonly involved. Etiology: Alkaline batteries are present in many household electronic products, including remote controls, hearing aids, toys, watches, computers, and calculators. Most alkaline dry cell batteries use potassiwn hydroxide or sodiwn hydroxide to generate currents. Nickel-cadmiwn and lithium batteties also tend to contain alkaline material. Pathogenesis: The alkaline gel in batteties causes liquefactive necrosis of tissues on contact, resulting in bums that can penetrate deeply into tissue. Lithiwn disk or "button" batteties may lodge in the esophagus and generate a current against the esophageal walls, resulting in circular ulcers that have the potential to be per­ forating. Some battery casings may contain metals such as zinc or mercury, posing hazards of foreign body obstruction and metal toxicosis if they remain in the stomach for prolonged petiods. Additionally, small batteties (especially disk batteries) may be inhaled and pose a choking hazard. Clinical Findings and Lesions: For discussion of alkaline burns, see p 3001. For­ eign body obstruction may present as vomit­ ing, anorexia, abdominal discomfort, or tenesmus. Respiratory obstruction due to battery inhalation may present with acute onset of dyspnea and cyanosis. Mucosa! bums may occur within the oral cavity, esophagus, and less commonly, stomach. Perforation of the esophagus may lead to secondary pyothorax, while gastric perforation may result in acute blood loss and/or peritonitis. Diagnosis: Radiographs may help to confirm the diagnosis as well as the location of the battery; however, some disk batteries do not show up well on radio­ graphs. Differential diagnoses include GI or respiratory foreign bodies and other oral, dermal, or ocular corrosive agents. Treatment: For batteries swallowed intact without any chewing, induction of emesis may result in expulsion. Because of the risk of leakage of alkaline gel onto oral and esophageal mucosa during vomiting, emesis should not be induced if there is any possibility that the battery

3003

casing has been punctured. When disk batteries have been ingested, 20 mL boluses of tap water every 15 min will decrease the severity and delay the development of current-induced esophageal ulceration. The decision on whether to remove a battery from the stomach depends on the size of the animal,.battery size, and evidence of battery puncture. Radiography may be performed to determine the location of the battery casing; generally, batteries that have passed through the pylorus will pass through the intestinal tract uneventfully (adding bulk to the diet and judicious use of cathartics may facilitate passage). Serial radiography to verify battery location is recommended until the battery is expelled. Batteries that do not pass through the pylorus within 48 hr of ingestion are unlikely to pass on their own and may require surgical or endoscopic removal. Batteries that have obviously been punctured should be removed surgically to prevent gastric or intestinal ulceration due to leakage of alkaline gel. Endoscopic removal is not recommended in cases in which it is suspected that the battery casing has been punctured. Treatment of cases with suspected oral, esophageal, or gastric ulceration is the same as for other alkaline corrosive injuries (seep 3001). Dermal or ocular exposures to alkaline gels should be managed by copious rinsing of the area with tap water (skin) or physiologic saline solution (eyes). The affected areas should be monitored for development of ulcers, and topical therapy administered as needed. Cationic Detergents Exposure to cationic detergents may result in local corrosive tissue injury as well as severe systemic effects. All species are susceptible. Cats are at increased tisk of oral exposure because of grooming habits. Etiology: Cationic detergents are present in a variety of algicides, germi­ cides (including quaternary ammonium compounds), sanitizers, fabric softeners (including dryer softener sheets), and liquid potpourris. Concentrations of cationic detergents �2% have been associated with oral mucosa! ulcers in cats. Pathogenesis: Cationic detergents are locally corrosive agents, causing dennal, ocular, and mucosa! injury similar to that

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HOUSEHOLD HAZARDS

of alkaline corrosive agents. Additionally, exposure to cationic detergents may result in systemic effects ranging from CNS depression to pulmonary edema. The mechanism for these systemic effects is not known. Clinical Findings and Lesions: Signs

of oral exposure include oral ulceration, stomatitis, pharyngitis, hypersalivation, swollen tongue, depression, vomiting, abdominal discomfort, and increased upper respiratory noises within 6-12 hr of ingestion. Affected animals frequently have significant fever and increases in WBC counts. Systemic effects include metabolic acidosis, CNS depression, hypotension, coma, seizures, muscular weakness and fasciculation, collapse, and pulmonary edema. Dermal irritation, erythema, ulceration, and pain are possible with dermal contact. Conjunc­ tivitis, blepharospasm, eyelid edema, lacrimation, and corneal ulceration may be seen secondary to ocular exposure. Lesions can include GI, ocular, or dermal irritation or ulceration. Treatment: Systemic signs should be

treated symptomatically, eg, diazepam (0.5-2 mg/kg, slow IV) for seizures, fluid therapy for hypotension, etc. Because of the potential for corrosive mucosa] injury, induction of emesis and administration of activated charcoal are contraindicated with cationic detergents. For recent oral exposures, milk or water can be given for dilution, and the anin1aJ monitored for development of oral or esophageal burns. Oral burns should be treated the same as other corrosive injuries (seep 3001). Dermal and ocular exposures should be managed by thorough flushing of the affected area with tepid water or physio­ logic saline, followed by monitoring for development of dem1aJ or ocular irritation or ulceration. Topical treatment for dem1al or ocular burns should be instituted as needed; in severe cases, analgesics may be indicated.

DETERGENTS, SOAPS, AND SHAMPOOS Exposures to products containing anionic and nonionic detergents generally cause mild GI irritation that responds well to symptomatic care. All animals are susceptible. Etiology: Mild detergents, soaps, and shampoos contain anionic and nonionic

detergents; products included in this group include human and pet shan1poos, liquid hand dishwashing soaps, bar bath soaps (except homemade soaps, which may contain lye), many laundry detergents, and many household all-purpose cleaners. Most are of moderate pH, but agents with pH>11 (eg, electric dishwasher detergents) are alkaline coITosives and should be treated as such (seep 3001). Pathogenesis: Anionic and nonionic detergents are mild irritants; many have been pH adjusted to have minirnaJ dermal irritation, although ocular and nrncosaJ irritation is possible. There is no appreci­ able systemic absorption of these a.gents, and toxicity is limited to ocular, oral, or GI ir1itation, which is usually mild and self-linliting. Ca.ts exposed to undiluted shampoos or other products containing sodium lauryl sulfate may develop signi­ ficant respiratory compronlise after inhalation during groonling, including dyspnea, increased bronchial secretions, and nlild pulmonary edema. Although the exact mechanism of this syndrome is not known, it may relate to interference by the detergent with normal pulmonary surfactants. Clinical Findings: Nausea, vomiting,

and diarrhea are the most common signs. Secondary dehydration and electrolyte in1balance may develop in rare instances due to protracted vomiting or diatThea. Mild ocular irritation is possible, with lacrima­ tion and blepharospasm. No significant lesions beyond mild local irritation are seen. Cats grooming after application of sodium lauryl sulfate-containing products may develop moist respiratory sounds, cyanosis, and dyspnea within 1-3 hr of exposure.

Treatment: Dilution witl1 milk or water

may reduce the risk of spontaneous vomiting. Vonliting is usually self-limiting and responds to short periods of food a11d water restriction. In severe cases or in aninlals with sensitive stomachs, antiemet­ ics may be required (eg, metoclopranlide, 0.2-0.4 mg/kg, PO, SC, or IM, qid). Rarely, parenteral fluid therapy is required to correct electrolyte or hydration abnom1ali­ ties due to protracted vomiting or diarrhea. For ocular exposures, irrigation of eyes using tepid water or physiologic saline for 5 min will usually suffice. For cats that have respiratory compromise, supplemental oxygen and general supportive care are recommended; in most cases, signs resolve within 24 hr.

MYCOTOXICOSES

3005

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MYCOTOXICOSES For discussion of mycotoxicoses in poultry,

see p2846.

Acute or chronic toxicoses can result from exposure to feed or bedding contami­ nated with toxins produced during growth of various saprophytic or phytopathogenic fungi or molds on cereals, hay, straw, pastures, or any other fodder. These toxins are not consistently produced by specific molds and are !mown as secondary (not essential) metabolites that are fom1ed under conditions of stress to the fungus or its plant host. A few principles characterize rnyco­ toxic diseases: 1) The cause may not be immediately identified. 2) They are not transmissible from one animal to another. 3) Treatment with drugs or antibiotics has little effect on the course of the disease. 4) Outbreaks are often seasonal, because particular climatic sequences may favor fungal growth and toxin production. 5) Study indicates specific association with a particular feed. 6) Large numbers of fungi or their spores found on examina­ tion of feedstuffs does not necessarily indicate that toxin production has occurred. However, absence of molds does not exclude mycotoxicosis, because feed storage or preparation conditions, eg, acid treatment or high pelleting, can destroy molds while the heat-tolerant mycotoxin persists. Diagnosis of mycotoxic disease requires a combination of information. Most veteri­ nary mycotoxicoses are found in large aninlal species, but important outbreaks can happen in pets and exotic aninlals. Especially impo1iant in diagnosis is the presence of a disease documented to be caused by a !mown mycotoxin, combined with detection of the mycotoxin in either feedstuffs or animal tissues. Sometimes more than one mycotoxin may be present in feedstuffs, and their different toxicologic properties may cause clinical signs and lesions inconsistent with tliose seen when animals are dosed experimentally with pure, single mycotox­ ins. Some mycotoxins are immunosuppres­ sive, which may allow viruses, bacteria, or parasites to create a secondary disease that is more obvious than tl1e primary. When immunosuppression by a mycotoxin is

suspected, differential diagnoses must be carefully established by thorough clinical and historical evaluation, examination of production records, and appropriate diagnostic testing. Mycotoxicoses are generally not successfully treated with medical therapy after diagnosis. A preventive approach with recognition of risk factors and avoiding or reducing exposure is pre­ ferred. Best management practices are aimed at prevention of the occurrence of mycotoxins, inactivation of the pre­ formed toxin in grain or feed, and adsorption or inactivation of the toxin in the GI tract. Testing of suspect grain at harvest, maintaining clean and dry storage facilities, using acid additives (eg, propionic acid) to control mold growth in storage, ensuring effective air exclusion in silage storage, and reducing storage time of prepared feeds are established procedures to prevent mycotoxin forma­ tion. Acidic additives control mold growth but do not destroy preformed toxins. There are no specific antidotes for mycotoxins; removal of the source of the toxin (ie, the moldy feedstuff) eliminates further exposure. The absorption of some mycotoxins (eg, aflatoxin) has been effea ctively prevented by aluminosilicates. If financial circumstances do not allow for disposal of the moldy feed, it can be blended with unspoiled feed just before feeding to reduce tne toxin concentra­ tion. This approach should be monitored by follow-up toxin analysis and may not be acceptable to regulatory agencies. Alternatively, feed with known myco­ toxin concentrations can be fed to less susceptible species, remembering that some mycotoxins such as aflatoxin could result in violative food residues in the absence of illness. When contaminated feed is blended witn good feed, care must be taken to prevent further mold growth by the toxigenic contaminants. This may be accomplished b y thorough drying or by addition of organic acids (eg, propionic acid). Important mycotoxic diseases occur in domestic anin1als worldwide (see TABLE 1).

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MYCOTOXICOSES

itM•il MYCOTOXICOSES IN DOMESTIC ANIMALS

Regions Where Reported

Disease

Toxins (When Known)

Aflatoxicosis

Aflatoxins

Aspergillus.fiavus, A parasiticus

Widespread (wanner climatic zones)

Diplodiosis

Unknown

Diplodia zeae

South Africa

Ergotism

Ergot alkaloids

Claviceps piirpurea Widespread

Paspalinine and paspalitrems, tremorgens

Cpaspali, C cinerea

Widespread

Zearalenone

Fusarium graminearum

Widespread

Estrogenism and vulvovaginitis

Fungi or Molds

Perfect state:

Gibberella zeae

Facial eczema (Pithomycotoxicosis)

Sporidesmins

Pithomyces charlarnm

Widespread

Fescue foot

Ergovaline

Neotyphodium coenophialum

USA, Australia, New Zealand, Italy

Fusariotoxicosis, vomiting and feed refusal in pigs

Nonmacrocyclic trichothecenes (deoxynivalenol, T-2 toxin, diacetoxyscirpenol [DAS], many other trichothecenes)

Fusarium sporotrichioides, Fculmorum, Fgraminearum, Fnivale; other

Widespread (except for deoxynivalenol, more likely in temperate to colder climates)

Fumonisin B,

Fusarium verticilloides

Egypt, USA, South Africa, Greece

Phomopsis leptostromiforrnis

Widespread

Leukoencephalomalacia

Mycotoxic lupinosis Phomopsins (as distinct from alkaloid poisoning)

fungal species

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MYCOTOXICOSES

•t#:iil• MYCOTOXICOSES IN DOMESTIC ANIMALS

3007

(continued)

Contaminated Toxic Foodstuff

Animals Affected

Signs and Lesions

Moldy peanuts, soybeans, cottonseeds, rice, sorghum, corn (maize), other cereals

All poultry, pigs, cattle, sheep, dogs

Major effects in all species are slow growth and hepatotoxicosis. See also AFLATOXICOSIS, p 3011, and MYCOTOXICOSES IN POULTRY, p 2846.

Moldy corn (maize)

Cattle, sheep

Nervous system disorders, cold and insensitive limbs. Recovery usual on removal of source.

Seed heads of many grasses, grains

Cattle, horses, pigs, poultry

Peripheral gangrene, late gestation suppression of lactation initiation. Seep 3012.

Seed heads of paspalum grasses

Cattle, horses, sheep

Acute tremors and ataxia. See PASPALUM STAGGEllS, p 3019.

Moldy corn (maize) and pelleted cereal feeds, standing corn, corn silage, other grains

Pigs, cattle, sheep, poultry

Vulvovaginitis in pigs, anestrus or pseudopregnancy in mature sows, early embryonic death of swine embryos, estrogenism in cattle and sheep, reduced egg produc­ tion in poultry. See also p 3014.

Toxic spores on pasture litter

Sheep, cattle, farmed deer

See also p 3015.

Tall fescue grass (Lolium arundinacea)

Cattle, horses

Lameness, weight Joss, hyper­ therrnia, heat intolerance, dry gangrene of extremities, agalactia, thickened fetal membranes. See also p 3016.

Cereal crops, moldy roughage

Pigs, cattle, horses, poultry

Vomiting and feed refusal (deoxynivalenol), loss of appetite and milk production, diarrhea, staggers, skin irritation, immuno­ suppression; recovery (from T-2, DAS) on removal of contaminated feed. See also p 3020.

Moldy corn (maize)

Horses, other Equidae, pigs

Depends on degree and specific site of brain lesion. See also p 3017.

Moldy seed, pods, stubble, and haulm of several Lupinus spp affected by Phomopsis stem blight

Sheep, occasion­ ally cattle, horses, pigs

Lassitude, inappetence, stupor, icterus, marked liver injury. Usually fatal. See also p 3018. (continued)

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3008

MYCOTOXICOSES

•4H•J• MYCOTOXICOSES IN DOMESTIC ANIMALS Disease Myrotheciotoxico­ sis, dendrodochio­ toxicosis

Ochratoxicosis

Fungi or Molds

Regions Where Reported

Macrocyclic trichothecenes (verrucarins, roridins, etc)

Myrothecium verrucaria, M roridum

Southeast Europe, former USSR

Macrocyclic trichothecenes (baccharinoids)

M verrucaria

Brazil

Ochratoxin,also citrinin

Aspergillus ochraceus and others, Penicillium viridicatum, Pcitrinum

Widespread

P crustosum, P cyclopium, P commune

Widespread

Toxins (When Known)

Penicillium-associ- Penitrem A ated tremorgens

Perennial ryegrass staggers

(continued)

Roquefortine

P roqueforti

Lolitrems

Lolium perenne, Neotyphodium lolii, an endophyte fungus confined to

Australia, New Zealand,Europe, USA

L perenne Poultry hemorrhagic syndrome

Probably aflatoxins and rubratoxins

Probably Aspergillusfiavus, A clavatus, Penicillium purpurogenum, Alternaria, sp

USA

Pulmonary edema, emphysema

4-lpomeanol

Fusarium solani

USA

Porcine pulmonary edema

Fumonisin 8 1 and Fumonisin 82

Fusarium verticilloides

USA,South Africa

Slobbers syndrome

Slaframine (and swainsonine)

Rhizoctonia leguminicola

USA

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MYCOTOXICOSES

•riN•i• MYCOTOXICOSES IN DOMESTIC ANIMALS

3009

(continued)

Contaminated Toxic Foodstuff

Animals Affected

Signs and Lesions

Moldy rye stubble, straw

Sheep, cattle, horses

Acute-dian·hea, respiratory distress, hemorrhagic gastroen­ teritis, immunosuppression, death. Ch�onic-ulceration of GI tract, unthriftiness, gradual recovery. See also p 3020.

Plants of Baccharis spp that contain the toxins

Cattle, other herbivores

Epithelial necrosis of GI tract. See also p 3020.

Moldy barley, corn (maize), wheat

Pigs, poultry

Perirenal edema, enlarged pale kidneys with cortical cysts, and tubular degeneration and fibrosis; immunosuppression, polyuria and polydipsia.

Cereal grains, cheese, fruit, Cattle, dogs, meats, nuts, refrigerated foods; horses, sheep compost

Neurotoxic signs, including continual tremors, seizures, hyperexcitability, ataxia. Vomiting and CNS signs in dogs.

As above, and in silage Endophyte-infected ryegrass pastures

Sheep, cattle, horses, deer

Tremors, incoordination, collapse, convulsive spasms. See also RYEGRASS STAGGERS, p 3153.

Moldy grain and meal

Growing chickens

Depression, anorexia, no weight gain, widespread internal hemorrhages, sometimes aplastic anemia, deatl1. See MYCOTOXICOSES IN POULTRY, p 2846.

Moldy sweet potatoes

Cattle

Acute pulmonary edema, leading to interstitial pneumonia and emphysema.

Com

Swine

Acute interlobular pulmonary edema and hydrotl10rax cause anoxia and cyanosis. Survivors may develop icterus and chronic hepatotoxicosis.

Black patch disease, legumes (notably red clover) eaten as forage or hay

Sheep, cattle

Salivation, bloat, diarrhea, sometimes death. Recovery usual when removed from clover. See also SLAFRAMINE TOXICOSIS, p 3019. (continued)

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3010

MYCOTOXICOSES

•#H•i• MYCOTOXICOSES IN DOMESTIC ANIMALS Disease

Toxins (When Known)

(continued)

Fungi or Molds

Regions Where Reported

Stachybotryo­ toxicosis

Macrocyclic trichothecenes (satratoxin,roridin, verrucarin)

Stachybotrys atra (S alternans)

Former USSR, southeast Europe

Sweet clover poisoning

Dicumarol

Penicillium spp, Mucorspp, Aspergillus spp

North America

Tremorgen ataxia syndrome

Penitrems,verruculo­ gen,paxilline, fumitremorgens, aflatrems,roquefortine

Penicillium USA,South Africa, probably crustosum, worldwide P puberulum, P verruculosum, P roqueforti, Aspergillusfiavus, Afumigatus,A clavatus, and others

Managing a Suspected Mycotoxicosis When mycotoxicosis is suspected,correc­ tive actions could include the following: 1) Change the feed even when a specific mycotoxin is not identified. 2) Thoroughly inspect storage bins,mixing equipment,and feeders for caking, molding,or musty odors. 3) Remove contaminated feed and clean equipment and sanitize with hypochlorite (laundry bleach) to reduce contammating fungi. 4) Analyze for lrnown mycotoxins. 5) Use spore counts or fungal cultures for some indication of potential mycotoxin production. 6) lf storage conditions or grain moisture are adverse,use a mold inhibitor to reduce or delay mold growth. Remember, mold inhibitors do not destroy preformed toxins. 7) Use a mycotoxin adsorbent if appropriate for the mycotoxin suspected. 8) Save a representative sample of each diet mixed until animals are at 1 mo beyond when the feed was consumed. 9) Take a represen­ tative sample of suspect feed after rn.illing by passing a cup through a moving auger stream at frequent intervals,mixing samples thoroughly,and saving a 4.5-kg (10-lb) san1ple for analysis. Alternatively, use probe sampling of recently blended grain in bins or trucks at five locations in each structure for each 6 feet of depth. Freeze or dry samples, and subm.it for analysis in a paper bag (not

plastic). Dry samples are preferable in a paper bag to prevent condensation during transport and storage. San1ples should be dried at l 76°-194° F (S0°-90° C) for -3 hr to reduce moisture to 12o/er-13%. lf mold stud.ies are to be done,dry at l 40° F (60° C) for 6-12 hr to preserve fw1gal activity.

Mycotoxin Adsorbents Adsorption ofrnycotoxins in contaminated feeds is an area of active research. A.tlatoxins are effectively adsorbed by the alun1inosili­ cate feed additives (see below). However,this group of adsorbents are of little or limited use for other mycototoxins. Trichothecene rnycotoxins,including deoXYnivalenol,are not readily adsorbed by common feed add.itives. The alun1inosilicate adsorbents tl1at are effective against afiatoxins have lirn.ited or no benefits against trichothecenes. Sodiwn bentonite is an effective adsorbent for afiatoxins in cattle and poultry but appears ineffective for trichothecenes and zearalenone. The polymeric glucomannan adsorbents (GM) are useful for poultry growth and feed conswnption with low natural concentrations of afiatoxin, ochratoxin,T -2 toxin,and zearalenone. When added to Pusarium-contan1inated d.iets, GM reduced the nwnber of stillborn piglets compared witl1 controls. GM adsorbent efficacy for ruminants has been

MYCOTOXICOSES

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•&N•J•

3011

MYCOTOXICOSES IN DOMESTIC ANIMALS (continued)

Contaminated Toxic Foodstuff

Animals Affected

Signs and Lesions

Moldy roughage, other contaminated feed

Horses, cattle, sheep,pigs

Stomatitis and ulceration, anorexia, leukopenia, extensive hemorrhages in many organs, inflammation and necrosis in the gut, inu11unosuppression. See also TRICHOTHECENE TOXJCOSIS, p 3020.

Sweet clover (Melilotus spp)

Cattle, horses, sheep

Vitamin K antagonism with coagu­ lopathy and hemorrhage. See also p 3156.

Moldy feed; high-protein food products, even under reftigeration, eg, cream cheese, walnuts

All species, but dogs are quite susceptible

Tremors, polypnea, ataxia, collapse, convulsive spasms.

variable in different studies. Cholestyramine has been an effective binder of fumonisins and zea.ralenone in vitro and for fumonisins in animal experiments, but response in cattle is unknown. Although various adsorbents are allowed for animal feed in various countries, none is FDA approved in the USA.

AFLATOXICOSIS Aflatoxins are produced by toxigenic strains of AspergiUus jlavus and A pamsiticus on peanuts, soybeans, com (maize), and other cereals either in the field or dtuing storage when moisture content and temperatures are sufficiently high for mold growth. Usually, this means consistent day and night temperatures > 70° F. The toxic response and disease in mammals and poultry varies in relation to species, sex, age, nutritional status, and the duration of intake and level of aflatoxins in the ration. Earlier recog­ nized disease outbreaks called "moldy com toxicosis," "poultry hemorrhagic syndrome," and ''AspergiUus toxicosis" may have been caused by aflatoxins. Aflatoxicosis occurs in many parts of the world and affects growing poultry (especially ducklings and turkey poults), young pigs, pregnant sows, calves, and dogs. Adult cattle, sheep, and goats are relatively resistant to the acute form of the disease but

are susceptible if toxic diets are fed over long periods. Experimentally, all species of animals tested have shown some degree of susceptibility. Dietary levels of aflatoxin (in ppb) generally tolerated are s50 in young poultry, s lOO in adult poultry, s50 in weaner pigs, s200 in finishing pigs, 75° -80°F (24 °-27°C) and if high nitrogen fertilizer has been applied to the grass. Medical treatment for equine agalactia/ reproductive syndrome is dompe1idone administered at 1.1 mg/kg, PO, bid for 10---14 days. For control ai.1d prevention, toxic tall fescue pastures must either be destroyed and reseeded with seed that does not contain endophytic fungus, or infected fields must be managed to avoid the high 1isk factor. Transfer of the fungus from plant to plant is primaiily, if not solely, llu-ough infected seed. Not using pastures drning hot weather, diluting tall fescue pastures with interseeded legwnes, clipping or close grazing of pastures to reduce seed fonnation, or offering other feedstuffs help reduce severity. Removing pregnant horses or cattle l mo before partu1ition will usually prevent parturition­ and lactation-related problems. Specific feed additives may provide some protec­ tion against contaminated hay. Yeast cell delivatives known as glucomatmatlS are reported to in1prove performance by prevent­ ing toxin absorption in cattle; a seaweed product is repo1ted to Jessen the inmluno­ suppressive effects of toxic tall fescue. (See a.I.so ABDOMINAL FAT NECROSIS, p 360.)

FUMONISIN TOXICOSIS Fwnonisins are responsible for two well-desclibed diseases of livestock, equine leukoencephalomalacia and porcine pulmonary edema. Equine leukoencephalomalacia is a mycotoxic disease of the CNS that affects horses, mules, at1d donkeys. It occurs sporadically in North and South An1erica, South Africa, Europe, and China. It is associated with the feeding of moldy com (maize), usually over a period of several weeks. Fwnonisins are produced world­ wide primarily by F'usarium verticillioides (previously Fmonil'if01me Sheldon) at1d Fprolijeratum. Conditions favoring ftunonisin production appeai· to include a period of drought during the growing season with subsequent cool, moist conditions during pollination and kernel fonnation. Tlu-ee toxins produced by the fungi have been classified as fumonisin B, (FB,), B2 (FB2), and B3 (FB3). CuITent evidence suggests that FB, at1d FB2 ai·e of sin1ilar toxicity, whereas FB3 is relatively nontoxic. Com grain may conunonly contain 1-3 ppm fumonisins, but occasionally some years as much as 20---100 ppm. The toxins are concentrated prilnai·iJy in molded, damaged, or light test weight com. Major health effects are seen in Equidae and swine.

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3018

MYCOTOXICOSES

Signs in Equidae include apathy, drowsiness, pharyngeal paralysis, blindness, circling, staggeting, and recwnbency. The clinical comse is usually 1-2 days but may be as short as several homs or as long as several weeks. Icterus may be present when the liver is involved. The characteristic lesion is liquefactive necrosis of the white matter of the cerebrwn; the necrosis is usually unilateral but may be asymmetrically bilateral. Some horses may have hepatic necrosis similar to that seen in aflatoxicosis. Horses may develop leukoencephalomalacia from prolonged exposure to as little as 8--10 ppm fumonisins in the diet, and onset of nemologic signs almost invariably leads to death. Fumonisins have also been repo1ted to cause acute epidemics of disease in weanling or adult pigs, characterized by pulmonary edema and hydrothorax. Porcine pulmonary edema (PPE) is usually an acute, fatal disease and appears to be caused by pulmona.r.y hypertension with transudation of fluids in the thorax, resulting in interstitial pulmona.r.y edema and hydrothorax. Acute PPE results after consumption offumonisins for 3-6 days at dietary concentrations>100 ppm. Morbidity within a herd may be>509i,, and mortality among affected pigs is 500/o--l 000/o. Signs include acute onset of dyspnea, cyanosis of mucous membranes, weakness, recun1bency, and death, often within 24 Ju· after the first clinical signs. Affected sows in late gestation that survive acute PPE may abort within 2--3 days, presumably as a result of fetal anoxia. Prolonged exposure of pigs to sublethal concentrations of fumonisins results in hepatotoxicosis characterized by reduced growth;-icterus; and increased serum levels of cholesterol, bilirubin, AST, lactate dehydrogenase, and -y-gluta.tnyltra.tIBferase. The biochemical mechanism of action for PPE or liver toxicosis is believed to be due to the ability offumonisins to interrupt sphingolipid synthesis in many animal species, and fatalities result from distur­ bances in cardiopulmonary dynamics leading to acute pulmonary edema. Cattle, sheep, and poultry a.r.·e consider­ ably less susceptible to fumonisins than are horses or swine. Cattle and sheep tolerate fumonisin concentrations of 100 ppm with little effect. Dieta.ty concentrations of 150-200 ppm cause inappetence, weight loss, and mild liver da.r.nage. Poultry are affected by concentrations of>200-400 ppm and may develop inappetence, weight loss, and skeletal abnormalities.

No effective treatment is available. Avoidance of moldy corn is the only prevention, although this is difficult because the corn may not be grossly moldy or may be contained in a mixed feed. However, most of the toxin is present in broken or small, poorly fom1ed kernels. Cleaning grain to remove the screenings markedly reduces fumonisin concentration. Corn suspected of containing fumonisins should not be given to horses. Binding offumonisins with glucose has been demonstrated to alleviate or eliminate toxicosis in pigs, but develop­ ment of the process on a commercial scale has not yet been accomplished. Advisory exposure guidelines by the FDA have reco.nm1ended total dieta.ty concentrations (ppm) as follows: horses 900/o; the time to peak serum concentration is -2 hr. In a 14--day study of dogs that received 10 mg/kg, no clinically observable adverse effects were seen. Dogs that received 25 mg/kg/day, 50 mg/kg/day, or 100 mg/kg/day for 10-11 days showed vomiting and melena; no hepatic or renal lesions were seen in these dogs. Dogs ingesting >100 mg/kg should be aggressively decontaminated and treated with IV fluids to prevent renal dan1age. Piroxicam Piroxican1 is an oxicam derivative. It is not approved in dogs and cats but has been used at 0.3 mg/kg, PO, every other day. Piroxican1 in dogs and people has a long half-life (40 hr and 50 hr, respectively) likely due to extensive enterohepatic recirculation. The LD.50 of piroxicam in dogs is > 700 mg/kg. Adverse GI effects were seen in 18% of dogs given piroxica.rn at 0.3 mg/kg/day, PO, for several months. Diclofenac Diclofenac is a phenylacetic acid derivative structmally related to meclofenamate sodium and mefenan1ic acid. After a single injection of diclofenac sqdiw11 at 1 mg/kg in dogs, 35%--400/o is excreted in the mine. The reported oral LD50 of diclofenac sodiw11 in dogs is 500 mg/kg. lndomethacin Indomethacin is an indole acetic acid derivative available as the base and as the sodium trihydrate salt. The drug is structurally and phan11acologically related to another NSAID, sulindac. The reported oral LD50 of indomethacin in rats is 12 mg/kg. Administration of indomethacin to dogs at 2 mg/kg for 30 days resulted in GI ulcers in 600/o of dogs and perforation in 200/o. Etodolac Etodolac, an indole acetic acid derivative, is used for pain relief, osteoarthritis, and rhew11atoid arthritis in people. It is approved in the USA for use in dogs (>12 mo old) to manage pain and inflamma­ tion associated with osteoarthritis. The suggested dosage in dogs is 10-15 mg/kg.

Etodolac is well absorbed orally in dogs, with peak plasma concentration seen in 2 hr. It is primarily excreted through bile, and the half-life in dogs is 8-12 hr. In dogs, etodolac at 40 mg/kg/day was associated with GI ulcers, weight loss, emesis, and local occult blood Joss. Dosages of 80 mg/kg/day caused 6 of 8 dogs to die or become moribund because of GI ulceration. Nabumetone Naburnetone differs from other NSAIDs in that it is neutral as opposed to acidic. The risk of GI ulcers from nabw11etone is considered less than that of other NSAIDs. Nabumetone is primarily excreted in the wine in most species. However, in dogs, when nabun1etone was administered at 20 mg/kg, only 27% of the dose was found in the urine. The reported oral LD50 of nabu.rnetone in rats is >2 glkg. At a dosage of >300 mg/kg, the lower GI tract and the kidneys were affected in rats, mice, rabbits, and rhesus monkeys.

irOXICITIES FROM ILLICIT ND ABUSED DRUGS Exposmes to illicit or abused drugs in pet animals can be accidental, intentional, or malicious. Occasionally, drug-sniffing dogs also ingest these substances. Because of the illegal nature of illicit or abused drugs, owners may provide inaccmate, incom­ plete, or misleading exposw·e histories. Illicit drugs are often adulterated with other pharmacologically active substances, making the diagnosis even more difficult. In suspected cases of exposure to illicit or abused drugs, an attempt should be made to gather infom1ation about the animal's environment; amount of exposme; and time of onset of clinical signs and their type, severity, and dmation. These questions will help include or exclude possible exposme to an illicit or abused drug. Illicit and abused drugs are often known by street names that vary from area to area. A call to a local police station, or anin1al or human poison control center, may help identify the illicit substance if its street name is known. Most human hospitals, emergency clinics, and some veterinary diagnostic laboratories have illicit drug screens available and can check for the presence of illicit drugs or their metabolites in different body fluids. The presence of a parent drug or its metabolites in blood or mine may help confim1 exposme in suspect cases. The laboratories should be contacted for information on the types of samples needed

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TOXICITIES FROM HUMAN DRUGS and time required to complete the screens or tests. Commonly available over-the-counter drug test kits may help exclude a suspected case of illicit drug toxicosis. They are designed to detect drug metabolites in the urine and can detect most commonly available illicit or recreational drugs such as amphetamines, cocaine, marijuana, opiates, and barbitmates. The sensitivities and specificities of these test kits may vary. The kits are inexpensive, efficient, and easy to use, but the instructions provided with each kit should be followed carefully for best results. Amphetamines and Related Drugs

Amphetamines and their derivatives are CNS and cardiovascular system stimulants commonly used in people for suppression of appetite, na.rcolepsy, attention deficit disorder, parkinsonism, and some behavior disorders. Some commonly encountered amphetamines or related drugs a.re benz­ phetamine, dextroamphetan1ine, lisdexam­ fetamine, pemoline, methylphenidate, phente1mine, diethylpropion, phendime­ trazine, methan1phetamine, and phenme­ trazine. Amphetamines sold on the street have common names such as speed, bennies, or uppers. Commonly used adulterants are caffeine, ephedrine, or phenylpropanolamine. Pharmacokinetics and Toxicity:

Amphetantlnes a.re rapidly absorbed in U1e GI tract, reaching peak plasma concentra­ tions in 1-2 hr. Sustained-release formula­ tions have a delayed absorption and relatively longer half-life. The plasma half-life of an1phetamines depends on the urinary pH. With an alkaline pH, the half-life is 15-30 hr; with an acidic pH, the half-life is 8-10 hr. The acute oral LD50 of amphetamine in rats and mice is 10---30 mg/kg. ln people, deaths have been repo1ted after ingestion of metharnphetamine at 1.3 mg/kg. Pathogenesis: Amphetanline stimulates

the release of n01·epinephrine, affecting both c,- and [3-adrenergic receptor sites. Amphetamine also stimulates catechola­ nline release centrally in U1e cerebral c01tex, medullruy respiratory center, and reticulru· activating system. It increases the amount of catecholantlne at ne1ve endings by increasing release and inhibiting reuptake and metabolism. The neurotrans­ mitters affected in the CNS a.re norepineph­ rine, dopanline, and serotonin.

3039

Clinical Findings and Diagnosis:

Clinical signs of ru11pheta.J.11ine and cocaine toxicosis are similar and difficult to differentiate clinically. The only difference may be U1e longer duration of clinical signs of amphetamine toxicosis because the half-life of an1phetamine is longer than U1at of cocaine. The most commonly reported signs a.re hyperactivity, aggression, hyperthennia, tremors, ataxia, tachycru·dia, hypertension, myd1iasis, circling, head bobbing, and death. Diagnosis is as for cocaine (see below) and relies mostly on owner knowledge of exposure. Most amphetamines and related drugs or their metabolites a.re detectable in the stomach contents and urine. They are difficult to detect in plasma unless large runounts have been ingested. Treatment: Phenothiazines are preferred

to control CNS signs in an1pheta.J.1line toxicosis (see below for cocaine toxicosis). Other anticonvulsants, such as diazepam, barbiturates, or isoflurane, may be used if needed. Acidifying the urine with ammo­ nium chloride (25-50 mg/kg/day, PO, qid) or ascorbic acid (20-30 mg/kg, PO, SC, IM, or IV) may enhance ru11phetamine elinlination in the wine. However, this should be done only if acid-base status can be monitored. Cyproheptadine (1.1 mg/kg, PO or per rectun1) may also be given once or twice (6--8 hr apart) for serotonin syndrome (disorientation, muscle stiffness, agitation). Heart rate and rhythm (see p 3040 for using 13 blockers to treat tachycardia), body temperature, and electrolytes should be monitored and treated as needed. Cocaine

Cocaine (benzoylmethylecgonine) alkaloid is obtained from the leaves of the coca plant, Erythroxylon coca and E monogym­ num. Some common street names for cocaine a.re coke, gold dust, stardust, snow, C, white girl, white lady, baseball, and speedball (cocaine and heroin). Cocaine alkaloid from coca leaves is processed into cocaine hydrochloride salt, then repro­ cessed to form cocaine alkaloid or free base (a process called free-basing or base balling), which is colorless, odorless, tra.J.1Spa.rent, and more heat stable. Free-base cocaine is also called crack, rock, or flake. Cocaine is cut (diluted) several times before it reaches the user. Xanthine alkaloids, local anesthetics, and deconges­ tants a.re some of the most common adulterants.

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TOXICITIES FROM HUMAN DRUGS

Cocaine is a schedule II drug approved for hwnan use. Its medical uses are restricted to topical administration as a local anesthetic on mucous membranes of the oral, laryn­ geal, and nasal cavities. However, it is mostly used as a recreational drug.

Pharmacokinetics and Toxicity:

Cocaine is absorbed from most routes. Orally, it is better absorbed in an alkaline mediwn (ie, intestine). In people, -200;6 of an oral dose is absorbed. The reported plasma half-life is 0.9-2.8 hr. Cocaine is extensively metabolized by liver and plasma cholines­ terases to several inactive metabolites that are p1imarily excreted in the urine. The acute LD5() of cocaine hydrochloride administered IV in dogs is 13 mg/kg; the LD IOo is 12 mg/kg in dogs and 15 mg/kg in cats. The oral LD5() in dogs is believed to be 2-4 times more than the IV dose.

Pathogenesis: Cocaine acts on the sympathetic division of the autonomic nervous system. It blocks the reuptake of dopamine and norepinephrine in the CNS, leading to feelings of euphoria, restlessness, and increased motor activity. Cocaine can also decrease concentrations of serotonin or its metabolites. Topical use of cocaine causes vasoconstriction of small vessels. Hyperthem1ia in cocaine toxicosis may develop either due to increased heat production from muscular activity or due to decreased heat loss from vasoconstriction. Clinical Findings and Diagnosis: CNS excitation, hyperactivity, shaking, ataxia, panting, agitation, mydriasis, nervousness, seizures, tachycardia, hype1tension, acidosis, or hyperthem1ia characterize cocaine toxicosis. CNS depression and coroa may follow CNS excitation. Death may be due to hyperthermia, cardiac arrest, or respiratory arrest. Some nonspecific chemistry changes may include hyperglycemia and increased CK and liver-specific enzymes. Diagnosis is based on a history of exposure and the presence of characteristic clinical signs. Identification of cocaine in plasma, stomach contents, or urine can confirm exposure. Differential diagnoses include amphetamines, pseudoephedrine, ephedrine, caffeine, chocolate, metalde­ hyde, strychnine, tremorgenic mycotoxins, lead, nicotine, perrnethrin (cats) and other pesticides, and encephalitis. Treatment: The objectives of treatment are GI decontamination, stabilization of CNS and cardiovascular effects, thennoregula­ tion, and supportive care. Anin1als with

clinical signs should be stabilized first before attempting decontamination. Emesis can be induced in a recent exposure if the anin1al is asymptomatic and has tl1e ability to guard its airway via a gag reflex. This should be followed by administration of activated charcoal with a cathartic. lithe anin1al's condition contraindicates induction of emesis (eg, presence of CNS signs or extreme tachycardia), a gastric lavage with a cuffed endotracheal tube to reduce the risk of aspiration should be perfonned. A dose of activated charcoal with a cathartic should be left in the stomach after the lavage. Controlling the CNS signs may require use of more than one anticonvulsant. Clinical signs of CNS excitation can be controlled with diazepam; however, the effects of diazepam are short-lived, and repeated administration may be needed. Phenothia­ zine tranquilizers such as acepromazine (0.05----1 mg/kg, IV, IM, or SC, repeated as needed) or chlorpromazine (0.5----1 mg/kg, IV or IM) also usually work well to control the CNS effects. However, phenothiazines should be used cautiously, because they may lower the seizLu-e threshold. lf phenothia­ zines are ineffective, phenobarbital at 3-4 mg/kg, IV, or pentobarbital, IV to effect, could be used. lf CNS signs are uncontrolled by the preceding measures, a gas anesthetic such as isoflw·ane may be useful. Blood pressure, heart rate and rhythm, ECG, and body temperature should be moni­ tored frequently and treated as needed. Propranolol at 0.02-0.06 mg/kg, IV, tid-qid, or other 13-blocking agents such as esmolol (0.2-0.5 mg/kg, slow IV over 1 min, or 25----200 mcg/kg/min as a constant-rate infusion) can be used to control tachycardia. After CNS and cardiovascular effects have been stabilized, IV fluids should be administered, and electrolyte changes and acid-base status monitored and corrected as needed. Treatment and monitoring should continue until all clinical signs have resolved.

Ecstasy (MDMA or 3,4-Methylene­ dioxymethamphetamine) Ecstasy is a semisynthetic psychoactive designer drug (developed by street chemists with minor structural changes in parent compounds) with hallucinogenic and an1phetarnine-like properties. Street nan1es include Adam, XTC, E, Roll, X, or Love Drug. A typical dose may be 75----150 mg. MDMA is believed to cause excessive release of serotonin. It also binds to serotonin transporter (a protein), which is responsible for removing serotonin from the synapse. The overall effect is increased serotonin and

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TOXICITIES FROM HUMAN DRUGS

serotonergic effects. MDMA also affects dopamine and norepinephrine. Studies in rodents indicate that use of MDMA can lead to permanent serotonergic neuronal injury. In pets, MDMA toxicosis is not conunon. It is usually acute and occurs from accidental ingestion (powder, pills, or capsules). Clinical signs develop within 30 min to 2hr after ingestion and may consist of syrnpathomirnetic effects (CNS excitation, agitation, hyperactivity, pacing, hyperthermia, tachycardia, hype1tension, seizures LJust like an1phetarnines ]), sedation, or signs thought to be related to hallucination ( vocalization, disorientation, muscle rigidity). The half-life in people is 7.6-8. 7 hr. Treatment is similar to that for amphetamine toxicosis (seep 3039). For serotonergic effects (agitation, muscle rigidity, nervousness), antiserotonergic drugs such as cyproheptadine can be tried (1.1 mg/kg, PO, repeated once in 6-8 hr). Marijuana Marijuana refers to a mixture of cut, dried, and ground flowers, leaves, and sterns of the leafy green hemp plant Cannabis saliva. Several cannabinoids are present in the plant resin, but delta-9-tetra11ydrocannabi­ nol (THC) is considered the most active and main psychoactive agent. The concentration of THC in marijuana varies between lo/o-8"Ai. Hashish is the resin extracted from the top of the flowering plant and is higher in THC concentration than marijuana. Street names for marijuana include pot, Mary Jane, hashish, weed, grass, THC, ganja, bhang, and charas. Pure THC is available by prescrip­ tion under the generic name dronabinol. A synthetic cannabinoid, nabilone, is also available. Marijuana or hashish sold on the streets may be contaminated with phency­ clidine, LSD, or other drugs. Marijuana is a schedule I controlled substance mostly used by people as a recreational drug. It is also used as an antiemetic for chemotherapy patients and to decrease intra.ocular pressure in glaucoma patients. Some clinicians advocate the use of dronabinol as an appetite stimulant, but tl1e dysphoric effects of this drug outweigh any benefit of appetite stimulation. Synthetic marijuana is a designer drug in which different herbs or incense or other leaJy materials are sprayed with laboratory­ synthesized chemicals. The use of syntl1etic marijuana produces psychoactive effects similar to those of THC. It is often claimed to be natural, safe, and legal. Spice, K-2, skunk, and moon rocks are some ofilie

3041

conunon street names. Clinical signs of toxicosis from ingestion of synthetic marijuana in dogs can be more severe and last longerilian those of THC. Pharmacokinetics and Toxicity: The most conunon route of exposure is oral. After ingestion, THC goes through a substantial first-pass effect. It is metabo­ lized by liver microsomal hydroxylation and nonmicro oma.l oxidation. In dogs, clinical signs begin within 30-90 min and can last up to 72 hr. THC is highly lipophilic and readily distributes to the brain and other fatty tissues after absorption. The oral LD50 of pure THC is 666 mg/kg in rats and 482mg/kg in mice. However, clinical effects of marijuana are seen at much lower doses than this. Pathogenesis: THC is believed to a.ct on a unique receptor in the brain that is selective for canna.binoids and is responsi­ ble for the CNS effects. Cannabinoids can enhance the fo1mation of norepinephrine, dopamine, and serotonin. They can also stimulate release of dopa.mine and enhance -y-aminobutyric acid turnover. Clinical Findings and Diagnosis: The most conunon signs of marijuana toxicosis arc depression, ataxia, bradycardia, hypo­ the1mia, vocalization, hypersalivation, vomiting, diarrhea., uiina.ry incontinence, seizures, and coma. Diagnosis is based on a history of exposure and typical clinical signs. THC is difficult to detect in body f1uids because of. the low levels foui1d inilie plasma. Urine testing at human hospitals or using an over-the-counter marijuana. drug test kit in the early course of exposure may help confirm the diagnosis. Marijuana toxicosis can be confused with ethylene glycol (antifreeze, seep 3046) or ivennectin Loxicosis; hypoglycemia; benzodia.zepine, barbiturate, or opioid overdose; interve1te­ bral disc problems; or head trauma. Treatment: Treatment consist.s of supportive ca.re. If the exposure is recent and there are no contraindications, emesis should be induced and activated charcoal administered. Comatose animals should be monitored for aspiration pneun10nia., given IV f1uids, treated for hypothermia., and rotated frequently to prevent dependent edema or decubital ulceration. Dia.zepa.m can be given for sedation or to control seizures. Treatment and monitoring should continue until all clinical signs have resolved (up to 72 hr in dogs). For cases of

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TOXICITIES FROM HUMAN DRUGS

synthetic marijuana toxicosis, in addition to the preceding treatment options, use of IV lipid emulsion solution may be considered.

Opiates

The term opiate initially referred to all naturally occLUTing alkaloids obtained from the sap of the opiLUn poppy (Papave,· somniferum). Opium sap contains mo1phine, codeine, and several other alkaloids. Cun·ently, opioid refers to all drugs, nat ural or syntl1etic, tl1at have morphine-like actions or actions mediated through opioid receptors. Structurally, opioids can be divided into five classes. Some of the common agents within each class are 1) phenanth.renes-morphi.ne, heroin, hydromorphone, oxymorphone, hydrocodone codeine and oxycodone· 2) morphina.n'-butorphanol; 3) diphen�l­ heptanes-methadone and propoxyphene; 4) phenylpiperidi.nes-meperidi.ne, diphenoxyiate, fentanyl, loperan1ide, and profadol; and 5) benzomorphans-pentazo­ cine and buprenorphine. Some of tl1e widely used opioids in veterinary medicine include trarnadol, buprenorphine, fentanyl, loperan1ide (antidiarrheal), and hydromor­ phone. The use of meperidine is no longer conunon. Opioids are used primarily for anal­ gesia. In addition, they are used as cough suppressants and to treat diarrhea Occasionally, opioids are used for sedation before smgery and as a supplement to anestl1esia.

Pharmacokinetics and Toxicity: Opi­ oids are generally well absorbed after oral, rectal, or Parenteral administration. Some more lipophilic opioids are also assorbed through n asal, buccal, respiratory(heroin, fentanyl, bu.prenorphine), or transdennal (fentanyl) routes. For some opioids, there is variable reduction in bioavailability because of a first-Pass effect when given orally. Opioids generally undergo hepatic metabolis111 with some fom1 of conjugation, hydrolysis, oxidation, dealkylation, or glucuronidation. Because cats are deficient in glucuronidase, the half-life of some opioids in cats may be prolonged. After absorption, opioids a.re rapidly cleared from blood and stored in kidney, liver, brain, lung, spleen, skeletal muscle, and placental _ tissue. Most of the opioid metabolites are excreted tl1.rough the kidneys. Toxicity of opioids in anin1als is highly variable. I n dogs, morphine administered at 100-200 mg/kg, SC or IV, is considered lethal. The estimated lethal dose of codeine

in hLUnan adults is 7-14 mg/kg; in infants, 2.5 mg of hydrocodone has been letl1al.

Pathogenesis: The effects of opioids are due to their interaction with opiate receptors(µ, K, l'i, er, ands) foLU1d in the limbic system, spinal cord, thalamus, hypothalan1us, striatum, and midbrain. Opioids may be agonists, mixed agonist­ antagonists, or antagonists at these receptors. Agonists bind and activate a receptor, whereas antagonists bind with­ out causing activation. Clinical Findings: The prin1ary effects of opioids are on the CNS, respiratory, cardiovascular, and GI systems. Conunonly reported clinical signs of toxicosis include CNS depression, drowsiness, ataxia, vomiting, seizmes, miosis, coma, respira­ tory depression, hypotension, constipation/ defecation, and death. Some animals-espe­ cially cats, horses, cattle, and swine--can show CNS excitation instead of CNS depres­ sion. Diagnosis: Diagnosis of opioid toxicosis is based on history of exposme and tl1e types of clinical signs(CNS and respiratory depression) present. Plasma opioid levels are usually not clinically useful. Urine may be used to detennine exposme to opioids using some of the over-the-counter illicit drug kits(manufacturer's instructions should be followed). Opioid toxicosis should be differentiated from ethylene glycol, ive1mectin, benzodiazepine, barbitmate, and marijuana toxicosis, as well as hypoglycemia-inducing conditions. Treatment: Clinical signs can be reversed

witl1 the opiate antagonist naloxone. The dosages in different species are dog and cat, 0.04-0.16 mg/kg, IV, IM, or SC; rabbit and rodent, 0.01-0.1 mg/kg, SC or IP; horse, 0.01-0.02 mg/kg, IV. Administration of naloxone should be repeated as needed (hourly), because its duration of action may be shorter than tl1at of the opioid toxicity being treated. A.tlin1als should be closely monitored for respiratory depression and ventilatory support provided if.needed. Other signs should be treated syn1ptomati­ cally. Dysphoric reactions (vocalization, agitation, restlessness, and excitation) can be treated with diazeparn or otl1er benzodiazepines. For serotonin-like syndrome( disorientation, muscle rigidity, agitation) induced by some opioids, cyproheptadine (1.1 mg/kg, PO or per rectrnn) once or twice (6-8 hr apart) can be tried.

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NON PROTEIN NITROGEN POISONING

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NONPROTEIN NITROGEN POISONING (Ammonia toxicosis) P oisoning by ingestion of excess urea or other sources of nonprotein nitrogen (NPN) is usually acute, rapidly progressive, and highly fatal.NPN is any source of nitrogen not present in a polypeptide (precipitable protein) fonn. Sources ofNPN have different toxicities in various species, but mature ruminants are affected most commonly. After ingestion, NPN undergoes hydrolysis and releases excess ammonia (NH3) into the GI tract, which is absorbed and leads to hyperammonemia. Etiology: Ruminants useNPN by con­ verting it via the nuninal microflora to anm1onia, which is then combined with carbohydrate-derived keto acids to fonn amino acids. The most conm1on sources ofNPN in feeds are urea, urea phosphate, ammonia (anliydrous), and salts such as monoammoniwn and dia.nm1oniw11 phosphate. Because feed-grade urea is Wlstable, it is formulated (usually pelleted) to prevent degradation toNH3. Biuret, a less toxic source ofNPN, is being used less frequently than in the past.Natural protein sources such as rice hulls, beet or citrus pulp, cottonseed meal, and straw or other low-{!uality forages may be treated with anllydrous an1monia to increase available nitrogen in supplemented livestock diets. Fermentation byproducts from alcohol (ethanol) manufacture are a source ofNPN that comes from incomplete proteins, and these products are conm10.nly used in liquid or feed supplements. Most sources ofNPN are provided to nuninants by direct addition of dry supplement to a complete mixed or blended diet, by free-choice access to NPN-containing range blocks or cubes, or by lick tank systems combined w;th molasses as a supplement. Ammonia orNPN poisoning is a common sequela of abrupt change to urea or otherNPN in the diet when only natural protein was previously fed; animals have to be gradually acclimated to NPN so that rumen rnicroflora can increase in nwnbers to use the NH3 produced. Also, farm animals sometimes drink liquid fertilizers or ingest diy granular fertilizers that contain anlllloniwn salts or urea. Ruminants are most sensitive, because urease is normally present in the functional rumen after 50 days of age. Dietary exposure of unacclin1ated ruminants to 0.3-0.5 g of

urea/kg body wt may cause adverse effects; dosages of 1-1.5 g/kg are usually lethal. Urease activ.ity in the equine cecwn is -25% that of the rumen, and horses may receive NPN as a feed additive; however, horses are more sensitive to urea than other monogas­ trics, and dosages ;:,:4 g/kg can be lethal. Ammoniwn salts at 0.3-0.5 g/kg may be toxic in all species and ages of fann animals; dosages ;:>:1.5 g/kg usually are fatal. P igs and neonatal calves are generally Wlaffected by ingestion of urea except for a transient diuresis. Wild birds (silver gulls) rep01tedly have been poisoned after consuming water contaminated with urea fertilizer spillage. Livestock may require days or weeks for total adaptation before nunen microflora can utilize the gradually increasing amoW1ts of urea or otherNPN in the diets; however, adaptation is lost relatively quickly ( 1-3 days) once NPN is removed from the diet. Diets low in energy and high in fiber are more commonly associated withNPN toxicosis, even in acclimated anin1als. Highly palatable supplements (such as liquid molasses or large protein blocks cnunbled by precipitation), range cubes, or improperly maintained lick tanks may lead to conswnption of lethal amounts ofNPN. A related CNS disorder in cattle fed anlllloniated high-{!uality hay, silage, molasses, and protein blocks is thought to be caused by fomiation of 4-methylirnidazole ( 4-MI) through the action ofNH3 on soluble carbohydrates (reducing sugars) in these feedstuffs. C attle fed dietary components containing 4-MI develop a syndrome known as the "bovine bonkers syndrome," named for the wildly abeJTant behavior exhibited. Signs relate to CNS effects, with stampeding, ear twitching, trembling, champing, salivating, and convulsions. Because nursing calves are affected, the toxic principle appar­ ently is excreted in milk Ammoniated low-{J_uality forages do not have sufficient concentrations of reducing sugars to form 4-MI, and thus serve as a relatively safe nitrogen sow·ce for acclimated animals. Another related disorder involves accidental excessive exposure of ruminants (cattle and sheep) to raw soybeans. Soybeans have high concentrations of both carbohydrates and proteins, as well as urease. Overconswnption can cause acute carbohydrate fermentation and excessive

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NONPROTEIN NITROGEN POISONING

ammonia release, resulting in ammonia toxicosis and lactic acidosis. Affected animals have engorged rumens with a gray, amorphous mass inside. Clinical Findings: The period from w·ea ingestion to onset of clinical signs is 20-60 min in cattle, 30-90 min in sheep, and longer in horses. Early signs include muscle tremors ( especially of face and ears), exophthalmia, abdominal pain, frothy salivation, polyuria, and bruxism. Tremors progress to incoordination and weakness. Pulmonruy edema leads to mru·ked salivation, dyspnea, and gasping. Horses may exhibit head pressing; cattle are often agitated, hyperi.rritable, aggressive, and belligerent as toxicosis progresses; sheep usually appear depressed. An eru"ly sign in cattle is ruminal atony; as toxicosis progresses, nuninal tympany is usually evident, and violent struggling ru1d bellowing, a mru·kedjugular pulse, severe twitching, tetanic spasms, and convulsions may be seen. Affected cattle with belligerent aberrant behavior may have produced some 4-MI in vivo tlu·ough reaction of excessive NH3, released from NPN, with cru·bohydrates and reducing sugars in the mmen. The PCV and serwn concentrations of NI-!3, glucose, lactate, potassitm1, phosphoms, AST, ALT, and BUN usually are significantly increased. As death nears, anin1als become cyanotic, dyspneic, anuric, and hyperthermic, and blood pH decreases from 7.4 to7.0. Regurgitation may occur, especially in sheep. Death related to excess NPN usually occw·s within 2 hr in cattle, 4 hr in sheep, ru1d 3-12 hr in horses. Sw-vivors recover in 12-24 hr with no sequelae. Carcasses of animals dying of NPN poisoning apperu· to bloat and decompose rapidly, witl1 no specific chru·acte1istic lesions. Gross brain lesions are not usually repo1ted in NPN-induced rumnonia toxicosis, but histopathologic lesions may include neuronal degeneration, spongy degeneration of the neuropil, and congestion and hemonhage in tl1e pia mater. Frequently, pubnonruy edema, congestion, ru1d petechial hemorrhages may be seen. Mild bronchitis and catru-rhal gastroenteritis are often reported. Regurgitated and inhaled mmen contents ru·e commonly found in the trachea and bronchi, especially in sheep. The odor of NH;, may or may not be appru·ent in ingesta from a freshly opened mrnen or cecwn. A ruminal or cecal pH 80 mg/100 mL in most cases of NPN poisoning and may be >200 mg/100 mL. Acclimated rwninants fed diets !ugh in legun1e hay, soybean meal, cottonseed meal, linseed meal, fish meal, or milk byproducts may have NH3-N concentrations in run1en fluid approaching 60 mg/100 mL witl1 no appru·ent toxicity. The pH of ruminal-reticulru· fluid should also be determined; a pH of7.5-8 (at ti.me of death) is indicative of NPN toxicity. Differential diagnoses include poisonings by nitrate/nitrite, cyru1ide, organophos­ phate/cru·brunate pesticides, raw soybean overload, 4-methylirnidazole, lead, chlorinated hydrocarbon pesticides, and toxic gases (cru·bon monoxide, hydrogen sulfide, nitrogen dioxide); acute infectious diseases; and noninfectious diseases such as encephalopathies (eg, Jeukoencephalo­ malacia, hepatic encephalopathy, polioen­ cephalomalacia), enterotoxemia or run1en autoi.ntoxication, protein engorgement, grain engorgement, rwninal tympany, and pulmonary adenomatosis. Nutritional ru1d metabolic disorders related to hypocalce1nia, hypomagnesenlia, and otl1er elemental aberrations should also be considered.

COAL-TAR PRODUCTS POISONING

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Treatment: Examination and treatment

may be difficult because of sudden and violent behavior. Animals that are recum­ bent and moribund usually do not respond favorably to treatment. If possible, affected animals should be treated by rwninal infusion of 5%acetic acid (vinegar, 0.5-2 Lin sheep and goats and 2--8 L in cattle). Ruminal-reticular fluid specimens for analysis should be taken before acetic acid therapy. Concomitant infusion of iced (0---4°C) water (up to 40 Lin adult cattle, proportionally less in sheep and goats) is also reconm1ended. Acetic acid lowers rumen pH and prevents further absorption of NH3 by converting tmcharged NH3 to the charged anunoniw11 ion (NH4•); administration may have to be repeated if affected animals again show clinical signs. Acetic acid inactivates existing NH3 in the GI tract and rapidly fonns anunoniwn acetate, which can be used by rwnen microflora but does not release NH3. Cold water lowers the rwnen temperatme and dilutes the reacting media, which slows mease activity. In severely affected valuable animals, removed rw11en contents should be replaced with a hay slwTy, and a transfer of some rwnen contents from a healthy animal may serve as an inoculwn to restore nonnal function. Rwninal tympany should be con-ected if indicated, and a trocar may be installed to prevent recun·ence.

3045

Supportive therapy is indicated and includes IV isotonic sal.ine solutions to correct dehydration, and IV calciun1 gluconate and magnesiun1 solutions to relieve tetanic seizures. Convulsions may also be controlled with sodiwn pentobarbi­ tal or other injectable anesthestic agents. Prevention and Control: Urea should not be fed at a rate exceeding 2%-3%of the concentrate or grain pdrtion of ruminant diets and should be limited to �1%of the total diet. Additionally, NPN should constitute no more than one-third of the total nitrogen in the rwninant diet. Once the decision is made to feed NPN, animals must be slowly adapted to, and maintained on, a consistent dietary NPN content with no significant deviation; cows fed range cubes with NPN must receive the cubes daily with no interruptions. Temporary absences of NPN from the diet should be avoided at all costs. Overconsun1ption of palatable liquid supplements can be controlled by the addition of phosphoric acid; l %phosphorus from phosphoric acid should restrict conswnption of liquid supplement to -2 lb/anirnal/day. Although properly adapted adult cattle can tolerate urea at a rate of up to l g/kg body wt/day, a safer feeding rate is no more than half that amow1t.

COAL-TAR PRODUCTS POISONING A variety of coal-tar de1ivatives induce acute to chronic disease in animals, with clinical signs that vary based on the con­ stituents. Clinical effects are acute to chronic hepatic dan1age with signs of icterus, ascites, anemia, and death. Phe­ nolic components may cause renal tubular damage. Coal tar-related poisoning has been reported in faun animals and pets. Etiology: The distillation of coal tar yields a variety of compounds, three of which are notably toxic: cresols (phenolic compounds), crude creosote (composed of cresols, heavy oils, and anthracene), and pitch. Tars are also produced from crude petrolew11 or wood. Creosote contains less volatile liquid and solid aromatic hydrocarbons of coal tar and some phenols. They have been used for restiicted applications as wood prese1va­ tives. Cresols, composed mainly of

hydroxytoluenes, are used in soaps and disirlfectants. Coal-tar and pine-tar pitch are the brown to black, amorphous, polynuclear hydrocarbon residues left after coal tar is redistilled. Access of animals to coal tars is often by direct chewing on or conswnption of product, rather than inclusion in feed or water. Clay pigeons ( older products), tar paper, creosote-treated wood, and bitwnen­ based flooring are typical sources. Phenol is the most important toxicant in coal-tar products and is found in antisep­ tics, creosote, gem1icides, cleaners, and disinfectants. The approxin1ate oral acute LD5() of phenol for most species is 0.5 g/kg, except for cats, which are more susceptible because of limited ability to fom1 glucuron­ ides and excrete phenols. Phenols are directly corrosive, and ingestion results in oral and upper gastroente1ic necrosis. After oral or dermal absorption, phenols

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COAL-TAR PRODUCTS POISONING

accwnulate in the liver and kidneys, conunonly resulting in liver damage and renal tubular necrosis. Cresols are readily absorbed orally and through the skin. The oral lethal dose is 100--200 mg/kg, except in cats, which are more sensitive. Sows in creosote-treated wooden farTowing crates delivered stillborn pigs. Coal tar-s may reduce absorption of vitan1in A by sows. Other species are less susceptible (eg, the leU1al dose of creosote in calves is 4 g!kg). Pitch is no longer used as a binder in clay pigeons, but road asphalt, some insulation, and tar· paper and roofing compounds may still contain cresols. Flo01i.ng wiU1 lignite pitch or asphalt can reduce growth rate and/or cause liver darnage in pigs. Clinical Findings: The cresols and

phenols are locally corrosive, causing necrosis and scarring of skin, mouth, and esophagus; CNS stimulation, trem01-s, and incoordi.nation; ar1d cardiovascular depression and shock. Capillary dan1age and hepatic or renal damage can occm. Icterus can result from intravascular· hemolysis and hepatic darnage. Death can occur from 15 min to several days after exposme. The fu-st sign of pitch poisoning often is several dead animals. Signs may progress to weakness, ataxia, sternal recumbency, icterus, coma, ar1d death. Secondary anemia may develop. Other problems have included stillbirths in pigs ar1d hyperkeratosis in calves. Lesions: Phenols, cresols, and creosote produce contact initation of sl2,000 mg/kg. Dogs have been commonly poisoned with malicious intent by tainting food. Cattle have been reported to be poisoned after consun1ption of forage inadvertently sprayed with methomyl. Propoxur: The oral LD00 is 95 mg/kg in rats and>800 mg/kg in goats. The dermal LD00 in rabbits is> 1,000 mg/kg.

Clinical Findings: The carbanmte

insecticides act similarly to the organophos­ phates (seep 3064) in that they inhibit acety­ lcholinesterase (AChE) at nerve synapses and neuromuscular junctions. This inhibition is reversible because the inhibiting bond is much less durable; thus, the inhibition of blood AChE frequently is not evident at tl1e laboratory. Signs include hypersalivation, GI hypem1otility, abdominal cramping, vomiting, diatThea, sweating, dyspnea, cyanosis, miosis, muscle fasciculations (in extreme cases, tetany followed by weakness and paralysis), and convulsions. In brief, the acronym SLUD (salivation, lacrimation, urination, and diatThea) describes the overall clinical features of carbanmte poisoning. Deatl1 usually results from respiratory failure at1d hypoxia due to bronchoconstriction leading to tracheobronchial secretion and pulmonary edema.

Diagnosis: Diagnosis of carbainate poisoning usually depends on history of exposure to a particular carbainate and response to atropine therapy. However, when a history of carbarnate poisoning is not provided, but cholinergic signs and a clear positive response to atropine suggest carbatnate or organophosphate poisoning, AChE activity levels should be deternlined

in RBCs or whole blood (live animals), or in brain cortex (dead animals). Enzyme activity that is significat1tly inhibited (>50%) is confirmatory. Signs of hypercholinergic activity are usually seen with AChE inhibition>700/o. Screening GI contents for cai·ban1ate insecticides by gas chromatogra­ phy coupled with mass spectrometry is helpful in identification, confirmation, and quantitation of a patticular carbainate ai1d aids in differential diagnosis if an organo­ phosphate insecticide is also involved.

Treatment: Treatment of carban1ate poison­

ing is similar to that of organophosphate poisoning in that atropine sulfate i.r\jections readily reverse the effects. Recommended dosages for atropine ai·e as follows: dogs and cats-dosed to effect (repeated as needed), usually 0.2-2 mg/kg, parenterally, one-fourtll of the dose given IV and the remainder given SC (cats should be dosed at the lower end of the ra11ge); cattle and sheep-0.6-1 mg/kg, one-fou1th of the dose IV and the remainder SC, repeated as needed; horses and pigs-0.1-0.2 mg/kg, IV, repeated as needed. Pralidoxime (2-PAM) should not be used to treat carbainate poisoning. 2-PAM can be beneficial if poisoning is caused by a mixture of organophosphates at1d cai·banmtes. Signs of excessive cholinergic activity may watTant its use, in case the cause is organophosphate exposure. 2-PAM can be fatal if given too rapidly; it must be administered slowly (ie, in 5% saline over a 10-min pe1iod). See also ORGANOPHOSPHATES, p 3064. Also, 2-PAM solution should be prepared freshly, because old solutions are known to produce cyanide. Use of morphine or barbiturates is contrain­ dicated.

CHLORINATED HYDROCARBON COMPOUNDS Because of persistent tissue residues and chronic toxicity, use of chlo1inated hydro­ cai'bon compounds has been drastically ctutailed. Only lindane and methoxychlor are approved for use on or ai·ound livestock. Detectable residues of some chlorinated hydrocarbon insecticides, including BHC, heptachlor, heptachlor epoxide, lindane, and oxychlordat1e, can be found in fatty tissue after acute or chronic exposure. Aldrin: Aldrin is a potent insecticide sinlilar to dieldrin with the san1e order of toxicit;y (see below). !tis no longer registered in the USA but was used for tennite control. The oral LD00 in rats is 39 mg/kg, and the dermal LD00 in rabbits is 65 mg/kg. In fann aninlals, the toxic dose is -15-30 mg/kg.

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INSECTICIDE AND ACARICIDE (ORGANIC) TOXICITY Benzene Hexachloride (BHC, HCH, Hexachlorocyclohexane): Benzene

hexachloride (BHC) is composed of 12%---45% 'I isomer.BHC was a useful insecticide for large animals and dogs but is highly toxic to cats in the concentrations necessary for parasite control. Only the 'I isomer ( '{-BHC, lindane) is a useful insecticidal agent; the other isomers are stored for excessively long periods in body tissues. Lindane, which contains >99"/o of the 'I isomer, should be used in preference to the technical grade ofBHC, which contains several isomers. The oral LDw of lindane in rats is 76 mg/kg, and the dermal LDw in rabbits is 500 mg/kg. Presently,BHC is not sold in the USA Cattle in good condition have tolerated 0.2% lindane applications, but stressed, emaciated cattle have been poisoned from spraying or dipping in 0.075% lindane. Horses and pigs appear to tolerate 0.2%-0.5%, and sheep and goats ordinarily tolerate 0.5% applications. Emaciation and lactation increase tl1e susceptibility of anin1als to poisoning by lindane; such animals should be treated with extreme caution. Young calves a.re very susceptible to lindane and are poisoned by a single oral dose of 4.4 mg/kg. Mild signs appear in sheep given 22 mg/kg, and death occurs at 100 mg/kg. Adult cattle have tolerated 13 mg/kg without signs.BHC is stored in body fat and excreted in milk. Chlordane: Chlordane is no longer registered as an insecticide in the USA Exposure occurs when livestock consume treated plants or when they come in direct contact through carelessness and accidents. The lethal dose of chlordane for most species is in the range of 200-300 mg/kg. Very young calves have been killed by doses of 44 mg/kg, and the minimum toxic dose for cattle is -88 mg/kg. Cattle fed chlordane at 25 ppm of their diet for 56 days showed 19 ppm in their fat at the end of the feeding. Topical emulsions and suspensions have been used safely on dogs at concentrations up to 0.25%, provided freshly diluted materials were used; dry powders up to 5% have been safe. The no-effect level in dogs in a 2-yr feeding study was 3 mg/kg. Pigeons and Leghorn cockerels and pullets suffered no effects after 1- 2 mo exposure to vapors emanating from chlordane-treated surfaces. The oral LDw in rats is 283 mg/kg, and the dern1al LDw in rabbits is 580 mg/kg. Dieldrin: Dieldrin is not a registered pesticide in the USA Residues limit its application, and it is one of the most toxic chlorinated hydrocarbon insecticides. The oral LDw in rats is 40 mg/kg, and the dennal LDw in rabbits is 65 mg/kg. YoW1g dairy calves are poisoned by 8.8 mg/kg, PO, but tolerate

3061

4.4 mg/kg, whereas adult cattle tolerate 8.8 mg/kg and are poisoned by 22 mg/kg. Pigs tolerate 22 mg/kg and are poisoned by 44 mg/kg. Horses are poisoned by 22 mg/kg. Because of its effectiveness against insect pests on crops and pasture and the low dosage per acre, dieldrin is not likely to poison livestock grazing the treated areas. Diets containing 25 ppm of dieldrin have been fed to cattle and sheep for 16 wk witl10ut harmful effects other than residues in fat, which a.re slow to disappear. Great ca.re must be exercised in marketing animals that have grazed treated areas or consumed products from previously treated areas. There is a zero tolerance level for residues in edible tissues. Statements pertaining to dield..Iin also apply, in general, to endrin, the most toxic of the three chlorinated cyclodiene insecticides. Endosulfan: Endosulfa.n is widely used to control insect and mite pests on a variety of crops and orchards. It is heavily used on tobacco. Endosulfan is very toxic to mammalian species. The oral LDw in rats is 18 mg/kg, and the dermal LDw in rabbits is 74 mg/kg. The LD50 of endosulfan in dogs is 77 mg/kg. Its lethal dose in cattle is 8 g. Generally, cattle a.re poisoned by acciden­ tal exposure, and dogs are poisoned by malicious intent. Exposure of cattle to endosulfan produces residues in the liver, kidneys, muscle, and milk. Heptachlor: Heptachlor is not currently registered in the USA and is not recom­ mended for use on livestock in the USA. Among its few agricultural applications, heptachlor is used for residual control of subterranean temtites. The oral LDw in rats is 40 mg/kg, and the dennal LDw in rabbits is 119 mg/kg.Because it is very effective against certain plant-feeding insects, it is encoW1tered from time to time in some geographic areas grazed by livestock. YoW1g dairy calves tolerate dosages as high as 13 mg/kg but are poisoned by 22 mg/kg. Sheep tolerate 22 mg/kg but a.re poisoned by 40 mg/ kg. Diets containing 60 ppm of heptachlor have been fed to cattle for 16 wk without harmful effects other than residues in fat. Heptachlor is converted to heptachlor epoxide by animals and stored in body fat. For this reason, a specific analysis pe1fonned for heptachlor usually yields negative results, while that for epoxide is positive. Methoxychlor: Methoxychlor is one of the safest chlolinated hydrocarbon insecticides and one of the few with active registration in the USA The oral LO"° in rats is 5,000 mg/kg, and tl1e dermal LDw in rabbits is 2,820 mg/kg. YoW1g dairy calves

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3062

INSECTICIDE AND ACARICIDE (ORGANIC) TOXICITY

tolerate 265 mg/kg; 500 mg/kg is mildly toxic. While 1 g/kg produces rather severe poisoning in young calves, sheep are not affected. One dog was given 990 mg/kg/day for 30 days without showing signs. Six applications to cattle of a 0.5% spray at 3-wk intervals produced fat residues of 2.4 ppm; -0.4 ppm of methoxychlor is found in milk 1 day after spraying a cow with a 0.5% concentration. Methoxychlor sprays are not approved for use on animals producing milk for human consumption. Cattle and sheep store essentially no methoxychlor when fed 25 ppm in the total diet for 112 days. If methoxychlor is used as recommended, the established tolerance in fat will not be exceeded. Commercial products are available for garden, orchard, and field crops, and for horses and ponies. Nun1erous reports suggest that methoxy­ chlor has negative reproductive effects in laboratory animal experiments, but this has not been seen in the field. Toxaphene:Toxaphene is no longer under active registration in the USA. It has been used with reasonable safety if recommendations were followed, but it can cause poisoning when applied or ingested in excessive quantities. The oral LD50 in rats is 40 mg/kg, and the dermal LD50 in rabbits is 600 mg/kg. Dogs and cats are particularly susceptible. Young calves have been poi­ soned by 1% toxaphene sprays, while all other fan11 animals except poultry can withstand 1 % or more as sprays or dips. Chickens have been poisoned bY. dipping in 0.1 % emulsions, and turkeys have been poisoned by spraying with 0.5% matetial. Toxaphene is primarily an acute toxicant and does not persist long in the tissues. Adult cattle have been mildly intoxicated by 4% sprays and severely affected by 8%. Adult cattle have been poisoned from being clipped in emulsions that contained only 0.5% toxaphene (an amount ordinarily safe) because the emulsions had begun to break down, allowing the fine droplets to coalesce into larger droplets that readily adllere to the hair of cattle. The resultant dosage becomes equivalent to that obtained by spray treatments of much higher concentra­ tions. Toxaphene is lethal to young calves at 8.8 mg/kg but not at 4.4 mg/kg. The minin1un1 toxic dose for cattle is -33 mg/kg, and for sheep between 22 and 33 mg/kg. Spraying Hereford cattle 12 times at 2-wk intervals with 0.5% toxaphene produced a maximum residue of 8 ppm in fat. Cattle fed 10 ppm of toxaphene in the diet for 30 days had no detectable toxaphene tissue residues, whereas steers fed 100 ppm for 112 days stored only 40 ppm in their fat (this

amount was elinunated 2 mo after the toxaphene was discontinued).

Clinical Findings: The chlorinated

hydrocarbon insecticides are general CNS stimulants. They produce a great variety of signs-the most obvious are neuromuscular tremors and convulsions--and there may be obvious behavioral changes common to other poisonings and CNS infections. Body temperature may be very high. Affected animals are generally first noted to be more alert or apprehensive. Muscle fasciculation occurs, becoming visible in the facial region and extending backward w1til the whole body is involved. Large doses of DDT, DOD, endosulfan, lindane, and methoxychlor cause progressive involvement leading to trembling or shivering, followed by convulsions and death. With the other chlorinated hydrocar­ bons, muscular twitching is followed by convulsions, usually without the intermedi­ ate trembling. Convulsions may be clonic or tonic lasting from a few minutes to several hours, or intermittent and leading to the animal becoming comatose. High fever may accompany convulsions, particularly in warm environments. Behavioral changes such as abnormal postures (eg, resting the sternum on the ground while remaining upright in the rear, keeping the head down between the forelegs, "head pressing" against a wall or fence, or continual chewing movements) may be seen. Occasionally, an affected animal becomes belligerent and attacks other animals, people, or moving objects. Vocalization is common. Some animals are depressed, almost oblivious to their surroundings, and do not eat or drink; they may last longer than those showing more violent symptoms. Usually, there is a copious flow of thick saliva and urinary incontinence. In certain cases, the. clinical signs alternate, with the animal first being extremely excited, then severely depressed. The sevetity of the signs seen at a given time is not a sure prognostic index. Some animals have only a single convulsion and die, whereas others suffer innumerable convulsions but subsequently recover. Animals showing acute excitability often have a fever > 106° F (41 ° C). The signs of poisoning by these insecticides are highly suggestive but not diagnostic; other poisons and encephalitis or meningitis must be considered. Signs of acute intoxication by chlordane in birds are nervous chirping, excitability, collapse on hocks or side, and mucous ex11dates in the nasal passages. Signs of subacute

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INSECTICIDE AND ACARICIDE (ORGANIC) TOXICITY

and chronic intoxication are molting, dehydration and cyanosis of the comb, weight loss, and cessation of egg production. Lesions: If death has occurred suddenly, there may be nothing more than cyanosis. More definite lesions occur as the duration of intoxication increases. Usually, there is congestion of various organs (particularly the lungs, liver, and kidneys) and a blanched appearance of all organs if the body temperature was high before death. The heart generally stops in systole, and there may be many hemorrhages of varying size on the epicardiwn. The appearance of the heart and lungs may suggest a peracute pnewnonia and, if the animal was affected for more than a few homs, there may be pulmonary edema. The trachea and bronchi may contain a blood-tinged froth. In many cases, the CSF volume is excessive, and the brain and spinal cord frequently are congested and edematous. Diagnosis: Chemical analysis of brain, liver, kidney, fat, and stomach or rumen contents is necessary to confinn chlorinated hydrocarbon compound poisoning. The suspected somce, if identified, should also be analyzed. Brain levels of the insecticide are the most useful. Whole blood, serum, and wine from live animals may be analyzed to evaluate exposme in the rest of the herd or flock In food animal poisoning, if exposme is more than just the anin1als visibly affected, fat biopsies from smvivors may be necessary to estin1ate the potential residue. Identification, confirmation, and quantitation of organochlo1ine insecticides are usually done by gas chromatography coupled with mass spectrometry. Treatment: There are no lmown specific antidotes to chlorinated hydrocarbon compound poisoning. When exposure is by spraying, dipping, or dusting, a thorough bathing without irritating the skin (no brushes), using detergents and copious quantities of cool water, is recommended. If exposme is by ingestion, gastric lavage and saline pmgatives are indicated. The use of digestible oils such as com oil is contraindi­ cated; however, heavy-grade mineral oil plus a pmgative hastens the removal of the chemical from the intestine. Activated charcoal appears to be useful in preventing absorption from the GI tract. When signs are excitatory, a sedative anticonvulsant such as a barbitmate or diazepa.m is indicated. Anything in the environment that stresses the animal (eg, noise, handling) should be reduced or removed if possible. If the animal shows marked depression, anorexia, and

3063

dehydration, therapy should be directed toward rehydration and nomishment either IV or by stomach tube. Residues in exposed animals may be reduced by giving a slmry of activated charcoal or providing charcoal in feed. Feeding phenobarbital, 5 g/day, may hasten residue removal.

INSECTICIDES DERIVED FROM PLANTS Most insecticides derived from plants (eg, rotenone from Denis and pyrethrins from Chrysanthemum or Pyreth1um) have traditionally been considered safe for use on anin1als. Nicotine in the form of nicotine sulfate is an exception. Unless it is carefully used, poisoning may result. Pets are exposed to tobacco by ingesting commercial tobacco products (eg, cigarettes or chewing tobacco), whereas livestock may consun1e discarded tobacco stalks or hay contaminated with tobacco plant drippings in the barn. The minin1wn lethal dose of nicotine is 1 g in cattle, 0.2----0.3 g in horses, 0.1--0.2 g in sheep, and 0.02--0.1 g in dogs and cats. Affected anin1als show tremors, incoordination, nausea, disturbed respiration, muscle paralysis, and finally coma and death. Nicotine and related alkaloids from tobacco can cross the placenta and produce terato­ genic effects. Recovery from sublethal doses is usually complete within 3 hr. Death occurs within a matter of homs from paralysis of thoracic respiratory muscles and cardiac arrest. Necropsy may reveal parts of tobacco leaves or stalks in the rumen contents. Lesions include pale mucous membranes, dark blood, hemorrhages on the heart and in the lungs, and congestion of the brain. Treatment consists of removing the material by washing or by gastric lavage with tannic acid, adnlinistering activated charcoal, providing artificial respiration, and treating for cardiac arrest and shock Pyrethrins: Pyrethrins are insecticides obtained from the flowers of C cinerariae­ folium and have been used as insecticides for many years. Pyrethrins and pyrethroids produce toxicity affecting primarily the sodiwn channel, but also chloride and calciwn channels of nerve cells. These insecticides also interact with nicotinic acetylcholine receptors. Synergists, such as piperonyl butoxide, sesamex, piperonyl cyclonene, etc, are added to increase stability and effectiveness. This is accom­ plished by inhibiting mixed function oxidases, enzymes that detoxify pyrethrins and pyrethroids; wuortunately, this also potentiates manunalian toxicity.

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3064

INSECTICIDE AND ACARICIDE (ORGANIC) TOXICITY

Pyrethroids: Pyrethroids are synthetic derivatives ofnatural pyrethrins. There are two types ofpyrethroids. Type I compounds that lack an a-cyano substituent include pyrethrin I, allethrin, tetramethrin, kadethrin, resmethrin, phenothrin, and perrnethrin. Type II compounds that contain a stabilizing a-cyano-3-phenoxybenzyl component include cyfluthrin, cypem1ethrin, fenpropanthrin, deltamethrin, cyphenothrin, fenva.Ierate, and fluva.Iinate. Type I pyrethroids produce a neurologic syndrome through their effects on both the central and peripheral nervous systems, with signs including tremors, incoordination, prostration, seizures, and death. Type II pyTethroids work primarily by CNS mechanisms to exert the choreoatheto­ sis/salivation syndrome, characterized by hyperactivity, hunched back, salivation, tremors, and incoordination progressing to sinuous writhing movements. Diagnosis ofpyrethrin/pyrethroid poison­ ing is based on clinical signs, history of exposure, and determination ofinsecticide residue in body tissues and fluids. These insecticides do not produce characteristic pathologic lesions. Generally, syn1ptomatic and supportive treatment is required after ingestion ofa dilute pyrethrin or pyretlu·oid preparation. Toxicity may also be due to the solvent. Induction ofemesis may be contraindicated. A slurry ofactivated charcoal at 2--8 g/kg may be administered, followed by a saline cathartic (magnesium or sodium sulfate [lQOA, solution] at 0.5 mg/kg). Vegetable oils and fats, which promote the· intestinal absorption ofpyretlmun, should be avoided. Ifdenna.I exposure occurs, tl1e aninla.I should be bathed with a mild detergent and cool water. The area should be washed very gently so as not to stimulate the circulation and enhance skin absorption. Initial assessment ofthe animal's respiratory and cardiovascular integrity is important. Further treatment involves continuing syn1ptomatic and supportive care. Seizures should be controlled with eitl1er diazepan1 (adnlinis­ tered to effect at 0.2-2 mg/kg, IV) or metho­ carban1ol (55-220 mg/kg, IV, not exceeding 200 mg/min). Phenobarbital or pentobarbital (IV), to effect, can be used if diazepam or methocarbamol are too short-acting. o-limonene: o-Limonene is the major

component ofthe oil extracted from citrus rind. It is used for tile control of fleas on cats and for other insect pests. Adult fleas and eggs appear to be most sensitive to o-limonene, which is more effective ifcom­ bined witll the synergist piperonyl butoxide. At recommended dosages, the solution containing o-lirnonene appears to be safe, but

increasing tl1e concentration 5-10 fold in sprays or dips increases the seve1ity of toxic signs, which include hypersalivation, muscle tremors, ataxia, and mild to severe hypother­ mia. The inclusion ofpiperonyl butoxide in tl1e f omutlation potentiates the toxicity in cats. Allergies have also been repo1ted in people in contact with o-lirnonene, and it appears to increase de1ma.I absorption of some chemicals. When orally administered to dogs, o-limonene causes vomiting (meclian effective dose 1.6 mllkg). No antidote is available.

ORGANOPHOSPHATES The organophosphates (0Ps) are derivatives ofphosphoric or phosphon.ic acid. OPs have replaced the banned organochJorine compounds and are a major cause ofanin1a.I poisoning. They vary greatly in toxicity, residue levels, and excretion. Many have been developed for plant and aninla.I protection, and in genera.I, tl1ey offer a distinct advantage by producing little tissue and environmental residue. Some ofthe OPs developed initially as pesticides are also used as antl1elrnintics. Five such compounds include dichlorvos, trichlo1fon, ha.Ioxon, naphtlla.Iophos, and crufomate. The first two are prin1aiily used against parasitic infestations in horses, dogs, and pigs; the latter three are used against pai·asites in runlinai1ts. Many ofthe OPs now used as pesticides (eg, chlorpyrifos, diazinon, fenitrotllion, ma.Iatllion, paratllion, etc) are not potent inhibitors ofcholinesterase until activated in the liver by nlicrosoma.I oxidation enzyn1es; they are generally less toxic, and intoxication occurs more slowly. Certain OP preparations are nlicroencapsulated, and tl1e active compound is released slowly; tllis increases the duration ofactivity and reduces toxicity, but the toxic properties ai·e still present.

Organophosphate Insecticides Azinphos-methyl (or -ethyl): The maxi­ mum nontoxic oral dose is 0.44 mg/kg f or ca.Ives, 2.2 mg/kg for cattle and goats, and 4.8 mg/kg for sheep. The oral LD50 in rats is 5 mg/kg, and the denna.I LD50 in rabbits is 220 mg/kg. Carbophenothion: Carbophenotllion has been used as a spray for fiuit trees and as a dip or spray for sheep blowfly, keels, and lice. Dairy ca.Ives 0.25%; 0.5% concentrations may be lethal. Adult cattle may show mild toxicity at 1 % concentrations. The minimum lethal dose for calves appears to be between 10 and 40 mg/kg. A dose of 25 mg/kg is usually fatal in sheep. The oral LD50 in rats is 13 mg/kg. Crotoxyphos: Crotoxyphos is used as a spray or powder for the control of ectopara­ sites on cattle and pigs. Crotoxyphos is of rather low toxicity; however, Bral1man cattle are markedly more susceptible than European breeds. Cattle (except as above), sheep, goats, and pigs all tolerate sprays containing crotoxyphos at 0.5% levels or higher. Crotoxyphos is safe at a level of 1%, although skin lesions have been found in pigs. Toxic doses appears to be in the 2% range, except for in Bralunan cattle, in which 0.144o/o-0.3% may be toxic. Demeton: Demeton is used as a systemic insecticide against sucking insects and mites. Demeton is used mainly as a foliage spray and has a relatively long residual life. It is a mixture of demeton-0 a11d demeton-S at1d is

3065

highly toxic to mat11111als. The oral LD50 is 8 mg/kg in goats and 2 mg/kg in rats; the dem1al LD50 in rats and rabbits is 8 mg/kg. Demeton­ O poisoning developed in several hrn1dred cattle grazing near cotton treated with this insecticide. The con-espondi.ng analogues of demeton (demeton-0-methyl at1d demeton-S­ methyl) ai·e also used for similai· purposes but ai·e les,s toxic than demeton. Diazinon: Young calves appear to tolerate 0.05% spray but are poisoned by 0.1% concen­ trations. Adult cattle may be sprayed at weekly intervals with 0.1% concentrations without inducing poisoning. Yorn1g calves tolerate 0.44 mg/kg, PO, but are poisoned by 0.88 mg/kg. Cattle tolerate 8.8 mg/kg, PO, but are poisoned by 22 mg/kg. Sheep tolerate 17.6 mg/kg but are poisoned by 26 mg/kg. TI1e oral LD50 in rats is 300 mg/kg, at1d the dermal LD50 in rabbits is 379 mg/kg. Dichlorvos: Dichlorvos has ma11y uses on both plants and animals. It is rapidly metabolized and excreted, and residues in meat and milk ai·e not a problem if label directions are followed. It is of moderate toxicity, with a minin1rn11 toxic dose of 10 mg/kg in yorn1g calves at1d 25 mg/kg in horses and sheep. The oral LD,,o in rats is 25 mg/kg, PO, and the dermal LD50 in rabbits is 59 mg/kg. A 1% dust was not toxic to cattle. Flea collars containing dichlorvos may cause skin reactions in some pets. Cats wearing dichlorvos-impregnated collars ca11 develop signs of ataxia-depression SY11drome, followed by death. Dimethoate: Dimethoate is used extensively in horticulture as a systemic insecticide, but it also kills insects by contact. When administered PO, the minin1Um toxic dose for yorn1g dairy calves was -48 mg/kg, while 22 mg/kg was lethal for cattle 1 Y1' old. Daily doses of 10 mg/kg for 5 days in adult cattle lowered blood cholinesterase activity to 20"Ai of normal but did not produce poisoning. Horses have been poisoned by doses of 60--80 mg/kg, PO. When applied topically, 1% sprays have been tolerated by calves, cattle, and adult sheep. The oral LD5() in rats is 215 mg/kg, and the dermal LD50 in rabbits is 400 mg/kg. Dioxathion: Dioxathion is a nonsystemic acaricide a11d insecticide for the control of ticks. Dioxathion is a mixture of cis- ai1d trat1S-isomers, usually in the ratio of 1:2. The cis-isomer is more toxic than the trat1S­ isomer. Used on both plants and ai1irnals, it is rapidly metabolized and not likely to produce residues in meat greater than the 1 ppm official tolera11ce. Concentrations of l day may become emaciated and dehydrated. Treatment: Tl1ree categmies of drugs are

used to treat OP poisoning:1) musca.iinic receptor- blocking agents, 2) cholinesterase reactivators, and 3) emetics, catha.itics, and adsorbents to decrease further absorption. Atropine sulfate blocks the central and peripheral musca.iirtic receptor-associated effects ofOPs; it is administered to effect in dogs and cats, usually at a dosage of 0.2-2 mgtkg ( cats at tile lower end of tile range), eve1y 3-6 hr or as often as clinical signs indicate. For horses and pigs, U1e dosage is 0.1--0.2 mgtkg, IV, repeated every 10 min as needed; for cattle and sheep, U1e dosage is 0.61 - mgtkg, one-Ulird given IV, the remainder IM or SC, and repeated as neeclecl. Atropiniza­ tion is adequate when tile pupils are dilated, salivation ceases, and U1e animal appears more alert. Artimals initially respond well to atropine sulfate; however, U1e response dinlirtishes after repeated treatments. Overtreatment witl1 atropine should be a.voided. Atropine does not alleviate tile nicotinic cholinergic effects, such as muscle fasciculations and muscle paralysis, so dea.U1 from massive overdoses ofOPs can still occur. Including cliazepan1 in U1e treatment reduced the incidence of seizures and increased survival of nonhwnan primates expe1imentally. An improved treatment combines atropine witl1 the cholinesterase-reactivating oxime, 2-pyridine aldoxime metilochloride (2-PAM, pralidoxime chloride). The dosage of2-PAM is20--50 mgtkg, given as a 5% solution IM or by slow IV ( over 5--10 min), repeated at half tile dose as needed. IV2-PAM must be given very slowly to a.void rnusculoskeletal pa.i·alysis a.i1d respiratory arres(;. Response to cholinesterase reactivators decreases with time after exposure; therefore, treatment witl1 oximes must be instituted as soon as possible ( within24-48 hr). The rate at which the enzyme/organophosphate complex becomes unresponsive to reactivators ( due to ageing phenomenon) varies with lhe pa.iticula.i· pesticide. Removal of the poison from U1e a.ilin1al also should be attempted. lf exposure was dermal, the animal should be washed with detergent and water ( a.bout room tempera­ ture) but without scrnbbing and irritating U1e skin. Emesis should be induced if oral exposure occurred 24hr

Primarily liver

Gyrornit1·a escutenta

Monomethylhydrazine

6---24hr

CNS

Lepiotaspp

a and 13 amanitins

6---14hr, rarely >24hr

Primarily liver

LATENT PERIOD :,3 HR AFTER INGESTION; NOT LIFE-THREATENING

Arnanita rnuscaria; Isoxazoles: ibotenic 30 min-2 hr; A pantherina acid muscimol recovery 4-24hr

CNS

Chtorophyllurn rnotybdiles

Unknown

30min-3hr; recovery1-2 days

GI

Ctitocybe deatbata; Ctitocybe spp; Inocybespp

Muscarine

30min-2 hr; recovery 6---24hr

Autonomic ne1vous system

Paxillus invotutus

Unknown

1-3hr; recovery 2-4days

Immune system

Psitocybe spp; Psilocybin and psilocin Conocybe smithii; Gyrnnopitus spectab'ilis; Panaeotus siibbalteatus

30-60min; rarely6hr

CNS

Russula ernetica

30min-3hr; recovery1-2 days

GI

Unknown

" No reported veterinary cases

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3098

POISONOUS MUSHROOMS

combination of non-lethal/lethal mushroom species growing in the same location (dilution effect, or dose determines toxicity). In mushroom species with clinical signs that appear 6 hr after ingestion are life-threatening. The sudden appearance of mushrooms and their short lifespan within the environment, coupled with the indiscrimi­ nate eating habits of many animals, creates diagnostic challenges. History and time after ingestion at which clinical signs are seen determine the treatment approach and prognosis. Establishing the tin1e of ingestion may be difficult to in1possible. With no proven antidotes to treat mush­ room poisonings, treatment is prima.tily directed at deconta.tnination, mushroom identification when possible, and intensive supportive care.

TOXIN LATENT PERIOD 6 HR AFTER INGESTION Amanita phalloides, A virosa, Lepiota helveo/a, Galerina autumna/is, G venenata, and Conocybe filaris These mushroom species account for >95% of the reported mushroom-induced deaths. They are common tl1roughout No1th America and a.i·e associated with oaks and birch trees. Amanila phalloicles and A virnsa have olive to green caps with veil patches, gills that a.i·e unattached to the stalk, a white spore print, and stalks with a ring (often but not always) and a cup (volva) or remnants at the base. The features of Lepiota helveola are simila.i· to those of Aman i/,a spp but without volva; they have scaly caps with a knob in the center and stalks with a. movable ring. Galerina aittumnalis (a.utwnn galerina.), G venenata, and Conocybefua1is have brownish, tacky caps with yellowish gills becoming rust and a ring on tlleir brownish stalks. They have no volva, a.i1d their spore print is brown to rust-brown. These species are abundant on well-decayed coniJerous and deciduous logs throughout North America. Toxin present in these mushrooms include cyclopeptide aniatoxins (bicyclic octapeptides), phallotoxins, and virotoxins (bicyclic heptapeptides). Amatoxins (o. and 13 an1aniti.n derivatives) are the most potent; tl1ey are not found in all Amanita spp. An estimated reported letllal dose is 0.1 mg/kg (equivalent to the concentrations in one cap of A phalloicles) across animal species. Whereas tile a.inatoxins are repmted to be well absorbed orally, phallotoxins and virotoxins are not. Amanitins a.i·e not protein bound and a.i·p excreted in urine (800/o--900!.i), feces, and bile (7%). A.ma.toxins bind to nuclea.i· RNA polymerase-11 (transcription phase), thus preventing the fo1ma.tion of phosphodiesterase bonds and subsequent RNA, DNA, and protein synthesis. High-protein synthesis cells a.i·e most sensitive. Amatoxins a.i·e prilna.i·ily liver toxins, but they also affect many organ systems, resulting in hypoglycemia, blood clotting defects, thyrnid/parathyroid functional anomalies, renal failure, and intestinal da.inage (enterohepatic recircula­ tion of the toxin).

Clinical Findings: Signs can be cha.i·acter­ ized in four phases: 1) latent (6-12 hr after

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POISONOUS MUSHROOMS ingestion), in which the anin1al shows no clinical signs; 2) GI signs (as long as 24 hr after ingestion); 3) remission (as long as 72 lu· after ingestion), in which the animal appears to have recovered; and 4) hepatid renal (3-6 days after ingestion), leading to recovery or death tlu·oughout the next 7-14 days. The reported long latent phase is of diagnostic importance. The GI phase, indicated by vomiting, abdominal discom­ fort, hepatitis, and pancreatitis follows and signals initial hepatic, hematologic, cardiovascular, endocrine, CNS, and renal changes. The remission phase follows, only to enter a fulminant hepatidrenal phase, indicated by icterus, hypoglycemia, and coma, 3--4 days after ingestion. Recovery or death (>500A,) from hepatic and/or renal failure occurs 7-14 days after muslu-oom ingestion. Diagnosis: Mushroom ident.ification . characteristics, coupled with consistent clinical signs as stated above, is diagnostic. Meixner test results (time taken, and color intensity of suspected mushroom specimen-fresh, vomited fragments) would be diagnostic. During the GI phase, animals should be monitored for decreased serum thyroxine levels, hypoglycemia, and/or increased insulin, calcitonin, and parathyroid levels. Routine blood and serum chemistry profiles are unremarkable until liver/kidney damage. Because the toxin is primarily hepatotoxic, changes in clotting factor V, fibrinogen, and kidney and liver profiles would also be helpful. Amanitins can be detected in urine from animals not showing clinical signs. They are also detectable in liver and kidney specimens as Jong as 22 days after ingestion.

Treatment: There are no specific antidotes.

Silibinin (not FDA approved), penicillin G (high levels), combined silibinin/penicillin, cimetidine, N-acetylcysteine, or vitan1in C therapies have been used with some success in people and could tl1erefore betJ.ied, altl1ough animal study data are not readily available. Hypoglycemia remains an adverse effect witl1 or witl1out treatJ.nent. Suppmtive care (IV fluids, dextJ.·ose, and antibiotics) counters the effects of severe liver and kidney damage. Early institution oftJ.·eatment is essential to save the animal; tl1e prognosis is poor after hepatidrenal patl1ology. Activated charcoal (1 g/kg witl1 catl1artic) during the first 24 hr after ingestion absorbs amanitin undergoing enterohepatic recirculation and tl1us may be helpful.

3101

Gyromitra esculenta These mushrooms have a non-gilled, yellow­ brown to dark-red, deeply Wiinkled, honeycomb (unlike true morels that are hallowed and not chambered), saddle­ shaped cap on a short stalk. They are found on the ground under conifers throughout North America. The toxin involved is the hydrazone gyromitrin, which on ingestion is hydrolyzed to'N-methyl-N-formylhydrazine (depletes hepatic cytochrome P-450) and monomethylliydrazine (inl1ibitor of the coenzyme pyridoxal phosphate and -y-aminobutyric acid in tl1e CNS 6--12 hr after ingestion. The concentration of gyromitrin varies witl1 enviromnental conditions.

Clinical Findings: Vomiting, watery diarThea, abdon1inal discomfo1t, convul­ sions and coma may be noted 6--24 hr after ingestion of a toxic dose. Methemoglobine­ mia and hemolytic anemia, hepatitis, jaundice, neplmtis, and death develop some time later. Deatl1 appears to be due to hepatorenal failure.

Treatment: Activated charcoal (1 g/kg) may be helpful if given early after ingestion. IV fluids should be given as needed. IV pyTidoxine controls neurologic signs, and methylene blue can be given in cyanotic and methemoglobin cases. PyTidoxine-induced peripheral neuropathy from adn1inistering high doses should be avoided. For the . induced hepatic encephalopathy, supp01t1ve tl1erapy is essential. In addition to monito r ­ ing methemoglobin levels, hepatic and renal functions should also be monitored. TOXIN LATENT PERIOD >24 HR AFTER INGESTION Cortinarius orellanus and C rainierensis TI1ese mushrooms have a colorful but mostly brownish cap, stalk, and young gills; the matured gills are orange-rust in color. The spore print is bright rust/orange-brown/ gray-brown but not purple-brown. Stalks may or may not have a ring-like zone. The toxins involved are orelline and orellanine, which are chemically related to the herbicide diquat (bipY)idyl derivatives). Thin-layer chromatography can detect orellanine in renal biopsy material long after clinical exposure but not in urine and/or blood during clinically active states. Ingestion of tlu-ee to ten caps is reported to be lethal. There have been no reported cases from ingestion of species grown in North America.

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POISONOUS MUSHROOMS

Clinical Findings: The onset of clinical

interfere with sulfur-containing amino acid incorporation. Drying decreases toxicity.

signs is delayed (17 days after ingestion). Signs include anorexia, vomiting, diarrhea/ constipation, gastritis, thirst, and polyuria progressing to oligUiic renal failure in 3-14 days after initial clinical signs. The kidney seems to be the target organ; lesions include interstitial nephritis, tubular damage, and fibrosis. Hepatic damage is infrequently reported. In most cases, marked improve­ ment over an extended period (6 mo) is seen; however, chronic renal failure occurs in some cases.

Clinical Findings: Signs may appear as early as 3 days but as long as 6 days after exposure and include anorexia, diarrhea, salivation, hypertherrnia, depression, hyperemic coronary band, hemorrhage (anterior chamber of eyes), oral ulceration, altered keratinization (hair/hoof loss, similar to selenitm1 poisoning), and recumbency. Death or recovery may be expected in 3-15 days.

Diagnosis: Urinalysis indicates concen­

Diagnosis: These mushrooms grow

trated urine, hematuria, protein, and RBC casts early in the latent period, followed by diluted urine with protein and few casts later. It therefore becomes necessary to monitor renal function. Renal pathology without hepatic involvement after a Jong latent period (days) has been reported in people. Blood, urinalysis, and kidney profile testing would be supportive. Mushroom identification can differentiate Cortinarius spp from Paxillus involutus, a mushroom reported to cause hypersensitivity leading to renal failure.

Treatment: Treatment should be focused

on decontan1ination, mushroom identifica­ tion (often difficult), and intensive supportive care. Hemodialysis should be instituted until nonnal kidney function retUins. Pentobarbital and/or furosemide usage should be avoided or lin1ited, because tl1ese drugs increase toxicity.

MISCELLANEOUS POISONOUS MUSHROOMS Ramaria flavo-brunnescens Ramariaflavo-brunnescens is found exclusively in eucalyptus woods in North America, Australia, Brazil, and Uruguay, and is easily identified from fue spore print color of pale buff to brownish yellow. It is reported to be poisonous to rUininants (cattle and sheep). The toxin is an unknown, volatile compound or compounds found throughout the plant that is reported to

exclusively among eucalyptus plants, so history of exposure to eucalyptus is key. Selenium exposure and toxicity causes simi­ lar signs. The duration and outcome of the clinical expression helps to confirm diagnosis.

Treatment: Treatment involves removing

the affected animal from fue source and offering supportive care. Recovery requires time.

Paxillus involutus Paxillus involutus has a dry or slimy, brownish cap with an in-rolled margin and yellowish gills descending a short distance on the brown, smooth stalk. The spore print is clay-brown. P involutus is widely distributed in North America. It may appear singly or in groups of several, near or on wood in mixed woods in the spring/autumn. The toxin is unknown, but it may cause hypersensitivity over time, leading to kidney failure.

Clinical Findings: Vomiting, diarrhea, cardiovascular irregularity, and RBC destruction may be noted 1-3 hr after ingestion. Recovery generally takes 2-4 days but could be longer. Acquired sensitivity develops over time.

Diagnosis and Treatment: A diagnosis

can be made based on mushroom identifica­ tion, consistent clinical signs, and response to supportive care. Treatment involves symptomatic and supportive measures.

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POISONOUS PLANTS

3103

POISONOUS PLANTS HOUSEPLANTS AND ORNAMENTALS Plants are an important part of the decor of homes; pets having access to these plants often chew on or ingest them, with toxicity a possible outcome (see TABLE 7). Inquiries to poison control centers on plants ingested by children 500/o oak buds and young leaves for a period of tin1e. Increased BUN with diet history diagnostic. Treatment symptomatic. Oral runlinatorics helpful. See also p 3152.

Large deciduous shrub with spiny stems. Fleshy, alternate, round in cross-section. Flowers inconspicu­ ous.

Oxalates (sodium and potassium) 1 O"/e>--15% dry weight Oeaves primarily, less so in stems and fruits). Dyspnea, weakness, depression, some salivation, atony of GI tract, coma, death (neurologic effects and renal failure). Hyperkalemia, hypocalce­ mia, increased BUN. Lesions include hemorrhage and edema of rumen wall, ascites, swollen kidneys (renal tubular necrosis and dilation).

Toxic when large quantity consumed in short time. Do not allow hungry animals to graze plant. Parenteral calciun1 solution offers temporary relief but relapses.

Coarse annual herb. Fruit covered with spines, 2-beaked, with 2 compartments.

Carboxyatractyloside (seeds and young seedlings). Anorexia, depression, nausea, vomiting, weakness, rapid weak pulse, dyspnea, muscle spasms, convul­ sions. Lesions include GI inflamma­ tion, acute hepatitis, nephritis.

Seedlings or grain contaminated with seeds. Oils and fats PO may be beneficial; parenteral glucose and bicarbonate are reported helpful; warmth, stimulants IM. (contim,ed)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORiH AMERICA• (cont.inued) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: SPRING (continued) Zygadenusspp

Death camas, Meadow death camas, Grassy death camas

Foothill grazing lands, occasionally boggy grasslands, low open woods; throughout North and Central America

Sheep, cattle, horses

DANGEROUS SEASON: SPRING AND SUMMER Aesculus spp Buckeye

Woods and thickets; eastern USA and California

All grazing animals

Amianthium muscaetoxicum

Open woods, fields, and acid bogs; eastern USA

All grazing animals

Delphinium spp

Either cultivated or wild, usually in open foothills or meadows and among aspen; mostly western USA. Dangerous season spring and summer, also seeds in fall.

All grazing animals, mostly cattle; sheep are somewhat resistant. .

Descurainia pinnata

Dense stands especially in wet years; arid southwest

Catt le

Fly poison, Stagger­ grass, Crow poison, Gray fly poison

Larkspurs

Tansy mustard

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3123

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: SPRING (continued) Perennial, bulbous, unbranched herbs with basal, flat, grass-like leaves. Flowers greenish, yellow, or pink; in racemes or pani­ cles. No onion odor.

Cevanine-type veratrurn azasteroid alkaloids, steroidal alkaloids, glycoalkaloids, and ester alkaloids (all parts). Salivation, vomiting, muscle weakness, ataxia or prostration, fast weak pulse, coma, death ( central respiratory depres­ sion). No distinctive lesions.

Seeds most toxic. Leaves and sterns lose toxicity as plant matures. Atropine sulfate and picrotoxin SC.

DANGEROUS SEASON: SPRING AND SUMMER Trees or shrubs. Leaves opposite and palmately compound. Seeds large, glossy brown, with large white scar.

Glycoside, aesculin; also alkaloids and saponins in all parts, especially seeds and leaves. Depression, incoordination, twitching, paralysis, inflanunation of mucous membranes.

Young shoots and seeds especially poisonous. Treatment only in severe cases. Stimu­ lants and purgatives. Prevent access to toxic plant. Recovery in days. Rarely fatal.

Bulbous perennial herb. Leaves basal, linear. White flowers in a compact raceme, the pedicels subtended by short, brownish bracts.

Unidentified alkaloid, similar to those with Zygadenus (all parts). Salivation, vomiting, rapid and irregular respiration, weakness, death from respiratory failure.

No practical treatment. Especially dangerous for animals new to pasture. Keep animals well fed.

Annual or perennial erect herbs. Flowers each with 1 spur, in racemes. Perennial with tuberous roots. Leaves palmately lobed or divided.

Polycyclic diterpenoid alkaloids (eg, delphinine) in all parts, fresh or dry. Straddled stance, arched back, repeated falling, forelegs first. Constipation, bloat, salivation, vomiting. Death from respiratory and cardiac failure. Most often no lesions.

Young plants and seeds more toxic. Toxicity decreases with maturity. Antidote physostigrnine rather than atropine.

Annual to 2 ft tall, stem and leaves covered with fine pubescence. Leaves alternate, deeply pinnately dissected. Inflores­ cence on elongated raceme. Flower small with 4 spreading yellow to yellow-green petals. Fruit is copula with 2 carpels and Jong waxy seeds in 2 rows.

Toxic principle unknown; must be grazed over relatively long period. Partial or complete blindness, inability to use tongue or swallow, "paralyzed tongue," "blind staggers," wandering, head pressing, emacia­ tion, death if not treated.

Administer 2-3 gal. (8-12 L) water bid with stomach tube. Include nomishment if animal weak. Prognosis good if treatment started early. Possibly mustards cause same condition.

(continued)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: SPRING AND SUMMER (continued)

Lantanaspp

Ornamentals and wild; in lower coastal plain of southeast USA, and southern California

All grazing anin1als except horses

Senna obtusifolia

Found in cultivated (corn, soybean, or sorghum) and abandoned fields, along fences, roadsides; naturalized in eastern USA

All grazing animals, mostly cattle, and poultry (seep 2861)

Senna occidentalis

Common along roadsides, waste areas and pastures; naturalized in eastern USA

Cattle, horses, chickens, goats, sheep, rabbits

Tetradymia spp

Arid foothills and higher desert and sagebrush ranges, dense stands along trails; western USA

Sheep

Lantana

Coffeepod, Sicklepod

Coffee senna, Coffee weed, Styptic weed, Wild coffee

Horsebrush

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POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: SPRING AND SUMMER (continued) Shrubs. Young sterns 4-angled. Leaves opposite. Flowers in flat-topped clusters, yellow, pink, orange, or red. Berries black.

Triterpenes (lantadene A and B) and tmknowns in all parts, especially leaves and green berries. Anorexia, jaundice, watery feces, photosensiti­ zation. Lesions include degenerative changes in liver and kidneys. Deatll clue to liver insufficiency, renal failure, myocardial damage.

Remove plants from pasture (herbicide 2,4-D susceptible). Keep animals out of light sources after eating plant.

Annual sluub frequently found in san1e fields as S occidentaiis. Distinguishing features include leaflets fewer in number and more rounded. Seed pods long, round to 4-sided and more curved. Seeds shiny, brown, and rhomboid.

Toxic principles tllought to be same as in S occidentalis. Clinical signs, although sinlilar, less severe with S obtusifolia.

Treatment ineffective in down animals; salvaging most economic. Heat labile toxins not known to persist as residue. Meat from affected animals should be safe for hw11a.n consumption.

Annual herb >3 ft tall, witl1 glandular, alternate pinnately compound leaves (8-12 ovate to lanceolate leaflets, terminal pair largest). Flowers are yellow, axillary, solitary, or in short racemes. Long, flat, straight to slightly curved pods with clearly outlined seed contents. Of the pods, seeds, and wilted foliage, seeds are most toxic.

Anthraquinones (emodinglycosides and oxyrnethylanthraquinone), chrysarobin and lectin (toxalbuniins), and alkaloids are associated with GI dysfunction and myodegeneration. Afebrile, ataxic, with ciian·hea and coffee-color urine, recw11bent but eat and are alert shmtly before deatl1. Increased semrn CK and isocitric dehydrogenase activities; hyper­ kalemia and myoglobinwia frequent. Lesions include cardiac and skeletal muscle degeneration. Congestion, fatty degeneration, and centrilobular necrosis (liver) in addition to tubular degeneration (kidneys) also repo1ted. Deatl1 probably due to hyperkalernic heart failure.

No specific treatment known. Symptomatic and supportive care essential. Although gross lesions similar to those of vitamin E/ selenium deficiency, this therapy is contraindicated. Mineraloco1ticoid therapy may facilitate potassium excretion. Remove animals from source. Salvaging for economic reasons (see Senna obtusifolia, above).

Shrubs witll yellow flowers in spring, not later. Leaves spiny, silvery white. Early deciduous.

Furanoeremophilanes (tetradymol and others). Photosensitization, "bighead," loss of hair and wool, skin ulcerations, blindness, secondary infections. Lesions include dermal necrosis and edema, hepatic and renal degeneration. Abmtions may occur.

Photosensitization seen witl1 conctm·ent ingestion of otl1er green forages. Remove aninlals from plant source and sunlight. Antihistamines, topical antibiotics, and parenteral corticoste­ roids beneficial. Recovery slow and possibly incomplete. (continued)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: SPRING AND SUMMER (continued) Veratrum spp False hellebore, Skunk cabbage

Low, moist woods and pastures, and Sheep, cattle high mountain valleys; western USA

DANGEROUS SEASON: SUMMER AND FALL Acer rubrzim Red maple

Moist land and swamps; eastern

Horses

Apocynum spp Dogbanes

Open woods, roadsides, fields; throughout North America

All

Centaurea 1·e-pens Russian knapweed

Waste areas, roadsides, railroads, and overgrazed rangeland; not common in cultivated or irrigated pastures; mostly western and upper midwestern USA

Horses

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3127

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (contin,,ed) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: SPRING AND SUMMER (continued) Steroidal alkaloids. Vomiting, ex­ cess salivation, cardiac arrhythmia, bradycardia, dyspnea, muscle weakness and paralysis, coma, congenital cyclops in lambs from ewes exposed to V californicum.

Erect herbs.Leafy throughout, leaves large and plaited. Flowers small and white or greenish.

Respiratory and heart stimulants.

DANGEROUS SEASON: SUMMER AND FALL Unknown toxic principle(s) in wilted Not common. A large tree at Methemoglobinemia a leaves. Methemoglobinemia, Heinz maturity. Leaves prognostic indicator. body anemia, and intravascular opposite, 2-6 in. Isotonic fluids, oxygen, across, palmately 3- or hemolysis; weakness, polypnea, and blood transfusion tachycardia, depression, icterus, 5-lobed each, roughly can be helpful. cyanosis, brownish discoloration triangular, and Methylene blue therapy coarsely toothed. Red of blood and urine. not rewarding. Early to yellow polygamous ascorbic acid treatment flowers. Fruit, a pair of essential for recovery. I-seeded winged units connected at base. Erect, branching, perennial herb with milky sap arising from creeping underground root stock. Leaves opposite. Flowers white to greenish white in terminal clusters. Fruit long, slender, paired, with silky­ haired seeds.

A resinoid and glucoside with some cardioactivity found in leaves and stems of green or dry plants. Increased temperature and pulse, dilated pupils, anorexia, discolored mucous membranes, cold extremi­ ties, death.

Symptomatic (cardio­ toxin) IV fluids and gastric protectants suggested.

Perennial weed with slender rhizomes. Stems erect and well branched.Leaves pinnately lobed to entire, not spiny, narrowed basally but not petioled and of decreasing length up the plant. Thinly pubescent or glabrous. Blue, pink, or white flowers. One-seeded fruit with whitish, slightly ridged attachment scar.

Unidentified alkaloid in fresh or dried plant. Chronic exposure, acute onset of signs. Inability to eat or drink, facial dystonia, chewing, yawning, standing with head down, severe facial edema, gait nonnal, head pressing, aimless walking or excitement most severe the first 2 days, become static thereafter. Death from starvation, dehydration, aspiration pneumonia.

More toxic than C solstitialis (below) but with similar pathology and prognosis. Some relief with massive doses of atropine but not an effective treatment. Euthanasia recommended.

( contin1led)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: SUMMER AND FALL (continued) Centaiireaso ls titialis

Waste areas, roadsides,pastures; mostly western

Eupatorium rugosum

Woods, cleared areas,waste places, Sheep,cattle,horses usually the moister and richer soils; eastern USA

Hypochaeris radicata Flatweed,Cat's-ear, Gosmore

Native to the Mediterranean and South America; widely distributed in the USA-Pacific states, eastern/ southeastern USA

Horses

Oxyt eniaacerosa, Ivaacerosa

Arid,alkaline soils in foothills, sagebrush plains; western USA

Cattle, sheep

Perillaf1 ·utes cens

Ornamental originally from India, escaped to moist pastures,fields, roadsides,and waste places; southeastern USA

Cattle primarily,horses and other livestock susceptible

Yellow star thistle, Yellow knapweed

White snakeroot

Copperweed

Perilla mint, Beefsteak plant

Horses

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3129

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: SUMMER AND FALL (continued) Annual weed. Leaves densely covered with cottony hair. Terminal spreading cluster of bright yellow flowers with spines below. Branches winged.

Unidentified alkaloid. Involuntary chewing movements, twitching of lips, flicking of tongue. Mouth commonly held open. Unable to eat; death from ciehyclration, starvation, aspiration pneumonia.

Horses graze because of lack of other forage. Extended pe1iod of consumption essential for toxicity. Liquefactive necrosis of substantia nigra and globus pallidus (brain) pathognomonic. No treatment. Euthana­ sia recommended.

Erect perennial herb. Tremetol leaves, opposite, simple, serrated. Flowers small, white, and many. Often grows in large patches.

Complex benzyl alcohol (tremetol in leaves and st.ems). Excreted via milk; cumulative. Weight loss, weakness, trembling (muzzle and legs) prominent after exercise, constipa­ tion, acetone odor, fatty degenera­ tion of liver, partial paralysis of throat, death in 1-3 days.

"Milk sickness" or "trembles." Treatment nonspecific and symptomatic. Heart and respiratory stimulants and laxative may be necessary. Remove animal from access to plant, discard milk (hazardous to people).

Perennial herb with viscid sap, stemless. Simple, serrated to lobed, basal, alternate leaves. One to several bright yellow flowers per plant.

Unknown; associated with but not proven cause of a neurologic condition in horses-stringhalt (hypermetria/hyperflexion of pelvic limb) in dry years. Sudden onset of abnormal gait; flexion/delayed extension of hocks, knuckling of carpal joints, laryngeal hemiplasia; spontaneous recovery possible, but condition could be permanent.

Tranquilizers, sedatives, mephenesin, and thiamine (questionable effectiveness); longterm phenytoin therapy seems helpful ..Treatment with baclofen also repo1ted helpful. Surgery (pelvic tenotomy of the lateral digital extensors) reported helpful.

Tall, annual/perennial herb with narrow leaflets. Flowers in many heads resem­ bling goldenrod.

Unknown (pseudoguaianolide sesquiterpene lactones found in species-consistent clinical signs with these toxins); all above-ground parts, green or dry. Metabolic disease, anorexia, marked depres­ sion, weakness, coma; death without struggle within 1-3 days.

No specific treatment. Supplement diet or change pasture.

Annual, freely branched, squared stems. Opposite, purple or green, coarsely serrated leaves. White to purple flowers. Strong pungent odor when crushed.

Green or dry, 3-substituted furans (perilla ketone, egomaketone, isoegomaketone). Signs 2-10 clays after exposure include dyspnea (especially on exhaling), open-mouth breathing, lowered head, reluctance to move, death on exertion. Lesions include pulmonary emphysema and edema.

Treatment ineffective once clinical signs severe. Parenteral steroids, antihistamines, and antibiotics may help. Handle gently (prevents exertion and death). Avoid/lin1it grazing during flowering and fruiting period. (continued)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (cont,inued) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: SUMMER AND FALL (continued) Prosopis glandulosa

Dry ranges, washes, draws; southwest

Primarily cattle, also goats; sheep resistant

Robinia pseudoacacia

Open woods, roadsides, pinelands, on clay soils preferably; eastern USA

All grazing animals, mostly horses

Rumex crispus

Commonly found on acid or sterile, graveled, seasonally moist soils of waste places, pastures, and fields throughout USA

Cattle, sheep

Mesquite

Black locust, False acacia, Locust tree

Curly dock, Dock, Sorrel

Solanumspp

Fence rows, waste areas, grain and Nightshades, Jerusalem hay fields; throughout No1th cherry, Potato, Horse America nettle, Buffalo bur

All

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3131

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: SUMMER AND FALL (continued) High sucrose content of beans alters rumen microflora, inhibiting cellulose digestion and B vitamin synthesis if grazed for extended period.

Perennials, deciduous shrub or small tree with smooth or furrowed gray bark, paired spines. Leaves divided. Legume pod long, constricted between seeds.

Unknown principle in the beans. Chronic wasting with rumen atony, excess salivation, continual chewing. Partial paralysis of tongue, facial muscle tremor, submandibular edema, anemia. Lesions include emaciation, small fu'm kidneys and liver, gastroenteritis, filled rumen.

Tree or shrub. Deciduous, alternate, pinnately compound (>10 elliptic to ovate leaflets) leaves. Pair of spines at base of each leaf. Flowers in loose, fragrant, white to cream, drooping racemes. Flattened, brown pods contain­ ing 4-8 seeds.

Laxatives and stinrn­ The glycoside robitin, a lectin (hernagglutinin), and the phytotoxins lants suggested. Treat­ ment symptomatic. robin and phasin found throughout plant, although flowers have been suggested as the toxic principles. Diarrhea, anorexia, weakness, posterior paralysis, depression, mydriasis, cold extremities; frequently lan1initis and weak pulse. Deat11 infrequent; recovery period extensive. Postmortem lesions restricted to GI tract.

Perennial herb with erect sterns, 3-4 ft tall. Leaves alternate, lanceolate to elliptic, finely crisped margins, base obtuse to cuneate, petioles form sheath around stern. Flowers small, numerous, greenish, in long terminal panicles; fruit an achene, papery 3-winged, with lustrous brown seeds.

Oxalic acid and soluble oxalate in leaves, stem, and seeds. Acute course (hypocalcernia, labored breathing, anorexia, depression, muscle fasciculation, tremor, weakness, teeth grinding, pulmonary edema, tetany, seizure, recurnbency, and prostration); subacute (hypocal­ cemia, altered kidney function) or chronic course (renal fibrosis, renal insufficiency, and urolithiasis). Hemorrhage, edema (rumen and abomasal walls), and ascites (intestinal mucosa) seen in toxic cases. Death resulting from shock and hemorrhagic rumenitis.

In acute cases, death is too rapid for any treatment. Sympto­ matic and supportive care can be helpful. Remove animals from source. Calcium IV to correct hypocalcernia is ineffective. Give lime water to precipitate oxalate and prevent absorption. Allow animals to develop tolerance to oxalate by exposure to small amounts over time. Do not allow animals to graze pasture or offer hay highly contan1i­ nated with oxalate­ producing plants.

Fruits small; yellow, red, or black when ripe; structurally like tomatoes; clustered on stalk arising from stern between leaves.

Glycoalkaloid solanine (leaves, shoots, unripe berries). Acute hemorrhagic gastroenteritis, weakness, excess salivation, dyspnea, trembling, progressive paralysis, prostration, death.

Pilocarpine, physostig­ rnine, GI protectants. Seeds may contanunate grain.

(co11tim,ed)

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POISONOUS PLANTS

POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (con1.in11ed) Scientific and Common Names

Habitat and Distribution

Affected Animals

DANGEROUS SEASON: FALL AND WINTER AlliU?n cepa, A canadense

Cultivated and grown on rich soils throughout USA

Cattle, horses, sheep, clogs

Astrolepis sinuata coch'isensis

Dry rocky slopes and crevices, chiefly limestone areas; southwest

Sheep, goats, cattle

Onions (cultivated and wild)

Jimmy fern, Cloak fern

Daubentonia puriicea Rattlebox, Purple sesbane

Cultivated and escaped, in waste • places; southeastern USA coastal plain

Glottidium vesicarium Mostly open, low ground, abanBladderpod, Rattlebox, Sesbane, Coffeebean

doned cultivated fields; southeastem USA coastal plain

All

All

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POISONOUS RANGE PLANTS OF TEMPERATE NORTH AMERICA• (continued) Important Characteristics

Toxic Principle and Effects

Comments and Treatment

DANGEROUS SEASON: FALL AND WINTER Biennials and perennials, bulb plants, onion odor. Leaves basal, green, hollow, cylindrical (A cepa), lustrous green, flat (A canadense); flowers on hollow flowering stalks, termi­ nal umbels of many small blooms; fruits 3-celled capsules with many seeds.

N -propyl disulfide, an oxidant, in all parts. Anemia develops within days of exposure. Toxicosis in cattle associated with prolonged ingestion of large amounts of onions. N-propyl disulfide inhibits RBC glucose6-phosphate dehydrogenase, leading to hemolysis and formation of Heinz bodies. Clinical signs are hemoglobi­ nuria, diarrhea, loss of appetite, jaundice, ataxia, collapse, and possible death if untreated. Hemolytic anemia reported in livestock ingesting wild onions. Heinz body anemia; swollen, pale, necrotic liver; hemosiderin in liver, kidneys, and spleen are reported pathologic lesions.

Clinical signs sin1ilar to toxicity induced by S-metl1ylcysteine sulfoxide (a rare toxic an1ino acid in Brassica spp) in livestock. Susceptibility to onion poisoning varies across animal species: cattle more susceptible than horses and dogs, which are more susceptible than sheep and goats. Remove animals from source and prevent future access to cull onions. Symptomatic and supportive care essential.

Evergreen from Unknown (excreted in milk). rhizomes, perennial, Nervous syndrome, incoordination, erect fem with divided arched back, trembling, increased respiratory rate and pulse. Death leaves, folding when when not allowed to rest. dry. Leaflets about as wide as long, scaly on back

No specific treatment. Supportive and general nursing care helps. Avoid driving during danger period. Provide ample watering, placed to avoid long walks. Allow rest if sign.s occur.

Annuals or perennials, shrub. Leaves pinnately compound with 24 lu· is required to completely restore coagulation. Either vitanlin K, or a blood

3157

transfusion is sufficient to cotTect mild cases if additional exposure is stopped. Prevention: Cultivars of sweet clover low in cmunarin and safe to feed (eg, Polara) have been developed. If one of these is not available, the only certain method of prevention is to avoid feeding sweet clover hay or silage. Although well-cured sweet clover is not dangerous, the absence of visible spoilage is insufficient evidence of safety. Alternating sweet clover hay suspected of containing dicumarol with other roughage such as alfalfa or a grass-legume hay mixture can be used to avoid severe poisoning. A 7- to l 0-day period on the sweet clover hay, followed by an equal time on the alternative hay, can prevent poisoning, but it will not completely prevent prolonged bleeding tinles. Because some animals have higher 1isks of serious hemotThage (surgical candidates or pending paiturition), they should not receive sweet clover hay for a minimw11 of2-3 wk, and preferably �4 wk, before surgery or paitwition.

CANTHARIDIN POISONING (Blister beetle poisoning) In natme, cantharidin is found in beetles belonging to the Meloidae fanlily. More tl1an 200 species of these beetles ai·e found throughout tl1e continental USA, but members of the genus Epicauta are most frequently associated with toxicosis in horses. TI1e striped blister beetles (E occi­ dentalis, E temexia, andEvittata) are paiticularly troublesome in the southwestern USA. The black blister beetle, E pennsyl­ vanica, has caused toxicosis in horses in Illinois. Cantharidin is the sole toxin, but its concentration in beetles varies widely. Blister beetles usually feed on various weeds and occasionally move into alfalfa fields in large swairns. These insects ai·e gregaiious and may be fowid in hay in lai·ge nun1 bers when it is baled. One flake of alfalfa may contain several hundred beetles, but a flake from tl1e other end of the saine bale may have none. Animals ai·e usually exposed by eating alfalfa hay or alfalfa products that have been contai11inated witll blister beetles. Pathogenesis: Cantharidin is an odor­ less, colorless compound that is soluble in

various orgai1ic solvents but only slightly soluble in water. It is highly irritating and causes acantholysis and vesicle formation when in contact with skin or mucous membranes. After ingestion, it is absorbed from tl1e GI tract and rapidly excreted by the kidneys. The minimun1 lethal oral dose in horses has not been established, but it appears to be ypocalcemia 571 small animals 407 Pancuroniurn 2587, 2588 Pandemic (epidemiology) 2397 Panfollicular cysts 948 Panhypopituitarism adult-onset 548 juvenile-onset 549

Pan'icum coloratum 343, 2321

spp 977, 2321 Panleukopenia, feline 796 Panniculitis, nutritional 1200 Panniculus 838 reflex 1218 Pannus 493 Panosteitis, dogs 1204 Pansteatitis, cats 2388 Panstrongylus 39 Pantothenic acid deficiency 1242 pigs 2345 poultry 2940

Papaver somniferum 3042 Papaveraceae spp 618

Paperflowers 3148 Papillar stomatitis, large animals 215 Papillary acanthoma 524 Papilledema 504 Papillitis 1701 Papillomas 952 congenital, foals 943 cutaneous, dogs 953 inverted 953 ear 524 fibrovascular 955 mouth, dogs 366 repti!es 1996 Papillomatosis 952 cloaca!, pet birds 1909 pet birds 1908 rabbits 1951 Papillomatosis, canine mucous membrane 953 Papillomatous lesions, nonvirusassociated 943 Papillomavirus, bovine 1386 Papio spp 1876 Papovavirus, birds 1907 Paracapillaria philippinensis 2456 Parachlamydia acanlham , oebae 506 Parachlorometaxylenol 2742 Paracoccidioides brasiliensis 2701

Parafilmia bovicola 894, 906 multipapillosa 907 ParajUaroides dec01us 1865 Parafluron poisoning 2998 Paragonimiasis 1312, 2448

Paragonimus afiicanus 2448 heterotremus 2448 kellicotti 1312, 1483 me.:r:icanus 2448 spp 1487

westermani 1312, 1483, 2448

Parainfluenza 3 virus 1433 vaccination, exotic manrn1als 2059 Parakeratosis 975 ruminal 237 Paralysis calving 1244 cattle 1088 femoral 1089 ischiatic 1089 obturator 1089 peroneal 1090 radial 1089 suprascapular 1088 tibial 1090 Coonhound 1240 curled-toe, poultry 2941 facial 1258 idiopathic 1239

VetBooks.ir

INDEX

Paralysis (continued) hyperkalemic periodic 1047, 1231 laryngeal 1420 limb 1259 pha.Jyngeal 186 range, poultry 1822 Stocka.J'd 1228 tick 1243, 1314, 2466 tongue, large a.J1imals 214 transient, poultry, Marek's disease 2850 Paralytic rabies 1304 Para.Jnesonephric duct, segmental aplasia 1331 Para.Jnphistomes 328 Paramphistomum spp, 328, 1620 p3.1·3.111yxovirus infections avia.J1 2856, 2858 ca.J1ine distemper 777 reptiles 1995 p3.1·3.11asal sinuses horses 1462 tumors, small a.J1imals 1484 P3.1·3.11eoplastic disorders, nervous system 1280 neuropathy 1242 Paranoplocephala mamillana 319 p3.1·aphimosis, small a.J1imals 1401 Pa.J·apoxvirus 2446 Paraprostatic cysts 1407 Pa.J·aquat (dichloride) 2986 poisoning 2996

Parascaris equorum 259, 291, 316, 682, 2156, 2644, 2649 sp 316 Parasites-See also Flukes, Helminths, Worms aberra.J1t 1311 a.Jnphibi3.11S 1740 aquaculture 1755 backyard poultry 1821 blood 18 calves 2124 carnivores 1310 chinchillas 2006 control in pregna.J1t m3.1·es 2195 erratic 1311 external, exa.J11ination for 1620 facultative 1311 ferrets 1826 fish 1799 fish f3.111ilies (table) 1780 gastrointestinal 159 cattle 307, 308 goats 312 horses 287, 315 pigs 298, 320 rumina.J1ts 303 sheep 308, 312 smaJl 3.11imals 412 horses 2156 incidental 1311

3279

internal, diagnosis l3.1·ge a.J1imals 1620 small animals 1619 Jl3.111as a.J1d alpacas 1850, 1854 marine ma.J11mals 1865 neurotropic affinity 1311 nonhLtn13.11 primates 1880 pet birds 1904 potbellied pigs 1930, 1934 rabbits 1952 repti!es 1996 ratites 1965 small a.J1imals 2170 spinal column a.J1d cord 1252 zoo a.J1imals 2047 zoonotic 2440, 2442, 2444 Parasiticides application methods 2516 external 2748 Parastrongyloides 2041

Parastrongylus cantonensis 2456 costmicensis 2454

Parathion toxicity 3066 p3.1·athyroid gla.J1ds 561 hormone 561 Paratuberculosis 762 goats 2151 p3.1·atyphoid infections, poultry 2866 Paraustrostrongylus 2041 Paravaccinia 868 Paregoric 2554 Parelaphostrongylus tenuis 1252, 1264, 1311, 1313 Parenteral route of administration, drugs 2511 Paresis facial 1258 parturient goats 991 sheep 991 progressive, Angora goats 1228 spastic 1231 cattle 1091 Paromomycin 2663 Paronchocerca helicina 1313 Paroxetine 1544, 2605, 3034 Parrot fever 2808 mouth (horses) 162, 176 Pa.J'S intermedia adenomas 547 Parturient paresis cows 988 goats 991 sheep 991 Parturition-See also Breeding, Reproduction goats 2186 mares 2196 pigs 2210 small a.J1imals 2227

VetBooks.ir

3280

INDEX

Parulis 362 Parvoviral enteritis,feline 796 Parvovirus 796 canine 373 nutrition in 2387 feline 796 goose 2826 mink 1825 porcine,and abo1tion 1342

Paspalum

spp 3019 staggers 3019

Passalurus arnlriguus 1954

Passerines,nutrition 2290 Passive immunization 2773 surveillance 2398 Pastern disorders,horses 1118

Pasleiirella anatipestifer infection,birds 2864 haemolytica 765 mullocida 64,533,724,756,765, 926,

1157,1263,1343,1413,1431,1432, 1436,1465,1466,1469,1472,1474, 1478,1863,1936,1944,1945,1946, 1954,2041,2131,2177,2428,2571, 2660,2668,2689,2769,2800,2819, 2822,2827,2864,2868,2871,2877, 2883,2898 gallicida 2822 mullocida 2822 septica, 2822 pneumonia marine mammals 1870 sheep and goats 1474 pneiimotropica 2032 spp 340,750,765,1205,1430,1443,1449, 1465,1469,1472,1474; 1478,1508, 1835,1896,1936,1945,2191,2654, 2655,2661,2665,2676,2688,2692, 2873,2896 trnhalosi 765,1474 Pasteurellosis 2428 pigs 1469 rabbits 1944 sheep and goats 765 Pasture bloat 229 dairy cattle 2280 fever 772 horses 2152 myopathy 1186 Patellar ligan1ent injuries, horses 1143 luxation catlle 1087 horses 1142 small animals 1194 Patent ductus arteriosus 72,79 urachus 2092 Pathologic thrombosis 54

Pattern baldness 523

Pcmllin·ia cupana 3032 Pavo spp 2292

Pawing,horses 1549 Paxillus involutus 3096,3102 Peaches 3148 Peat scours 3082 Pebulate 2986 poisoning 2996 Pedal bone cyst,horses 1107 osteitis,horses 1114 Pedicinus oblusus 1881 Pediculosis-See Lice Peduncle disease 1759 Pedunculated lipomas,horses 261 Peestersiekte 1373 Peganum hcn·mala 3120 Pegaspargase 2735 Pelger-Huet anomaly 59

Pelodem

dermatitis D07

slmngyloides 907,908

Pelvic fracture,horses 1145 limbs,evaluation 1218 Pemoline 3039 Pemphigoid,bullous 828 Pemphigus canine benign familial chronic 850 erythematosus 525 foliaceus 525,SD vulgaris 828 Penciclovir 2745 Pendimethalin 2986 Pendular nystagmus 1236 Pendulous crop, poultry 2874 Penicillins 2654 adverse events and toxicity 2658 classes 2654 dose rates/dosages 2657,2658 (table) effects on laboratory tests 2658 elimination, distribution,clearance 2657 interactions 2658 milk discard times 2659,2659 (table) pharmacokinetics 2656 structure-activity relationships 2656 therapeutic indications 2657 withdrawal times (table) 2659 Penicilliosis 643

Penicillium

associated tremorgens 3008 citrinmn 3008 commune 3008 crnslocum 3008 cycloµiwn 3008 griseoj'ulvum 643 mamejfei 643 roquefu rti 3008 spp 640,643, 1489,1901,1993, 2701, 2847,2860 viriclicatwn 2847,3008

VetBooks.ir

INDEX

Penile frenulum, persistent 1331 Penis, short, congenital 1331 Pennisetum spp 2321 Penta poisoning 3052 Pentachlorophenol poisoning 3052 Pentastomid infections 2464 reptiles 1998 Pentazocine 2602, 3042 Pentobarbit.al 3035 Pentosan polysulfate sodium 2721 Pentoxifylline 2584 Peptococcus spp 2696

Peptostreptococcus anaerobius 1263

spp 178, 731, 1449, 1991, 2696 Peracetic acid 2740 Perennial ryegrass staggers 3008, 3154 Perfom1ance modifiers, beef cattle 2264 Peri anal fistula 187 gland tumors 951 tumors 188 Periarteritis nodosa 830 Pericardia! disease 122 effusion 123 Pe1icarditis, septic 123

Perilla frutescens 1442

ketone toxicity 1442 mint 3128 Perimyotis subjlmms 1303 Perinatal asphyxia syndrome 2094 management goats 2149 horses 2159 Perinea! hernia 188 Perineuromas 958, 959 Periodic ophthalmia 508 paralysis, hyperkalemic 1047, 1231 pinna! alopecia 522 Periodontal disease large animals 177 small animals 178 Periodontitis, small animals 178, 361 Periparturient hypocalcemia, small animals 992 hypogalactia syndrome, sows 1373 problems, small animals 2228 Peripheral Cushing disease, horses 1006 neTVe and muscle disorders, congenital 1222 neTVe diseases 1238 injuries 1244 sheath tumors 958 trauma 1243 tumors 1242, 1276 neTVous system 1209

3281

Perirenal hemorrhage syndrome, turkeys 2789 pseudocysts 1497 Peritoneal fluid, characteristics 674 Peritoneopericardial hernia 86, 167 Peritonitis 670 bile, small animals 480 cattle 673 dogs and cats 673 egg, poultry 2896 feline infectious 453, 780, 1251 horses, 251, 673 New World camelids 673 pigs 673 small ruminants 673 Periwinkle 3108 Permethrin 2750, 2756, 2757 Peroneal paralysis, cattle 1090 nerve injuries 1244 Peroneus longus muscle rupture, turkeys 2885 tertius rupture cattle 1091 horses 1137 Perosis, poult1y 2933, 2939, 2940, 2942, 2943 Perosomus elumbis 620, 1045 Per·sea americana 2964, 3112 Persistent atrial standstill 120 halogenated aromatics poisoning 3056 penile frenulum large animals 1331 small animals 2220 pupillary membranes 496 right aortic arch 85 Personal protective equipment 2952 Peste des petits ruminants 766 du canard 2799 Pesticide potentiating agents 3069 residue, animal fibers 2521 Pet birds 1885-See also Avian, Birds, Poult1y food labels 2373 types 2374

Petaurus breviceps 2035 gracilis 2042

Petechial fever, bovine 745

Pethia conchonius 1810

Petroleum product poisoning 3053

Phacochoerus aethiopicus 711

Phacoclastic uveitis, rabbits 1958

Phaenicia sericata 898

spp 895, 897 Phaeohyphomycosis 643

VetBooks.ir

3282

INDEX

Phagocytes 5 Phagocytosis 818 deficiencies in 818 Phalangeal fractures, horses 1108, 1118 Phantom moose disease 930 Pharn1acodynamics (general) 2502 Pharmacokinetics (general) 2499 Pharmacology 2490 Pharmacotherapeutics-See also Principles of therapy cardiovascular system 2525 digestive system 2544 eye 2565 integumentary system 2571 muscular system 2586 nervous system 2590 reproductive system 2606 respiratory system 2608 urinary system 2617 Pharyngeal lymphoid hyperplasia, horses 1427, 1459 mucocele 068 paralysis 186 trauma 1427 Pharyngitis 1426 horses 1459 small animals 361 Phaseolus limatus 2960 Pheasants, nutrition (table) 2919 Pheidole megacephala 941 Phellodendron amurense 1543, 1567 Phenazopyridine hydrochloride 2744 Phendimetrazine 3039 Phenethicillin 2654 Phenicols 2683 adverse events and toxicity 2686 antimicrobial activity.2684 bacterial resistance 2684 effects on laboratory tests 2687 interactions 2687 mild discard times 2687 mode of action 2684 pharmacokinetic features 2684 therapeutic indications 2686 withdrawal times 2687 Phenmedipham 2986 Phenmetrazine 3039 Phenobarbital 1220, 1545, 2592, 2595, 2596, 1545 Phenols and related compounds 2742 substituted 2638, 2650 Phenothiazine tranquilizers 2548 toxicity 3036 Phenothrin 2750 Phenoxy acid derivatives poisoning 2997 Phenoxybenzamine 2627 Phenoxyrnethyl-penicillin 2654 Phentermine 3039 Phenylarsonic compounds 3073 Phenylbutazone 2604, 2717

Phenylephrine 2626 poisoning 3026 Phenylimidazoles 2701 Phenylmercmic nitrate 2741 Phenylpropanolamine 2626 toxicity 3033 Phenylpyrazoles 2756 Phenytoin 2537, 2589, 2600 Pheochromocytomas 548, 575, 576 Phialophora spp 643, 1739, 2703 Phialosimplex 640 Philodendron spp 3112 Philometra sp 1808 Phimosis, small animals 1402 Phlebotomus spp 887 Phobias 1536 dogs 1560 horses 1549 Phoca hispida 1870 sibirica 1856 vitulina 1859 Phocoena phocoena 1860 spinipinnis 1869 Phodopus roborovskii 2021 sungonts 2021 Phomopsis leptostromiforrnis 343, 3018 Phoradendron.fl,avescens 3112 Phorate toxicity 3067 Phorrnia regina 897 spp 895, 897 Phortica vmiegala 512 Phosmet 2750, 2754 toxicity 3067 Phosphate 1592 enema toxicity 571 Phosphine workplace exposure 2955 Phosphodiesterase inhibitors 109, 2531 Phosphoglycolipid antibiotics 2766 Phosphonoacetic acid 2748 Phosphorus deficiency 1000, 1050 goats 2309 horses 2326 pet birds 1918 pigs 2344 poultry 2930 metabolism disorders 999 requirement pigs 2336 sheep 2346 Phosphorylase deficiency, Charolais cattle 1175 Photonia fmseri 3146 glabra 3146 sm7ulata 3146 Pholobactmium spp 1809 Photodynamic dermatitis 3015

VetBooks.ir

INDEX

Photosensitization 976 congenital, sheep 978 hepatogenous 977 primary 976 secondary 977 type IV 977 Phthalylsulfathiazole 2674 Phlhirus pubis 913 PhyUanthus abnormis 344 Phylloerythrin 977 Physaloptera spp 387, 413, 1997 Physeal dysplasia, horses 1149 Physiologic data common domestic animals (tables) 3173 laboratory animals (table) 1842 Physitis, horses 1149 Physocephalus 322 sexalatus 322 Phytolacca americana 3120 PI-3 1433 Pica dogs 1568 horses 1548 Picloram 2986 PIE syndrome 825, 1479 Pietrain creeper syndrome 1043 Pigeon fever 66 fly 2876 malaria 2783 nutrition 2290 Pigeonpox 1910 Pigment abnormalities, skin 848 metabolism, aberrant 977 Pigs-See also Porcine, Swine boar management 2203 breeding 2207 feeding 2340 flu (swine influenza) 1470 gastrointestinal parasites 320 health-management interaction 2160 lameness 1151 management 2160 nutrition 2329 nutritional diseases 2343 parturition 2210 potbellied 1929 pregnancy tests 2211 respiratory diseases 1464 reproduction, management of 2201 teacup 1929 Pilar cysts 947 Pilomatricomas 949 Pilonidal sinus, small animals 1230 Pimaricin 2698, 2700 Pirnobendan 75, 105, 2531 Pindone poisoning 3166 Pine Ponderosa 3146 tar 2742 Western yellow 3146

3283

Ping, abdominal 156 Pingue 3116 Pink tooth 986 Pinkeye 512 Pinky syndrome 849 Pinna-See also Ear alopecia 522 dermatitis, arthropod bite 520 diseases 520 Pinus ponderosa 3146 Pinworms horses 316 rabbits 1954 Pioniis spp 1886 Piperacillin 2655 Piperazine 2638, 2639, 2651 penicillins 2655 Piperonyl butoxide 2752, 2757, 3069 Piping, fish 1771 Pirimiphos 2750 Piroxicam 3038 Piscinoodinium spp 1740, 1802 Piscirickellsia salmonis 1760 Piscivorous birds, nutrition 2291 Pitch poisoning 3045 Pillwmyces chartanun 340, 3015 Pithomycotoxicosis 3006, 3015 Pituitary adenomas 547, 549 pet birds 1916 dwarfism 549 gland 542 tumors 1274 nonfunctional 547, 548 Pityriasis rosea, pigs 848, 979 Pityrosporum spp 2705 Pivampicillin 2655 Pizzle disease 1373 rot 1372 sheep 2168 Placenta, retained, large animals 1381 Placental sites, subinvolution, small animals 1399 Placentitis, mycotic, equine 1346 Plague 677, 2428 cattle 771 duck 2799 fowl 2902 goose 2826 Planktothrix 2956 Plantation flies 895 Plants, poisonous 3103 Plaques, aural, equine 524 Plasma biochemistry analysis 1590 Plasmacytic-lyrnphocytic synovitis 822 Plasmacytomas 1604 extran1edullary 952, 961 Plasmacytosis, mink 1872

Plasmodium durae 2784 cynomolgi 2444

VetBooks.ir

3284

INDEX

Plasmoclium (contimiecl) gallinaceum 2784,2879 heimani 2784,2879 infection,birds 2784

juxtanucleare 2784 knowlesi 2444 relictum 2784

spp 888,1881,1904,1905,2444,2780, 2784,2879 Platelets 7,1613 evaluation 1615 disorders 46,49,50 Platynosomum concinnum 428,484 Play aggression,dogs 1563

Pleistophora hyphessob'lyconis 1811

spp 1740,1782 Pleocytosis 1608

Plesiomonas shigelloicles 1863

Pleural space disease 1664 Pleurisy 1414 horses 1449 Pleuritis 1414 horses 1449 Pleuroperitoneal hernia 167 Pleuropneumonia contagious bovine 1438 caprine 1474 horses 1449 pigs 1469 Plum bladders,mink 1871 Pneumocystis 821 jiroveci 1425,1452,1487 Pneumoencephalitis,avian 2856 Pnewnomycosis 2438 poultry 2901 Pneumonia 1413 acute bronchointerstitial,foals 1452 aspiration 1417 bacterial,cattle 1436 bovine atypical interstitial 11139 brooder 2901 chlamydia!,cattle 1438 dairy calf 1431 enzootic calves 1431 pigs 1467 foreign body 1417 gangrenous 1417 hemorrhagic,mink 1817 inhalation 1417 Mannheimia, sheep and goats 1474 marine mammals 1861 metastatic,cattle 1442 morbillivirus, equine 707 mycoplasmal cattle 1438,1439 pigs 1467 mycotic 1425 poultry 2901 nocardial 666

nonhuman primates 1879 Pasteurella, sheep and goats 1474 potbellied pigs 1936 progressive,sheep and goats 1475 rabbits 1945 reptiles 1992 Rhoclococcus equi 1451 shipping fever 1431,1432 small animals 1486 summer,beef calves 1431 vern1inous 1421 viral,calves 1431 Pneumonitis allergic,small animals 1478 feline 506,1481 hypersensitivity 829 cattle 1441 pet birds 1929 Pneumonysso·icles ca,ninum 974,1480

Pnmimonyssus caninum 974,1480

spp 1880 Pneumothorax 1414 horses 1717 tension 1664 Pneumovirus,avian 2904 Pododermatitis circwnscripta,cattle 1076 infectious,zoo animals 2052 pet birds 1913 ulcerative,rabbits 1958 Podophyllotoxin 2735 Podotrochlitis,horses 1112 Podotrochlosis,horses 1112 Poinsettia 3110 4-Point block,horse 1104 Point-of-care tests 1594 Poison hemlock 3140 Poisonings 2948--See also Toxicities, Toxicoses ACE inhibitors 3032 acetan1ides 2996 acetan1inophen 3029 acetochlor 2999 acorns 3152 alachlor 2999 alcohol 3000 algae 2956 alkaline battery 3003 aluminum phosphide 3169 amet1yn 2999 an1ides 2996 an1monium sulfarnate 2995 arnphetan1ines 3039 analgesics 3027 angiotensin-converting enzyme inhibitors 3032 anilide 2996 annual ryegrass 3153 antacid 3030 anticoagulant rodenticides 3165 anticonvulsants 3034

VetBooks.ir

INDEX

Poisonings (continiied) antidepressants 3034 antifreeze3046 antihistamine 3025 arsenic 1254, 2994,3071 arsenic trioxide 2994 aryloxyphenoxypropionics 2998 asulam 2996 atrazine 2999 avocado 2964 barbiturates 3035 battery, alkaline 3003 bensulide 2D96, 2997 benzodiazepines 3034 binapacryl 2997 bipyridyl compotmds 2996 bleach, chlorine 3001 blister beetle3157 13-blockers 3033 borax 2996 bracken fem3090 bread dough 2965 brodifacoum 3166 bromacil 2999 bromadiolone 3166 bromethalin 3167 bromoxynil 2999 butachlor 2999 buturon 2998 butylate 2996 caffPine 3032 calcipotriene 3037 calcium channel blockers 3032 Cannabis 3041 cantharidin3157 carbamate 2992, 2996, 3059 carbon monoxide, poultry 2861 carboxazole 2996 cationic detergents 3003 chlomequat 2999 chloramben 2997 chlorbromuron 2998 chlorenmron 2998 chlorinated hydrocarbon, mink 1875 chlorine bleach 3001 chlorophacinone 3166 chloroxuron 2998 chlorsulfuron 2998 chlo1toluron 2998 chocolate 2966 cholecalciferol 3168 clomiprop 2996 cloransulan1-methyl 2998 coal-tar products3045 cocaine 3039 coffee weed seed, poultry 2861 cold and cough medications 3025 copper3073 poultry 2861 coumachlor 3166 coumafuryl 3166 creosote 3045

cresol 3045

3285

Crntalaria, poultry 2861 cyanazine 2999 cyanide2959 cyanobacteria2956 cypromid 2996 2,4-D 2997 dalapon 2997 2,4-DB 2997 decongestant 3026 DEF 2999 demethenamid 2996 detergents 3004 cationic 3003 dew343 diagnosis 2950 diazinon, poultry 2861 dicamba 2997 dichlorprop 2997 diclofop 2998 diclosula.m 2998 dicumarol 3156 diesel fuel 3053 diethylstilbestrol, mink 1875 difenoxmon 2998 difethiolone 3166 dinitrocresol 2997 dinitrophenol 2997 dinoseb 2997 dioxin 2997 diquat 2996 diuretics 3034 diw·on 2998 DMNA, mink 1875 drugs (human) cardiovascular 3032 drugs (human) gastrointestinal 3030 drugs (human) ove1°the-collllter 3024 drugs (hw11an) prescription 3032 Ecstasy 3040 ephedrine 3027, 3032 EPTC 2996 ergot 974 ethametsulfuron 2998 fenoxaprop 2998 fenthiaprop 2998 fenuron 2998 fescue 3016 florasulam-methyl 2998 fluazifop 2998 flumetsulam 2998 fluometuron 2998 fluoride3075 5-f1uorouracil 3036 5-FU 3036 fuel 3053 fumonisin 3017 gasoline 3053 gltLfosinate 2997 glyphosate 2997 gossypol3092 poultry 2861 grapes 2968

VetBooks.ir

3286

INDEX

Poisonings (continued) guarana 3032 Hz-receptor antagonists 3030 haloxyfop 2998 hashish 3041 herbal supplements 3032 herbicides 2969 household chemicals/products 3000 houseplants 3103 5-HTP 3032 human drugs 3024 5-hydroxytryptophan 3032 illicit drugs 3038 imazamethabenz-methyl 2999 imazamox 2999 imazapic 2999 imazapyr 2999 imazaquin 2999 imazethapyr 2999 imidazoline 3026 imidazolinones 2999 insecticide, mink 1875 iodides 974 ioxynil 2999 iron 3030 isoproturon 2998 isovaleryl indanedione 3166 kerosene 3053 lasalocid, poultry 2862 lead 3078 mink 1875 poultry 2861 linuron 2998 lupines 3018 ma huang 3032 mackerel, marine mammals 1860 marijuana 3041 MCPA2997 MCPB2997 MDMA3040 mecoprop 2997 mercury 974, 3080 poultry 2861 merphos 2999 metaJdehyde 3070 methiuron 2998 metobromuron 2998 metolachlor 2999 metosulam 2998 metoxuron 2998 mink 1875 molybdenum 3081 monensin, poultry 2863 monoamine oxidase inhibitors 3035 monuron 2998 mulga fern 3091 multivitamin 3030 muscle relaxants 3036 mushrooms 3095 naptalam 2997 narasin, poultry 2862 neburon 2998 nicarbazin, poultry 2861

nitrate 3049 nitrite 3049 nitrofurazone, poultry 2861 3-nitro-4-hydroxyphenylarsonic acid, poultry 2861 nonprotein nitrogen 3043 nonsteroidal anti-inflammatory drugs 3027, 3037 NSAIDs 3027, 3037 oak bud 3152 opiates 3042 organophosphate 1243, 2997, 3064 ornamental plants 3103 parafluron 2998 paraquat 2996 pebulate 2996 pent.a3052 pentachlorophenol 3052 perennial ryegrass 3008, 3154 petroleum products 3053 phenothiazine tranquilizers 3036 phPnoxy acid derivatives 2997 phenylephrine 3026 phenylpropanolamine 3033 pindone 3166 pitch 3045 plants 3103 polybrominated biphenyls, mink 1875 polychlorinated biphenyls mink 1875 poultry 2862 polycyclic alkanoic acids 2998 polyether ionophore poultry 2862 polytetrafluoroethylene, poultry 2862 polyureas 2998 poultry 2859 prescription drugs 3032 prometon 2999 prometryn 2999 propachlor 2999 propane, poultry 2862 propanil 2996 propazine 2999 propylene glycol 3048 pseudoephedrine 3027 ptaquiloside 3090 quaternary ammonia, poultry 2862 Quercus 3152 raisins 2968 range plants of temperate No1th America 3103 relay 3165 rock fern 3091 rodenticide 3165 ryegrass 3153 salinomycin, poultry 2862 salt, poultry 2863 secondary 3165 selective serotonin reuptake inhibitors 3034 selenium 3085 poultry 2863

VetBooks.ir

INDEX Poisonings (continued) Senecio 3150 scombroid, marine mammals 1860 shampoo 3004 siduron 2998 silvex 2997 simazine 2999 slaframine 3019 sleep aids 3034, 3035 soap 3004 sodiw11 arsenite 2994 chlorate 2996 chloride 3083 sorghum 3155 SSRis 3034 street drugs 3038 streptomycin, mink 1875 strychnine 3170 sudan grass 3155 sulfaquinoxaline mink 1875 poultry 2863 sulfometuron 2998 sulfonamides, poultry 2863 sulfonylureas 2998 sulfur, poultry 2863 sweet clover 3010, 3156 2,4,5-T 2997 tebuthiuron 2998 terbacil 2999 terbucarb 2996 terbutryn 2999 tetrail uron 2998 thallium sulfate 974 therapy 2951 thidiazuron 2998 thiobencarb 2996 thiocarbamate 2996 thioureas 2998 thiran1, poultry 2863 triallate 2996 triazines 2999 triazinylsulfonylureas 2998 triazoles 2999 triazolopyrimides 2998 tricyclic antidepressants 3034 toad 3161 topical agents/drugs 3031, 3036 toxic fat, poultry 2863 tranquilizers 3034 phenothiazine 3036 treatment 2951 ureas 2998 vernolate 2996 vitamin 3030, 3031 warfarin and congeners 3165 wood preservatives, mink 1875 xylitol 2968 zinc 3088 oxide 3031 phosphide 3169

3287

Poisonous plants 3103 Poke 3120 Pokeweed 3120 Polioencephalomalacia 1281 goats 2311 Polioencephalomyelitis feline 1252 porcine 1251, 1307 Poliomyelitis, vaccination, exotic mammals 2059 Poll evil 1064, 1350 Polled intersex goat 615 Poloxan1er-iocline 2741 Polyarteritis nodosa 830 Polyarthritis epidemic 2466, 2478 idiopathic 822 infectious, swine 720 nonsuppurative, lambs 628 pigs 720, 1156 serositis, chlan1yclial, large animals 1065 small animals 1198 Polybrominated biphenyl poisoning 3056 mink 1875 poultry 2862 diphenyl ethers 3056 Polychlorinatecl biphenyl poisoning 3056 mink 1875 poultry 2862 dibenzo-p-dioxins 3056 Polychromasia 1611 Polyclonal gammopathies 832 Polycyclic alkanoic poisoning 2998 Polycystic kidneys 1497 Polycythemia 43, 1611 Polycythemia vera 43 Polydactyly 1045, 1050 Polydipsia clogs 1568 horses 1548 potbellied pigs 1937 Polyene macrolide antibiotics 2698 adverse effects and toxicity 2700 antifungal spectra 2698 dose rates 2699, 2700 (table) effects on laboratory tests 2701 fungal resistance 2698 interactions 2700 mode of action 2698 pharmacokinetic features 2699 therapeutic indications 2699 Polyether ionophore poisoning, poultry 2862 Polyethylene glycol 2560 Polygonum 977 Polymer fume fever 3022 Polymicrogyria 1224 Polymyopathy, hypokalemic, feline 1201

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3288

INDEX

Polymyositis dogs 1201 immune-mediated, horses 1182 Polymyxins 2692 Polyneuritis equi 1241 Polyneuropathy Alaskan Malamute 1231 demyelinating, clu·onic inflammato1y 1240 distal, Rottweilers 1239 inherited, Leonberger dogs 1232 Polyodontia 164, 177 heterotopic 165 Polyomavirus, avian 1907 Polyphagia, dogs 1568 Polypogon monspeliensis 3154 Polyps nasal, horses 1461 nasopharyngeal 535 rectal 189 Polyradiculonemitis idiopathic acute 1240 chronic relapsing 1240 protozoa! 1241 Polysaccharide storage myopathy 1048, 1179 Polyserositis, porcine 720 Polysulfated glycosaminoglycan 2721 Polytetrafluoroethylene poisoning pet birds 1924 poultry 2862 Polyurea poisoning 2998 Polyuria, potbellied pigs 1937 Ponderosa pine 3146 Poor man's alfalfa 3144 Population at risk 2397 Porcine-See also Pigs, Swine circovirus disease 723, 1342 cystitis-pyelonephritis 1500 dermatitis and nephropathy syndrome 723 enteroviral encephalomyelitis 1307 epidemic diarrhea 298 hemagglutinating encephalomyelitis 728, 1251 herpesvirus 1342 intestinal adenomatosis 299 juvenile pustular psoriasiform dem1atitis 979 malignant hyperthennia 1176 paivovirns 1342 polioencephalomyelitis 1251, 1307 polyserositis 720 proliferative enteritis 299 pulmonai·y edema 3008, 3018 reproductive and respiratoty syndrome 729, 1341 respiratory and neurologic syndrome 721 RN(-) glycogen storage disease 1176 stress syndrome 1027, 1231

Pores of Winer, dilated 948 Pork tapeworm disease 2454 Porphyria 4, 852 congenital e1ytlu·opoietic 986 etythropoietic 852 feline acute intermittent 987 Porphyrinuria 986 Porphyrnmonas denlicanis 178 gulae 178 levii 1392 salivosa 178 Portal hepatitis, lyn1phocytic, feline 482 hypertension 445 Portosystemic shunts 169 acquired 450 congenital lai·ge animals 351 small animals 430 vasculai· anomalies 447 malformations 446 Posaconazole 2701 Positive compression test 1199 inotropes 2529 predictive value 2404 punislunent 1541 reinforcement 1541 Positron emission tomography 1639 Possessive aggression, dogs 1563 Postanesthetic hemorrhagic myelopathy, horses 1255 Postanesthetic myopathy, horses 1186 Postcastration evi ceration, horses 1722 Postdipping lameness, sheep 629 Posthitis, sheep and goats 1372, 2168 Postinftai1m1atory hyperpigmentation 970 Postmaturity, foals 1726 Postmortem inspection 1644 Postpaitum care, small animals 2228 dysgalactia syndrome, sows 1373 hypocalcemia, small animals 992 period, mares 2200 Postpaiturient hemoglobinuria 1002 Postresuscitation care 1674 Postvaccinal hepatitis, horses 338 Postweai1ing mastitis, sows 1375 multisystemic wasting syndrome, swine 723 Polmnochoerus porcus 711 Potassium 1591 bromide 1545 citrate 2625 clavulanate, ainoxicillin 2658 deficiency horses 2326 poultry 2821, 2934

VetBooks.ir

INDEX Potassium (continued) iodide 2706 metabolism disorders 1003 permanganate 2741 in aquaculture 1752 peroxymonosulfate 2740 requirement, pigs 2337 sparing diuretics 104, 2529, 2624 Potato (plant) 3130 Potbellied pigs 1929 dental care 1931 diseases 1933 feeding and nutrition 1932 gastrointestinal diseases 1933 integw11entary system problems 1934 management 1929 musculoskeletal disorders 1934 nervous system disorders 1935 reproduction 1931 respirato1y problems 1936 urinary system problems 1936 vaccinations 1930 Potentiated sulfonamides 2674 Potentiating agents, pesticides 3069 Potomac horse fever 283, 808, 1346 Poult enteritis mortality syndrome 2840 Poultry-See also Aviar1, Birds artificial insemination 2895 backyar·d 1815 hemorrhagic syndrome 3008, 3011 hobby 1815 mite 2877 nutrition 2914 orgar1ic production 2925 vaccination 2920 Povidone-iodine 2741 Powassan virus encephalitis 2476 Pox birds 2824, 2826 diseases 867 nonhwnan primates 1882 pet birds 1910 rickettsial 2436 Poxvirus marine marrn11als 1869 ratites 1965 Poxviruses, vaccinia-related 2480 Pradofloxacin 2619, 2670, 2673 Pralidoxime chloride 3068 Prallethrin 2750 Prayer beads 3104 Praziquantel 2650 Prazosin 2535 Precatory bean 3104 Precocious mar11rnar-y development, heifers 1387 Preconditioning, feeder calves 2131 Predato1-y aggression, dogs 1565 Preclnisolone 2712, 2734 Prednisone 2712, 2731, 2734, 2737 Pregnancy-See also Gestation determination

3289

cows 2120, 2176 clogs and cats 2225 goats 2185 rnar·es 2194 pigs (table) 2211 sheep 2216 false, small animals 1395 goats 2186 ketosis, ewes and does 1021 pigs 2186 prevention, small animals 2226 tem1ination, small ar1imals 2226 toxemia cows 1020 ewes and does 1021, 2167, 2312 primary 1022 rabbits 1957 secondar-y 1022 Preirnmunization, feeder calves 2131 Prekallikrein deficiency 53 Prelar11initic syndrome, horses 1006 Premack principle 1542 Premature ventricular contractions 72 Prematurity, foals 1726 Premises disinfection 1639 Premortem inspection 1644 Prepuce abnormalities 1311 prolapse, bulls 1331 Prepurchase exar11ination horses 1647 ruminants and swine 1649 Presbycusis 519 Prescription drug toxicities 3032 Pressure wounds 1708 Presystolic gallop heart sound 88 Prevalence 2398 Prevention of flight, zoo birds 2053 Preventive health care, small animals 2169

Prevolella ·intennedia 178 melaninogenica 1368

spp 1075 Preweaning mortality, pigs 2211 Priapism, small animals 1402 Prickle cell carcinomas 945 Prima1-y atrial fibrillation 95 cutaneous neuroenclocrine tumors 952 erythrocytosis 43 hyperarm11onemia, horses 350 hyperoxaluria 1232 hyperpar·athyroidism 564, 1054 immune-mediated thrombocytopenia 47 Jung tll111ors, small animals 1485 photosensitization 976 pregnancy toxemia 1022 ruminal tyrnpany 227 screwworm 899 skeletal tumors 1274 visceral gout, reptiles 2000

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3290

INDEX

Primates (nonhuman)-See Nonhuman primates Primidone 2598, 3035 Principles or therapy-See also Pharmacotherapeutics cardiovascular system 74 digestive system 161 endocrine system 542 integumentary system, topical 844 nervous system 1220 poisoning 2951 reproductive system 1328 respiratory system 1416 urinary systeml496 Prion diseases 2482 Privet 3144 Probenecid 2658 Probenzirnidazoles 2638, 2639 Probiotics 2766 Procainamide 2536 Procarbazine 2731, 2734, 2735 Prochlorperazine 2548, 2604 Procoagulant disorders 54 Production enliancers 2758 related metabolic disorders 985 Proestrus bitches 2222 Profaclol 3042 ProjUicollis spp 1865 Proflavine 2744 Progesterone 573, 2581, 2607, 2759, 2760 assay 1394 canine 1624, 2223 Progestins, synthetic 2607 Prognathia 163 Progressive alopecia 851 ataxia, Charolais cattle 1227 axonopathy, Boxer dogs 1229 degenerative myeloencephalopathy, bovine 1227 dermal collagenosis, pigs 852 myelopathy, Murray Grey cattle 1227 paresis, Angora goats 1228 pnewnonia, sheep and goats 1475 retinal atrophy 502 Proinsulin 579 Prokinetic drugs, gastrointestinal 2556, 2557 (table) Prolactin 542 Prolapse eye 504 oviduct, poultry 2898 prepuce 1331 rectal 189 uterine 1389 vaginal and cervical 1390, 1399 Proliferative enteritis, porcine 299 enteropathy equine 289 rabbits 1948

gill disease 1755, 1807 hemorrhagic enteropathy, pigs 299 keratoconjunctivitis 957 kidney disease, fish 1755, 1807 and necrotizing otitis externa, feline 525 thrombovascular necrosis, pinnae, clogs 526 Prolonged gestation, cattle and sheep 1377 Promazine 2600, 3036 Promethazine 3025 Prometon poisoning 2999 Prometryn 2986 poisoning 2999 Propachlor poisoning 2999 Propane poisoning, poultry 2862 Propanil 2986 poisoning 2996 Propanolol 3033 Propazine poisoning 2999 Propentofylline 1545 Propionate 2606

P1·opionibacte1iiim acnes 787, 955, 2582, 2768

spp 1263, 2696 Propofol 2595 Propoxur 2750, 2754 toxicity 3060 Propoxycarbazone 2986 Propoxyphene 3042 Propranolol 76, 1544, 2538 Proptosis eye 504 trmui1atic 1696 Propylene glycol toxicosis 3048 oxide 2744 Propylthiouracil 560 Propyzamide 2988 Prosopis glandulosa 3130 Prospective cohort study 2400 Prostaglandin F,0 2607 Prostatic calculi 1408 cysts 1407 diseases 1405 hyperplasia, benign 1406 neoplasms 1407 Prostatitis 1406 bacterial 2622 Prosthenorchis 1881

Proslhogonimus macrorchis

2874 Protective aggression, dogs 1564 Protein deficiency horses 2325 pigs 2343 poultry 2930 losing enteropathy 155, 168 nephropathy 168

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INDEX

Protein (continued) requirement beef cattle 2249 dairy cattle 2271 dogs and cats 2366 goats 2309 horses 2316 pigs 2335 sheep 2346 in urine 1616

Pseudochromis spp 1779

spp 341,580,671,1204,1249,1383,1397, 1508,1527, 1720,1737,1825,1872, 1896,1913,1984,1992,1993,2191, 2571,2617,2619,2620,2622,2654, 2655,2659,2660,2665,2669,2671, 2676,2680,2684,2692,2695,2859, 2908 vulga1is 2660 Prothrombin disorders 51 time 44 Protistan parasites,fish (table) 1798 Protists 1755 Protodiastolic gallop heart sound 88 Proloopalina spp 1784 Prolophormia le17·aenovae 897 Protoporphyria 852 Proloslrongylus rufescens 1421,1473

Pse-udoloma new'Ophilia 1811

Proteus mirabilis 528,864,2622

Prototheca wickm·hamii 1264

spp 158,505, 1362, 1366

zopfii 1264,1367

Protozoa in avian blood (table) 2781 nonhwnan primates 1881 pet birds 1904 ratites 1965 reptiles 1998 zoonotic 2440,2442,2444 Protozoa! diseases liver,small animals 455 spinal column and cord 1251 myeloencephalitis,equine 1251,1309 polyradiculoneuritis 1241 Proventricular dilatation disease,pet birds 1909 Proximal enteritis-jejunitis,horses 260 suspensory desmitis,horses 1122

P1unus caroliniana 3146 spp 2960,3148 Pruritus 843

Pseudalleschmia 640 boydii 640 Pseudechis 3159

Pseudo-lumpy skin disease 869

Pseudocapillaroides 1740 xenopi 1740

3291

Pseudocowpox 868,2474 teat skin 1386 Pseudocyesis,dogs 1395 Pseudocysts arachnoid,small animals 1230 perirenal 1497 Pseucloephedrine 2626 poisoning 3027 Pseucloglanders 661,2426 Pseuclohermaphroditism 1330 Pseuclohypoparathyroidism 1057 spp 1782

Pseitclolynchici 894 canariensis 894,2876 Pseiulomonas ae-ruginosa 528,530,1345,1359,1365,

1369,1374,1383,1443,1452,1871, 1878,2005,2007,2177,2191,2196, 2200,2235,2630,2653,2655,2659, 2662,2663,2664,2670,2671,2680, 2684,2688,2695,2739,3160 Jtuoresce-ns 1779 spp 340,530,533,671,856,864,898, 1205,1397,1492,1508,1720,1735, 1737,1809,1871,1873,1896,1935, 1945,1946,1957,1964,1971,1984, 1991,1992,1993,2000,2006,2089, 2191,2235,2571,2617,2619,2654, 2655,2660,2676,2692,2739, 2859 Pseudomyiasis 903 Pseudomyotonia,cattle 1176 Pseilclonaja textilis 3159 Pseudoneoplastic skin conditions,pet birds 1915 Pseuclophylliclean tapeworms 2454 Pseuclopox,dolphins 1863 Pseudopregnancy clogs 1395 goats 1381 Pseudopterygiurn, rabbits 1958 Pseudoptyalism 367 Pseudorabies mink 1874 pigs 1300,1342 virus,and abortion 1333 Pseuclote11-anova spp 2456

Psilocybe cubensis 3096,3099 spp 3097

Psilostrophe spp 3148

Psittacine beak and feather disease 1908 nutrition 2288 pediatric diseases 1892 polyomavirus 1907 proventricular dilatation disease 1909 Psittacosis 599,2428,2808 pet birds 1897

VetBooks.ir

3292

INDEX

PsorergaIes bos 917 ovis 918

spp 914, 1881 Psorergatic mange cattle 917 sheep 918 Psoriasiform dermatitis, juvenile pustular, pigs 979 lichenoid clermatosis, clogs 848

Psornbia bos 917 ovis 918, 2576 spp 914

Psornplw1-a colwnbiae 888

spp 888, 889, 2879

Pso1-optes cuniculi 527, 915, 918, 1953 eqiii 918 ovis 915, 917, 918, 2751

spp 843, 914, 918, 1854, 2576 Psoroptic mange cattle 915 horses 918 sheep 918 Psychic estrus, horses 1550 Psychogenic water consumption, potbellied pigs 1937 Psychological well-being, nonhuman primates 1884 Psychotropic agents 2601 for feather plucking pet birds (table) 1928 for skin disorders 2584 Ptaquilosicle poisoning 3090

Pte1·idium aquilinum 506, 1282, 2960, 3089, 3094, 3148 spp 273

Pternlichus obtusus 2878 Pternphyllwn scalare 1814 Pternp11 s spp 708, 721

Ptyalism, small animals 367 Public health 2390 agencies 2390 essential fw1ctions 2396 foci of prevention 2396 law 2411 national indicators 2395 roles of veterinarians 2391 significant achievements 2393 surveillance 2398 Puerperal hypocalcemia, small animals 571, 992 mastitis, sows 1373 metritis, acute 1368 tetany, small animals 571, 992 Puffy hock, cattle 1088 Pug encephalitis 1224

Pu lex iiritans 1953 simulans 880

Pullets, nutrition (table) 2915 Pullorum disease, poultry 2865 Pulmonary abscessation, cattle 1437 acariasis, nonhuman primates 1880 adenocarcinoma, sheep and goats 1477 aclenomatosis, sheep 1477 capillariasis 2456 disease, chronic obstructive, horses 1443, 1455 edema 1414, 3008 porcine 3008, 3018 emphysema 1428, 3008 and edema, bovine 1439 fibrosis, equine multinoclular 1446 hemorrhage, exercise-induced, horses 1457 hypersensitivity syndrome, macaws 1889 hypertension 125 pet birds 1914 syndrome, poultry 2871 hype1tensive hea1t disease, bovine 137 infiltration with eosinophilia 825, 1479 noclulru· eosinophilic granulomatous syndrome 1479 syndrome, hantaviral 2470 thromboernbolism, small ru1imals 1487 Pulmonic stenosis 71, 78 Pulpitis, small animals 180 Pulpy kidney disease 610 Pulse deficits 90 Pulseless electrical activity 1673 Pulses, types 90 Pulsion cliverticula, small animals 373 Pulsus alternans 90 bigeminus 90 paracloxus 90 pru-vus et tru·dus 90 Puncture wounds, foot, horses 1114 Punishment negative 1541 positive 1541 Punkies 887 Punlignis tetrazona 1810 Pupillru-y light reflex 1215 membranes, persistent 496 Puppy hypoglycemia 1225 Pure reel cell aplasia 13, 827 Purine analogues 2732 nucleosicles 2745 Purple allamancla 3116 mint toxicity 1442 sesbane 3132 Purpura hemorrhagica, horses 830, 1182 Pustular psoriasiform dermatitis, pigs 979 vulvovaginitis, infectious 1392, 1434

INDEX

VetBooks.ir

Puumala virus 2470

Pycnoscelus sw-inmnensis 2830

Pyelonephritis cattle 1499 pigs 1500 small animals 1510 Pyloric stenosis 167 Pyode1111a 863 Pyogranulomatous meningoencephalitis 1264 Pyometra large animals 1370 small animals 1397 stump 1397 Pyramidal disease, horses 1115 Pyrantel 2647 Pyrazon 2988 Pyrethrins 2750, 2756 toxicity 3058, 3063 Pyrethroids 2750, 2756 toxicity 3058, 3064 Pyrethrum 3063 Pyridate 2988 Pyridostigmine 2588 Pyridoxine deficiency, poultry 2943 Pyrimetharnine 2674, 2796 Pyrimidines analogues 2732 nucleosides 2745 Pyriprole 2756 Pyriproxyfen 2752, 2755 Pyrithiobac-sodium 2988 Pyrrolizidine alkaloidosis 3150 Pythiosis 641

Pylhium insidiosum 378, 641 spp 402, 2698

Q

Q fever 623, 2434 Quadriceps contracture, small animals 1202 tie-down, dogs 1202 Quadriplegia, hereditary, Irish Setters 1235 Quail bronchitis 2913 disease 2805 nutrition (table) 2920 Quarantine, zoo animals 2047 Quarter crack, horses 1116 Quaternary ammonia poisoning, poultry 2862 Queening 2227 Queensland itch 887 tick typhus 2436

Qu,ercus

poisoning 3152 spp 3120, 3152 Que1y fever 623, 2434 Quillaja saponaria 2768

3293

Quinclorac 2988 Quinidine 2536 Quinolines 2796 Quinolones 2669 adverse effects and toxicity 2673 antimicrobial activity 2670 bacterial resistance 2671 classes 2669 dosages (table) 2673 effects on laboratory tests 2674 general properties 2670 interactions 2674 mode of action 2670 pharmacokinetic features 2671 therapeutic indications 2672 Quiscalus quiscua 1313 Quittor, horses 1115 Quizalofop-p-ethyl 2988

R

Rabbitpox 1951 Rabbits 1937 bacterial diseases 1944 bots 901 calicivirus disease 1951 dental disease 1954, 1955 dysautonomia 1257 euthanasia 1941 fibroma virus 1950 heritable diseases 1959 housing 1941 intestinal diseases 1947 management 1937 mycotic diseases 1944 neoplasia 1959 noninfectious diseases 1954 nutrient requirements (table) 1944 nutrition 1943 orphaned kits 1939 parasites 1952 restraint 1938 Shope fibroma virus 1950 therapeutics 1938 viral diseases 1950 Rabies 1251, 1302, 2478 f1.ufous form 1304 management 1306 paralytic or dumb form 1304 ringed seal 1870 vaccination, exotic mammals 2059 zoonotic risk 1306 Rachycentron canadum 1764

Radfo1·d'ia affinis 2029 ensifera 2030

Radial and ulnar dysplasia, dogs 1203 paralysis, cattle 1089 Radiation safety 1630 scatter 1627

VetBooks.ir

3294

INDEX

Radiation (continued) therapy 1651 pet birds 1917 Radiculomyelopathy, chronic degenerative 1246 Radiography 1626 contrast procedures 1632, 1635 direct digital 1628 interpretation 1631 patient restraint 1629 processing 1628 safety 1630 thoracic 91 Radiology, interventional 1655 Rafoxanide 2650 Ragwort 3150 toxicity 3150

Raillietina celebensis 2454 cesticillus 2830 demeraiiensis 2454 echinobolhrida 2831

infection 2454 spp 2454, 2828 tetragona 2831 Railroad disease/siclmess 1030 Rain lily 3118 Raisins, poisoning 2968 Ramaiiaflavo-brunnescens 3102 Ramichlo1idiwn 643 Ramphas/os spp 2293 Rams feeding 2351 reproductive management 2217

Ram.a catesbeiana 1738, 1743 pipiens 1741, 1743

Randomized controlled trials 2402 Range paralysis, poultry 1822 plants, poisonous 3103 supplements, sheep (table) 2352° Rangifer spp 1313 Ranitidine 2551, 2558, 3030 Ranula, small animals 368

Ranunculus bulbosus 977 spp 977

Raphanus spp 3138 Raphidiopsis 2956

Raptors, nutrition 2291 Rash illness, Southern tick-associated 2420 Rat bite fever 2428 tail syndrome 615 tailed maggot 903 tapeworm 2454 Rathayibacter toxicus 3153 Rations dairy cattle 2278 goats 2311

Ratites 1960 chick management 1964 digestive system disorders 1965 infectious diseases 1964 management 1960 musculoskeletal disorders 1966 nutrition 2292 parasites 1965 reproduction 1962 toxicities 1966 trauma 1966 Rats 2025-See also Rodents as laboratory animals, management 2032 as pets, diseases of 2028 biology 2025 husbandry 2025 neoplasia 2030 physical examination 2027 zoonotic risk 2032 Rattle belly, lambs 274 weed 3118 Rattlebox 3132, 3140

Rattus no1'Vegicus 1838, 2030, 2470 rattus 2030, 2470

spp 2456 Rayless goldenrod 3134 Reactive aitway disease, horses 1443 Recall bias 2401, 2402 Recirculating aquaculture systems 1754 Recording, digital lesions, cattle 1068 Rectal atresia 169 diseases 187 neoplasms 189 polyps 189 prolapse 189 potbellied pigs 1934 strictures 189 pigs 300 tears 190 horses 1721 temperature ranges (table) 3173 Rectourethral fistula 169 Rectovaginal constriction 1332 fistula 169, 1499 Recurnbency, bovine secondary 1188 Recurrent aitway obstruction, horses 1455, 2152 diarrhea, horses 288 uveitis, equine 508 Red bag delivery 2094 blood cell(s) 4 count 1610 evaluation 1614 indices/measurements 8, 1610 in urine 1617 cell aplasia, pure 827 eye 1699

VetBooks.ir

INDEX

Red (continued) leaf photinia 3146 leg syndrome, amphibians 1737 maple 3126 mites 2877 pet birds 1906 nose, cattle 1434 sea bream iridovirus 1814 stomach worm, pigs 322 tears, rats 2032 tip photinia 3146 water disease 341, 601 worm disease, fish 1808 worms, horses 316 Redirected aggression, dogs 1563 behavior 1537 Regenerative anemias 9 Regional anesthesia cattle 1068 horses llOl Regurgitation, pet birds (table) 1900 Reinforcement negative 1541 positive 1541 Reinforcers, second-order 1541 Rejection of lambs 1556 Relapsing fever 2420 Relative erythrocytosis 43 risk 2401 Relaxants, skeletal muscle 2588 Relaxin 1624 Relay poisoning 3165 Renal-See also Kidney agenesis 1497 anomalies 1496, 1497 cysts 1497 disease anemia in 13 ferrets 1828 goldfish 1806 horses, nutiition in 2329 hypocalcemia 571 pet birds 1913 dropsy, goldfish 1806 dysfunction diagnostic tests 1496 small animals 1512 dysplasia 1496 failure, hypercalcemia 565 glucosuria, small animals 1521 hypoplasia 1496 lipidosis, mink 1876 secondary hyperparathyroidism 1056 tubular acidosis, horses 1507 defects, small animals 1520 Rendering 1640 Renibacteriiim salmoninarum 1759 Reoviral infection, poultry 2886 Reoviridae 696

3295

Repetitive behaviors 1535 canine 1561 Replacement breeding progran1, cattle 2172 heifers 2125 Reproduction-See also Breeding, Partmition backyard poultry 1818 hormonal control 2244 llamas and alpacas 1848 management cattle 2120, 2171, 2174 goats 2182 horses 2187 pigs 2201 potbellied pigs 1931 sheep 2212 small animals 2219 nutrition in, small animals 2378 phannacologic control 1329 rabbits 1939 ratites 19G2 zoo animals 2046 Reproductive cycle, features 1326, 1327 diseases female small animals 1393 male small animals 1400 pet birds 1920 poultry 2896 reptiles 2001 indices, swine 2202 and respiratory syndrome, porcine 729 system congenital and inherited anomalies 1329 introduction 1323 phannacotherapeutics 2606 principles of therapy 1328 technologies 1329 therapy, effect on fetus or neonate 2608 Reptiles 1967 anestl1esia and analgesia 1977, 1978 (table) antimicrobial drugs used in (table) 1985 bacterial diseases 1991 drug used in (table) 1989 endocrine diseases 2000 environmental diseases 1999 food composition (tables) 1972 husbandry requirements (table) 1970 management 1968 metabolic diseases 2000 mycotic diseases 1993 neoplastic diseases 2002 nutrition 1969, 2302 parasites 1996 parasiticides used in (table) 1987 physical examination 1971 pneumonia 1992 protozoa! diseases 1998 reproductive diseases 2001

VetBooks.ir

3296

INDEX

Reptiles (continued) respiratory infections 1992 restraint 1971 space requirements (table) 1968 traumatic injuries 1999 viral diseases 1994 Residues chemical,food and fiber 2518 in foodstuffs 2519 Resistance anthelmintics 2644 antifungals 2697,2698, 2701, 2703, 2704 antimicrobials 2622,2630, 2631, 2633, 2653,2660,2664,2671, 2676,2680, 2684,2688,2690 antineoplastic agents 2723 Resorptive lesion (tooth),small animals 181 Resource guarding,dogs 1563 Respiratory diseases cattle 1429 control 1415 horses 1443 llamas and alpacas 1854 pigs 1464 reptiles 1992 sheep and goats 1471 small animals 1478 nutrition in 2384 distress syndrome, acute, feedlot cattle 1442 and neurologic syndrome, porcine 721 rates,resting (table) 3174 severe acute syndrome 2478 sinus arrhythmia 68 sounds 90 stimulants 2616 syncytial virus, bovine 1433 system introduction 1411 neoplasia,small animals 1484 pharmacotherapeutics 2608 principles of therapy 1416 tract inflammation,horses 1456 viral infections,cattle 1433,1436 Response substitution 1542 Reston ebolavirus 2470 Restraint marine mammals 1856 zoo animals 2049 Restrictive cardiomyopathy 119 Resuscitation cardiopulmonary 1670 endpoints (table) 1683 foals 1724 Retained fetal membranes, large animals 1381 placenta,large animals 1381 spectacles,reptiles 1974 ulnar cartilage cores,dogs 1204

Reticuloendotheliosis,poultry 2854 Reticulopericarditis,tratm1atic 123 Reticuloperitonitis, traumatic 230 Reticulosis inflarnmato1y 1252 neoplastic 1252 pagetoid 962 Reticulum cell sarcomas 961 Retinal atrophy 503 degeneration 1701 detachment 503,1701 dysplasia 502 pigment epithelial dystrophy 503 Retinoids 2737 Retinopathies, inherited 502 Retractor penis muscle,short 1331 Retrobulbar hemorrhage,traumatic 1696 Retrospective cohort study 2400 Reverse sneeze 1488 T, 553 Rhctbclias spp 1736,1740,1997 Rhabditic dermatitis 907 Rhabditorids causing CNS disease 1313 Rhabdomyolysis horses 1176 small animals 1202 syndrome,horses 1048

Rhect americanct 1960 pennala 1960

Rheas 1960 Rheumatoid arthritis,canine 822 Rhinella marina 3161 Rhinitis 1413 allergic 824 cattle 1429 atrophic,pigs 1465 necrotic,pigs 1468 rabbits 1945 small animals 1488 Rhinoclaclosporium spp 1739 Rhinoeslius pwpiinms 2464 Rhinopneumonitis,equine 34.1 viral 1344,1444 Rhinoplem bonasus 1806 Rhinosporidiosis 644,2444

Rhinospoi·icliwn seeberi 644,2444

spp 2697 Rhinotracheitis feline viral 1481 infectious bovine 1434 and abortion 1334 vaccination of exotic mammals 2055 turkey 2904, 2907

Rhipicentoi· bicornis 935 nullctll'i 935 spp 928, 935

VetBooks.ir

INDEX

Rhipicephalus annulatus 936,2441 cippendiculatus 34,761,937,940,2435 bergeoni 938 Boophilus (subgenus) 935 bursa 23,935 camicasi 938 capensis 938 compositus 938 decolorntus 936,2435 duttoni 937,939 evertsi 935,937 evei·tsi 937,1315 mimeticus 937,1315 gertrudae 938 gla brnscutatiirn 935 , 937 guilhoni 938 haeinaphysalo·ides 936 hurti 938 jeanelli 938 kochi (neavi) 937 longus 938 liinulatus 938 micrnplus 935,940,941,2441,2576, 2752

moiicheti 938 muhleiisi 938 nitens 937 occulatus 937 pilans 936 praetextal.us 938 prnvus 937 pseudolongus 938 pulchellus 937 piimilio 936,2437 punctatus 937,1315 pusillus 936 Rhipicephalus (subgenus) 936 rossicus 936 sanguineus 23,29,803,806,935,936, 941, 1315,2435,2437

sanguineus 696 schulzei 936 seiiegaleiisis 938 simus 938 seiisu stricto 938

spp 19, 21,23,761,803,927,928,935, 941,1314,2435,2471 sulcatus 938 supert1·itus 938 tricuspis 938 turanicus 936,938 zambeziensis 937 Rh'izoctonia legmninicola 214,3019 Rhizopus spp 1335,1739,1901 Rhodnius 39 Rhodococcosis 679

Rhodococcus equi 67, 158,289,316,341,354,359,505, 679,1263,1443,1451,1452,1709, 2153,2196,2688,2694 pnemnonia 1451

3297

1ubropei·tinctus 1345

spp 666, 671,679,2689

Rhoclocleiidrnn spp 3094,3112 Rhodotomla mucilaginos'is 1904

spp 2699 Ribavirin 2745,2746 Ribeirnla 1740 Riboflavin deficiency horses 2328 pigs 2344 poultry 1242,2941 Ricinus communis 3148 Rickets 1051 adult 1052 mink 1875 nonhuman primates 1883 pigs 1161,1163 poultry 2881,2930 Rickettsia 624 aeschlimannii 933, 2436 a.fi'icae 929,2434 akari 2032,2436 amblyomnii 928,2436 australis 2436 con01ii 933,936,2434 felis 807,882 heilongjiangensis 931,2436 helvetica 2436 honei 930,2436 japonica 2436 massiliae 937,2436 monaceiisi 2436 moosei·i 2436 parkeri 520,806,929,2436 prowazekii 909, 2348 moultii 931,2436 1·hipicephali 937 ricketts'ii. 51,803,806,928,929,930, 937,1250 salmonis 1760 sibirica 931,2436 slovaca 931,2436 spp 520, 623,911,928,1760,1971,2032, 2416,2567,2684,2688 typhi 807,882 Rickettsial diseases fish 1760 small animals 803 spinal column and cord 1250 thrombocytopenia 48 zoonotic 2432,2434,2436,2438 pox 2436 Rickettsiosis,chigge r b - orne 2438 Rieinernlla 2894 anal'ipest�fe1· 2800,2827,2894,2929 infection,birds 2864 Rifamide 2694 Rifampicin 2694 Rifampin 2694 Rifan1ycins 2694,2748

VetBooks.ir

3298

INDEX

Rift Valley fever 768, 2478 Right displaced abomasum 238 dorsal colitis,horses 265 dorsal displacement of colon, horses 264 heart failure 103 hepatic lobe atrophy, horses 350 torsion, abomasum 238 ventricular cardiomyopathy, arrhythmogenic 117 Rirnantadine 2746, 2747 Rirnsulfuron 2988 Rindcrpcst 771 Ringbone 1119 Ringtail, rats 2031 Ringworm 872, 2440-See also Dermatophytosis backyard poultry 1823 nonhw11an primates 1880 rabbits 1949 Risperidone 2604 Risus sardonicus 1255 Roachback 1047 Roaring, horses 1458 Robenacoxib 2720 Robenidine 2797 Robinia pseudoacacia 3130 Rock fern poisoning 3091 Rocky Mountain spotted fever 51,806,926, 1250, 2436 wood tick 930 Rodenticides, anticoagulant ingestion 53 poisoning 3165 poultry 2860 Rodenlolepis nana 2013 Rodents 2002--See also Mice,Rats biologic data (table) 2003 bots 901 nutrition 2300 Rolitetracycline 2679 Romanowsky stains 1598 Ronidazole 2696 Ronne! toxicity 3067 Roost mite 2877 Rosary pea 3104 Ross River fever 2478 Rostral cerebellar vermis herniation 1277 displacement of palatopharyngeal arch, horses 1461 Rotational defonnities, birds 1895,2881 Rotavirus birds 2803 cattle 272 enteritis, pigs 301 foals 144,290 lan1bs 273 rabbits 1951 ruminants 276 Rotenone 3063 Rotlaufseuche 701

Round cells 1602 tw11ors, differentiation 1604 Rowid heart disease, turkeys 2790 Roundworms-See also Nematodes birds 1905 pigs 320 raccoon 416 small animals 415 turkey 2831 zoonotic infections 2454, 2456, 2458, 2460,2462 Roup, birds 2804 Roxarsone 2797 Rubber jaw syndrome 1054, 1057,1205 puppy disease 50 tree 3110 vine 119 Rubeola infection, nonhuman primates 1882 Ruelene toxicity 3067 Rule of 20 1685 Rumen impaction 222 flukes 328 Rwnenitis 222 Rumex crispus 3130 Ruminal acidosis 225 drinking 236 fluid transfer 2562 parakeratosis 237 tynlpany 227 Rw11inant digestive system, pharmacotherapeutics 2561 forestomach, diseases 221 prepmchase examination 1649 urolithiasis 1502 Ruminoreticular acidifying agents 2563 antacids 2562 motility modifiers 2563 Ruminoreticulum, drug disposition 2564 Ruminotorics 2562 Rwiting-stunting syndrome, chickens 2840 Rupture cranial cruciate ligament, small animals 1198 fibularis longus muscle, turkeys 2885 gastrocnemius muscle/tendon cattle 1091 poultry 2885 longus capitis muscle,horses 1464 peroneus longus muscle, turkeys 2885 tertius, cattle 1091 Russian knapweed 3126 spring-summer encephalitis 2480 Russula emelica 3096,3099

VetBooks.ir

INDEX

Rust, fish 1802 Ryegrass staggers annual 3153 perennial 3008,3154 toxicity 3153

s

Saaremaa virus 2470 Sabelhes spp 2482 Sabia virus 2476 Sacahuista 3118

Saccharomyces boulardii 286 cernvisiae 2343,2848 Sacchm·omycopsis guttulat.a 2009 Saccharopolyspora Spinosa 2756

Sacrocaudal dysgenesis 1230 Sacroiliac joint abormalities,horses 1147 Saddle sores 979 S-Adenosylmethionine 2561 Sagenomella 640 Saguinus spp 1876 Saimiri sciureus 1876 Saint Bernard's lily 3108 John's wort 3144 Louis encephalitis 2478 Salbutamol 2610,2614 Salicyclic acid 2739 Salicylanilides 2638,2641,2650 Salicylazosulfapyridine 2674 Salinomycin 2765,2796 poisoning, poultry 2862 Salivary disorders,small animals 367 fistula,small anin1als 368 gland infarction 369 necrosis 369 tumors, small animals 368 mucocele,small animals 368 Salmeterol 2614 Salmo spp 1762 Salmon anemia,infectious 1764 poisoning disease 808 poisoning fluke 426 River virus 2468

Salmonella

Abortusovis 195,1339,2217 Agona 281 Anaturn 195 Arizonae 1993,2865,2866 Choleraesuis 195,199,297,627,671, 721,730,733,1825,1933,1935 kunzendorf 297 Derby 297 Dublin 195,199,275,1339 enlerica 195,281,2420,2823,2865 Enteritidis 195,199,1823,1835,2191, 2866,2877

3299

Gallinarum 195,199,1815,1822,2865, 2866 Hadar 2866 Heidelberg 297,1822,2866 Infantis 297 Kentucky 1822,2866 Montevideo 195 Muenchen 282 Newport 195,282,1825 Paratyphi 195 Pullorum 195,1815,1822,2865,2866 SaintpauJ 2866 spp 119,158,195,272,275,281,287,288, 289,300,325,329,340,354,374, 378,396,399,403,459,623,671, 682,749,1263,1337,1343,1473, 1711,1823,1830, 1832,1835,1853, 1863,1878,1897,1933,1962,1964, 1971,1991,1993,2006,2016,2045, 2048,2052,2068,2089,2092,2123, 2130,2135,2170,2376,2394,2406, 2410,2414,2654,2655,2659,2665, 2671,2684,2692,2695,2696,2766, 2798,2805,2865,2866,2871,2883, 2894,2896,2898 TiJene 1835 Typhi 195 lyphimurium 195,199,275,280,281, 297,300,1339,1822,1825,1835, 1933,2866 Typhisuis 297 vaccines 199 W01thington 297 Salmonellosis 195, 2430 backyard poultry 1822 cattle and sheep 196 dogs and cats 197 horses 196,281 pigs 196 intestinal 296 poultry 2865 sheep 274 and abortion 1339 Salmon poisoning disease 808 fluke 426 Salmonid alphaviruses 1765 Salpingitis,poultry 2898

Salsola, luberculali}'