Case studies in infectious disease: norovirus 9780203853986, 9780815341420, 0203853989, 0815341423, 9781136986154, 1136986154, 9781136986192, 1136986197, 9781136986208, 1136986200

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Norovirus

Peter M. Lydyard Michael F. Cole John Holton William L. Irving Nino Porakishvili Pradhib Venkatesan Katherine N. Ward

This edition published in the Taylor & Francis e-Library, 2009. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.

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©2010 by Garland Science, Taylor & Francis Group, LLC

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. No part of this book covered by the copyright heron may be reproduced or used in any format in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the publisher.

The publisher makes no representation, express or implied, that the drug doses in this book are correct. Readers must check up to date product information and clinical procedures with the manufacturers, current codes of conduct, and current safety regulations. ISBN 978-0-8153-4142-0 Library of Congress Cataloging-in-Publication Data Case studies in infectious disease / Peter M Lydyard ... [et al.]. p. ; cm. Includes bibliographical references. SBN 978-0-8153-4142-0 1. Communicable diseases--Case studies. I. Lydyard, Peter M. [DNLM: 1. Communicable Diseases--Case Reports. 2. Bacterial Infections--Case Reports. 3. Mycoses--Case Reports. 4. Parasitic Diseases-Case Reports. 5. Virus Diseases--Case Reports. WC 100 C337 2009] RC112.C37 2009 616.9--dc22 2009004968

Published by Garland Science, Taylor & Francis Group, LLC, an informa business 270 Madison Avenue, New York NY 10016, USA, and 2 Park Square, Milton Park, Abingdon, OX14 4RN, UK. Visit our web site at http://www.garlandscience.com ISBN 0-203-85398-9 Master e-book ISBN

Peter M. Lydyard, Emeritus Professor of Immunology, University College Medical School, London, UK and Honorary Professor of Immunology, School of Biosciences, University of Westminster, London, UK. Michael F. Cole, Professor of Microbiology & Immunology, Georgetown University School of Medicine, Washington, DC, USA. John Holton, Reader and Honorary Consultant in Clinical Microbiology, Windeyer Institute of Medical Sciences, University College London and University College London Hospital Foundation Trust, London, UK. William L. Irving, Professor and Honorary Consultant in Virology, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK. Nino Porakishvili, Senior Lecturer, School of Biosciences, University of Westminster, London, UK and Honorary Professor, Javakhishvili Tbilisi State University, Tbilisi, Georgia. Pradhib Venkatesan, Consultant in Infectious Diseases, Nottingham University Hospitals NHS Trust, Nottingham, UK. Katherine N. Ward, Consultant Virologist and Honorary Senior Lecturer, University College Medical School, London, UK and Honorary Consultant, Health Protection Agency, UK.

Preface to Case Studies in Infectious Disease The idea for this book came from a successful course in a medical school setting. Each of the forty cases has been selected by the authors as being those that cause the most morbidity and mortality worldwide. The cases themselves follow the natural history of infection from point of entry of the pathogen through pathogenesis, clinical presentation, diagnosis, and treatment. We believe that this approach provides the reader with a logical basis for understanding these diverse medically-important organisms. Following the description of a case history, the same five sets of core questions are asked to encourage the student to think about infections in a common sequence. The initial set concerns the nature of the infectious agent, how it gains access to the body, what cells are infected, and how the organism spreads; the second set asks about host defense mechanisms against the agent and how disease is caused; the third set enquires about the clinical manifestations of the infection and the complications that can occur; the fourth set is related to how the infection is diagnosed, and what is the differential diagnosis, and the final set asks how the infection is managed, and what preventative measures can be taken to avoid the infection. In order to facilitate the learning process, each case includes summary bullet points, a reference list, a further reading list and some relevant reliable websites. Some of the websites contain images that are referred to in the text. Each chapter concludes with multiple-choice questions for self-testing with the answers given in the back of the book. In the contents section, diseases are listed alphabetically under the causative agent. A separate table categorizes the pathogens as bacterial, viral, protozoal/worm/fungal and acts as a guide to the relative involvement of each body system affected. Finally, there is a comprehensive glossary to allow rapid access to microbiology and medical terms highlighted in bold in the text. All figures are available in JPEG and PowerPoint® format at www.garlandscience.com/gs_textbooks.asp We believe that this book would be an excellent textbook for any course in microbiology and in particular for medical students who need instant access to key information about specific infections. Happy learning!!

The authors March, 2009

Table of Contents The glossary for Case Studies in Infectious Disease can be found at http://www.garlandscience.com/textbooks/0815341423.asp Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12 Case 13 Case 14 Case 15 Case 16 Case 17 Case 18 Case 19 Case 20 Case 21 Case 22 Case 23 Case 24 Case 25 Case 26 Case 27 Case 28 Case 29 Case 30 Case 31 Case 32 Case 33 Case 34 Case 35 Case 36 Case 37 Case 38 Case 39 Case 40

Aspergillus fumigatus Borellia burgdorferi and related species Campylobacter jejuni Chlamydia trachomatis Clostridium difficile Coxiella burnetti Coxsackie B virus Echinococcus spp. Epstein-Barr virus Escherichia coli Giardia lamblia Helicobacter pylori Hepatitis B virus Herpes simplex virus 1 Herpes simplex virus 2 Histoplasma capsulatum Human immunodeficiency virus Influenza virus Leishmania spp. Leptospira spp. Listeria monocytogenes Mycobacterium leprae Mycobacterium tuberculosis Neisseria gonorrhoeae Neisseria meningitidis Norovirus Parvovirus Plasmodium spp. Respiratory syncytial virus Rickettsia spp. Salmonella typhi Schistosoma spp. Staphylococcus aureus Streptococcus mitis Streptococcus pneumoniae Streptococcus pyogenes Toxoplasma gondii Trypanosoma spp. Varicella-zoster virus Wuchereia bancrofti

Guide to the relative involvement of each body system affected by the infectious organisms described in this book: the organisms are categorized into bacteria, viruses, and protozoa/fungi/worms

Organism

Resp

MS

GI

H/B

GU

CNS

CV

Skin

Syst

1+

1+

L/H

Bacteria Borrelia burgdorferi

4+

Campylobacter jejuni

4+

Chlamydia trachomatis

2+ 2+

Clostridium difficile

4+

4+

Coxiella burnetti

4+

Escherichia coli

4+

4+

Helicobacter pylori

4+

4+

4+

4+

4+

Listeria monocytogenes

2+

4+

Mycobacterium leprae

4+ 4+

4+

2+ 4+

Neisseria meningitidis

2+ 4+

Rickettsia spp.

4+ 4+

Salmonella typhi

4+

4+ 1+

1+

2+

1+ 1+

4+

Streptococcus pyogenes

4+ 4+

Streptococcus mitis Streptococcus pneumoniae

2+

2+

Neisseria gonorrhoeae

Staphylococcus aureus

4+

4+

Leptospira spp.

Mycobacterium tuberculosis

2+

4+

1+

4+

3+

4+

4+ 3+

Viruses Coxsackie B virus

1+

1+

4+

1+

Epstein-Barr virus Hepatitis B virus

4+

2+

4+

4+

Herpes simplex virus 1

2+

4+

4+

Herpes simplex virus 2

4+

2+

4+

2+

Human immunodeficiency virus

Influenza virus

2+

4+

1+

Norovirus

1+

4+

Parvovirus

2+

Respiratory syncytial virus

4+

Varicella-zoster virus

2+

3+

4+ 2+

4+

2+

Protozoa/Fungi/Worms Aspergillus fumigatus

4+

Echinococcus spp.

2+

Giardia lamblia Histoplasma capsulatum

1+ 4+ 4+

3+

1+

Leishmania spp.

4+

4+ 4+

4+

4+ 4+

Toxoplasma gondii Trypanosoma spp.

4+ 4+

Plasmodium spp. Schistosoma spp.

2+

2+ 4+

Wuchereria bancrofti

4+

4+ 4+ 4+

The rating system (+4 the strongest, +1 the weakest) indicates the greater to lesser involvement of the body system. KEY: Resp = Respiratory: MS = Musculoskeletal: GI = Gastrointestinal H/B = Hepatobiliary: GU = Genitourinary: CNS = Central Nervous System Skin = Dermatological: Syst = Systemic: L/H = Lymphatic-Hematological

Norovirus

number of cases

A doctor was called to a home for the elderly because two residents had developed vomiting and watery diarrhea within 2 days of each other – an 80-year-old woman followed by an 87-year-old man. On taking a history the doctor found that both patients had flatulence and stomach cramps during the first 24 hours of illness followed by vomiting, diarrhea, aching joints, and neck pains. The doctor examined the patients; the first case had recovered and the symptoms were resolving in the second case. She requested a stool sample from both patients to be sent to the local microbiology laboratory to be tested for bacterial and viral pathogens. On the doctor’s return to the home the next day both patients were well and a telephone message from the laboratory reported norovirus detected in both stool samples. The local health authority was notified of a potential outbreak. In response, the community physician advised scrupulous attention to hand-washing to prevent further spread of the infection. However, the next day another resident became ill with diarrhea and vomiting and a few days later a member of staff developed the same symptoms and had to leave work as she was unwell. Five days afterwards a five further members of staff telephoned to say that they were sick. A nonresident day-patient also reported vomiting 2 days after her last attendance at the home. An outbreak of norovirus-induced vomiting and diarrhea was declared.

Course of the outbreak Setting The setting was a home for the elderly that had been recently refurbished. A total of 51 full-time and part-time staff cared for 50 resident and 60 nonresident day-patients who each attended 1 day a week. Course The entire outbreak lasted 9 weeks (Figure 1). Most of those affected recovered completely within 72 hours. The first case reported was in a resident who had little contact with the outside community. The first day-patient to be affected became ill 2 days after the initial case. None of the staff became unwell until 9 days after the outbreak began. In all, 34/51 (67%) staff, 27/50 (53%) residents, and 9/60 (15%) day-patients were affected. Investigation of the outbreak The time course of the outbreak (Figure 1) suggested serial transfer from one individual to another. After several visits to the home, Environmental Health Officers reported that, although the kitchens and preparation of food were adequate, hand-washing facilities were poor throughout the home, with very few paper towel dispensers. Because of the design of the building soiled bedpans had to be carried though the dining area so that they could be

Figure 1. Time course of the norovirus outbreak.

16 staff non-residents residents

14 12 10 8 6 4 2 0 1

5

10

15 April

20

25

30

4

16 19 May

30

3 June

2

NOROVIRUS

emptied into uncovered sluices located in rooms alongside baths. This meant that the surrounding surfaces in both the dining area and around the sluices would be contaminated with virus particles as a result of air-borne dispersal of fecal material. Thus fecal contamination of the environment in the dining and washing areas accounted at least in part for the continuing person to person spread of norovirus infection. Control measures Several measures, which caused considerable practical difficulties for both residents and staff, were instituted in an effort to restrict the spread of infection. The home was closed to new admissions and the meals-on-wheels service to the local community was suspended. However, no attempt was made to isolate affected residents and visiting continued. The transfer of day-patients from the home to a local hospital was discontinued after a secondary outbreak of gastroenteritis involving several hospital patients. Three bathrooms in the home were designated sluice rooms, the baths being no longer used, and the remaining three were used for bathing only. All toilets were separate from the bathrooms and some were designated for the exclusive use of those with gastroenteritis. Staff who wished to return to work as soon as their symptoms subsided were advised to remain away

for an additional 48 hours so that they did not reintroduce the infection into the home. Soiled bedpans were placed in polythene bags and then into a closed bin before being transported through the dining room into the sluice room. Hand-washing facilities were improved with the installation of more paper towel dispensers. Comment The high attack rate and long duration of the outbreak were related to the vulnerability of the elderly population (average age 84 years) and the difficulties in maintaining high standards of hygiene. Although the home had recently been refurbished and internally redesigned, the planners had not fully considered the facilities necessary for the care of aged and infirm residents, nor had they consulted community physicians or microbiologists at any stage of the planning process. The standards should have been comparable to those of a hospital ward for the care of the elderly. More building work, at considerable cost, was undertaken in order to redesign parts of the building so as to separate sluice rooms from rooms with baths. Note – This description of an outbreak is adapted from a report of a real one that happened 20 years ago (Gray et al:. see References section) but the principles it illustrates still stand.

1. What is the causative agent, how does it enter the body and how does it spread a) within the body and b) from person to person? Causative agent Noroviruses are unenveloped single stranded RNA viruses with an icosahedral capsid, that were formerly known as Norwalk viruses (because of their first identification in Norwalk, USA) or small round structured viruses (SRSVs) – the latter term arose because of their characteristic feathery, ragged appearance lacking a distinct surface structure as seen by electron microscopy (Figure 2A). The noroviruses belong to the family of caliciviruses – the other group of human caliciviruses are the sapoviruses, which when visualized by electron microscopy have a structure distinct from noroviruses with cup-shaped surface depressions giving a ‘Star of David’ appearance (Figure 2B). Sapovirus infection is endemic in childhood, causing occasional cases of diarrhea. There are 3 genogroups of human noroviruses (genogroups I, II, and IV; genogroups III and V contain exclusively animal noroviruses) subdivided into altogether about 30 genotypes – genetic variability rapidly evolves due to point mutations and frequent recombination between different viruses. Because they lack an envelope the noroviruses are very resistant to adverse environmental conditions and even to commonly used disinfectants – this

NOROVIRUS

A

B

property together with genetic variability facilitates their propensity to cause outbreaks (see below).

Entry and spread within the body After ingestion with food or drink, the virus passes through the stomach and due to its inherent resistance to acid arrives undamaged in the small intestine. Infection is thought to be limited to the small intestine but direct evidence for this is very difficult to obtain in the human host (see Pathogenesis below). The incubation period is 24–48 hours. Virus is found in vomit and shed in feces during the illness and fecal shedding continues for 3 weeks or more after recovery. Person to person spread Noroviruses are usually spread via the fecal–oral route, either directly from person to person or indirectly. The latter occurs because noroviruses are unenveloped and hence resistant to disinfectants and able to persist in the environment. Indirect transmission occurs after consumption of food (commonly salads and vegetables), or water and ice contaminated by the feces of an infected person. Shellfish are a common source of infection, especially oysters – these are filter feeders and concentrate virus from sewage-polluted water. Swimming in sewage-polluted water also carries the risk of norovirus infection. The infection is highly contagious – aerosolized vomit and transmission by fomites facilitates spread during outbreaks. Epidemiology Norovirus gastroenteritis is very common, usually, but not always, occurring in the winter and with norovirus infection sweeping through the community with a high attack rate. In the developed world by the fifth decade of life more than 60% of the population have norovirus antibodies, whereas antibodies are acquired much earlier in developing countries.

Figure 2. Electron microscopic appearance of human enteric caliciviruses. (A) Noroviruses lack the distinctive surface morphology characteristic of sapoviruses, although a ragged edge is clearly visible surrounding some of the particles. (B) The distinctive surface structures on a sapovirus viewed along the two-, three- and five-fold (indicated) axes of symmetry. Bar: 100 nm for each panel.

3

4

NOROVIRUS

Noroviruses cause the majority of gastroenteritis cases identified in community-based studies in developed countries and these viruses are the most common cause of outbreaks of nonbacterial gastroenteritis in both children and adults; in the UK since the turn of the 21st century over 2000 norovirus-associated outbreaks have been reported. In developing countries noroviruses are present but less is known about their contribution to the burden of disease. Figure 3 gives an example of the settings and presumptive modes of transmission for outbreaks of norovirus gastroenteritis in the USA. From this it can be seen that outbreaks are a common problem in hospitals and in residential homes for the elderly. Persistent outbreaks occur on cruise ships and frequently involve multiple routes of transmission including by consumption of food or water, directly from person to person, and from contamination of the environment (fomites). Such outbreaks can only be terminated by closing the ship and deep-cleaning all possibly infected surfaces including carpets and curtains. Interestingly, norovirus was also identified as a cause of outbreaks among American military personnel during the Gulf War.

2. What is the host response to the infection and what is the disease pathogenesis?

Figure 3. Settings and presumptive modes of transmission for 90 outbreaks of nonbacterial gastroenteritis in the United States from January 1996 to June 1997. Noroviruses were detected in 86 (96%) of the 90 outbreaks by reverse transcription PCR.

Host response to infection The nature of immunity to norovirus infection is difficult to study because the virus cannot be grown in tissue culture. The limited information available comes from volunteer studies where it has been suggested that the minimal infectious dose is low, being 10–100 virions. Immunity to norovirus re-infection persists for up to about 14 weeks in volunteers after previously induced norovirus illness. However, long-term immunity is not maintained. For example, in one volunteer study, 6 of 12 individuals developed gastroenteritis upon exposure to a norovirus and the same 6 individuals became ill again upon rechallenge 27–42 months later. Although pre-existing serum antibodies do not correlate with resistance to re-infection, the importance of the adaptive immune response for the rapid resolution of norovirus infection is apparent because immunocompromised persons may be symptomatic and shed virus for months. Part of the explanation for the lack of resistance to re-infection may lie in the genetic variability of the virus, that is the adaptive immune response

settings

mode of transmission food-borne (21%)

other (3%) oyster consumption (6%)

nursing homes and hospitals (43%)

oyster consumption (6%)

vacation settings, including cruise ships (11%)

schools and day-care centers (11%)

person to person (11%)

water-borne (3%) no data (43%) restaurants and catered meals (26%)

unknown (16%)

NOROVIRUS

may be specific for a particular genotype of the virus. Indeed a new variant of norovirus genogroup II genotype 4 has recently appeared in Europe and has been responsible for many outbreaks (Lopman et al.: see References). However, intriguingly, the genetic make-up of the individual infected with a norovirus also appears to play a role in susceptibility. For example, about 20% of the population seem to be endowed with long-term resistance to norovirus infection. Evidence has recently emerged that this may result from a genetically determined variation in virus receptors in the intestinal tract involving ABH and Lewis carbohydrate blood group antigens. However, individual noroviruses use different blood group antigens as receptors and thus no one is resistant to all of the noroviruses. It is important to note that genetic variation, either viral or host, cannot solely explain the absence of long-term immunity to noroviruses; the human volunteer studies that first provided evidence for this atypical pattern of immunity involved repeated challenge of the same individual with the identical inoculum of virus. Thus, there was no genetic variation in this case and susceptible individuals still failed to develop lasting protective immunity.

Pathogenesis As regards the vomiting that is characteristic of norovirus infection, a marked delay in gastric emptying was observed in volunteers who became ill after experimental infection. It has therefore been proposed that abnormal gastric motor function is responsible for nausea and vomiting but the precise mechanism is unknown. Another equally plausible explanation would be inflammation of the pyloric junction between the stomach and the intestine. The pathogenesis of norovirus-induced diarrhea seems to be noninflammatory or secretory resulting from damage to and blunting of the small intestinal villi (Figure 4) but the exact mechanism is presently unknown. While most enteric viruses replicate in and kill enterocytes, resulting in decreased fluid absorption causing diarrhea with loss of water, sugar, and

virus invasion

cell death villus atrophy

crypt hyperplasia malabsorption

secretion

Figure 4. Presumed mechanism of norovirus pathogenesis – development of damage to gut mucosa and ensuing diarrhea.

villus regeneration

recovery

5

6

NOROVIRUS

A

salts, there is accumulating evidence that noroviruses do not infect enterocytes: (1) when intestinal biopsy samples from norovirus-infected volunteers were stained with convalescent serum, no viral antigen could be detected in the enterocytes; (2) recent unpublished work demonstrates instead the detection of viral antigen in cells of the lamina propria underlying the enterocytes (M.K. Estes, American Society of Virology conference 2008, keynote address); and (3) a related mouse norovirus replicates in lamina propria cells but not epithelial cells. It is not clear how infection of lamina propria cells could result in diarrhea but there is an intricate interplay between these cells and the overlying enterocytes.

3. What is the typical clinical presentation and what complications can occur? The typical clinical presentation includes vomiting and because of its seasonal occurrence the illness is known as ‘winter vomiting disease.’ Symptoms begin abruptly with nausea, abdominal cramps, and vomiting which is characteristically projectile. Diarrhea may be absent, mild or severe but when present it is not bloody, lacks mucus and may be watery. Headache and myalgia are common and low grade fever occurs in 50% of cases. Although infections in the very young and elderly can be quite severe, the disease is usually self-limiting and symptoms subside within 24–48 hours.

B

Complications are rare but the effects of dehydration (metabolic alkalosis, hyponatremia, hypokalemia, and renal failure) may occur in the elderly. Immunosuppressed individuals are at risk of prolonged diarrhea, perhaps lasting for months, requiring fluid replacement and in severe cases enteral and/or parenteral feeding to combat malnutrition and weight loss.

4. How is this disease diagnosed and what is the differential diagnosis?

Figure 5. Immune-electron microscopy to show antibody seroconversion. Noroviruses (size 27nm) from a patient with gastroenteritis visualized by electron microscopy (A) after incubation with serum taken from the patient in the acute phase of illness and (B) after incubation with serum taken from the patient in the convalescent phase of illness. Specific antibody molecules in the convalescent serum of the patient aggregate and coat the virus particles.

Sporadic cases are rarely investigated and what follows concerns the differential diagnosis of outbreaks of gastroenteritis. Such diagnosis is based on the characteristic clinical features of the illness, that is vomiting in over 50% of cases and mild diarrhea without blood or mucus with a duration of about 48 hours, together with detection of norovirus in feces. A fecal sample, preferably obtained while the patient is still symptomatic, should be tested by reverse transcription polymerase chain reaction (RT-PCR), so as to detect viral RNA. Before the development of such highly sensitive molecular testing, electron microscopy was widely used but this technique is limited by its insensitivity as it requires large numbers of virus particles in a stool sample, that is >106 m–1 for detection. Notably immune-electron microscopy (Figure 5A and B) can be used to prove antibody seroconversion in patients with norovirus gastroenteritis and is still used today in the research setting to concentrate virus. Note – RT-PCR for viral nucleic acid is the method of choice for investigation of outbreaks because of its high sensitivity but nevertheless in an outbreak at least five fecal samples from five different individuals should be tested to ensure detection.

NOROVIRUS

Table 1. Viruses causing gastroenteritis and their epidemiological features Family

Virus

Epidemiological features Endemic infection in children

Outbreaks of infection in all ages

Group A rotavirus

Major cause of childhood diarrhea

Occasional in adults – most often among the elderly in hospitals or in residential homes

No

Group B rotavirus

–

Large outbreaks in China

No

Group C rotavirus

–

Occur but uncommon

No

Noroviruses

–

Major cause of outbreaks

Yes

Sapoviruses

Less common cause of childhood diarrhea

–

No

Adenovirus

Adenovirus types 40 and 41

Second most common cause of childhood diarrhea

–

No

Astrovirus

Human astrovirus

5–10% of childhood diarrhea cases

Family outbreaks occur

No

Reovirus

Caliciviruses

Differential diagnosis The other possible viral causes are given in Table 1 – notably outbreaks of diarrhea are commonly caused by rotavirus in young children and the elderly. Bacterial causes and fecal samples should be tested for Salmonella, Shigella, and Campylobacter spp. In addition, Clostridium difficile can cause serious outbreaks with high morbidity and even mortality in hospitals.

5. How is the disease managed and prevented? Management The illness is usually short and requires attention only to fluid and electrolyte replacement, except in the case of persistent diarrhea in the immunosuppressed, which may also require enteral or parenteral nutrition. Prevention This relies not only on clean drinking water and efficient sewage disposal but also on good standards of personal and food hygiene plus adequate cleaning arrangements in hospitals and residential homes. Raw shellfish should be cooked before consumption and fruit washed if to be eaten raw. Outbreak control As illustrated in the example of an outbreak in a residential home given above, this is a difficult issue and outbreaks can grumble on for long periods and often do not end until the majority of susceptible people have been

Food- or water-borne

7

8

NOROVIRUS

infected. Control measures rely firstly on limiting contact between ill and susceptible persons, for example by isolation of those affected in single rooms in hospital or nursing homes, and using contact (enteric) precautions – gloves, aprons, and scrupulous hand-washing or if more than one case by closing the hospital ward or relevant section of a nursing home to new admissions. Secondly, they rely on measures to prevent water-borne, food-borne, fomite-borne, and person to person spread – transmission is often by more than one route in an outbreak. Thirdly, exclusion of those affected from food-handling is required for 48 hours after recovery. Note – although the latest evidence suggests that virus is shed in feces for longer than this after recovery, it should be remembered that the virus load will be decreasing and it is impractical to exclude staff from work for 2 weeks. Vaccine: Given the lack of understanding of the nature of immunity to norovirus, it is not surprising that there is no vaccine available.

SUMMARY the intestine instead of enterocytes; it is unclear how this leads to diarrhea.

1. What is the causative agent, how does it enter the body and how does it spread a) within the body and b) from person to person? ●

Norovirus – an unenveloped single-stranded RNA virus.

●

Noroviruses were formerly known as Norwalk or small round structured viruses.

●

Three genogroups, GI, GII, and GIV, of norovirus infect humans.

●

Norovirus infection has a seasonal incidence – ‘winter vomiting disease.’

●

Noroviruses are spread by the fecal–oral route.

●

The main source of virus is another infected person, contaminated food, or water.

●

3. What is the typical clinical presentation and what complications can occur? ●

Self-limiting vomiting and diarrhea.

●

Main complication is dehydration.

●

Causes persistent diarrhea in the immunocompromised.

4. How is this disease diagnosed and what is the differential diagnosis? ●

The virus cannot be routinely grown in cell culture so diagnosis relies on RT-PCR to detect viral nucleic acid in feces.

●

Differential diagnosis includes infection with rotavirus, Salmonella, Shigella, and Campylobacter spp, and in the hospital setting Clostridium difficile.

Norovirus outbreaks are common in health-care settings and cruise ships.

2. What is the host response to the infection and what is the disease pathogenesis? ●

Immunity is short-lived and re-infection is common.

●

Very little is known regarding the pathogenesis of norovirus infection.

●

The cause of the delay in gastric emptying that is most likely responsible for the high incidence of vomiting episodes is unknown.

●

The virus appears to infect lamina propria cells in

5. How is the disease managed and prevented? ●

There is no specific treatment.

●

There is no vaccine.

●

Control of outbreaks includes reinforcing good hygiene, closure of hospital wards, and isolation of ill persons until 48 hours after symptoms have resolved.

NOROVIRUS

9

FURTHER READING Atmar RL, Estes MK. Norwalk virus and related caliciviruses causing gastroenteritis. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 2nd edition. ASM Press, Washington, DC, 2002: Chapter 47.

Desselberger U, Gray JJ. Viruses associated with acute diarrhoeal disease. In: Zuckerman AJ, Banatvala JE, Pattison JR, Griffiths PD, Shaub BD, editors. Principles and Practice of Clinical Virology, 5th edition. Wiley, Chichester, 2004: Chapter 4.

REFERENCES Gray JJ, Ward KN, Clarke IR. A protracted outbreak of viral gastroenteritis in a residential home for the elderly. Communicable Diseases Report No. 52, 30 December 1988. Lopman B, Vennema H, Kohli E, et al. Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet, 2004, 363: 682–688.

PHLS Advisory Committee on Gastrointestinal Infections. Preventing person-to-person spread following gastrointestinal infections: guidelines for public health physicians and environmental health officers. Commun Dis Public Health, 2004, 7: 362–384. (Review.)

WEB SITES Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, April 16, 2004/53(RR04);1–33, Atlanta, GA, USA: http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5304a1.htm Centers for Disease Control and Prevention, National Centre for Immunization and Respitory Diseases, Atlanta GA, USA: http://www.cdc.gov/ncidod/dvrd/revb/gastro/faq.htm

Centre for Infections, Health Protection Agency, HPA Copyright, 2008: http://www.hpa.org.uk/webw/ HPAweb&Page&HPAwebAutoListName/Page/11919421729 66?p=1191942172966

10

NOROVIRUS

MULTIPLE CHOICE QUESTIONS The questions should be answered either by selecting True (T) or False (F) for each answer statement, or by selecting the answer statements which best answer the question. Answers can be found in the back of the book. 1. Which of the following are true of norovirus? A. This virus is the most usual cause of infantile diarrhea. B. Genetic variation arises by reassortment.

B. RT-PCR for norovirus protein in feces. C. Examination of a fecal sample by electron microscopy. D. Fecal microscopy to detect pus cells. E. A characteristic appearance of the intestine on endoscopy. 4. Which of the following are true for the clinical presentation of norovirus infection?

C. It is closely genetically related to rotavirus.

A. It presents with dysentery.

D. It is closely genetically related to sapovirus.

B. After 2 weeks the illness resolves. C. A complication may be hypokalemia.

2. Which of the following are true concerning the spread of norovirus? A. It is susceptible to adverse environmental conditions. B. It can be transmitted via fomites.

D. Abdominal pain is severe. 5. Which of the following are useful in the prevention of transmission of norovirus infection?

C. It may be acquired by fecal–oral spread.

A. Isolation of infected patients.

D. Infection may be acquired transplacentally.

B. Hand-washing.

E. Only a very small proportion of the population are susceptible.

C. Chlorine compounds.

F. Re-infection may occur. 3. Which of the following tests would be helpful in the diagnosis of norovirus gastroenteritis? A. Inoculation of a cell culture with feces from an infected person.

D. Persons with norovirus gastroenteritis may prepare food for others if scrupulous hand-washing is observed. E. Ward closure.

Answers to Multiple Choice Questions 1. Which of the following are true of norovirus? A. This virus is the most usual cause of infantile diarrhea. FALSE: the usual cause of infantile diarrhea is rotavirus. B. Genetic variation arises by reassortment. FALSE: noroviruses are single-stranded RNA viruses in which genetic variation arises by point mutation and recombination but not reassortment, which requires a segmented genome. C. It is closely genetically related to rotavirus. FALSE: rotavirus is a reovirus, namely a double-stranded segmented RNA virus. D. It is closely genetically related to sapovirus. TRUE: both are caliciviruses. sapovirus is an infrequent cause of infantile diarrhea. 2. Which of the following are true concerning the spread of norovirus? A. It is susceptible to adverse environmental conditions. FALSE: it persists in the environment mainly due to the lack of a viral envelope. B. It can be transmitted via fomites. TRUE: norovirus persists in the environment and may be transmitted via fomites, i.e. inanimate objects such as door handles, carpets or writing utensils that may be contaminated with infectious agents. C. It may be acquired by feco–oral spread. TRUE: most infections are acquired via this route, whereas infection is only rarely acquired from aerosolized vomit. D. Infection may be acquired transplacentally. FALSE: the infection is thought to be limited to the gut. E. Only a very small proportion of the population are susceptible. FALSE: immunity is short-lived and at any one time a large proportion of the population are susceptible. F. Re-infection may occur. TRUE: immunity is short-lasting and strain-specific. 3. Which of the following tests would be helpful in the diagnosis of norovirus gastroenteritis? A. Inoculation of a cell culture with feces from an infected person. FALSE: the virus cannot be grown in cell culture. B. RT-PCR for norovirus protein in feces. FALSE: RT-PCR does not detect viral protein. However RT-PCR to detect viral RNA is the mainstay of diagnosis. C. Examination of a fecal sample by electron microscopy. TRUE: the virus is seen by electron microscopy as a small round structured virus. However, this method is very insensitive as there have to be at least a million particles per ml of feces for the virus to be visualized. D. Fecal microscopy to detect pus cells. FALSE: norovirus infection causes a secretory diarrhea and pus cells are absent.

E. A characteristic appearance of the intestine on endoscopy. TRUE: the intestinal villi are blunted. Nevertheless this method is not recommended for routine diagnosis as the disease is short-lived and also rotavirus infection gives the same appearance. 4. Which of the following are true for the clinical presentation of norovirus infection? A. It presents with dysentery. FALSE: the typical presentation is with vomiting and watery not bloody diarrhea. B. After 2 weeks the illness resolves. FALSE: the illness lasts about 2 days in the immunocompetent, although it may persist for weeks to months in organ transplant recipients. C. A complication may be hypokalemia. TRUE: if part of dehydration. D. Abdominal pain is severe. FALSE: abdominal cramps are characteristically mild. 5. Which of the following are useful in the prevention of transmission of norovirus infection? A. Isolation of infected patients. TRUE: patients with norovirus gastroenteritis should be nursed in an appropriate single room using precautions to prevent transmission of norovirus by contact, e.g. use of gloves and aprons. This is one of the main ways of limiting the spread of infection in the hospital setting. B. Hand-washing. TRUE: the virus may be spread on hands. C. Chlorine compounds. TRUE: these agents are effective when used as disinfectants to clean contaminated surfaces. D. Persons with norovirus gastroenteritis may prepare food for others if scrupulous hand-washing is observed. FALSE: those infected should not prepare food until at least 48 hours after their symptoms. The infectious dose is very low and hand-washing is insufficient to prevent transmission on hands. There is also a major risk of contamination of food and the surrounding environment with vomit. E. Ward closure. TRUE: norovirus outbreaks are notoriously difficult to control in the hospital setting. It is usually necessary to close an affected ward to new admissions and wait for the outbreak to burn out.

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NOROVIRUS

Figure Acknowledgements Figure 1. This figure was produced specifically for this publication. Figure 2. Reprint permission kindly given for image by Hodder Education. Originally published in Topley & Wilson Microbiology and Microbial Infection, 10th edition CD Set, 2005, Figure 42.7, Brian E. J. Mahey et al. Reproduced by permission of Edward Arnold (Publishers) Ltd. Figure 3. This figure was produced specifically for this publication. Figure 4. This figure was produced specifically for this publication. Figure 5a. Reprint permission kindly given by Dr. James Gray of the Health Protection Agency (originator of the image) and by Elsevier Publishing. Originally due to be published as Figure 23.3 in Notes on

Medical Microbiology by Dr. Kate Ward. Figure 5b. Reprint permission kindly given by Dr. James Gray of the Health Protection Agency (originator of the image) and by Elsevier Publishing. Originally due to be published as Figure 23.3 in Notes on Medical Microbiology by Dr. Kate Ward.