Essential Tuberculosis 3030667057, 9783030667054

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Essential Tuberculosis Giovanni Battista Migliori Mario C. Raviglione Editors

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Essential Tuberculosis

Giovanni Battista Migliori Mario C. Raviglione Editors

Essential Tuberculosis

Editors Giovanni Battista Migliori Servizio di Epidemiologia Clinica delle Malattie Respiratorie Istituti Clinici Scientifici Maugeri IRCCS Tradate Italy

Mario C. Raviglione Centre for Multidisciplinary Research in Health Science (MACH) University of Milan Milan Italy

ISBN 978-3-030-66705-4    ISBN 978-3-030-66703-0 (eBook) https://doi.org/10.1007/978-3-030-66703-0 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Tuberculosis (TB) is among the top causes of death worldwide and a major public health threat in spite of the important efforts by some governments, the World Health Organization and the other stakeholders over the past decades. The situation is now even more alarming given the impact of the COVID-19 pandemic directly on TB and through the stress imposed on health systems and the economy in general. In 2021, health workers of every kind, at all levels and everywhere as well as patients, administrators and civil society need rapid access to information and constant updates on the ‘White Plague’ to be able to face it with strong evidence-based interventions. This book covers the full spectrum of tuberculosis-related topics in a comprehensive and yet easy-to-follow and readily accessible format. Filling a significant gap in tuberculosis literature, it addresses tuberculosis sensu lato and also mirrors the content of the Queen Mary University of London Tuberculosis Diploma. Covering all aspects related to this condition, from prevention, diagnosis and treatment to public and global health implications, it provides a complete overview of the science around tuberculosis and its management. Further, it includes a wealth of case studies and exercises, making it an essential guide for all staff involved in the fight against tuberculosis. Written by an international and interdisciplinary panel of experts, the book will appeal to a broad readership including, among others, students, postdoctoral fellows, clinicians, researchers and nurses, as well as public health officers working in tuberculosis control programmes. The book was designed to be practical, including a wealth of case studies and exercises offering a perspective from different continents and settings. While acknowledging the extraordinary support provided by Dr. Simon Tiberi of Queen Mary University, London, we have put into this book our enthusiasm and experience accumulated during an entire professional life devoted to the global fight against tuberculosis. We do hope it responds to the expectations of those who face the sad effects of the TB epidemic every day and also of those who are simply interested to know more about this ancient plague that has caused death and suffering of

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hundreds of human generations. We live in an era of discoveries, of innovations, and of unprecedented visibility of health threats. Let’s make sure that the war against TB keeps being supported by all: this book is our contributions to ‘ending TB’ once and for all in the decades to come. Tradate, Italy Milan, Italy 

Giovanni Battista Migliori Mario C. Raviglione

Contents

Part I Introduction 1 History of Tuberculosis������������������������������������������������������������������������������   3 Robert Loddenkemper and John F. Murray 2 Mycobacterium tuberculosis: The Organism’s Genomics and Evolution ��������������������������������������������������������������������������������������������  11 Daniela Maria Cirillo, Arash Ghodousi, and Enrico Tortoli 3 Pathogenesis and Immunology of Tuberculosis��������������������������������������  19 Delia Goletti and Adrian R. Martineau 4 Basic and Descriptive Epidemiology of Tuberculosis ����������������������������  29 David W. Dowdy and Mario C. Raviglione 5 Tuberculosis: WHO-Recommended Strategies and Global Health Perspectives ����������������������������������������������������������������������  37 Alberto L. García-Basteiro and Mario C. Raviglione Part II Prevention 6 Tuberculosis Vaccines��������������������������������������������������������������������������������  49 Hazel Morrison, Dereck R. Tait, Helen McShane, and Ann M. Ginsberg 7 Latent Tuberculosis Infection Diagnosis and Treatment������������������������  59 Dominik Zenner, Heinke Kunst, Lynn Altass, Alberto Matteelli, and Judith Bruchfeld 8 Tuberculosis Infection Control ����������������������������������������������������������������  67 Giovanni Battista Migliori and Grigory Volchenkov Part III Diagnosis 9 Tuberculosis Clinical Presentation and Differential Diagnosis��������������  79 Kavina Manalan, Jessica Barrett, and Onn Min Kon

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10 Microbiological Diagnosis of Tuberculosis Disease��������������������������������  87 Riccardo Alagna, Andrea M. Cabibbe, Enrico Tortoli, and Daniela M. Cirillo 11 Radiology in the Diagnosis of Tuberculosis: How to Read the Chest X-Ray (CXR)������������������������������������������������������  97 Steve Ellis Part IV Treatment of Tuberculosis 12 Rationale for Anti-Tuberculosis Chemotherapy ������������������������������������ 109 José Caminero Luna and Giovanni Battista Migliori 13 Anti-Tuberculosis Drugs and Adverse Events���������������������������������������� 121 Hannah Yejin Kim, Jin-Gun Cho, Onno W. Akkerman, Xavier Padanilam, Barbara Seaworth, and Jan-Willem C. Alffenaar 14 Treatment of Drug-Susceptible Tuberculosis������������������������������������������ 131 Marcela Munoz-Torrico, Norma Téllez-Navarrete, Heinke Kunst, and Nguyen Nhat Linh 15 The Role of Surgery in Tuberculosis Management: Indications and Contraindications ���������������������������������������������������������� 141 Richard Zaleskis, Alessandro Wasum Mariani, Francesco Inzirillo, and Irina Vasilyeva 16 How to Design the Regimen for Drug-­Resistant Tuberculosis (and Clinical Cases)������������������������������������������������������������ 149 Medea Gegia, Rupak Singla, Adrian Rendon, Berenice Soto, Catherine Dominic, and Simon Tiberi 17 The Shorter Regimen for Multidrug-­Resistant or Rifampicin-Resistant Tuberculosis������������������������������������������������������ 157 Francesca Conradie 18 Monitoring Treatment: Clinical and Programmatic Approach for Drug-Susceptible and Drug-Resistant Tuberculosis ������ 163 Jan-Willem C. Alffenaar, Hannah Yejin Kim, Anthony Byrne, Alberto Piubello, and Giovanni Battista Migliori 19 Tuberculosis Treatment and Adherence�������������������������������������������������� 171 Al Story 20 Tuberculosis Patient-Centred Care���������������������������������������������������������� 177 Onno W. Akkerman and Tjip S. van der Werf Part V Risk Factors, Risk Groups, Challenges 21 Tuberculosis, Alcohol, Smoking, Diabetes, Immune Deficiencies and Immunomodulating Drugs ������������������������������������������ 187 Jean-Pierre Zellweger, Raquel Duarte, and Marcela Munoz Torrico

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22 Tuberculosis and Prisons�������������������������������������������������������������������������� 195 Emanuele Pontali and Selene Manga 23 Tuberculosis and Migration���������������������������������������������������������������������� 203 Claudia Caroline Dobler and Luigi Ruffo Codecasa 24 Tuberculosis in People Living with HIV�������������������������������������������������� 213 Svetlana Degtyareva, Scott Heysell, Nashaba Matin, Zelalem Temesgen, and Marc Lipman 25 Tuberculosis and COVID-19 Comorbidity: A New Twenty-First-Century Cursed Duet �������������������������������������������������������� 221 Giovanni Battista Migliori and Mario C. Raviglione 26 Childhood Tuberculosis ���������������������������������������������������������������������������� 229 H. Simon Schaaf and James A. Seddon 27 Tuberculosis in Women������������������������������������������������������������������������������ 245 Paul P. Nunn, Araksya Hovhannesyan, and Aamna Rashid 28 Tuberculosis in the Elderly������������������������������������������������������������������������ 253 Lisa Kawatsu, Takashi Yoshiyama, and Seiya Kato 29 Extrapulmonary Tuberculosis������������������������������������������������������������������ 259 Judith Bruchfeld, Lina Davies Forsman, Gabrielle Fröberg, and Katarina Niward 30 Clinical and Programmatic Aspects of Kidney and Liver Failure and Its Impact on Tuberculosis���������������������������������������������������������������� 267 Domingo Palmero and Alberto Mendoza 31 Tuberculosis Rehabilitation and Palliative Care������������������������������������ 275 Dina Visca, Rosella Centis, and Antonio Spanevello 32 Post-Tuberculosis Infections and Chronic Lung Disease ���������������������� 283 Jamilah Meghji, James Brown, and Marc Lipman Part VI Public Health 33 The National Tuberculosis Programme: Role and Functions���������������� 295 Lia D’Ambrosio and Denise Rossato Silva 34 National Tuberculosis Strategic Planning������������������������������������������������ 307 Giovanni Battista Migliori, Giuliano Gargioni, and Clarisse Veylon Hervet 35 Active Tuberculosis Case Finding and Hard-to-Reach Groups������������ 319 Lynn Altass, Sue Dart, and Jacqui White 36 Managing Tuberculosis Outbreaks in Low-­Incidence Settings ������������ 331 Giovanni Sotgiu

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Part VII Global Health Perspective 37 Global Epidemiology of Tuberculosis������������������������������������������������������ 341 Philippe Glaziou, Charalambos Sismanidis, and Katherine Floyd 38 A Multisectoral Approach to Tuberculosis Control and Elimination in the Era of the United Nations Sustainable Development Goals���������������������������������������������������������������� 349 Simone Villa, Tereza Kasaeva, and Mario C. Raviglione 39 A One Health Approach to Zoonotic Tuberculosis �������������������������������� 359 Francisco Olea-Popelka, Paula I. Fujiwara, and Anna S. Dean 40 Health Systems and Tuberculosis Control ���������������������������������������������� 367 Mukund Uplekar and Sachin Atre 41 The Global and Individual Economics of Tuberculosis�������������������������� 375 Inés García Baena, Katherine Floyd, and Lucy Cunnama Part VIII Research 42 An Overview of Research Priorities in Tuberculosis������������������������������ 385 Christian Lienhardt, Dennis Falzon, Matteo Zignol, and Afranio Kritski 43 The Tuberculosis Vaccine Development Pipeline: Present and Future Priorities and Challenges for Research and Innovation�������������������������������������������������������������������������� 395 Stefan H. E. Kaufmann 44 Priority Areas for Research on Tuberculosis Diagnosis ������������������������ 407 Morten Ruhwald 45 Tuberculosis Preventive Treatment: Key Research Areas and the Clinical Pipeline for New Treatments������������������������������ 415 Nebiat Gebreselassie, Dennis Falzon, Alberto Matteelli, and Matteo Zignol 46 Priority Areas for Research on Anti-Tuberculosis Treatment �������������� 423 Barbara Laughon, Christian Lienhardt, and Melvin Spigelman 47 Tuberculosis Research in European Countries: A Model for Programmatic Scale Up ������������������������������������������������������ 429 Andrei Dadu, Oleksandr Korotych, Askar Yedilbayev, and Masoud Dara

Part I Introduction

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History of Tuberculosis Robert Loddenkemper and John F. Murray

Abstract

History of tuberculosis (TB) most probably begins around 70,000 years ago when Mycobacterium tuberculosis (Mtb) and humans co-evolved during their partnership. During the Neolithic Revolution, the size of the population and its farming and animal domestication activities contributed to the maintenance and transmission of Mtb. TB continued its increase beginning around 1750 owing to the deplorable conditions prevailing during the Industrial Revolution: overcrowding, malnutrition, absent sanitation. Even after Robert Koch’s seminal discovery of Mtb in 1882, methods of diagnosis, treatment, and prevention advanced only slowly. After a continuous decline in the nineteenth century, TB mortality increased sharply in many countries during World Wars I and II. In 1944, first effective anti-TB antibiotics were developed and better ones followed in the next years. Major impediments to TB eradication or elimination today are drug resistances and human immunodeficiency virus (HIV) infection. The World Health Organization (WHO) created the End TB Strategy in 2014, but achieving its goals appears unlikely by 2030. Possible solutions include widespread treatment for latent TB infection and an effective vaccine. Keywords

Tuberculosis · History · Neolithic revolution · Industrial revolution · World wars Anti-TB-antibiotics The Author Prof. Loddenkemper would like to pay tribute to Prof. J.F. Murray who passed away after having completed the writing of this chapter. Prof. Murray will be remembered for his major contributions to the global fight against tuberculosis throughout his career. The Editors join Prof. Loddenkemper in the recognition of the remarkable work of Prof. Murray and express their admiration for his achievements. R. Loddenkemper (*) German Central Committee against Tuberculosis (DZK), Berlin, Germany e-mail: [email protected] J. F. Murray (Deceased) San Francisco General Hospital, San Francisco, CA, USA © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_1

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Fig. 1.1  Out-of-Africa and Neolithic expansion of Mtb. The map summarizes the results of the phylogeographic and dating analyses for Mtbx. The major splits are annotated with the median value (in thousands of years) of the dating of the relevant node. (Reused from [2] with permission from Springer Nature)

The precise origins of tuberculosis (TB) are still unknown [1]. A study based on the genomic analysis of more than 250 strains of Mycobacterium tuberculosis complex (Mtb-complex) suggests that it originated in Africa approximately 73,000 years ago [2]. Until the 1990s it was thought that Mtb had passed from M. bovis to humans through domesticated animals during the Neolithic period [1]. However, whole genome sequence-based studies in the late 1990s revealed that the animal-adapted strains were derived from human-adapted Mtb. On Fig. 1.1, the assumed neolithic expansion of Mtb to different regions of Africa, Europe, and Asia is delineated. The branching of Mtb into different lineages is estimated to have occurred between 73,000 and 42,000 years ago, which coincides with the estimated migration and dispersal of human populations out of Africa [2]. These data suggest that both Mtb-complex and humans have co-evolved for the last 70,000 years [3]. The Neolithic Demographic Revolution started roughly 10,000  years ago when hunter-gatherers began to settle down permanently and adopt a new life of agriculture and animal domestication [1]. This monumental change evolved at different times in different regions: 10,000 years B.C. in Mesopotamia and around 7000 B.C. in Greece and 3000 B.C. in Egypt. It is believed that the number of humans with TB increased during the Neolithic period, not only because of an increased size and density of the host populations but also because of changes in the virulence of Mtb [4]. For several hundred years, there were only few reports on TB. Since the cause of the disease was unknown, superstition prevailed. A classic example is the practice of the “King’s Evil Ceremony,” which was celebrated for more than 500 years, until 1714 in England and even until 1825 in France [5].

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The pre-modern era of scientific TB research began with Laennec who suggested that the several different manifestations he observed were all one and the same disease, called later TB [1]. Robert Koch discovered Mycobacterium tuberculosis as cause of TB [6], although others like Henle, Cohnheim, or Villemin had assumed the infectious etiology before [1]. Koch presented his famous lecture in Berlin on 24 March 1882 (since 1997, on this day World TB Day is recognized annually). He failed in 1890 with tuberculin as a remedy for TB [1]. However, tuberculin became later important for the diagnosis of latent TB infections. In the following years, some progress in the diagnosis of TB was achieved [1, 8]: microscopic and cultural diagnosis of TB were refined. In 1895 Röntgen discovered X-rays. Pirquet realized in 1907 that tuberculin is helpful in detecting TB. Mantoux in France developed in the following year the so-called Mantoux test, which became a diagnostic test for latent TB. X-rays were not used routinely until shortly before or after the Second World War (WWII), either for individuals suspected of TB or for screening large populations. But photofluorography was better suited to screening and therefore was first extensively used in military services already before the First World War (WWI) [7]. Developments in treatment were slow [1, 8]. Brehmer opened in 1859 a TB sanatorium in Lower Silesia/Germany (today Sokolow in Poland). His open-air facility at an altitude of 500 m featured bed rest, a rich diet, and structured exercise. The idea caught on and spread widely to many parts of world. In 1882, Forlanini in Italy invented pneumothorax for collapse treatment of TB. In 1885, de Cérenville in Switzerland was the first who performed an invasive surgical intervention to create a collapse of the diseased lung, called later thoracoplasty. In 1916, Jacobaeus in Sweden developed diagnostic thoracoscopy further to a pulmonary collapse procedure to complete a pneumothorax by cauterizing pleuro-pulmonary adhesions. The European TB epidemic was already flourishing in 1750, roughly at the beginning of the Industrial Revolution [9]. In Western Europe during the seventeenth, eighteenth, and nineteenth centuries, TB was by far the most important cause of death, and it remained the highest or one of the highest causes of mortality until the beginning of the twentieth century. The early and late phases of the Industrial Revolution were accompanied by strikingly different socioeconomic outcomes and TB rose because conditions in the mills and factories as well as housing deteriorated enormously. Although millions of workers continued to suffer in TB-enhancing conditions as overcrowding, poor nutrition, absence of sanitation and medical care, and hazardous employment of children, millions of others benefitted from improved living circumstances and TB death rates declined. First, there were peaks around 1800 when TB mortality increased in London to an astronomic extent of 1000 per 100,000 population. Afterward, London TB deaths decreased erratically, whereas those in Europe declined continuously [1]. Advances in prevention started gradually [1, 8]: In 1887, the first TB dispensary was opened by Philip in Edinburgh. At the end of the nineteenth century, several national TB organizations and many dispensaries were founded. In 1921, Calmette and Guérin in France introduced Bacillus Calmette–Guérin (BCG) vaccination.

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In 1948, due to the health disaster caused by WWII, the World Health Organization (WHO) was founded [1, 7]. TB, malaria, and venereal diseases were declared as the “three main scourges demanding prior and special attention” (still valid today). Important to mention in addition are the many non-governmental charitable organizations (NGOs), which supported countries or certain populations as refugees, Jews, and prisoners [7]. The International Union against TB (IUAT) was officially recognized by WHO as first nongovernmental organization (NGO) [1]. Exemplary international models that helped to eliminate famine after the Second World War (WWII) are UN partnerships such as the United Nations Relief and Rehabilitation Administration, founded in 1943, to help displaced persons and, later, refugees (today United Nations High Commissioner for Refugees—UNHCR). In 1946, the United Nations International Children’s Emergency Fund—UNICEF— was created to provide food and health care to children in countries devastated by WWII [1]. BCG vaccination with the attenuated M. bovis strain was initially accepted reluctantly and virtually stopped following the Lübeck disaster in 1930, when 72 children died from TB after accidental vaccination with live TB mycobacterial strains. After WWII, BCG vaccination was vigorously promoted, particularly by UNICEF.  For decades, BCG was the most frequently used vaccination worldwide [1, 7]. TB is one of the most frequent and deadly diseases to complicate the special circumstances of warfare [1]. When TB and war occur simultaneously, the inevitable consequences are disease, human misery, suffering, and heightened mortality. This has been observed in particular in the two World Wars. After a particular summit of TB mortality was reached around 1750–1800, a nearly consistent decline followed that lasted as long as 100 years, sometimes even longer (nearly all death rates from TB in various Western European cities and countries from the mid-­ eighteenth through the mid-nineteenth centuries show similar configurations). Figure 1.2 shows that in 1885 TB mortality was high, 200–300 per 100,000 population, and that suddenly the monotonous decline abruptly stopped shortly after the beginning of WWI [10]. Most of the striking upsurge of TB mortality rates reached their peaks in 1918, the year WWI ended. This was succeeded by equally precipitous decreases in fatalities, which may have been prolonged slightly to 1920 or even a year or 2 afterward, because of the overlapping death toll triggered by the “Spanish Influenza Pandemic” in 1918. However, astonishingly, the lengthy, well-established pre-war reductions of TB deaths resumed their previous downward tracks in around 1920: as if the war and its remarkable 6- to 7-year-long harvest of suffering and death hadn’t actually happened. Possible culprits include both ordinary and war-related factors that promote the onset, spread, severity, and death from TB [1]. Ordinary factors are inadequate ventilation and overcrowding in narrow accommodations. Malnutrition may cause immune deficiency. Inadequate medical care and facilities may have contributed to the increase of TB, too. WWII is up to now by far the deadliest conflict in human history [1]. More than 60 million fatalities are estimated, including about 20 million military personnel

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and 40 million civilians. Many of the civilians died because of deliberate genocide, massacres, mass bombings, starvation, and disease. According to the British TB specialist Daniels, who analyzed the TB outcome in several countries after the war, TB was the major health disaster of WWII [11]. Conspicuous sharp rises in TB mortality were seen in seven major European cities: Warsaw and Rome peaked in 1944 and in Berlin, Budapest, Vienna, Hamburg, and Amsterdam in 1945, the year WWII ended. After peaking, mortality declined strikingly in all affected cities except Berlin and Hamburg, which had less distinct decreases. Here, it must be mentioned that there exist uncertainties and difficulties in the retrieval of reliable epidemiological data during wartime. But at least it is likely that the observed trends in most involved countries are germane and plausible [7]. Crowded living conditions in the ghettos and concentration camps, poor sanitation, and near starvation diets contributed to the spread of TB [7]. Prisoner of war camps and the Nazi labor camps were also high-risk situations for TB, as observed in displaced persons (DPs) after the war. New international organizations and new technologies helped to lessen the burden. Shortly before the end of WWII, in 1944, the first two effective anti-TB-­ antibiotics were developed: streptomycin (SM) in the USA by Waksman and his team and para-aminosalicylic acid (PAS) in Sweden by Lehmann and his team [12].

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Soon after, it was discovered that isoniazid (INH), which had been synthetized already in 1912, showed excellent anti-TB effects. The problem was that treatment with only one antibiotic created usually drug resistances. Therefore, in 1952, in order to prevent or delay drug resistance, “triple therapy” (INH, SM, PAS) became the standard treatment for all forms of TB [1, 7]. Karel Styblo of the International Union Against Tuberculosis and Lung Disease (IUATLD) using this triple therapy, developed in the 1980s the Directly Observed Treatment, Short course (DOTS) strategy [12]. DOTS as part of the Stop TB Strategy had the following targets: Detection rate of more than 70% of new smear positive cases and cure rate in more than 85% of these cases. Since it was soon proven effective in Africa among poor and illiterate populations, the WHO endorsed the strategy in 1986. In 1993, when the WHO declared TB to be a global emergency, DOTS was recommended worldwide as the best approach for TB treatment and containment [1]. In the following years, the length of treatment could be reduced stepwise [1, 12]. Triple therapy with INH, SM, and PAS had to be given for 2 years. In 1960, PAS was replaced by ethambutol (EMB), which shortened the duration to 18 months. The addition of rifampicin (RMP) in 1970 shortened it to 9 months, and the addition of pyrazinamide (PZA) to 6 months. This is at present still the recommended therapy in drug-susceptible TB. The big question is, if treatment in the future may be shortened, to 1–2  months or even shorter, which would certainly facilitate TB management and probably improve the adherence of patients. Major impediments to TB elimination or eradication are advanced drug resistances and human immunodeficiency virus (HIV) infection [1, 7]. Other potential factors are: demographic factors with population growth and older age, increasing poverty due to slower socioeconomic developments with poorer quality of medical facilities. Inefficient treatment and increased transmission in high incidence regions cause advanced drug resistances such as multi-drug and extensive drug resistance, and the HIV epidemic, which started suddenly in the 1980s. Until now, it caused many million cases with HIV/TB-coinfection and high mortality rates. In 1998, the genome of M. tuberculosis was deciphered by Cole and his team at the Pasteur-Institute in Paris [13]. The sequencing of Mtb rapidly progressed from a research tool to clinical application for the diagnosis and management of TB and in public health surveillance: For example, for first-line drug testing and for identifying subspecies and associated lineages of Mtb, or for the detection of transmission clusters [14]. In 2014 the WHO created the End TB Strategy, whose goal is “to end” the global TB epidemic: Specific targets for 2030 set in the End TB Strategy are a reduction in the absolute number of TB deaths and an 80% reduction in TB incidence compared with the levels in 2015 [15]. While the “end” is not quantified, milestones and targets are specified and are highly ambitious.

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References 1. Loddenkemper R, Murray JF, Gradmann C, Hopewell PC, Kato-Maeda M. History of tuberculosis. In: Migliori GB, Bothamley G, Duarte R, et al., editors. Tuberculosis (ERS monograph). Sheffield: European Respiratory Society; 2018. p.  8–27. https://doi.org/10.118 3/2312508X.10020617. 2. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet. 2013;45:1176–82. 3. Brites D, Gagneux S.  Co-evolution of Mycobacterium tuberculosis and homo sapiens. Immunol Rev. 2015;264:6–24. 4. Barnes I, Duda A, Pybus OG, Thomas MG. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution. 2011;65:842–8. 5. Murray JF, Rieder HL, Finley-Croswhite A. The King’s evil and the royal touch: the medical history of scrofula. Int J Tuberc Lung Dis. 2016;20:713–6. 6. Koch R. Die Aetiologie der Tuberkulose. Berlin klin Wschr. 1882;19:221–30. 7. Murray JF, Loddenkemper R, editors. Tuberculosis and war. Lessons learned from world war II. Karger: Basel; 2018. 8. Daniel TM. The history of tuberculosis. Respir Med. 2006;100:1862–70. 9. Murray JF.  The industrial revolution and the decline in death rates from tuberculosis. Int J Tuberc Lung Dis. 2015;19:502–3. 10. Drolet GJ.  World war I and tuberculosis. A statistical summary and review. Am J Public Health. 1945;35:689–97. 11. Daniels M.  Tuberculosis in Europe during and after the second world war. Br Med J. 1949;2:1065–72. 12. Murray JF, Schraufnagel DE, Hopewell PC. Treatment of tuberculosis. A historical perspective. Ann Am Thorac Soc. 2015;12:1749–59. 13. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et  al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393(6685):537–44. 14. Nikolayevskyy V, Niemann S, Anthony R, van Soolingen D, Tagliani E, Ködmön C, et al. Role and value of whole genome sequencing in studying tuberculosis transmission. Clin Microbiol Infect. 2019;25:1377–82. https://doi.org/10.1016/j.cmi.2019.03.022. 15. World Health Organization. The end TB strategy. Geneva: WHO; 2014.

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Mycobacterium tuberculosis: The Organism’s Genomics and Evolution Daniela Maria Cirillo, Arash Ghodousi, and Enrico Tortoli

Abstract

Tuberculosis is still the leading cause of human death due to an infectious disease. The causative agents of tuberculosis are a group of closely related slow growing mycobacteria known as the Mycobacterium tuberculosis complex (MTBC). Thanks to recent advances in whole-genome sequencing technologies coupled with analyses of large collections of MTBC isolates from all over the world, several new insights have been achieved, including an improved understanding of the origin of the MTBC as an obligate pathogen, its molecular evolution and population genetic characteristics both between and within hosts, as well as many aspects related to antibiotic resistance. The purpose of this chapter is to summarize these recent discoveries and discuss their relevance for better understanding of this organism, genomics, and evolution. Keywords

Tuberculosis · Mycobacterium tuberculosis complex · Mycobacteria · Whole-­ genome sequencing · MTBC · Comparative genomics

2.1

Introduction

The human pathogen Mycobacterium tuberculosis complex (MTBC), one of the most ancient cause of disease of human beings, is responsible for devastating mortality and morbidity in humans [1] and animals [2]. MTBC is also one of the leading causes of suffering and catastrophic economic losses in weaker economies [1]. MTBC is part of slow growing mycobacteria (characterized by one cell division D. M. Cirillo (*) · A. Ghodousi · E. Tortoli IRCCS San Raffaele Scientific Institute, Milan, Italy e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_2

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every 18–24 h), a subgroup of the genus Mycobacterium which includes most of the pathogenic species. In this chapter, we review the latest insights into phylogeny and genomics of MTBC and summarize the current understanding of how the different phylogenetic lineages of the MTBC are distributed around the world, how this relates to their epidemiology and ecological niche of these microorganisms. Finally, we discuss about the evolution of MTBC from an environmental organism into an obligate pathogen of humans and other mammalian species.

2.2

The Organism

The MTBC consists of 11 members, many of which display host adaptation, and 1 culture-adapted strain, the Mycobacterium bovis Bacillus Calmette–Guérin. The different members and phylogenetic lineages of the MTBC share a high degree of genome similarity having an average nucleotide identity greater than 99% and sharing a single clonal ancestor, but differ notably in their host niche, geographic distribution, and pathogenicity [3].

2.3

Phylogeny and Genomics of Mycobacterium tuberculosis

The first whole-genome sequence of a MTBC member dates back to 1998 with the publication of the Mycobacterium tuberculosis reference genome (H37Rv laboratory strain). This genome includes a GC-rich single-chromosome of 4.4 Mb comprising ~4000 protein genes [4]. The regions of difference (RDs) are commonly considered the gold standard genetic markers for MTBC phylogeny [3], while the single-nucleotide polymorphisms (SNPs) analysis represents the state of art genotyping approach [5]. Other molecular typing methods used for the identification of different species within the MTBC include the spacer oligonucleotide typing (spoligotyping), the IS6110restriction fragment length polymorphism (RFLP), the repetitive-sequence-based polymerase chain reaction (rep-PCR), the mycobacterial interspersed repetitive unitsvariable number tandem repeats (MIRU-VNTR), and the whole-genome sequencing [6]. The use of molecular typing techniques also allows the recognition within the MTBC of distinct lineages and sub-lineages. The strains of Mycobacterium tuberculosis sensu stricto belong to lineages (L) 1–4, and 7, while the strains of the species Mycobacterium africanum (primarily isolated in West Africa) [7] belong to L5 and L6. Different lineages include pathogens isolated from other mammalian species such as Mycobacterium bovis which affects numerous domestic and wildlife species and Mycobacterium caprae which mainly causes tuberculosis (TB) in goats (Fig. 2.1). Moreover, among the animal-adapted members of the MTBC, some primarily infect wild mammalian species [8]: Mycobacterium microti (a pathogen of voles), Mycobacterium orygis (a pathogen of antelopes), Mycobacterium pinnipedii (a pathogen of seals and sea lions), and the “Dassie bacillus” (a pathogen of rock

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Fig. 2.1  The best-scoring maximum likelihood phylogenetic tree of 47 human-adapted and animal-­adapted MTBC whole-genome sequences. Branch lengths are proportional to nucleotide substitutions and the topology is rooted with Mycobacterium canettii. The six global MTBC lineages have been defined (L1: Indo-Oceanic, L2: East-Asian including Beijing, L3: East-African-­ Indian, L4: Euro-American, L5: West Africa or M. africanum I, L6: West Africa or M. africanum II). Lineages 1, 5, and 6 are considered as ancient lineages having an intact TbD1, and 2–4 as modern lineages having deleted TbD1. L7 appears to be intermediate between the ancient and modern.

hyraxes), which have been known for a long period of time, as well as the more recently discovered Mycobacterium suricattae (a pathogen of meerkats), Mycobacterium mungi (a pathogen of mongooses), and the “chimpanzee bacillus” (a pathogen of chimpanzees). In many cases, the nomenclature of the animal-­ adapted MTBC species were originally chosen based on the animal they were first isolated from. For instance, Mycobacterium orygis was first isolated from a captive oryx but has since then been isolated from many different host species including humans [8] (Fig. 2.1).

2.4

 ifferences in Geographic Distribution, Pathogenesis, D and Drug Resistance

The seven human-adapted lineages of MTBC show distinct features such as strong geographic association, virulence, and drug resistance [9]. Lineages 1 and 3 are more diffusely distributed, with L1 mostly isolated from proximity to the Indian

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Ocean (therefore it’s known as Indo-Oceanic lineage), whereas lineage 3 is mainly found in Eastern Africa as well as South and Central Asia. Other lineages such as L2 (known as East-Asian lineage, including the Beijing family of strains) and L4 (known as the Euro-American lineage, including the Haarlem strains) are widely distributed geographically, more virulent in terms of disease severity and more transmissible [10], while the other three lineages are more geographically restricted and less transmissible; L5 and L6 are generally restricted to West Africa and L7 to Ethiopia [11]. It is assumed that the reasons for this variable geographical distribution are both biologically (e.g., interactions with different human genetic backgrounds) and historically related (e.g., trades, conquests, globalization). There is limited transmissibility of human-adapted strains in other animals, and, conversely, animal-adapted strains transmit poorly among humans. Africa is the only continent where we find a representation of all known seven human-adapted lineages. Moreover, three lineages including L5, L6, and L7 are exclusively confined to this continent [12]. Current evidences suggest the emergence of MTBC from a common ancestor in Africa and the clonal expansion around the world following migratory events of human beings [13]. However, the genomic characteristics of this common ancestor and the area from which this expansion took place in Africa remain unexplored. The vast distribution of some lineages, such as L2 and L4, and their presence in Africa has been attributed to the different waves of exploration, commercial trades, and invasions. For instance, an important part of the TB epidemics in subSaharan Africa is caused by a sub-lineage of L4 called “Latin–American– Mediterranean (LAM),” which is assumed to have been introduced to the continent during the European colonization [14]. Moreover, it has been shown that the emergence of drug resistance is relatively higher in L2 strains (known as one of the most virulent MTBC lineages) than in other lineages. It has been hypothesized that the frequent acquisition of resistance is the result of the higher rates of mutation in this lineage [15]. Additionally, it has been shown in an animal model that the risk of multidrug resistance acquisition before treatment is higher with L2 than in L4 strains. These findings are in line with the high drug resistance potential of L2 stains observed in other epidemiological studies [16].

2.5

Insights from Comparison with Mycobacterium canettii

Despite the wide range of hosts infected by the different members of the MTBC, whole-genome sequencing has shown that there is a maximum of ~2500 SNPs distance between any couple of MTBC genomes with the exception of Mycobacterium canettii (M. canettii) [17]. M. canettii strains differ from other MTBC members by tens of thousands of SNPs mostly resulting from recombination events between strains [3]. M. canettii strains are rare human tuberculosis bacilli (predominantly isolated in children, often in association with extra-pulmonary disease), morphologically characterized by unusual smooth colonies and the strains are highly restricted to the Horn of Africa [16]. Genomic comparisons of representative

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M. canettii isolates showed that they belong to the MTBC, being most closely related to the last common progenitor of this complex. Other phylogenetic analysis has demonstrated that M. canettii represents an early evolutionary branching lineage that predates the emergence of the most recent common ancestor of the MTBC (or of the rest of the MTBC) [18]. Other studies consider M. canettii and other smooth tubercle bacilli, as the closest relatives of the MTBC [3]. In comparison to MTBC which is an obligate pathogen, M. canettii strains are less virulent and have the unique feature of possessing highly mosaic genome, possibly reflecting primal adaptation to an environmental reservoir favoring active lateral gene flow [19]. The hypothesis of environmental reservoir for M. canettii is mainly based on the observation of the absence of human-to-human transmission. However, the putative environmental sources of infection and reservoirs of M. canettii are poorly understood [20]. Comparative genomics has also identified differences in gene content between MTBC, M. canettii, and other mycobacteria [19], as well as genetic differences in virulence-related loci [21].

2.6

 he Evolution of the Human-Adapted Mycobacterium T Tuberculosis Complex

Evolution of MTBC and M. canettii from a shared genetic pool in Africa has been suggested by a couple of evidences [17]. Firstly, strains of the MTBC have an average nucleotide identity value to M. canettii strains of almost 98% [3], suggesting incomplete or recent speciation (an established cut-off score of >95% indicates belonging to the same species). Additionally, most of the published data suggest lack of ongoing recombination between M. canettii and MTBC and within the MTBC [3], proposing complete separation; however, this was confuted in other studies [22]. The second piece of evidence roots from genetic diversity and phylogeographic analyses that identified the origin of the tuberculosis bacilli in Africa, the likely area of origin of M. canettii [20]. Altogether, the data suggest that ancestral MTBC including M. canettii strains at least partially shared the same niche and genetic pool [3]. Comparative genomic approaches, using other slow growing mycobacteria like Mycobacterium kansasii or Mycobacterium marinum as outgroups, suggest that a high level of genomic changes led to MTBC differentiation [3], including marked genomic reduction, horizontal gene transfer, and toxin–antitoxin massive expansion. These studies demonstrate a wide evolutionary gap separating the genomic structures of MTBC in comparison to those of related environmental mycobacteria, suggesting the existence of unknown intermediate evolutionary steps that may have helped the MTBC for host adaption [23]. Furthermore, unlike other mycobacteria, there is no evidence of lateral gene transfer mechanisms in extant MTBC members except M. canettii [20]. However, it is hypothesized that lateral gene transfer events have occurred in the branch resulting in formation of the MTBC ancestor, as suggested by the presence of genomic regions with high degree of similarity to plasmids of phylogenetically distant mycobacteria [20]. This trait might have been lost in present MTBC strains characterized

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by extremely conserved genomes and presenting very low intra-species genetic diversity [21]. In contrast, there are evidences suggesting the occurrence of genetic exchanges among M. canettii strains but not between M. canettii and other MTBC members [18]. Nevertheless, whole-genome evolutionary reconstruction has indicated the presence of recombination footprints in MTBC members [22]. However, there are studies suggesting that these recombination footprints could result from artifacts occurring during genome assembly process [24]. Other attempts to detect recombination events have identified several recombination hotspots in highly repetitive regions of MTBC genome as potential recombination targets like proline-­ glutamic acid (PE)/proline-proline-glutamic acid (PPE) genes [25]. However, those recombination events can be traced back to intra-genome recombination and not inter-genome [3] or they lack an experimental validation. Extensive and systematic studies are needed for detection of inter-genome recombination events in MTBC.

2.7

Conclusions

We have increased our understanding on the origin, ecology, and evolution of humanadapted MTBC, but much work remains to be done. We have evidences that the MTBC developed into a professional pathogen from an environmental organism through the acquisition and loss of genes. However, no single genomic feature in the MTBC can account for the obligate pathogenic lifestyle of these organisms or the different host preferences of the various MTBC ecotypes. We also know that the transition to a professional pathogen most likely occurred in Africa as this continent is the only place we find all known seven human-adapted lineages. Finally, based on current evidences we know that horizontal genetic transfer in MTBC is negligible and this may explain the strict clonal population structure of this microorganism. More work is needed to detect the possible inter-genome recombination events in MTBC.

References 1. World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization; 2019. https://www.who.int/tb/publications/global_report/en/. 2. Roadmap for zoontic tuberculosis. WHO, OIE, FAO and The Union; 2017. https://www.who. int/tb/publications/2017/zoonotic_TB/en/. 3. Gagneux S.  Ecology and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol. 2018;16(4):202–13. 4. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et  al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393(6685):537–44. 5. Garcia De Viedma D, Perez-Lago L. The evolution of genotyping strategies to detect, analyze, and control transmission of tuberculosis. Microbiol Spectr. 2018;6(5):MTBP-0002-2016. 6. Ei PW, Aung WW, Lee JS, Choi GE, Chang CL. Molecular strain typing of Mycobacterium tuberculosis: a review of frequently used methods. J Korean Med Sci. 2016;31:1673–83. 7. Brites D, Gagneux S. The nature and evolution of genomic diversity in the Mycobacterium tuberculosis complex. Adv Exp Med Biol. 2017;1019:1–26.

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8. Malone KM, Gordon SV. Mycobacterium tuberculosis complex members adapted to wild and domestic animals. Adv Exp Med Biol. 2017;1019:135–54. 9. Coscolla M. Biological and epidemiological consequences of MTBC diversity. In: Gagneux S, editor. Strain variation in the Mycobacterium tuberculosis complex: its role in biology, epidemiology and control. Cham: Springer International Publishing; 2017. p. 95–116. https://doi. org/10.1007/978-­3-­319-­64371-­7_5. 10. Correa-Macedo W, Cambri G, Schurr E. The interplay of human and Mycobacterium tuberculosis genomic variability. Front Genet. 2019;10:865. 11. Ofori-Anyinam B, Riley AJ, Jobarteh T, Gitteh E, Sarr B, Faal-Jawara TI, et al. Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension. Tuberculosis (Edinb). 2020;120:101899. 12. Rutaihwa LK, Menardo F, Stucki D, Gygli SM, Ley SD, Malla B, et al. Multiple introductions of Mycobacterium tuberculosis lineage 2–Beijing into Africa over centuries. Front Ecol Evol. 2019;7:112. 13. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet. 2013;45(10):1176–82. 14. Brynildsrud OB, Pepperell CS, Suffys P, Grandjean L, Monteserin J, Debech N, et al. Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation. Sci Adv. 2018;4(10):eaat5869. 15. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB, Cohen T, et  al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet. 2013;45(7):784–90. 16. Merker M, Blin C, Mona S, Duforet-Frebourg N, Lecher S, Willery E, et  al. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat Genet. 2015;47(3):242–9. 17. Chiner-Oms Á, Sánchez-Busó L, Corander J, Gagneux S, Harris SR, Young D, et al. Genomic determinants of speciation and spread of the Mycobacterium tuberculosis complex. Sci Adv. 2019;5(6):eaaw3307. 18. Supply P, Marceau M, Mangenot S, Roche D, Rouanet C, Khanna V, et al. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis. Nat Genet. 2013;45(2):172–9. 19. Brennan PJ.  Bacterial evolution: emergence of virulence in TB.  Nat Microbiol. 2016;1:15031. 20. Semuto Ngabonziza JC, Loiseau C, Marceau M, Jouet A, Menardo F, Tzfadia O, et al. A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region. bioRxiv. 2020. https://doi.org/10.1101/2020.01.20.912998. 21. Boritsch EC, Khanna V, Pawlik A, Honore N, Navas VH, Ma L, et al. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc Natl Acad Sci U S A. 2016;113(35):9876–81. 22. Namouchi A, Didelot X, Schock U, Gicquel B, Rocha EPC. After the bottleneck: genome-­ wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res. 2012;22(4):721–34. 23. Sapriel G, Brosch R.  Shared pathogenomic patterns characterize a new phylotype, revealing transition toward host-adaptation long before speciation of Mycobacterium tuberculosis. Genome Biol Evol. 2019;11(8):2420–38. 24. Godfroid M, Dagan T, Kupczok A.  Recombination signal in Mycobacterium tuberculo sis stems from reference-guided assemblies and alignment artefacts. Genome Biol Evol. 2018;10(8):1920–6. 25. Phelan JE, Coll F, Bergval I, Anthony RM, Warren R, Sampson SL, et al. Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages. BMC Genomics. 2016;17:151.

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Pathogenesis and Immunology of Tuberculosis Delia Goletti and Adrian R. Martineau

Abstract

Tuberculosis (TB) is still a worldwide spread infectious disease caused by Mycobacterium tuberculosis which is transmitted through bacilli-containing aerosol droplets which are released from diseased persons, typically through sneezing or coughing. The World Health Organization (WHO) in 2018 estimated 10 million new TB cases worldwide that led to 1.5 million deaths, thus ranking TB as the main cause of mortality from a single pathogen. In this chapter, we briefly describe the immune pathogenesis of the infection and disease of tuberculosis. We provide insights on the importance of the innate and adaptive immunity and on the granuloma structure and functions. We also describe latent tuberculosis infection (LTBI) and the routine immune-based tests used to detect it. The accuracy issues of these tests to predict active TB development are discussed. Evaluation of potential microbiological biomarkers of latent M. tuberculosis infection is described as in process. Keywords

Tuberculosis · Latent tuberculosis · M. tuberculosis · Immune pathogenesis · IGRA · TST · Accuracy · Immune response

D. Goletti (*) Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases-IRCCS L. Spallanzani, Rome, Italy e-mail: [email protected] A. R. Martineau Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_3

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3.1

Introduction

Tuberculosis (TB) is still a worldwide spread infectious disease caused by Mycobacterium tuberculosis. M. tuberculosis is transmitted through bacilli-­ containing aerosol droplets which are released from diseased persons, typically through sneezing or coughing. The World Health Organization (WHO) in 2018 estimated 10 million new TB cases worldwide that led to 1.5 million deaths, thus ranking TB as the main cause of mortality from a single pathogen [1]. After exposure to M. tuberculosis an estimated 20–25% of those exposed become infected. Among those infected, 5–10% can rapidly develop active disease, while 90% controls the replication of the pathogen with reactivation occurring in around 10% in the course of their life due to different factors as M. tuberculosis lineages drug susceptibility of the M. tuberculosis strains co-infection with human immunodeficiency virus (HIV), comorbidities like diabetes, genetic predisposing factors, malnutrition, treatment with glucocorticoids or biological agents, solid organ transplantation, and certain malignancies. Pathogenesis of the infection and disease is not fully understood and the diagnosis of latent tuberculosis infection is still challenging (Box 3.1).

Box 3.1

1. The outcome of M. tuberculosis infection is the result of a complex interplay of both innate and adaptive responses against the pathogen. This interplay depends on several host factors as genetic predisposition, environment and comorbidities as well as the heterogeneity of tuberculosis clinical presentations. 2. Tests to detect host response to latent M. tuberculosis infection as a surrogate for detection of infection itself are well validated, but their low positive predictive value for development of active tuberculosis limits their value as tools to identify individuals who will benefit from chemoprophylaxis. 3. Recent reports that M. tuberculosis DNA can be detected in peripheral blood of individuals with latent M. tuberculosis infection raise the possibility that microbiological tests for latent tuberculosis infection could be developed in the future.

TB infection has been traditionally called “latent TB infection (LTBI)”. This terminology has been used to define a state of persistent immune response to stimulation by M. tuberculosis antigens through tests such as the tuberculin skin test or an interferon gamma release assay (IGRA) without clinically active TB. This chapter uses the term LTBI throughout. However, this term may be progressively replaced by the simpler term “TB infection”. For this chapter the authors have decided for the time being to maintain the traditional terminology.

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3.2

21

Aims of This Chapter

We briefly describe the immune pathogenesis of the infection and disease of tuberculosis providing details of innate and adaptive immunity and on the granuloma structure and functions. We also describe latent tuberculosis infection and the tests used to detect it.

3.3

Pathogenesis of Tuberculosis

The outcome of M. tuberculosis infection is the result of a complex interplay of both innate and adaptive responses against the pathogen. This interplay depends on several host factors as genetic predisposition, environment and comorbidities as well as the heterogeneity of TB clinical presentations. Several in vivo studies analyzed both compartments of the immune response during the course of the infection allowing a better comprehension of the key mechanisms of the immune response to M. tuberculosis.

3.3.1 Immunology 3.3.1.1 Innate Immune Responses Innate immune response against M. tuberculosis is important to provide the first line of defense. M. tuberculosis interacts with innate immune cells [monocytes macrophages, dendritic cells (DCs), neutrophils, natural killer cells] via surface exposed receptors, including toll-like receptors (TLRs), complement receptor (CR) 3, mannose receptor, scavenger receptors, and DCs-specific intercellular-adhesion-­ molecule-­ 3-grabbing nonintegrin (DC-SIGN), leading to the generation of responses that either clear the M. tuberculosis infection or initiate granuloma formation. In mice models, type I-interferon (IFN) is induced during acute infection with M. tuberculosis. Subsequently, type I-IFNs mediate the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 (CCL2/CCR2)-dependent migration of macrophages and DC in the lungs. Then, a deep cytokine interplay modulates the clinical outcome. It is known that a sustained interleukin (IL)-1ß signaling may lead to an excessive inflammation in TB that may be limited by type I-IFNs or IFN-γ to prevent an exaggerated inflammation mediated by the neutrophils. In 2010, an IFN-inducible transcriptional signature was reported in circulating leukocytes of TB patients, thus linking increased type I-IFN signaling with active disease. This finding has been validated in several independent studies [2]. 3.3.1.2 Adaptive Immune Responses The adaptive response to M. tuberculosis involves both the cellular and the humoral responses. The antigen presenting cells (APC) as the DCs and macrophages, phagocytize M. tuberculosis and then present its antigens to CD4+ T lymphocytes. Consequently, lymphocytes are activated and proliferate and, based on the cytokine environment, a Th1 response can be established with the production of pro-inflammatory cytokines IL-12, IL-18, and IFN-γ, enhancing the killing of intracellular M. tuberculosis through nitric oxide (NO) and reactive oxygen species (ROS)

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production in macrophages [3]. It is generally thought that M. tuberculosis-specific CD4+ producing IFN-γ are essential for M. tuberculosis containment; however, it is still unclear the role of CD4 polyfunctional M. tuberculosis-specific CD4 cells, which simultaneously secrete several cytokines. Also CD8+ cytotoxic T cells are important because lyse M. tuberculosis-infected macrophages by perforin secretion and may kill M. tuberculosis by releasing granulysin [4]. Infected DCs and macrophages may also secrete cytokines, including IL-12, IL-23, IL-7, IL-15, and tumor necrosis factor (TNF)-α, leading to attraction of more leukocytes to the site of infection [10]. Th17 cells, secreting IL-17, stimulated by IL-6, IL-21, IL-23, and low levels of transforming growth factor (TGF)-β, are involved in the recruitment of innate immune cells and Th1 cells at the site of infection. Regulatory T cells (Treg) produce anti-inflammatory cytokines such as IL-10 and suppress microbicidal mechanisms in macrophages [5]. On the other hand, a Th2 response may be induced with IL-4, IL-5, IL-10, and IL-13 release promoting B lymphocyte activation with antibody production, and anti-inflammatory macrophage responses. B cells and antibodies may exert several mechanisms that may be important for control of M. tuberculosis. Indeed, B cells are abundant in the lung granuloma, where they act as APCs and modulate inflammation secreting IL-10. Moreover, TB patients show a reduced B-cell number and a dysfunction of these B cells that display impaired proliferation, and immunoglobulin- and cytokine production [6].

3.3.2 Granuloma Formation The granuloma formation is the hallmark of TB and it is the result of the accumulation of immune cells surrounding the M. tuberculosis-infected phagocytes, in response to secreted cytokines and chemokines with the aim to contain and control the infection. The granulomas may show a great morphological heterogeneity; however, the basic structure includes a necrotic core surrounded by macrophages followed by a ring of CD4+ and CD8+ T cells and B cells. Neutrophils, dendritic cells, and fibroblasts are also present. Macrophages within the granuloma may show different stages of activation. Infected APC produce TNF-α that acts synergically with IFN-γ, mainly produced by T cells, to control M. tuberculosis. TNF-α is crucial for the containment of M. tuberculosis within the granuloma because if neutralized active TB develop, as shown in animal models [7], and in vivo in those treated with TNF inhibitors (Fig. 3.1).

3.3.3 H  istorical Approaches to Diagnosis of Latent Tuberculosis Infection: The Tuberculin Skin Test Latent tuberculosis infection is a paucibacillary state. Historically, the lack of technologies sensitive enough to detect tiny amounts of bacillary material in latently infected individuals, coupled with the fact that M. tuberculosis expresses an array of highly immunogenic antigens, has led to a focus on detection of host responses to

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dendriticcell neutrophil macrophage

T cell

B cell

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NKcell

fibroblast

collagen M.tuberculosis

Fig. 3.1  Modulation of the granuloma integrity. Granuloma is a complex and well organized cellular structure in which M. tuberculosis is contained within a necrotic region surrounded by epithelioid macrophages and a rim of B and T lymphocytes. TNF-α is a key factor for the maintenance of this structure and changes in its levels, as induced by therapies with TNF-α inhibitors may disrupt the granuloma integrity losing the bacterial containment and this may contribute to TB reactivation

M. tuberculosis as a surrogate for detection of the bacillus itself. This approach was pioneered in the early twentieth century by Clemens von Pirquet, a pediatrician working in Vienna, Austria, who originally coined the term “latent tuberculosis infection.” He developed the tuberculin skin test, in which Koch’s “old tuberculin” was applied to a superficial skin abrasion, and observed that the prevalence of positive skin reactions in children attending his clinic rose with age, from 5% of infants to 80% of 10-year-olds [8]. Positive skin reactions were subsequently shown to associate with increased risk of developing active tuberculosis [9]. The fact that the test could be performed inexpensively and without need for laboratory facilities led to its wide uptake as a means of detecting LTBI both in clinical practice and epidemiological surveys. However, there were limitations: the need for patients to attend two visits (the first for instillation, the second for reading) was inconvenient. Moreover, it became apparent that a significant proportion of immunosuppressed individuals displayed false-negative results, while there was potential for false-positive results to arise in Bacillus Calmette–Guérin (BCG)vaccinated individuals and non-­tuberculous mycobacterial infection, due to crossreactivity between antigens in tuberculin and those expressed by non-pathogenic mycobacteria.

3.3.3.1 IFN-γ Release Assays Development of a new generation of tests for LTBI with greater specificity than the tuberculin skin test (TST) was made possible by findings of studies that identified a region of the M. tuberculosis chromosome (RD1) that is missing from M. bovis

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BCG and present in organisms of the M. tuberculosis complex. This region encodes two M. tuberculosis-specific secreted antigens ESAT-6 and CFP-10. The ability of peripheral blood mononuclear cells (PBMC) to secrete interferon (IFN)-γ in response to ex vivo stimulation with recombinant ESAT-6 and CFP-10 was subsequently shown to correlate with intensity of exposure to an infectious index case more tightly than results of the TST [10]. This finding led to the development of commercial IFN-γ release assays (IGRAs) in which either whole blood or PBMC were stimulated with RD1-encoded antigens, with quantification of IFN-γ responses as the read-out. Introduction of the IGRAs largely overcame the problems with poor specificity of the TST, but some limitations remained: in particular, sensitivity was still impaired in young children and in immunosuppressed individuals. Moreover, prospective studies evaluating performance of the TST against two commercial IGRAs have revealed broadly similar performance: in a recent study conducted among TB contacts and recent immigrants to a low-incidence setting, the QuantiFERON-TB Gold In-Tube (a whole blood IGRA) had a positive predictive value (PPV) for subsequent development of active TB of 3.3%, while the T-SPOT TB assay (a PBMC-­ based IGRA) had a PPV of 4.2% and the TST (using a 15  mm cut-off to define positivity) had a PPV of 3.5% [11]. The implication of these low PPV values is that treatment for LTBI (so-called chemoprophylaxis) needs to be given to many IGRA-­ positive individuals in order to prevent a single case of active TB. If elimination of LTBI is to be achieved, new diagnostic tools are needed, which can better predict which individuals are at highest risk of progression to active TB.

3.3.4 N  ovel Approaches to Detection of Host Response to Latent M. tuberculosis Infection One approach to this problem has been to refine attempts to identify host responses associated with LTBI. Different antigen cocktails and different antigen-stimulated cytokine read-outs have been explored in ex vivo assays, and skin tests employing RD1-encoded antigens have been developed. The growing realization that LTBI comprises a spectrum of disease states ranging from truly quiescent infection to incipient or percolating disease has prompted efforts to identify individuals at the latter end of the spectrum. Whole blood gene expression signatures that can predict short-term progression to active disease have been identified [12] and positron emission tomography–computed tomography (PET-CT) imaging has also revealed intra-thoracic lesions exhibiting increased uptake of radio-labelled glucose in the absence of symptoms or chest X-ray abnormalities [13].

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3.3.4.1 Towards a Microbiological Biomarker of Latent M. tuberculosis Infection While these approaches may hold some promise, tests for LTBI that are based on detection of host responses to M. tuberculosis are ultimately limited by their inability to distinguish sensitized but uninfected individuals (in whom infection may have been eliminated by the host response or by chemoprophylaxis) from those who are sensitized and still harboring viable infection. Separation of these states requires detection of mycobacterial, rather than host, factors. Despite skepticism from some quarters that this feat is achievable, a body of historical evidence attests to the fact that M. tuberculosis can be cultured from macroscopically normal tissues excised from cadavers of individuals who had no sign of active TB and who died of trauma or stroke [14]. This observation paved the way for necropsy studies in the modern era that used polymerase chain reaction (PCR) to demonstrate presence of M. tuberculosis DNA in diverse cell types in the lung, spleen, liver, kidney, and adipose tissue. Interest in detection of M. tuberculosis DNA as a biomarker of LTBI gained new momentum with the discovery that M. tuberculosis DNA could be detected in CD34-positive long-term pluripotent hematopoietic stem cells harvested from the peripheral blood of IGRA-positive asymptomatic individuals living in a low-­ incidence setting (Austria) [8]. Subsequently, PCR has also been used to detect M. tuberculosis DNA in peripheral blood of 3/18 asymptomatic TB contacts living in a different low-incidence setting (UK), of whom 2 went on to develop active TB after 7 months. The first study to investigate this phenomenon in a high-incidence setting (Ethiopia) has found that M. tuberculosis DNA was detectable in PBMC of 79% of asymptomatic participants, with its presence being more common in HIVinfected vs. HIV-uninfected individuals. Administration of preventive therapy to HIV-infected participants reduced prevalence of PCR-­detected M. tuberculosis from 95% at baseline to 54% post-treatment—the first time that a biomarker of LTBI has been shown to be responsive to treatment [15]. It is hoped that these exciting findings will form the basis for development of a new generation of LTBI biomarkers based on the detection of bacillary, rather than host, factors. Table  3.1 summarizes the main concepts.

3.4

Main Conclusions

Tuberculosis pathogenesis is still not fully understood. IGRA are routine tests to measure latent tuberculosis infection, but the accuracy to predict active TB development is not high. Evaluation of potential microbiological biomarkers of latent M. tuberculosis infection is in process.

No

Laboratory/imaging facilities needed Negativization of the response after preventive therapy

Yes

Possible in higher resource settings Medium/high

TB tuberculosis, LTBI latent tuberculosis infection

Usually Usually no no

Low

Cost

Accuracy to detect those Low at high risk of developing active TB Large scale tests for Yes screening

Accuracy for active TB from LTBI discrimination

TST No

Experimental tests

Unlikely

Yes

Possible in higher resource settings Medium/high

Improved IGRA (e.g., different Existing IGRA antigens) No Potential utility to “rule-out” active TB Low Low

Routine tests

Unlikely

No

Possible

Possible if operationalized for field use Potentially medium if operationalized for field use Yes

Yes Low

Possible

Transcriptomic signature in whole blood Possible

Low

Skin testing with RD1-­ encoded antigens Unlikely

Table 3.1  Accuracy and cost of routine vs. experimental tests for latent tuberculosis infection

Possible

Yes

Possible

Possible if operationalized for field use Potentially medium/high if operationalized for field use Yes

No High

Possible

Microbiological tests for LTBI Unlikely

Possible

PET/ CTSCAN Possible

26 D. Goletti and A. R. Martineau

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27

References 1. WHO. Global tuberculosis report 2019. https://www.who.int/tb/publications/global_report/en/. 2. Berry MP, Graham CM, McNab FW, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466:973–7. 3. Zak DE, Penn-Nicholson A, Scriba TJ, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387:2312–22. 4. Petruccioli E, Petrone L, Vanini V, et  al. IFNgamma/TNFalpha specific-cells and effector memory phenotype associate with active tuberculosis. J Infect. 2013;66:475–86. 5. Chiacchio T, Casetti R, Butera O, et  al. Characterization of regulatory T cells identified as CD4(+)CD25(high)CD39(+) in patients with active tuberculosis. Clin Exp Immunol. 2009;156:463–70. 6. Joosten SA, van Meijgaarden KE, Del Nonno F, et al. Patients with tuberculosis have a dysfunctional circulating B-cell compartment, which normalizes following successful treatment. PLoS Pathog. 2016;12:e1005687. 7. Lin PL, Myers A, Smith L, et al. Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum. 2010;62:340–50. 8. Von Pirquet C. Frequency of tuberculosis in childhood. JAMA. 1909;52:675–8. 9. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis. 1993;17(6):968–75. 10. Ewer K, et  al. Comparison of T-cell-based assay with tuberculin skin test for diagno sis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet. 2003;361(9364):1168–73. 11. Abubakar I, et al. Prognostic value of interferon-gamma release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study. Lancet Infect Dis. 2018;18(10):1077–87. 12. Zak DE, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387:2312. 13. Esmail H, et  al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography. Nat Med. 2016;22(10):1090–3. 14. Mayito J, et al. Anatomic and cellular niches for Mycobacterium tuberculosis in latent tuberculosis infection. J Infect Dis. 2019;219(5):685–94. 15. Martineau A, et al. S89 Detection of M. Tuberculosis DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic TB contacts. Thorax. 2021;76:A54–A55.

4

Basic and Descriptive Epidemiology of Tuberculosis David W. Dowdy and Mario C. Raviglione

Abstract

Tuberculosis (TB) is a disease characterized by airborne transmission, slow dynamics, and heterogeneities in burden across populations. The spectrum of TB natural history includes latent infection (an asymptomatic and non-infectious state), early subclinical disease (in which symptoms are not prominent but transmission may presumably occur), and “active” disease (which is symptomatic and frequently infectious). Exposure to TB is environmentally driven and particularly intense in congregate living settings (e.g., prisons and mines), healthcare settings, households of people with active TB, and crowded locations often characterized by poverty. Progression of TB disease is halted by the host immune system; thus, risk factors for developing active TB include immunocompromising conditions such as HIV, undernutrition, diabetes, smoking, heavy alcohol use, end-stage renal disease, and certain medications. Active TB causes death in approximately 50% of untreated individuals, highlighting the importance of early diagnosis and initiation of effective treatment, plus prevention in high-risk populations. In low-incidence settings, TB is often concentrated among foreign-­ born individuals (particularly recent immigrants), and targets for “pre-­ elimination” (10% per year [7]. Unfortunately, while many countries have approached or surpassed these targets, declines in TB burden have been much slower. It is therefore widely recognized that more aggressive targets are necessary. The current End TB Strategy, endorsed by the World Health Assembly in 2014, aims to achieve much more ambitious targets including a 90% reduction in deaths and 80% reduction in incidence rate in 2030 compared to 2015 [8]. One of the successes of the DOTS strategy was the development of standardized categories of treatment outcomes. Since 1996, uniform definitions of six mutually exclusive categories (cure, treatment completed, failure, death, treatment interrupted, and transfer out) have been recommended by the World Health Organization and adopted widely at the country level [9]. “Treatment success” has typically been defined as either cure (completion of therapy with confirmed conversion of sputum smear or TB culture to negative) or treatment completed (without bacteriological confirmation of cure). These standardized definitions have been instrumental in benchmarking global success in the fight against TB, but they also have limitations, including difficulty in confirming cure using molecular tests (which may not convert despite effective treatment).

4.4

Major Determinants of Tuberculosis Risk

The risk of TB infection and disease is unequally distributed in populations. Demographically, TB prevalence is more than twice as high among men than women; prevalence-to-notification ratios are also higher among men, suggesting that some (but not all) of this difference reflects access to care and other social challenges [10]. This sex difference is not prominent among children. The risk of TB

4  Basic and Descriptive Epidemiology of Tuberculosis

33

disease also varies with age; “age-period-cohort” analyses demonstrate that the risk of TB progression and death is very high in infancy, falls sharply during childhood and early adolescence, rises with puberty, and remains consistently high throughout adulthood, increasing gradually with age. Thus, the elderly experience the greatest risk of TB on a per-person-year basis; however, since young adults greatly outnumber the elderly in most high-burden countries, the absolute number of TB cases is the highest between the ages of 20 and 34 [11]. The number of deaths instead is the highest between ages 45 and 74. Furthermore, as countries succeed in lowering rates of TB infection over time, reactivation (rather than recent transmission) may account for a larger proportion of TB disease, and older individuals—who were exposed in earlier decades—have disproportionately higher prevalence of TB infection. As such, one indicator of success in TB control at the population level in a country where TB incidence is decreasing is an increase in the mean age of incident TB disease among the native-born population. HIV is the strongest risk factor for TB disease, with untreated HIV increasing the risk of TB progression at least 20-fold [12]. As a result, regions characterized by generalized HIV epidemics (for example, southern Africa) are also those with the highest incidence and mortality rates of TB worldwide. In these areas, TB incidence has more than doubled since the onset of the HIV epidemic, and more than half of all people with TB disease are HIV-positive. As a result, anyone diagnosed with TB must be tested for HIV, so that proper HIV care can be offered, and all people with HIV must be provided preventive therapy for TB. In general, TB risk factors can be classified as environmental characteristics that increase the risk of TB exposure, factors that impair host immunity and thus increase the risk of TB progression, and inadequacies of health systems that increase the risk of delayed diagnosis and failed treatment, thus perpetuating TB transmission and increasing mortality (Box 4.1). TB is the quintessential disease of poverty; as such, social determinants such as economic inequalities, lack of universal health coverage, and barriers to care (including out-of-pocket patient costs) play a disproportionate role in the epidemiology of TB. Similarly, because they are highly prevalent on a population level, undernutrition, indoor air pollution, heavy alcohol use, and smoking are associated with the greatest population attributable fractions of TB worldwide [13]. Silicosis, end-stage renal disease, and immunosuppressive medications (particularly steroids and tumor necrosis factor [TNF]-alpha inhibitors) greatly increase the risk of TB disease and (like HIV) warrant treatment for latent TB infection if present. Other populations at markedly increased risk of TB include household and close contacts of known TB cases, people living in congregate settings (especially prisons and mines), people with diabetes, healthcare workers, and (in low-incidence settings) people born in high-incidence countries. These known risk factors enable targeted delivery of interventions, including structural interventions to address the social determinants of TB and disease-specific interventions such as case finding and testing/treatment for latent TB infection.

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D. W. Dowdy and M. C. Raviglione

Box 4.1 Major Risk Factors for Tuberculosis Environmental characteristics increasing risk of TB exposure Household contact with an infectious case Poor living or working conditions especially within congregate settings (e.g., prisons and mines) Healthcare settings (patients and healthcare workers) Crowded settings with poor ventilation (e.g., urban slums) Poverty, inequalities, inequities

Host immune characteristics increasing risk of TB infection and progression HIV

Characteristics of health systems increasing risk of TB mortality and transmission Delayed diagnosis

Undernutrition

Inadequate healthcare access

Immunosuppressive medications (particularly steroids and TNF-α inhibitors) End-stage renal disease

Inadequate treatment

Diabetes mellitus

Time spent in high-incidence Active smoking and countries tobacco-­related pulmonary disease Indoor air pollution

Inadequate patient support (e.g., financial, nutritional) Inadequate treatment for HIV and other associated conditions Drug resistance (and inadequate detection thereof) Inadequate infection control

Heavy alcohol use Old and very young age Male sex

4.5

Epidemiology of Anti-Tuberculosis Drug Resistance

Worldwide, approximately 5% of all new cases of TB are resistant to rifampin (RR-­ TB) or rifampin and isoniazid (multidrug-resistant or MDR-TB); over 11% are resistant to at least one anti-TB drug [14]. Our ability to detect RR-TB/MDR-TB has improved with the use of Xpert MTB/RIF®, which detects resistance to rifampin in addition to M. tuberculosis itself; nevertheless, in 2019, only half of all people with bacteriologically confirmed TB received testing for rifampin resistance [1]. The prevalence of MDR-TB in new cases varies widely across populations, from less than 1% (for example, among native-born people in the United States) to 35% in Belarus, Russia, and other countries of the former Soviet Union [14]. The prevalence of RR-TB/MDR-TB has been relatively stable over time and has never exceeded 5% globally. However, “hotspots” of high and increasing levels of drug-resistant TB are widely recognized. While drug-resistant TB is a consequence of ineffective treatment linked to health system failures, the majority of drug-­ resistant TB now occurs through primary transmission. Thus, while drug-resistant

4  Basic and Descriptive Epidemiology of Tuberculosis

35

TB is more common in people with recurrent episodes of TB, this often reflects failure to detect drug-resistant TB (and subsequent failure of treatment) rather than de novo development of drug resistance during treatment. Since drug-resistant TB is linked to transmission, levels of TB drug resistance are the highest in settings of most intense transmission. As such, drug resistance is commonly seen in prisons, during outbreaks, and occasionally in children (whose TB reflects more recent transmission). Fortunately, drug-resistant TB also responds to effective control measures; for example, as an outbreak of MDR-TB in New York City was brought under control with an influx of resources for appropriate diagnosis and treatment, the incidence of MDR-TB fell more rapidly than that of TB as a whole [15].

4.6

Summary

In summary, the epidemiology of TB is characterized by substantial heterogeneity, with rates of incidence and mortality that vary more than 100-fold across countries. In high-burden countries, TB disease often reflects recent transmission and is thus most commonly seen in young adults. By contrast, in low-burden settings, TB largely occurs via reactivation and is concentrated in the elderly and non-native-­ born. The epidemiology of TB is tightly interwoven with poverty and HIV. Determinants of TB reflect the biology of the disease and include environmental risks for increased airborne exposure, host immune risks for breakdown in the containment of latent infection, and health system risks that cause delays in diagnosis and effective treatment. A better understanding of the heterogeneous epidemiology of TB can inform interventions to more effectively combat TB epidemics, both locally and globally.

References 1. World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization; 2020. 2. Lönnroth K, Migliori GB, Abubakar I, D’Ambrosio L, De Vries G, Diel R, et  al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45:928–52. 3. Onozaki I, Law I, Sismanidis C, Zignol M, Glaziou P, Floyd K. National tuberculosis prevalence surveys in Asia, 1990–2012: an overview of results and lessons learned. Tropical Med Int Health. 2015;20:1128–45. 4. Wang L, Zhang H, Ruan Y, Chin DP, Xia Y, Cheng S, et al. Tuberculosis prevalence in China, 1990–2010; a longitudinal analysis of national survey data. Lancet. 2014;383:2057–64. 5. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One. 2011;6:e17601. 6. Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13:e1002152. 7. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet. 1998;352:1886–91. 8. Uplekar M, Weid D, Lönnroth K, et al. WHO’s end TB strategy. Lancet. 2015;385:1799–801.

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9. Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of worldwide tuberculosis control. WHO global surveillance and monitoring project. Lancet. 1997;350:624–9. 10. Horton KC, MacPherson P, Houben RM, White RG, Corbett EL. Sex differences in tuberculosis burden and notifications in low- and middle-income countries: a systematic review and meta-analysis. PLoS Med. 2016;13:e1002119. 11. Kyu HH, Maddison ER, Henry NJ, Mumford JE, Barber R, Shields C, et al. The global burden of tuberculosis: results from the global burden of disease study 2015. Lancet Infect Dis. 2018;18:261–84. 12. Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G. Tuberculosis and HIV co-­ infection. PLoS Pathog. 2012;8:e1002464. 13. Lönnroth K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, Raviglione MC.  Tuberculosis control and elimination 2010–50: cure, care, and social development. Lancet. 2010;375(9728):1814–29. 14. Wright A, Zignol M, Van Deun A, Falzon D, Gerdes SR, Feldman K, et al. Epidemiology of antituberculosis drug resistance 2002–07: an updated analysis of the global project on anti-­ tuberculosis drug resistance surveillance. Lancet. 2009;373:1861–73. 15. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med. 1995;333:229–33.

5

Tuberculosis: WHO-Recommended Strategies and Global Health Perspectives Alberto L. García-Basteiro and Mario C. Raviglione

Abstract

In order to address the human suffering as well as the health and socioeconomic challenges posed by tuberculosis (TB), a global, coordinated, multi-sectoral strategy needs to be urgently funded and implemented. In this chapter we provide an overview of the principles, pillars, and main indicators of the World Health Organization (WHO)’s End TB Strategy, which is intended to serve as a comprehensive framework for countries to achieve the ambitious targets of disease incidence and mortality reduction, as well as elimination of households facing catastrophic costs due to TB.  This strategy, conceived for the period 2015–2035, paves the road towards subsequent TB elimination and is fully aligned with the TB-specific indicators of the Sustainable Development Goals (SDGs). Keywords

WHO · End TB · Tuberculosis · Stop TB · Research · Innovation · National Control Programme · DOTS · Sustainable Development Goals (SDGs)

A. L. García-Basteiro (*) Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain Centro de Investigação em Saúde de Manhiça (CISM), Manhiça, Mozambique e-mail: [email protected] M. C. Raviglione Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_5

37

38

5.1

A. L. García-Basteiro and M. C. Raviglione

Introduction

Ending the suffering and damage that tuberculosis (TB) has posed and keeps posing to human society is an ambitious goal, but also a clamorous and necessary global societal commitment. In 2005, the World Health Organization (WHO) launched the Stop TB Strategy (2006–2015) [1], which focused on reducing the TB burden through a series of key programmatic objectives. These included expanding and enhancing DOTS (an essential control strategy first promoted by WHO in 1994–1995), addressing the problem of TB-human immunodeficiency virus (HIV), multidrug-resistant TB (MDR-TB), contributing to health system strengthening based on primary health care, engaging with care providers and empowering people with TB, as well as their communities, through continuous partnership and promotion of research. The Stop TB Strategy was aligned with the TB-related targets of the Millennium Development Goals (MDGs) set in 2000 [1]. It was built around the challenges emerging in the new millennium and was aligned with the first Global Plan to Stop TB (2001–2005) [2], which helped unify and coordinate the TB control efforts in the advent of the twenty-first century. To fully execute this strategy, important funding commitment was necessary although not met by member states.

5.2

The WHO End TB Strategy

With the new era of the Sustainable Development Goals (SDGs) soon beginning, the global TB strategy needed a re-thinking and adaptation to incorporate the new way of conceiving societal development centred on multi-sectoriality, cross-­ disciplinarity, integration of aims and interventions, equitable access and, ultimately, sustainability. In 2014, during the 67th World Health Assembly, WHO’s Member States adopted the End TB Strategy (2015–2035), a 20-year strategy for global TB prevention, care, and control with an emphasis on ambitious targets which would pave the road to “ending TB” and for subsequent TB elimination [3]. This strategy is fully aligned with the objectives set within the SDGs. It sets clear targets to be achieved by 2035, including a 95% reduction in TB deaths (compared with 2015), 90% reduction in TB incidence rate (less than 10 cases per 100,000 population), and no affected families facing catastrophic costs due to TB (a situation when the total costs of having TB exceed 20% of the annual household income) (Box 5.1). The WHO End TB Strategy, that evolved from previous global strategies promoted by WHO (Fig. 5.1), is the outcome of a 2-year preparation process which included high-level discussions with multiple key actors in TB control such as national control programme managers, delegates of ministries of health, as well as representatives of nongovernmental organizations (NGOs), academia, technical support institutions, civil society, private sector, development partners, and multisectoral stakeholders. The basic premise that justifies the strategy is that if the trends on TB incidence rate reduction (which in the past decade was of 1–2% per year) are maintained [4], TB will still cause millions of unnecessary disease episodes and

5  Tuberculosis: WHO-Recommended Strategies and Global Health Perspectives

39

Box 5.1 Vision, Goal, and Key Global Indicators of the End TB strategy VISION GOAL INDICATORS (compared with 2015 baseline) Percentage reduction in tuberculosis deaths Percentage reduction in the TB incidence rate (less than 55 TB cases per 100,000 population) Percentage of TB-affected households experiencing catastrophic costs due to TB

A WORLD FREE OF TB - zero deaths, disease and suffering due to TB END THE GLOBAL TB PANDEMIC MILESTONES TARGETS 2020 2025 SDGa 2030 END TB 2035 35% 75% 90% 95% 20%

50%

80%

90%

0%

0%

0%

0%

Sustainable Development Goals’ targets for TB by 2030

a

Fig. 5.1  Evolution of the WHO-recommended global TB control strategies (1994 to 2030)

deaths in the upcoming decades. This could be avoided with a clear, well-financed, strategic plan, underpinned by a visionary strategy, that addresses the TB programme in a comprehensive manner, tackling all potential development fields associated with the determinants of the disease. Achieving the ambitious targets of the End TB strategy will require bold policies and supportive systems that need to be in place throughout the strategy’s term of action and until the final and foremost objectives are achieved. These policies and systems are inspired by the so-called principles of this global strategy, which include: (a) government stewardship and accountability with monitoring and evaluation; (b) strong coalition with civil society organizations and communities; (c) protection and promotion of human rights, ethics, and equity; and (d) adaptation of the strategy and targets at country level, with global collaboration (Table 5.1) [5]. Not all countries face the End TB strategy with the same levels of disease or the

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Table 5.1  Principles, pillars, and components of the End TB Strategy Principles 1. Government stewardship and accountability, with monitoring and evaluation 2. Strong coalition with civil society organization and communities 3. Protection and promotion of human rights, ethics, and equity 4. Adaptation of the strategy and targets at country level, with global collaboration Pillars and components Integrated, patient-centred Bold policies and supportive Intensified research and care and prevention systems innovation Discovery, development, Political commitment with Early diagnosis of TB adequate resources for TB care and and rapid uptake of new including universal drug-­ tools, interventions, and prevention susceptibility testing, and strategies systematic screening of contacts and high-risk groups Engagement of communities, civil Research to optimize Treatment of all people with implementation and society organizations, and public TB including drug-resistant impact, and promote and private care providers TB, and patient support innovations Universal health coverage policy, Collaborative TB/HIV activities, and management of and regulatory frameworks for case notification, vital registration, comorbidities quality and rational use of medicines, and infection control Social protection, poverty Preventive treatment of alleviation, and actions on other persons at high risk, and determinants of TB vaccination against TB

same amount of resources to fight it. It is critical that national TB plans are in line with international priorities, but, at the same time, are adapted to the local health systems and epidemiology while establishing mechanisms for cross-sectoral and cross-country strategic actions in a whole-of-society and all-of-government framework. The WHO’s End TB Strategy has been shaped around three strategic and synergistic pillars, which embed ten thematic areas or components. Different activities and indicators stem from these major components. Table 5.2 shows the top-ten indicators for monitoring the implementation of the End TB strategy at global and national levels.

5.2.1 P  illar One: Integrated, Patient-Centred Care and Prevention At the centre and the focus of recommended approaches included in this pillar is the person affected by, or at risk of, TB. It includes four key components. The first one calls on ensuring early diagnosis for all TB patients. Around 1/3 of all estimated TB cases are not diagnosed or notified by health authorities. Undiagnosed TB is associated with a fatal outcome in most occasions. Thus, it is vital to implement WHO recommendations for rapid diagnosis, including molecular testing and rapid

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Table 5.2  Top-ten priority indicators (not ranked) for monitoring implementation of the End TB strategy at global and national levels, with recommended target levels that apply to all countries Component TB treatment coverage TB treatment success rate % TB-affected households that experience catastrophic costs due to TB % new and relapse TB patients tested using WHO-recommended rapid tests at the time of diagnosis Preventive TB Infection treatment coverage

Indicator Number of new and relapse cases notified and treated, divided by the estimated number of incident TB cases in the same year, expressed as a % % notified TB patients who were successfully treated. The target is for drug-susceptible and drug-resistant TB combined, although outcomes should also be reported separately Number of people treated for TB (and their households) who incur catastrophic costs (direct and indirect combined), divided by the total number of people treated for TB Patients tested using a WHO-recommended rapid test at time of diagnosis, divided by total number of new and relapse

Number of people living with HIV newly enrolled in HIV care and number of children aged 50% in adolescents and/or adults; higher vaccine efficacy than BCG for use in infants. •  Minimal number of initial doses and boosters required. •  Evidence of favourable immunogenicitya. • Dosage, regimen and costs amenable to affordable supply, including in low and middle income countries (LMICs). Specific to Prophylactic Vaccines •  At least 10 years protection after primary vaccination. •  No immunological interference with other vaccines. Specific to Therapeutic Vaccine •  Increase the proportion of cure at end of drug treatment. •  Reduce recurrence rates at 1 year follow-up. Whilst accepting that no defined immune correlates of protection have yet been determined

a

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6.5.2 Potential New Tuberculosis Vaccines In 2000, there were virtually no new TB vaccines in clinical development. This situation has improved, with at least 25 vaccine candidates under preclinical and clinical development as of the end of 2019 and more than a dozen of these having progressed to human trials (see Table 6.2) [11]. TB vaccine candidates can be broadly divided into three main types by vaccine platform (See Table 6.3 [15]). Whole cell vaccines (either live or inactivated) elicit diverse immune responses to a wide range of antigens within the inoculating organism. This strategy does not require knowing which specific mycobacterial antigens are essential for generating protective immune responses. However, a broader immune response often comes at the cost of a reduction in the magnitude of responses to specific virulence factors. Candidates of this type include recombinant BCG, with genetic modifications to promote immunogenicity; attenuated strains of M. tb, with selected virulence genes deleted; and recombinant NTMs. Subunit vaccines allow more focussed immunological targeting, containing only the desired antigenic component of the pathogen. The antigens can be expressed via viral platforms (viral-vectored, known to induce a strong T-cell responses), Table 6.2  TB vaccine candidates. Pipeline of candidates in clinical development. Adapted from the Stop TB Partnership Working Group on New TB Vaccines [17] Phase 1

Phase 2a

Phase 2b

Phase 3

AEC/BC02 Anhui Zhifei Longcom

RUTI Archivel Farma, S.L

DAR-901 Dartmouth, GHIT

Vaccae™ Anhui Zhifei Longcom

Ad5Ag85A McMaster, CanSino

MTBVAC Biofabri, TBVI, Zaragosa

M72/AS01E GSK, Aeras/IAVI, gates MRI

VPM1002 SII, max Planck, TBVI (phase 2b/3)

ChAdOx1 85A/MVA85A (IM/aerosol) Univ of Oxford

TB/FLU-04L RIBSP

H56:IC31 SSI, IAVI, Valneva

Immuvac ICMR, Cadila pharmaceuticals

GamTBvac Ministry of Health, Russia

ID93+ GLASE IDRI, Wellcome Trust, Quratis

Subunit (viral-vector)

Subunit (protein-adjuvant)

Viable whole cell

Inactivated whole cell or lysate

  BVI TB Vaccine Initiative, IDRI Infectious Disease Research Institute, RIBSP Research Institute T for Biological Safety Problems, GHIT Global Health Innovative Technology Fund, GSK GlaxoSmithKline, SSI Statens Serum Institut, IAVI International Aids Vaccine Initiative, GMRI Gates Medical Research Institute, SSI Serum Institute of India; ICMR Indian Council of Medical Research, Gates MRI Gates Medical Research Institute

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55

Table 6.3  TB vaccine candidates. TB vaccine candidates by platform type Description Type Viable whole Whole live cell organism

Examples MTBVAC (attenuated M. tb) VPM1002 (recombinant BCG) BCG revaccination

Inactivated whole cell

M. vaccae/M. obuense (SRL172/ DAR-901) Immuvac (M. indicus pranii) Protein-adjuvant M72/AS01E, H56:IC31, ID93+ GLA-SE Viral-Vectored ChadOx 85A, MVA85A, CMV-TB 6Ag

Subunit

Advantages and disadvantages Longer antigenic stimulation by replicating organism may be more likely to elicit memory effect Multiple antigens included, some may have undesirable effects Potential risk of disseminated infection in immunocompromised May require multiple doses, due to Whole killed shorter lived immune stimulation organism or Multiple antigens included, some may lysate have undesirable effects No risk of disseminated disease One or multiple No guarantee of immunological M. tb antigens memory effects if not replicating Can be very immunogenic but only a small number of antigens can be delivered with each vaccine Often safest and most stable vaccines

delivered as proteins combined with adjuvants (specific substances designed to enhance vaccine-induced immune responses) or administered as nucleic acids [15, 16]. The heat-inactivated whole cell vaccine Mycobacterium vaccae has been approved for use as an adjunctive therapeutic vaccine in China where it is also being evaluated for prevention of TB disease in LTBI+ individuals. A closely related NTM candidate, DAR-901 (Mycobacterium obuense) is being evaluated for prevention of infection (clinicaltrials.gov NT01979900). VPM1002 and ID93+ GLA-SE are currently being assessed for therapeutic and prophylactic uses; H56:IC31 for therapeutic use only. The other stated examples are currently being developed predominantly as prophylactic vaccines.

6.5.3 Selected Recent Tuberculosis Vaccine Clinical Trials Selected recent clinical efficacy trials of some of the most promising TB vaccine candidates are briefly outlined below (trial sponsors noted in parentheses after each trial and vaccine sponsor in italics after each vaccine, where applicable).

6.5.3.1 M72/AS01E M72/AS01E (GlaxoSmithKline; GSK and Gates Medical Research Institute) is an adjuvanted recombinant protein vaccine, comprising two main M. tb antigens together with the adjuvant, AS01E. A recent phase IIb study (GSK) demonstrated 50% reduction in progression to active pulmonary TB disease in LTBI+,

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HIV-uninfected adults following vaccination. It is the first vaccine candidate to demonstrate protection in previously infected individuals and the first subunit candidate to demonstrate significant efficacy against TB disease. A safety and immunogenicity study in HIV-infected individuals and a confirmatory Phase III trial are being planned (with Gates Medical Research Institute; GMRI serving as vaccine and trial sponsors). It will be important to ascertain whether M72/AS01E also offers protection to M. tb-uninfected individuals. Importantly, participants from the phase IIB trial consented to samples being retained for research into potential COPs and correlates of risk to aid in future TB vaccine development [18].

6.5.3.2 H4:IC31 or BCG Revaccination H4:IC31 (Sanofi Pasteur, Statens Serum Institut, Valneva), a subunit vaccine candidate, and BCG (SSI) revaccination were each evaluated for their ability to prevent M. tb infection in previously BCG-vaccinated, M. tb- and HIV-uninfected adolescents at high risk of acquiring M. tb infection (Aeras). New infection was determined by conversion to positive QuantiFERON (QFT) IGRA status (interferon gamma release assay—a standard clinical test to diagnose LTBI). Whilst neither intervention reached statistical significance for the primary end-point of initial QFT conversion, BCG revaccination provided statistically significant vaccine efficacy of 45.4% (p = 0.03) in reducing sustained QFT conversion (believed to indicate established M. tb infection). H4:IC31 demonstrated a non-statistically significant efficacy of 30.5% (p = 0.08). BCG revaccination could represent a safe and cost-effective public health intervention to protect selected high-risk populations [19]. A larger confirmatory trial of these BCG revaccination findings is underway (GMRI; clinicaltrials.gov NCT04152161); H4:IC31 is no longer in development. 6.5.3.3 VPM1002 Both BCG and M. tb are known to be ingested and retained by host macrophages. VPM1002 (Serum Institute of India, SII; VPM) is a genetically modified live vaccine, formed by recombination of BCG with a Listeria monocytogenes gene that confers phagosomal disruption properties and results in increased mycobacterial antigen presentation and immunological stimulation. In phase I/II trials (VPM, SII), VPM1002 demonstrated an acceptable safety profile and was immunogenic, inducing CD4+ and CD8+ T-cell responses thought to be necessary for protection. Preliminary efficacy results are awaited [20] and a Phase III trial in African infants is in planning. A phase II/III trial is ongoing in India (SII), assessing prevention of recurrence following VPM1002 vaccination in recently treated adult TB patients (clinicaltrial.gov identifier NCT03152903). Another Phase III trial in India (Indian Council for Medical Research—ICMR) is evaluating the safety and protective efficacy against TB disease in household contacts (Clinical Trial Registry India CTRI/2019/01/017026). 6.5.3.4 MTBVAC MTBVAC (Biofabri) represents the first rationally attenuated M. tb vaccine candidate to be tested in human clinical trials. Attenuation was achieved by deletion

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of the genes phoP and fadD26, which encode two major M. tb virulence factors. MTBVAC conserves many genetic regions encoding immunologically significant M. tb antigens that are absent from BCG. MTBVAC demonstrated improved protective efficacy compared to BCG in several animal models and has shown an acceptable safety profile in phase I clinical trials. Phase II dose-defining safety and immunogenicity studies in infants and M. tb-infected and -uninfected adults are underway (Biofabri, IAVI) [21] and a Phase III trial in infants is being planned.

6.6

Main Conclusions and Recommendations

TB vaccine research and development is a hugely complex and challenging field. Despite this, significant progress has been made over the last two decades with positive signals in recent human efficacy trials. The most promising vaccine candidates still need to be evaluated in Phase III clinical trials and a robust pipeline of ‘next generation’ candidates should be built on knowledge gained from current clinical candidates. Political will and continued financial backing from governments, pharmaceutical companies and other funders will be crucial in maintaining the necessary momentum to identify safe, effective, deployable TB vaccine(s) needed to end TB as a global public health emergency.

References 1. World Health, O. The end TB strategy. 2015 [cited 2020 28 March]. 2. Dockrell HM, Smith SG. What have we learnt about BCG vaccination in the last 20 years? Front Immunol. 2017;8:1134. 3. Schrager LK, et  al. The status of tuberculosis vaccine development. Lancet Infect Dis. 2020;20(3):e28–37. 4. Luca S, Mihaescu T. History of BCG vaccine. Maedica (Buchar). 2013;8(1):53–8. 5. Mangtani P, et  al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis. 2014;58(4):470–80. 6. Trial TP. Trial of BCG vaccines in south India for tuberculosis prevention: first report--tuberculosis prevention trial. Bull World Health Organ. 1979;57(5):819–27. 7. Rodrigues LC, et al. Effect of BCG revaccination on incidence of tuberculosis in schoolaged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet. 2005; 366(9493):1290–5. 8. Trial TKP. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention Trial Group. Lancet. 1996;348(9019):17–24. 9. Aaby P, et  al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011;204(2):245–52. 10. O’Garra A, et al. The immune response in tuberculosis. Annu Rev Immunol. 2013;31:475–527. 11. McShane H. Insights and challenges in tuberculosis vaccine development. Lancet Respir Med. 2019;7(9):810–9. 12. Ginsberg AM.  What’s new in tuberculosis vaccines? Bull World Health Organ. 2002;80(6):483–8. 13. World Health Organization. WHO preferred product characteristics for new tuberculosis vaccines. World Health Organization: Geneva; 2018.

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14. Vekemans J, et al. Preferred product characteristics for therapeutic vaccines to improve tuberculosis treatment outcomes: key considerations from World Health Organization consultations. Vaccine. 2020;38(2):135–42. 15. Hatherill M, White RG, Hawn TR. Clinical development of new TB vaccines: recent advances and next steps. Front Microbiol. 2019;10:3154. 16. Kaufmann SHE, Weiner J, von Reyn CF. Novel approaches to tuberculosis vaccine development. Int J Infect Dis. 2017;56:263–7. 17. Vaccines NT. TB vaccines pipeline. 2019 [cited 2020 17th April]. 18. Tait DR, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. 2019 (1533-4406 (Electronic)). 19. Nemes E, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379(2):138–49. 20. Nieuwenhuizen NE, et al. The recombinant bacille Calmette-Guerin vaccine VPM1002: ready for clinical efficacy testing. Front Immunol. 2017;8:1147. 21. Tameris M, et al. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial. Lancet Respir Med. 2019;7(9):757–70.

7

Latent Tuberculosis Infection Diagnosis and Treatment Dominik Zenner, Heinke Kunst, Lynn Altass, Alberto Matteelli, and Judith Bruchfeld

Abstract

This book chapter provides an overview over the latent tuberculosis infection (LTBI) testing and treatment. It provides details of the currently available immunological diagnostic tests, as well as LTBI treatment, referring to the best available evidence and international guidance. It then reviews the evidence for use of LTBI testing and treatment in different settings and populations and discusses the trade-offs between an individual risk-based approach and a population-based approach when considering LTBI programmes. Keywords

Latent TB infection · TB screening · TB risk populations · LTBI treatment

D. Zenner (*) Centre for Global Public Health, Queen Mary University, London, UK e-mail: [email protected] H. Kunst Blizzard Institute, Queen Mary University, London, UK e-mail: [email protected] L. Altass NHS England, London, UK e-mail: [email protected] A. Matteelli Clinic of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV and TB Elimination, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy e-mail: [email protected] J. Bruchfeld Department of Medicine, Karolinska Institutet, Stockholm, Sweden e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_7

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I ntroduction: Latent Tuberculosis Infection Management as Essential Intervention for Tuberculosis Elimination

Despite significant progress in recent years, tuberculosis (TB) is still the most important cause of death among infectious diseases, with an estimated 10 million new cases and 1.45 million deaths in 2018 [1]. The urgency to tackle this significant burden has been well recognised, leading to the ambitious targets of the World Health Organization (WHO) End TB strategy to achieve TB elimination in low incidence countries [2] and the Sustainable development Goals (SDG 3.3). United Nations (UN) member states furnished a political declaration at the end of the first UN General Assembly High Level meeting to support the End TB strategy; this included expanding access to TB diagnosis and treatment and preventive treatment for latent TB infection (LTBI) [3]. The achievement of these targets will require the combination of currently available TB control tools, accelerated development of new vaccines and treatments, and focus on priority action areas outlined in the End TB strategy [2]. Given the high prevalence of LTBI globally (estimated 25%) [4] and the fact that in low incidence countries most new TB cases are a result of LTBI reactivation [5], significant progress towards TB elimination can only be made if efforts include control of LTBI [6].

7.2

 atent Tuberculosis Infection Diagnosis: Tuberculin L Skin Test and IGRAs

To date only few immunological tests are available for routine clinical use in LTBI diagnosis, despite significant efforts to find biomarkers or transcriptional signatures for LTBI [7]. LTBI is referred to as an asymptomatic state with increased M. tuberculosisspecific immunoreactivity. Three tests are commercially available, the in  vivo Tuberculin Skin Test (TST), and two in  vitro interferon gamma release assays (IGRAs)—an ELISA test (QuantiFERON Gold InTube) and an ELISPOT test (T-Spot. TB). There are differences in modalities and test properties, but none are able to reliably distinguish between recent and remote infection, and the positive predictive value for TB reactivation remains low in unstratified population samples [8]. Transcriptional signatures are promising new biomarkers but not yet available for routine clinical use. The TST involves a T-cell mediated hypersensitivity reaction caused by an intradermal application of purified protein derivate from Mycobacterium tuberculosis. The correct injection and the reading of a delayed hypersensitivity reaction (skin induration) after 48–72 h requires specialist training. The test has a reasonable sensitivity, reduced TB infection has been traditionally called “latent TB infection (LTBI)”. This terminology has been used to define a state of persistent immune response to stimulation by M. tuberculosis antigens through tests such as the tuberculin skin test or an interferon gamma release assay (IGRA) without clinically active TB. This chapter uses the term LTBI throughout. However, this term may be progressively replaced by the simpler term “TB infection”. For this chapter the authors have decided for the time being to maintain the traditional terminology.

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in persons with immunodeficiency. However, since the TST contains many antigens, some shared by Bacille Camille Guérin (BCG) and non-tuberculous mycobacteria (NTM), the test has poor specificity. In addition to this cross-reactivity, different preparations of TST can lead to differential reactions. Guidelines have taken these modalities into account and recommended cut-offs for induration size in individuals with previous BCG vaccination, TB risk factors or immunosuppression when determining positivity. IGRA tests work through quantitative measurements of antigen-sensitised T-cell mediated interferon gamma release. There is some minor variation between assays and generations of assays, but the two systematically included antigens are ESAT-6 and CFP-10, both of which are specific to the Mycobacterium tuberculosis complex, minimising cross-reactivity and achieving a higher specificity, with similar sensitivity to TST.  There is a more recent iteration of the skin test (C-TB), which only includes these antigens, and therefore achieves a comparable specificity to the IGRAs; C-TB has completed phase III trials and is awaiting registration. Both the QuantiFERON ELISA test and the T.SPOT.TB ELISPOT are blood-based specialised laboratory tests which obviate the need for specialised administration and reading, as well as the need for the patient to return to health services after 48–72 h. A recent, large cohort study (n  =  9610) found annual TB progression rates between 1% and 1.3% for all three tests, although for TST a 15 mm cut-off threshold was used and lower thresholds were associated with lower predictive values. The authors concluded that for LTBI diagnosis either IGRAs or BCG-stratified TST have the best predictive values [9]. The specific choice of test will also depend on the practicalities and population tested, for example favouring IGRAs for large population cohorts, or simultaneous TST and IGRA testing, when expecting a risk of anergy, for example in the immunosuppressed [10] (Table 7.1).

7.3

 atent Tuberculosis Infection Treatment Options L and Recommendations

For a long time, the preferred LTBI treatment was 6–9 months of isoniazid (INH) monotherapy with acceptable safety and about 60–90% risk reduction compared to no treatment. Length of treatment and the resulting decreased completion rates are key limitations of INH. Drug induced liver injury (DILI) of severe grade occurs in about 0.36% during a 6-month course; this tends to increase with longer courses of INH [11]. Very few deaths due to DILI have been described in the literature—almost all of these in long-term INH regimens (>12  months) [12]. INH monotherapy is often used and recommended for specific population groups, such as persons living with human immunodeficiency virus (HIV) (minimise drug interactions with antiretroviral therapy (ART)) or for children under 2 years [13]. However, an important limitation is the length of therapy (Table 7.2). Rifamycin-based regimens have recently been shown to have at least equivalent efficacy and lower toxicity than INH monotherapy, and with reduced treatment duration [12]. WHO-recommended rifamycin-based treatment regimens include a 3-month course of rifampicin and isoniazid, 1-month daily or 3-month weekly

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Table 7.1  Currently recommended drug regimens for preventive therapy of drug-sensitive TB. (Adapted from WHO [13]) Drugs Isoniazid

Dosing Advantages 9H 9 months Daily Excellent efficacy, avoids rifamycin-­ related interaction with ART 6H Isoniazid 6 months Daily Excellent efficacy, avoids rifamycin-­ related interaction with ART 3RH Isoniazid, 3 months Daily Excellent efficacy, rifampicin shorter duration than monotherapy 3HP Isoniazid, 3 months Weekly Good safety and rifapentine efficacy profile, once-weekly dosing regimen may appeal to patients 4R Rifampicin 4 months Daily Good safety and efficacy profile, less hepatotoxicity than isoniazid based regimens 1HP Isoniazid, 1 month Daily Good safety and rifapentine efficacy profile, short regimen improves adherence

Disadvantages Hepatotoxicity, long treatment duration, risk of non-completion Hepatotoxicity, long treatment duration, risk of non-completion Rifampicin interaction with ART Rifapentine not available in some countries

WHO guidance Recommended

Recommended

Recommended Recommended

Fewer studies and Alternative experience option

Fewer studies. Rifapentine not available in some countries

Alternative option

ART antiretroviral therapy Table 7.2  Considerations for LTBI testing. (Adapted from ECDC (2018) Programmatic management of latent tuberculosis infection in the European Union [10]) Target groups Children under 5 years of age Vulnerable and hard-to-­ reach populations Immunocompromised individuals (including PLHIV) Migrant populations BCG-vaccinated individuals

Preferred test TST

Reason Children’s immune system, difficulty drawing blood, insufficient data on performance of IGRAs in young children. IGRA No need for a second visit to read the test result. Combination of Lower sensitivity of LTBI tests in TST and IGRA immunocompromised individuals. Combination TST/IGRA testing is suggested to avoid missing individuals who could benefit from LTBI treatment . IGRA testing preferred as no need for a IGRA or TST acceptable. (IGRA second visit to read the test result. for large numbers) IGRA TST may be affected by prior BCG vaccination.

TST tuberculin skin test, BCG-vaccinated vaccinated with Bacillus Calmette-Guérin vaccine, IGRA interferon gamma release assay, PLHIV Persons living with HIV

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courses of rifapentine and INH [13] and a 4-month course of rifampicin. The rifapentine-INH combination is the only regimen that can be given as a once-­weekly dosing scheme, reducing the daily pill burden. Rifapentine use in Europe is currently limited by licensing and distribution issues. There is currently scarce evidence in respect of treatment of LTBI in TB contacts of an index case with multi-drug resistant (MDR)-TB, and of the 21 articles included in a recent systematic review, only 6 provided a comparative analysis (treatment versus non-treatment). Whilst the point estimate of risk reduction (90%) was encouraging, its range (9–99%) and heterogeneity and toxicity of some regimens (including pyrazinamide) are less reassuring [14]. WHO has provided a conditional recommendation to limit LTBI treatment to selected high-risk contacts of MDR-TB patients, if there is robust clinical justification [13]. At population level, the prevalence of latent MDR-TB is still considered low [15] making population-based LTBI programmes feasible. There are currently several drug trials under way evaluating the efficacy and safety of preventive treatment in contacts of patients with MDR-TB including mono- or combination therapy with fluoroquinolones or delamanid.

7.4

 reatment of Latent Tuberculosis Infection: Individually T or Population Based?

Since only indirect tests for Mycobacterium tuberculosis immune-reactivity with a relatively low predictive value are currently commercially available [8, 9], the decision for LTBI testing and treatment depends on the evaluation of individual risks and benefits as well as trade-offs at the population level. The positive predictive value of LTBI tests largely depends on pre-test probability and can range widely. Most guidelines recommend treating individuals who are at high risk of reactivation either because of evidence for recent infection, immunosuppression, or because of co-morbidities such as renal replacement therapy, organ or haematological transplant or with silicosis. Current WHO LTBI guidelines include strong recommendations to treat adolescents and adults living with HIV with any CD4 count irrespective of the LTBI test and children living with HIV (CLWH) if they are household contacts and less than 12 months old regardless of TB incidence and to treat all CLWH over 12 months in high TB incidence areas. They also strongly recommend systematic testing and treatment for those on dialysis, with silicosis or prior to solid organ or haematological transplant [13]. Other strong recommendations include LTBI treatment of household contacts of active TB cases without HIV, if they are under 5 years old, or for LTBI testing if they are adult household contacts from low incidence countries [13]. Limiting LTBI control to selected high-risk individuals is valid, optimises the risk/ benefit ratio, and limits costs and number of adverse events. The WHO guidelines also provided a number of conditional recommendations for low TB incidence countries, including LTBI testing and treatment for prisoners, health workers, immigrants from countries with a high TB burden, homeless people and people who use illicit drugs. These recommendations are largely consistent with European Centre for Disease Prevention and Control (ECDC) guidance [10]. However, such high-risk strategies may have a minimal impact for TB elimination at population level. Ronald et al. have demonstrated that the population level impact

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of LTBI control, limited to the application of the WHO recommendations, will not prevent the vast majority of cases and that even adding additional risk groups (such as those individuals on disease-modifying anti-rheumatic drugs or steroids or those with cancer) will only have modest additional impact. Since these individuals represent a small proportion of the infected population and of TB cases, such strategies cannot sufficiently reduce TB incidence to achieve TB elimination [16]. This creates a dilemma, similar to the well-described “prevention paradox” applied to LTBI: a large number of LTBI positive persons need to be treated to make an impact at population level, balancing benefits with costs and risk of adverse effects. Campbell and colleagues argued that in some settings and “…with some strategies, the QALYs lost due to treatment adverse effects among those with false-­positive diagnostic results may be greater than the QALYs gained by averted TB in those with true-positive diagnostic results” [17]. This may change with the tests under development where the aim is to identify those at highest risk of TB reactivation. In order to balance these competing parameters, a number of different approaches have been taken. Traditional tools of stratification have been age group, duration and proximity of contact to or infectivity of the index TB case for contact tracing (CT), but the shortcomings of such crude approach are demonstrated by the fact that overscreening of TB contacts may lead to potential adverse effects of LTBI treatment and underscreening to missing cases of active TB as well as a missed opportunity of TB prevention. New approaches have tried to factor in other considerations, including air flow-informed contact tracing and mathematical risk modelling; however, there is currently insufficient evidence to recommend alternative approaches over conventional contact tracing approaches, which therefore remain standard practice. New molecular techniques such as whole genome sequencing (WGS) appear to have better specificity to define relatedness of cases compared to earlier methods such as spoligotyping or variable number tandem repeat (VNTR) techniques and have raised expectations that they can revolutionise contact tracing. WGS has been utilised to support contact tracing [18] and has raised the potential for detecting previously undetected transmissions as well as excluding suspected transmission. However, these techniques rely on isolates from active TB cases and are by definition sensitive to TB notification. It is therefore not clear how they could be used to increase the effectiveness and cost-effectiveness of contact tracing and LTBI testing, particularly in the majority of outbreaks with one or few cases apart from potentially earlier detection of active TB cases and reduction of transmission. For migrant screening, commonly used thresholds include migrant typologies (e.g. asylum seeker), TB incidence thresholds in countries of origin, time since exposure and age groups, although more granularity is possible [19]. There is significant variability in these thresholds between programmes and no widely shared consensus [20]. There has been some work on effectiveness and cost-effectiveness to decide on these thresholds [21]. Decisions on thresholds carefully balance trade-­ offs between costs and benefits, and online decision tools are available for individual and population risk-benefit estimation. One example to balance the trade-offs is the LTBI programme in England which, based on cost-effectiveness studies, offers

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testing and treatment to individuals who arrive from countries with an incidence of 150 per 100,000 or Sub Saharan Africa within the previous 5 years [22], focussed in areas of England with high TB rates.

7.5

Conclusions

LTBI testing and treatment is key to achieving the End TB strategy targets and TB elimination. This strategy is increasingly implemented, including in high TB incidence countries. Immunological diagnostic tests and effective treatment options are available. However, population-based testing is limited by the low predictive values of current LTBI tests and the unavailability of short, safe and effective treatment regimens. There remains an urgent need for improving LTBI tests and treatments and to better define target populations and interventions as well as to optimise the balance between costs and benefits of testing and treatment.

References 1. World Health Organization. Global tuberculosis report 2019 [Internet]. http://www.who.int/tb/ publications/global_report/en/. 2. The World Health Organization. The end TB strategy. Geneva: World Health Organization; 2015. 3. United Nations. World leaders reaffirm commitment to end tuberculosis by 2030, as general assembly adopts declaration outlining actions for increased financing, treatment access meetings coverage and press releases [Internet]. [cited 2020 Jan 27]. https://www.un.org/press/ en/2018/ga12067.doc.htm. 4. Houben RMGJ, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med [Internet]. 2016 [cited 2019 Mar 3]. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC5079585/. 5. Aldridge RW, Zenner D, White PJ, Williamson EJ, Muzyamba MC, Dhavan P, et  al. Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland. Lancet. 2016;388:2510. 6. Dye C, Glaziou P, Floyd K, Raviglione M. Prospects for tuberculosis elimination. Annu Rev Public Health. 2013;34:271–86. 7. Gupta RK, Turner CT, Venturini C, Esmail H, Rangaka MX, Copas A, et al. Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-­ level pooled meta-analysis. Lancet Respir Med. 2020;8:395. 8. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, et al. Predictive value of interferon-? Release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12:45–55. 9. Abubakar I, Drobniewski F, Southern J, Sitch AJ, Jackson C, Lipman M, et  al. Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study. Lancet Infect Dis. 2018;18:1077–87. 10. European Centre for Disease Prevention and Control. Programmatic management of latent tuberculosis infection in the European Union [Internet]. 2018 [cited 2019 Mar 2]. http://ecdc.europa.eu/en/publications-­data/ programmatic-­management-­latent-­tuberculosis-­infection-­european-­union.

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11. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-­ HIV infected persons. Cochrane Database Syst Rev 2000;(2):CD001363. 12. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of latent tuberculosis infection: an updated network meta-analysis. Ann Intern Med. 2017;167:248–55. 13. World Health Organization. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment [Internet]. https://www.who.int/publications-­detail/ who-­consolidated-­guidelines-­on-­tuberculosis-­module-­1-­prevention-­tuberculosis-­preventive-­ treatment. 14. Marks SM, Mase SR, Morris SB. Systematic review, meta-analysis, and cost-effectiveness of treatment of latent tuberculosis to reduce progression to multidrug-resistant tuberculosis. Clin Infect Dis. 2017;64:1670–7. 15. Knight GM, McQuaid CF, Dodd PJ, Houben RMGJ.  Global burden of latent multidrug-­ resistant tuberculosis: trends and estimates based on mathematical modelling. Lancet Infect Dis. 2019;19:903–12. 16. Ronald LA, Campbell JR, Rose C, Balshaw R, Romanowski K, Roth DZ, et al. Estimated impact of World Health Organization latent tuberculosis screening guidelines in a region with a low tuberculosis incidence: retrospective cohort study. Clin Infect Dis. 2019;69(12):2101–8. 17. Campbell JR, Johnston JC, Cook VJ, Sadatsafavi M, Elwood RK, Marra F. Cost-effectiveness of latent tuberculosis infection screening before immigration to low-incidence countries. Emerg Infect Dis. 2019;25:661–71. 18. Sanchini A, Andrés M, Fiebig L, Albrecht S, Hauer B, Haas W. Assessment of the use and need for an integrated molecular surveillance of tuberculosis: an online survey in Germany. BMC Public Health. 2019;19:321. 19. Kruijshaar ME, Abubakar I, Stagg HR, Pedrazzoli D, Lipman M. Migration and tuberculosis in the UK: targeting screening for latent infection to those at greatest risk of disease. Thorax. 2013;68:1172–4. 20. Kunst H, Burman M, Arnesen TM, Fiebig L, Hergens MP, Kalkouni O, et al. Tuberculosis and latent tuberculous infection screening of migrants in Europe: comparative analysis of policies, surveillance systems and results. Int J Tubercul Lung Dis. 2017;21:840–51. 21. Greenaway C, Pareek M, Abou Chakra C-N, Walji M, Makarenko I, Alabdulkarim B, et al. The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review. Euro Surveill. 2018;23(14):17-00543. 22. Public Health England. Collaborative tuberculosis strategy for England 2015 to 2020 [Internet]. 2015. https://www.gov.uk/government/publications/collaborative-­tuberculosis-­strategy-­for-­england.

8

Tuberculosis Infection Control Giovanni Battista Migliori and Grigory Volchenkov

Abstract

The present debate on multidrug-resistant tuberculosis (TB), and the evidence from existing hotspots, suggest that priority actions are necessary to prevent transmission, particularly in hospitals and other health care facilities as well as in congregate settings. This chapter describes the traditional infection control pillars (administrative, environmental controls and personal respiratory protection measures) and discusses the approaches to limit transmission. In particular, it describes the FAST (Find cases Actively by cough surveillance and rapid molecular sputum testing, Separate safely and Treat effectively based on rapid drug susceptibility testing) approach, and the importance to reduce unnecessary hospitalization. Based on recent evidence guidance is provided as to define the need and requirement for hospital admission and discharge. The chapter includes a ‘questions and answers’ section taking advantages from a recent consensus document of experts published by the WHO European Region. Furthermore, the chapter proposes an exercise for self-learning. Keywords

Tuberculosis · Infection control · Prevention · Administrative control · Environmental control · Personal respiratory protection · Workplace safety · Hospital admission criteria · Hospital discharge criteria

G. B. Migliori (*) Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy e-mail: [email protected] G. Volchenkov Vladimir Regional TB Control Center, Vladimir, Russian Federation © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_8

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G. B. Migliori and G. Volchenkov

Introduction

The effort of eliminating tuberculosis (TB) requires not only sterilizing the existing cases, but also breaking the chain of TB transmission through complex airborne infection control (IC) measures, including early diagnosis and prompt effective treatment of the existing TB cases. Furthermore, Latent TB Infection (LTBI) needs to be diagnosed and treated, as to prevent future cases of active TB to occur. While anti-TB treatment has a pivotal role, any effort needs to be ensured to limit transmission of as well as infection and re-infection with tubercle bacilli [1–5].

8.2

Background

The present debate on multidrug-resistant (MDR) TB, and the evidence from existing hotspots, suggest that priority actions are necessary to prevent transmission, particularly in hospitals and other health care facilities as well as in congregate settings. For example, in Former Soviet Union (FSU) countries transmission has been attributed mainly to ‘hyper-transmitters’ due to a combination of prolonged hospitalization, delayed diagnosis and treatment initiation of drug resistance/MDR-TB as well as inadequate ventilation [1–3, 6–9]. TB transmission is a probabilistic phenomenon, and several factors are involved including inhalation of multiple droplet nuclei containing viable M. tuberculosis, which need to reach the alveolar macrophages in the lung and overcome the immunological defences of the host [1–3].

8.3

Aim of the Chapter

The aims of this chapter are to describe the traditional pillars of IC: administrative, environmental controls and personal respiratory protection measures and discuss the approaches to limit transmission. In particular, it will describe the FAST (Find cases Actively by cough surveillance and rapid molecular sputum testing, Separate safely and Treat effectively based on rapid drug susceptibility testing—DST) approach, and the importance to reduce unnecessary hospitalization. Based on recent evidence guidance will be provided as to define the need and requirement for hospital admission. We took advantage of recent comprehensive reviews of the evidence [1–3], for which we updated the search to January 2020. TB infection has been traditionally called “latent TB infection (LTBI)”. This terminology has been used to define a state of persistent immune response to stimulation by M. tuberculosis antigens through tests such as the tuberculin skin test or an interferon gamma release assay (IGRA) without clinically active TB. This chapter uses the term LTBI throughout. However, this term may be progressively replaced by the simpler term “TB infection”. For this chapter the authors have decided for the time being to maintain the traditional terminology.

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Principles of IC

Traditionally the IC control pillars include administrative controls, environmental controls and personal respiratory protection [1–4]. Ideally, IC plans with these three elements should be developed in all health care facilities as part of a comprehensive national or sub-national plan to prevent airborne infections.

8.5

Administrative Controls

Administrative controls are policies and work practices to reduce the risk of exposure, infection and disease (Box 8.1).

8.6

Environmental Controls

Environmental controls are effective use of natural factors and/or equipment to reduce the concentration of infectious aerosol in areas where TB transmission is likely (Box 8.1). Ventilation, which can be natural, mechanical or mixed mode, is measured in ACH (air changes per hour, or the volume of fresh air supplied into the room in 1 h: ACH  =  Flowrate/Room Volume; the flowrate is measured in m3/h and the room volume in m3). Just to have an idea, with 12 ACH we need 23 min to reduce aerosol concentration of droplet nuclei by 99% in a room and 35 min to reduce concentration by 99.9% (meaning reduction of airborne infection transmission risk by 1000 times). With the previously recommended six ACH the time needed is the double. Natural ventilation (e.g. opening windows, or using exhaust stacks, roof turbines or other extractors) can be very effective in warm weather/climate settings but has limitations, especially since many buildings have not been specifically designed for this purpose: wind speed and direction are often unpredictable (as are temperature and humidity) and windows often cannot be left open (e.g. for security reasons, vermin or cold weather) [1–4]. Furthermore, the desirable outdoor waiting areas are usually not suitable in cold climates or are difficult to provide in urban settings. Although mechanical ventilation is more expensive to install, operate, and maintain, it is not subject to the variability typical of natural ventilation, which depends on prevailing winds, temperature and humidity. Other technical opportunities are represented by air cleaners (potentially effective but often underperforming) and URGUV (upper-room germicidal ultraviolet) recently demonstrated to be effective as complementary measures in different settings if adequately designed, built, installed and maintained [1–4, 10, 11]. According to the systematic review performed by the World Health Organization (WHO) [4] URGUV reduces the risk of LTBI by 8.8–14.8% (5 studies), while ventilation systems reduce it by 2.9–11.5% (10 studies). Room air cleaners theoretically can be effective in terms of infectious aerosol concentration reduction, but most of such marketed units have low capacity relative to health care facility areas volume and therefore are currently not recommended for high TB transmission risk health care settings.

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Box 8.1 World Health Organization Recommendations on the Core Infection Control Activities [from [4]] ADMINISTRATIVE CONTROLS Recommendation 1 Triage of people with TB signs and symptoms, or with TB disease, is recommended to reduce M. tuberculosis transmission to health workers (including community health workers), persons attending health care facilities or other persons in settings with a high risk of transmission. (Conditional recommendation based on very low certainty in the estimates of effects) Recommendation 2 Respiratory separation/isolation of people with presumed or demonstrated infectious TB is recommended to reduce M. tuberculosis transmission to health workers or other persons attending health care facilities. (Conditional recommendation based on very low certainty in the estimates of effects) Recommendation 3 Prompt initiation of effective TB treatment of people with TB disease is recommended to reduce M. tuberculosis transmission to health workers, persons attending health care facilities or other persons in settings with a high risk of transmission. (Strong recommendation based on very low certainty in the estimates of effects) Recommendation 4 Respiratory hygiene (including cough etiquette) in people with presumed or confirmed TB is recommended to reduce M. tuberculosis transmission to health workers, persons attending health care facilities or other persons in settings with a high risk of transmission. (Strong recommendation based on low certainty in the estimates of effects) ENVIRONMENTAL CONTROLS Recommendation 5 Upper-room germicidal ultraviolet (GUV) systems are recommended to reduce M. tuberculosis transmission to health workers, persons attending health care facilities or other persons in settings with a high risk of transmission. (Conditional recommendation based on moderate certainty in the estimates of effects) Recommendation 6 Ventilation systems (including natural, mixed mode, mechanical ventilation and recirculated air through high-efficiency particulate air [HEPA] filters) are recommended to reduce M. tuberculosis transmission to health workers, persons attending health care facilities or other persons in settings with a high risk of transmission. (Conditional recommendation based on very low certainty in the estimates of effects) RESPIRATORY PROTECTION Recommendation 7 Particulate respirators, within the framework of a respiratory protection programme, are recommended to reduce M. tuberculosis transmission to health workers, persons attending health care facilities or other persons in settings with a high risk of transmission. (Conditional recommendation based on very low certainty in the estimates of effects)

8.7

Personal Respiratory Protection

The aim of personal respiratory protection is to reduce exposures in personnel working in environments with contaminated air (Box 8.1) [1–5]. Surgical masks are indicated for patients, while certified respirators are indicated to protect staff and visitors from inhaling infectious droplet nuclei [1–5, 12].

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Surgical masks stop large particles from becoming infectious droplets at the source, as cough hygiene using a tissue or hand does. Respirators are intended for short-­ term use and cannot be worn continuously, e.g. when eating and sleeping. As face-­ seal leakage might hamper their effectiveness respirator fit testing is necessary to prevent it [1, 2, 13]. Developed for industrial purposes initially, respirators are classified according to the US or European norms (e.g. N95/FFP2 capture 95% of the infecting particles, adequate for clinical use) [1, 2]. They can be reused for a cumulative time of several hours until they are damaged or contaminated with blood or body fluids, they become wet or straps are stretched or break and breathing becomes difficult, as per device-specific instructions. According to the WHO systematic review [4], personal protection reduces the risk of LTBI by 4.3–14.8%.

8.8

Questions and Answers

A recent consensus document of experts from the WHO European Region [1, 2] identified a few core questions providing answers to them.

8.8.1 Who Is Infectious? There is clear evidence that the main sources of transmission (‘hyper-transmitters’) in hospitals are patients (or health staff) with undetected, untreated TB or patients with known TB, but unknown drug resistance (thus receiving ineffective therapy) [6–9]. The core problem is that most transmission control efforts focus on those patients with known TB (e.g. the majority being no more infectious as on effective therapy) while most transmission occurs elsewhere [6–9]. Until effective treatment is ensured, sputum smear microscopy positivity can be used to estimate infectiousness.

8.8.2 W  hat Is the Exposure Time Necessary to Generate Infection? It is not possible to establish a cut-off time or threshold (for example the ‘traditional’ 8 h contact) for infection as several factors contribute (e.g. source strength, dilution/ventilation, exposure time, virulence of the infectious agent and host susceptibility). The best approach available to establish infectiousness is the concentric circle approach to contact investigation [6–9, 14].

8.8.3 What Is the Effect of Treatment on Infectiousness? The studies by Gunnels, Loudon, Riley and Dharmadhikar [15–18] provide convincing evidence that patients with susceptible TB and MDR-TB undergoing effective treatment do not infect their contacts, regardless of smear or culture status, suggesting the rapid effect of adequate treatment on infectiousness. More caution is

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necessary for (pre)extensively drug-resistant TB (XDR-TB) cases until new evidence will be available on the effectiveness of new treatment regimens on patient infectiousness. Furthermore, the difficulty to know on real time the drug-resistance profile to prescribe an effective treatment is well known [1–3].

8.8.4 Which Patients Need Hospital Admission? A proportion of TB cases needs admission for medical reasons (including severe cases, life-threatening conditions, comorbidities, psychiatric problems, adverse drug reactions) or for social or logistical reasons [1, 2]. Effective treatment based on reliable drug susceptibility testing should be provided for all hospitalized patients. The WHO European document includes the following main criteria: 1. TB complications including, among others, respiratory failure and conditions requiring surgical interventions (e.g. haemorrhage, pneumothorax, pleural effusion). 2. Severe forms of disease such as TB meningitis and/or severe clinical manifestations due to comorbidities (e.g. liver disease, renal disease, uncontrolled diabetes). 3. Life-threatening conditions and serious medical events resulting due to adverse reactions to anti-TB drugs (e.g. severe arrhythmias, psychosis, renal failure, hearing loss). Additional criteria include those patients who cannot effectively and safely be treated at home or on out-patient basis (homeless, risk of exposure of young children or pregnant mothers, overcrowding conditions), with accessibility problems and specific non-adherence situations as the last based on the legal framework in force.

8.8.5 W  hich Are the Requirements for Hospitals Admitting Tuberculosis Patients? The same document [1, 2] suggests the following requirements: 1. Adequate number of trained staff with clinical expertise to manage MDR/ XDR-­TB and other difficult-to-treat cases, ensuring adequate supervision and treatment support. 2. Access to quality-controlled laboratory services. 3. Availability of respiratory isolation capacity and adequate infection control measures (including the WHO-recommended 12 ACH ventilation—natural or mechanical—or professionally installed and maintained URGUV and adequately implemented personal respiratory protection programme). 4. Open spaces allowing social activities for patients. 5. Patient-centred approach in place including psychological support, palliative care, link with home care and social services for the post-discharge home-­care phase.

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Approach to Solutions

Based on the principle that the ‘dangerous’ case of TB is the undetected (unknown/ undiagnosed) one, the FAST approach (rapid diagnosis and effective treatment tailored to drug-resistance profile with focus on undetected cases) has been proposed to reduce TB transmission [6–9].

8.10 The FAST Approach Health care workers must keep a high level of clinical suspicion when dealing with patients reporting signs and symptoms compatible with TB: ‘in primis’ cough since 2–3 weeks, (accompanied by general malaise, night sweats, fever, haemoptysis and weight loss). Bacteriological examinations (rapid diagnostic tests, sputum smear, sputum culture and DST to confirm TB and exclude MDR-TB) and chest radiography need to be promptly requested as to allow the patient to be prescribed an effective treatment regimen as soon as possible [6–9].

8.11 T  he Importance of Reducing Unnecessary Hospitalization The recent WHO European guidance document [1, 2] underlines that the reduction of unnecessary hospitalization goes directly into the direction of preventing TB transmission. Furthermore, a shift from hospital-based to home-care management models supports the WHO’s recommended patient’s centred approach. It is important to comment that this shift would be possible only when health systems will change their refunding schemes from ‘for-bed’ to ‘home-care based’ ones.

8.12 Exercises We propose two exercises, one focused at identifying the priority interventions for infection control and the other to help considering what changes can be proposed on a simple out-patient unit to improve infection control.

8.12.1 Exercise 1 The exercise is based on identification of priority infection control activities to be conducted in your own setting. Taking into account the specific problems and opportunities of your own country or region, fill-in the form (Table 8.1) proposing three prioritized activities for administrative controls, environmental controls and respiratory protection. You also look at Chap. 32 for further information on how to conduct National Strategic Planning.

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Table 8.1  Exercise 1. Based on your own setting, fill-in the form proposing three prioritized activities for administrative controls, environmental controls and respiratory protection. You also look at Chap. 33 for further information on how to conduct National Strategic Planning

How to Priority Description implement

When to implement

What Budget obstacles (short- and might you long-term) face?

Administrative controls Environmental controls Respiratory protection

WC

Supply room Door Way

Exam room

WC

Counc room

Exam room Waiting area

Store

Ramp Elevator

Elevator

Fig. 8.1  Exercise 2. You have been asked to propose how to implement simple measures to improve infection control in this simple out-patient TB clinic in a rural African setting. You should describe the changes needed (see text for details)

8.12.2 Exercise 2 The map proposed for this exercise (Fig. 8.1) shows a TB/human immunodeficiency virus (HIV) out-patient clinic in a rural African setting. This clinic offers several opportunities for discussion. Which is, in your opinion, the flow of patients in this clinic? Is there significant risk of TB transmission with the present organization of the clinic?

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Any main problem noticed? Possible solutions to recommend? What climate is there, warm, humid, windy? What areas are near this department? This is a tropical disease clinic. What happens to the air? What administrative controls should be in place? These are just some of the questions that you are usually asked during facility assessment. Please, look at potential solutions. What administrative controls should be recommended? What environmental controls should be recommended? What respiratory protection measures should be implemented?

8.13 Main Conclusions and Recommendations The availability of a sound infection control plan, both at national/sub-national and facility level, is of paramount importance in reducing transmission of TB as well as of other respiratory diseases. This chapter provides rapid guidance on the core principles of infection control, on how to promote the FAST approach and on how to reduce unnecessary hospitalization. The ‘questions and answers’ section provides rapid reference to the evidence available so far.

References 1. Migliori GB, D’Ambrosio L, Centis R, van den Boom MV, Ehsani S, Dara M.  Guiding principles to reduce tuberculosis transmission in the WHO European Region. World Health Organization Regional Office for Europe: Denmark; 2018. 2. Migliori GB, Nardell E, Yedilbayev A, D’Ambrosio L, Centis R, Tadolini M, van den Boom M, Ehsani S, Sotgiu G, Dara M. Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe. Eur Respir J. 2019;53(6). pii: 1900391. https://doi.org/10.1183/13993003.00391-­2019 3. Nardell E, Volchenkov G.  Transmission control: a refocused approach. In: Migliori GB, Bothamley G, Duarte R, Rendon A, editors. Tuberculosis (ERS monograph). Sheffield: European Respiratory Society; 2018. p. 364–80. 4. World Health Organization. WHO guidelines on tuberculosis infection prevention and control, 2019 update. WHO/CDS/TB/2019.1 Geneva: World Health Organization; 2019. https:// apps.who.int/iris/bitstream/handle/10665/311259/9789241550512-­eng.pdf?ua=1&ua=1. Last accessed 5 Mar 2020. 5. Jensen PA, Lambert LA, Iademarco MF, Ridzon R, Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep. 2005;54(RR-17):1–141. 6. Gelmanova IY, Keshavjee S, Golubchikova VT, Berezina VI, Strelis AK, Yanova GV, et  al. Barriers to successful tuberculosis treatment in Tomsk, Russian Federation: non-­ adherence, default and the acquisition of multidrug resistance. Bull World Health Organ. 2007;85(9):703–11. 7. van Cutsem G, Isaakidis P, Farley J, Nardell E, Volchenkov G, Cox H.  Infection control for drug-resistant tuberculosis: early diagnosis and treatment is the key. Clin Infect Dis. 2016;62(Suppl 3):S238–43. 8. Yuen CM, Amanullah F, Dharmadhikari A, Nardell EA, Seddon JA, Vasilyeva I, et al. Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet. 2015;386(10010):2334–43.

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9. Barrera E, Livchits V, Nardell E. F-A-S-T: a refocused, intensified, administrative tuberculosis transmission control strategy. Int J Tuberc Lung Dis. 2015;19(4):381–4. 10. Nardell EA. Indoor environmental control of tuberculosis and other airborne infections. Indoor Air. 2016;26(1):79–87. 11. Vincent RL. Maintenance of upper-room germicidal ultraviolet (GUV) air disinfection systems for TB transmission control. End TB transmission initiative (ETTi). 2017. http://www. stoptb.org/wg/ett/assets/documents/MaintenanceManual.pdf. Last accessed 5 Mar 2020. 12. Personal respiratory protection. Technical information sheet. End TB transmission initiative (ETTi). 2019. http://www.stoptb.org/wg/ett/assets/documents/ETTI_InfoSheet_Respirators_ Final.pdf. Last accessed 5 Mar 2020. 13. Respirator fit testing. Technical information sheet. End TB transmission initiative (ETTi). 2019. http://www.stoptb.org/wg/ett/assets/documents/ETTI_InfoSheet_FitTesting_Final.pdf. Last accessed 5 Mar 2020. 14. Veen J.  Microepidemics of tuberculosis: the stone-in-the-pond principle. Tuberc Lung Dis. 1992;73(2):73–6. 15. Gunnels JJ, Bates JH, Swindoll H. Infectivity of sputum-positive tuberculous patients on chemotherapy. Am Rev Respir Dis. 1974;109(3):323–30. 16. Loudon RG, Bumgarner LR, Lacy J, Coffman GK. Aerial transmission of mycobacteria. Am Rev Respir Dis. 1969;100(2):165–71. 17. Riley RL. The contagiosity of tuberculosis. Schweiz Med Wochenschr. 1983;113(3):75–9. 18. Dharmadhikari AS, Mphahlele M, Venter K, Stoltz A, Mathebula R, Masotla T, et al. Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2014;18(9):1019–25.

Part III Diagnosis

9

Tuberculosis Clinical Presentation and Differential Diagnosis Kavina Manalan, Jessica Barrett, and Onn Min Kon

Abstract

Active tuberculosis (TB) disease presents with a variety of symptoms and signs. Mycobacterium tuberculosis (MTB) can affect multiple organs; within this chapter we review common symptoms and signs of active TB in the lung and extra-pulmonary sites. The sites of disease explored include: pulmonary infections, lymph node disease and central nervous system disease amongst others. Possible differential diagnoses to be considered are discussed within each organ, though often there may be overlap in the clinical presentations. Individuals may have localised presentations for example with abdominal or musculoskeletal disease with or without constitutional symptoms. Sometimes localised TB may precede systemic infection or be the only manifestation of active disease, for example ocular and cutaneous TB, and the spectrum of clinical manifestations are described which should prompt a clinician to investigate further. Atypical infection in those with underlying immunosuppression is also explored within this chapter. Keywords

Pulmonary tuberculosis · Extra-pulmonary tuberculosis · Signs · Symptoms · Localised · Systemic

K. Manalan Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK e-mail: [email protected] J. Barrett Imperial College London, London, UK e-mail: [email protected] O. M. Kon (*) Imperial College Healthcare NHS Trust, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_9

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Introduction to the Issue

Active tuberculosis (TB) disease presents with a variety of symptoms and signs. It is important to maintain a high clinical suspicion for TB not only in those with a known recent exposure, history of immunosuppression or from a high incidence country, but also in those with less typical risk profiles. Importantly Mycobacterium tuberculosis (MTB) can affect multiple organs and is capable of causing extra-pulmonary tuberculosis (EPTB) disease.

9.2

Background

It is estimated that 5–10% of individuals with latent TB infection will develop active TB and individuals may develop symptoms a substantial time after the initial infection. The most common site of TB disease is the lung but there can be a high percentage of extra-pulmonary involvement, more prevalent in women [1], ranging from 8% in the Western Pacific to 24% in the Eastern Mediterranean [2]. The clinical presentation and clinical signs are dependent on the site of infection and may cause organ specific symptoms (for example cough) or generalised, non-specific symptoms such as fever and weight loss. The less common manifestations of TB such as erythema induratum or ocular TB can be extremely challenging in the setting of paucibacillary disease.

9.3

Aims

In this chapter, we review the common symptoms and signs of active TB in the lung and extra-pulmonary sites. As a patient may present with generalised symptoms or multisystem involvement, there may be some clinical overlap. We also discuss the differential diagnoses to consider when patients present with particular clinical presentations.

9.3.1 Pulmonary The lungs are the most common site of tuberculosis disease. Pulmonary TB typically presents with a productive cough or haemoptysis, if a pulmonary vessel has been damaged by cavitation. Systemic features such as weight loss, anorexia, night sweats, fever and malaise are common [3]. Breathlessness is not a common presentation unless TB infection is advanced, or a large pleural or pericardial effusion has developed. It is worth noting that in the early stages of disease, symptoms may be absent as shown by active case finding studies in Asia [4]. Pleural disease or infection abutting the pleura may cause pleuritic pain. Tuberculous pleural effusion occurs in approximately 5% of patients with MTB infection [5].

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Even extensive pulmonary disease may present with no abnormal clinical signs; however, crepitations, wheeze or bronchial breathing may be heard, most often affecting the upper lobe. Pleural and pericardial effusions are usually slow to accumulate but can result in respiratory or haemodynamic compromise due to lung collapse or cardiac tamponade. Clinical signs associated with a pleural effusion are reduced breath sounds and ‘stony’ dullness on percussion. Cardiac tamponade can be demonstrated clinically by assessing Beck’s triad (sinus tachycardia, elevated jugular venous pressure and low blood pressure) and pulsus paradoxus. TB pericarditis is a rare manifestation and if present is characterised by symptoms of chest pain, cough and dyspnoea and clinical findings include tachycardia and a pericardial rub. Cachexia is also a recognised presentation. The classical presentation of pulmonary tuberculosis with haemoptysis and weight loss can easily be confused with lung cancer. Other differentials include bacterial pneumonia, particularly with cavitating pathogens such as Klebsiella pneumoniae, Staphylococcus aureus and other non-tuberculous mycobacterial infections. Bacterial pneumonia may present more acutely and fever is often present. In patients with other risk factors, e.g. coma or alcohol excess, cavities associated with aspiration pneumonia may be seen radiologically. These cavities tend to be thick walled and may have an air fluid level. In endemic countries of hydatid disease, lung involvement with hydatid disease can cause chronic cough with haemoptysis and cysts may mimic TB cavities. Non-infectious differentials of TB include sarcoidosis or silicosis. Tuberculosis of the larynx, due to direct spread of MTB, is a rare form of tuberculosis. Patients may present with hoarseness of voice, dysphagia or other non-specific constitutional symptoms like fever or localised pain.

9.3.2 Lymph Node Lymph nodes are the second commonest site of infection. Peripheral infection presents with an enlarged node, often in the cervical region, historically known as scrofula. Lymph nodes may be small and firm early in infection, but as they increase in size the central regions necrose, neighbouring nodes coalesce, and the mass will become fluctuant. There may be overlying erythema, warmth and tenderness and may fistulate through the skin if left untreated. Intrathoracic lymphadenopathy is not infrequently an incidental finding on imaging. If the nodes are large enough, they may cause symptoms by pressing on adjacent structures. If an airway is significantly obstructed a monophonic wheeze may be heard, or signs of lobar collapse may be found. Cervical adenopathy is commonly reactive, but lymphoma is an important differential to consider. Viral causes of cervical lymphadenopathy include adenovirus, herpesvirus, coxsackievirus and cytomegalovirus. Other, rarer infective causes are brucellosis, Bartonella henselae, Coxiella burnetii (Q-fever) and fungi such as

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Cryptococcus neoformans. Some autoimmune conditions may present with lymphadenopathy including systemic lupus erythematosus or dermatomyositis. Kikuchi disease is a benign condition which causes lymphadenopathy, fever and night sweats, but it is usually self-limiting. Mediastinal lymphadenopathy may be caused by primary lung cancer and is a common site of metastases of oesophageal, breast and thyroid malignancies.

9.3.3 Abdominal Abdominal tuberculosis can present in a number of ways which may confuse and delay the diagnosis. Isolated lymphadenopathy may be an incidental finding, or cause symptoms via mass effect. Luminal TB most frequently involves the ileocaecal region and presents variably with right iliac fossa pain, abdominal distension, altered bowel habit and signs of a mass or subacute obstruction. TB hepatitis is often asymptomatic and only identified by abnormal liver enzyme tests. TB peritonitis is characterised most commonly by abdominal pain, fever and weight loss. Other gastrointestinal manifestations of abdominal tuberculosis include ascites, hepatomegaly and splenomegaly. The differential diagnosis of ileal and caecal disease includes Crohn’s disease, appendicitis and bowel malignancy. Presentation with ascites and abdominal adenopathy may be confused with ovarian malignancy or lymphoma.

9.3.4 Central Nervous System TB meningitis (TBM) typically has a more indolent presentation than bacterial meningitis, although the symptoms may worsen rapidly. A slowly worsening headache may be accompanied by symptoms of raised intracranial pressure such as blurred vision, confusion and vomiting. The other features typically associated with more acute forms of meningitis such as photophobia and neck stiffness may be absent. As tuberculosis usually causes a basal meningitis, cranial nerves may be damaged, most commonly the abducens and oculomotor and facial nerves, causing ophthalmoplegia and facial palsies. Differential diagnoses include pyogenic meningitis, leptomeningeal carcinomatosis, fungal meningitis and neurosarcoidosis. Intracranial tuberculomas can be associated with TBM. They present with single or multiple lesions and can present similarly to space occupying lesions. They may present with seizures, focal neurological signs or raised intracranial pressure due to obstruction of cerebrospinal fluid pathways. The radiological differentials for a single tuberculoma include cysticercosis or toxoplasmosis. Intracranial tuberculous abscesses present similarly, and are an uncommon manifestation of central nervous system (CNS) tuberculosis mainly seen in immunocompromised individuals. Radiological differentials of a tuberculous abscess include other pyogenic cerebral abscesses.

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9.3.5 Musculoskeletal Spinal tuberculosis, the most common site of bony TB, causes pain and tenderness at the site of infection. It may progress to a kyphotic deformity known as a Pott’s disease, radiculopathy, spinal cord compression or cauda equina syndrome, if left untreated. Symptoms may take many weeks to develop, and it is common for several levels of the spine to be involved. Local spread of a paraspinal abscess results in psoas involvement which typically causes pain on hip flexion. Whilst there are radiological features commonly found with spinal tuberculosis, it may be difficult to differentiate this from bacterial discitis or metastatic malignancy. One important differential in some parts of the world is brucellosis which may present in a very similar manner to TB. Extra-axial skeletal TB can affect any joint or long bone metaphysis, and presents with swelling, pain, and signs of an effusion if affecting a joint. Again, the course is usually indolent but may be confused with septic arthritis caused by other pathogens, or a crystal arthropathy. Poncet’s disease, associated with extra-pulmonary infection, is a reactive polyarthritis associated with tuberculosis. It is a rare para-infective manifestation of the immunopathogenic effects of tuberculosis and most commonly affects knees, ankles and wrists. It is not associated with chronic arthritis sequelae.

9.3.6 Genitourinary Genitourinary tuberculosis is frequently asymptomatic and diagnosed following the investigation of ‘sterile’ pyuria, but may present with frequency, haematuria, or in advanced cases obstruction. Signs and symptoms are determined by the anatomical structures involved, so presentation in men may be with prostatitis or epididymo-­ orchitis and in women with endometritis or mimicking pelvic inflammatory disease. Other differentials of sterile pyuria and haematuria include sexually transmitted infections, schistosomiasis and urinary tract malignancy.

9.3.7 Cutaneous Cutaneous manifestations of TB are rare (1%) [6]. Scrofuloderma is the breakdown and ulceration of skin overlying tuberculous lymphadenitis and often indicates systemic TB infection. Lupus vulgaris usually presents as thickened, keratotic plaques, which can ulcerate, and is most common amongst children. The ulceration can be severe, resulting in destruction of underlying tissue such as nasal cartilage. Erythema nodosum is the commonest cutaneous manifestation of tuberculosis, usually in the pretibial areas, and may precede the development of overt signs of infection by months or years. Erythema induratum (nodular vasculitis or Bazin’s disease) is a related but distinctly different pattern of the subcutaneous fat with painful, indurated but sometimes ulcerated lesions in the lower limbs.

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9.3.8 Ocular Tuberculosis Ocular TB may precede symptomatic evidence of systemic TB.  The phenotypic variations associated with TB include serpiginous-like choroiditis (46%), tuberculoma (13.5%), multifocal choroiditis (9.4%) and ampiginous choroiditis (9%) [7]. Tuberculous uveitis should be considered in the differential diagnosis of any type of intraocular inflammation when there are epidemiological risk factors.

9.3.9 Miliary Tuberculosis Miliary TB, which usually presents subacutely, results from hematogenous spread of MTB. Acute miliary TB may be fulminant and cause multiorgan system failure, whilst chronic disease may present with failure to thrive or pyrexia of unknown origin. Differential diagnoses may be formulated based on the typical miliary pattern seen on chest radiography; other conditions with bilateral nodular shadowing include sarcoidosis, histoplasmosis, pneumoconiosis, bronchoalveolar carcinoma, pulmonary siderosis and haematogenous spread of other malignancies. Miliary TB can cause cutaneous manifestations of small (millet-­sized) erythematous lesions that develop into ulcers and abscesses.

9.3.10 Immune-Suppression Whilst TB in immune-suppression may present with typical symptoms, this is not always the case. Immunosuppression increases the risk of reactivation of prior infection with MTB leading to TB disease. Systemic symptoms may be more prominent, and dissemination is more common though the degree of underlying immunosuppression should be taken into consideration. The clinical presentation and course of active TB in human immunodeficiency virus (HIV)infected individuals may be altered, particularly in those with advanced immunosuppression (CD4 counts 95% SP: >95%

Reference lab RIF—SE: 98.4% SP: 100% INH—SE: 88.5.9% SP: 98% EMB—SE: 64.3% SP: 95.5% OFL—SE: 100% SP:91.8% MOX—SE: 95.8% SP: 81.3% AMK—SE: 96.3% SP: 100% KAN—SE: 96.8% SP: 98.8% MTBC detection and/or genotypic DST: molecular methods Determine TB LAM Immunoassay Community CD4 count (Alere) Detection of MTBC ≤100—SE: 54% SP: 88% CD4 count >100—SE: 17% SP: 95% CD4 count ≤200—SE: 45% SP: 89% CD4 count >200—SE: 16% SP: 94% (continued)

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Table 10.1 (continued) Laboratory level Community

Test SILVAMP TB LAM

Type Immunoassay Detection of MTBC

TB-LAMP

Loop-mediated isothermal amplification Detection of MTBC

Sub-district lab

Xpert MTB/RIF

PCR Detection of MTBC + rifampicin

District/ sub-district lab

Xpert ultra

PCR Detection of MTBC + rifampicin

District/ sub-district lab

Truenat MTB/MTB plus PCR Detection of MTBC Truenat MTB-Rif dx

PCR Detection of rifampicin

GenoType MTBDRplus PCR LPA Detection of MTBC + rifampicin/isoniazid NTM + MDRTB

PCR LPA Detection of MTBC + NMT + rifampicin/isoniazid

GenoType MTBDRsl

PCR LPA Detection of MTBC + fluoroquinolones/SLIDs

Accuracy CD4 count ≤100—SE: 84.2% SP: 85% CD4 count 101–200—SE: 60.6% SP: 89.6% CD4 count >200—SE: 44% SP: 97% Pulmonary TB—Replacement for SSM SE: 77.7% SP: 98.1% Pulmonary TB—SE: 85% SP: 98% RIF—SE: 96% SP: 98% Pulmonary TB—SE: 88% SP: 96% RIF—SE: 95% SP: 98% Pulmonary TB—SE: 73–80% SP: 96–98% RIF—SE: 84% SP: 97%

District/ sub-district lab District/ sub-district lab Reference lab Sputum specimens RIF—SE: 95.8% SP: 98.4% INH—SE: 94.5% SP: 99.3% Reference lab Sputum specimens RIF—SE: 96.5% SP: 97.5% INH—SE: 94.9% SP: 97.6% Reference lab Sputum specimens FLQs—SE: 86.2% SP: 98.6% SLID—SE: 87% SP: 99.5% XDR-TB—SE: 69.4% SP: 99.4%

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Table 10.1 (continued) Type Test Genoscholar PZA-TB II PCR LPA assay Detection of MTBC + pyrazinamide Abbott RealTime MTB PCR Detection of MTBC + and MTB RIF/INH rifampicin/isoniazid assays, Roche cobas® MTB and PCR MTBRIF/INH assays Detection of MTBC + rifampicin/isoniazid Hain FluoroType® MTBDR assay

PCR Detection of MTBC + rifampicin/isoniazid

BD MAX™ MDR-TB assay

PCR Detection of MTBC + rifampicin/isoniazid

Laboratory level Accuracy Reference lab SE: 93.2%–94.3% SP: 91.2–94.9% Reference lab SE: 71.7%–96.7% SP: 97–100% Reference lab RIF—SE: 97.2% SP: 98.6% INH—SE: 96.9% SP: 99.4% Reference lab RIF—SE: 98.9% SP: 100% INH—SE: 91.7% SP: 100% Reference lab RIF—SE: 90% SP: 95% INH—SE: 82% SP: 100%

PCR polymerase chain reaction, LPA line probe assays, SLID second-line injectable drugs, SE sensitivity, SP specificity, DST drug susceptibility testing, RIF rifampicin, INH isoniazid, EMB ethambutol, OFLO ofloxacin, MOX moxifloxacin, AMK amikacin, KAN kanamycin, SSM sputum smear microscopy, FLQ fluoroquinolone, XDR extensively drug-resistant

10.3.2 Culture Methods Culture is the gold standard test for diagnosis of TB. It has at least 100-folds more sensitive than microscopy but requires long times due to the slow growth of Mycobacterium tuberculosis. As the large majority of clinical samples are not sterile, the rapid overgrowth of the contaminating flora can make impossible the isolation of mycobacteria in culture. Various approaches have been proposed to contrast the contaminations; the most widely used is a mixture of a mucolytic agent, N-acetylcysteine, and 2% NaOH, which is bactericidal. When carefully used it allows to keep the contamination rate below 5%; a contamination rate 5% may indicate a risk of missing positive cultures. For culture of Mycobacterium tuberculosis, both solid and liquid media are available. The egg-based Löwenstein–Jensen is the most popular solid medium within a number of egg- and agar-based media available. The Mycobacteria Growth Indicator Tube (MGIT) Becton Dickinson is the liquid medium monopolizing the market in the last years. The tubes containing Middlebrook 7H9 broth are supplemented with an antimicrobial blend to contrast contaminations by Gram-positive and -negative bacteria and by yeast as well. The growth in the MGIT tube is detected by the fluorescence of an indicator revealing the oxygen consumption produced by

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mycobacterial growth. A fully automatic machine is used for the incubation of tubes and the detection of positive cultures, BACTEC MGIT 960 system. Liquid media are more sensitive and positivize earlier than solid media; however, to maximize the yield, the culture in parallel in solid and liquid media is recommended. Identification of Mycobacteria can be performed by molecular methods (in this case all mycobacteria can be identified) or by fast immunochromatographic assays targeting TB specific antigens.

10.3.3 Rapid Molecular Methods for Tuberculosis Detection The Xpert MTB/RIF (Cepheid) and the newly developed Xpert MTB/RIF Ultra [2], is a fully automated real-time PCR method for detection of M. tuberculosis and rifampicin resistance directly from clinical specimens. A main improvement of the Ultra version is the enhancement of sensitivity due to the addition to rpoB of other genetic targets (multicopy insertion elements IS6110 and IS1081) supported by the introduction of a new semiquantitative category (trace) to indicate the detection of at least one of the multicopy targets with cycle thresholds (Cts) less than 37 cycles concomitantly with at least two rpoB probes with Cts less than 40 cycles. This was however associated with a reduction of specificity that led the World Health Organization (WHO) to suggest the repetition, on a new sample, of the tests scoring trace and to report positivity only in case of confirmation [3]. Only in people living with human immunodeficiency virus (HIV), in children and on extrapulmonary specimens a single trace call is suggested to be considered a true positive. Additional methods recently evaluated include the Molbio Truenat MTB, MTB Plus for TB detection compatible with a close to point of need diagnosis and several high throughput platforms more appropriate for centralized laboratories running a large number of samples [4]. The Truenat MTB and MTB Plus assays showed a diagnostic performance comparable to the TB-LAMP, Xpert MTB/RIF, and Xpert Ultra for the detection of active TB. In 2020, the WHO issued a policy guideline recommending the use of Truenat MTB and MTB Plus assays as initial test for TB. A commercial molecular assay Loopamp MTBC Detection Kit based on loop-­ mediated isothermal amplification developed by Eiken Chemical Company Ltd. was endorsed by WHO in 2016 as a replacement for smear microscopy in adults and children with signs and symptoms of TB for the detection of Mycobacterium tuberculosis complex (TB-LAMP). The assay can be implemented at peripheral level and leads to a result in less than 1  h through a specific nucleic acid amplification of MTBC. The lateral flow urine lipoarabinomannan (LAM) assay from Alere, LF-LAM, allows the detection of LAM antigen released in the urine of people with active TB disease. WHO recommend its use in HIV positive TB presumptive patients with a CD4 count of 60 ms from baseline) has also been reported during clofazimine use in a small study (6.7%) and case reports [11].

13.3.9  Cycloserine/Terizidone Cycloserine and its structural analogue terizidone are poorly tolerated in most patients across diverse ethnicities. On average, about 9.1% of patients treated with cycloserine experience treatment discontinuation due to adverse effects, with some studies reporting up to 20–30% of patients with treatment cessation. Psychiatric adverse effects including psychosis, depression, and suicidal ideations are most commonly observed in 5.7% of patients, and central nervous system related adverse effects such as seizure and peripheral neuropathy are reported in 1.1% of patients [12]. Frequency of adverse effects is reported to be similar between cycloserine and terizidone, although data is very limited. These adverse effects are generally dose-related, and reversible upon cessation of the drug. The exception to this is severe peripheral neuropathy, which may not fully resolve. High-dose pyridoxine (not exceeding 75 mg daily) may have a protective effect and is usually co-prescribed.

13.3.10  Meropenem/Imipenem Meropenem and imipenem are generally well tolerated. Most common adverse effects are mild and include diarrhea (2.5%), skin rash (1.4%), and nausea/vomiting (1.2%). Prolonged intravenous use can be associated with injection site inflammation in 1.1% of patients. In pediatric patients, adverse effects were more frequently observed with meropenem compared with imipenem/cilastatin.

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13.3.11  Delamanid Prolongation of QTc interval is a recognized adverse effect of delamanid, reported in about 9.9–13.1% of patients at a dose of 100 or 200 mg twice daily [13]. The main metabolite DM-6705 contributes to QTc prolongation, despite its lack of antimycobacterial activity. Hypoalbuminemia is correlated with increased risk of QTc prolongation, as albumin is involved in the regulation of DM-6705. Delamanid is contraindicated in patients with albumin  500 ms. Replacing moxifloxacin with levofloxacin may be considered to reduce QTc prolongation in delamanid-based regimens also containing bedaquiline or clofazimine. If delamanid is to be used concomitantly with bedaquiline, baseline QTc should not exceed 450 ms due to the increased risk of cardiotoxicity, although more prospective data are required for the long-term safety of their combination [14].

13.3.12  Prothionamide/Ethionamide A common adverse drug reaction of ethionamide and prothionamide is gastrointestinal intolerance (25.6–33.5%), including nausea, vomiting, diarrhea, and abdominal discomfort, especially at daily doses greater than 750 mg. There is a suggestion that ethionamide is slightly better tolerated than prothionamide. The gastrointestinal intolerance may be severe enough to interfere with absorption of concomitant anti­TB drugs. Dividing the dose (250 mg three times daily) or pre-medication with an antiemetic such as ondansetron (4–8 mg) may provide a benefit. Endocrine effect such as hypothyroidism occurs in 20% of patients and requires thyroid hormone supplementation during treatment.

13.3.13  Amikacin/Streptomycin Amikacin and streptomycin are associated with ototoxicity, which is potentially severe and irreversible. Risk increases with cumulative dose, duration, and age. Hearing loss occurs in up to 39% of patients and vestibular toxicity in 14% of patients. Nephrotoxicity occurs in 5–15% of patients and is usually reversible, although it has led to chronic kidney failure. Risk increases with older age, dehydration, and previous exposure to the drug. Electrolyte disturbances may also be observed due to renal tubular excretion of potassium, calcium, and magnesium.

13.3.14  p-Aminosalicylic Acid Gastrointestinal intolerance due to p-aminosalicylic acid (PAS) includes symptoms of nausea, vomiting, bloating, abdominal pain, and diarrhea. Severe symptoms occur in about 4% of patients, requiring treatment interruption. Improvement with diarrhea often occurs after several weeks, and nausea and vomiting can sometimes

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Box 13.1. Management of Adverse Effects of First-Line Anti-TB Drugs Isoniazid, rifampicin, pyrazinamide-induced hepatotoxicity • Isoniazid, rifampicin, and pyrazinamide should be ceased when ALT ≥3 x ULN with symptoms or ALT ≥5 x ULN without symptoms • Rechallenge can be considered in a sequential manner, once ALT 500 ms, these drugs should be ceased •  Moxifloxacin can be replaced by levofloxacin to reduce the risk Linezolid induced polyneuropathy and optic neuritis •  Prompt cessation of linezolid is required if complaints related to PNP are reported •  If an electromyography shows no linezolid induced polyneuropathy, and if possible, linezolid can be restarted at a lower dose • Prompt and permanent cessation of linezolid is required if visual abnormalities are detected Psychiatric adverse effects due to cycloserine or terizidone • Prompt and permanent cessation of cycloserine/terizidone is required when symptoms of psychosis, depression, and suicidal ideations are observed

be managed with antiemetic drugs. Concurrent PAS and ethionamide are poorly tolerated. Hypothyroidism may occur in up to 40% of patients but thyroid function generally returns to normal upon drug cessation.

13.4 Main Conclusions and Recommendations Adverse drug reactions are common during drug susceptible as well as drug resistant TB treatment. Baseline assessment of risk factors and monitoring during treatment (see Chap. 18) are important to prevent adverse drug reactions and treatment interruption.

128 Ear (10 -40%) Drugs: aminoglycosides

Heart ( 3 –13.1%) Drugs: clofazimine, bedaquiline, fluoroquinolones, delamanid

Gastrointestinal tract (1.2 -50%) Drugs: carbapenems, linezolid, prothionamide/ethionamide, PAS, clofazimine

H. Y. Kim et al. Central nervous system (5.7%) Drugs: cycloserine/terizidone,

Eye (2-13.2%) Drugs: ethambutol, linezolid

Liver (1.6 -5%) Drugs: isoniazid, rifampicin, pyrazinamide, bedaquiline,

Blood (11.8 -38.1%) Drugs: linezolid Kidney (5 -15%) Drugs: aminoglycosides

Peripheral nervous system (1.1 –47.1%) Drugs: cycloserine/terizidone, isoniazid, linezolid,

Skin (1.4 -100%) Drugs: carbapenems, cycloserine/terizidone, clofazimine

Fig. 13.1  Overview of adverse drug effect by organ/system

As many drugs have overlapping toxicity profiles (see Fig.  13.1) which may aggravate the severity of the adverse drug reaction, prompt response is required when toxicity is observed. Recommendations on severe and frequently occurring adverse drug reactions are summarized below. • Hepatotoxicity. • Alcohol and concomittant use of other hepatotoxic drugs should be avoided to minimize the risk of elevated AST/ALT/bilirubin. When drug-induced hepatotoxicity is encountered, other causes such as viral hepatitis, biliary disease, or alcohol-induced liver disease should be ruled out and potential causative drugs should be stopped. • Peripheral neuropathy. • Patients with alcohol dependence, diabetes, and human immunodeficiency virus (HIV) have an increased risk for peripheral neuropathy. Prophylactic pyridoxine (vitamin B6) to prevent peripheral neuropathy in addition to early detection and supplementation of pyridoxine may lead to improvement or resolution of symptoms and occassionally allow drug to be continued. • QTc prolongation. • In addition to baseline QTc assessement, combined use of anti-TB drugs known to cause QTc prolongation such as bedaquiline, clofazimine, delamanid, or fluoroquinolones requires regular and more frequent electrocardiogram (ECG) monitoring (e.g., at 2, 4, 8, 12, and 24 weeks), especially if on bedaquiline+delamanid or >3 QTc-­prolonging drugs [15]. Patients should also be asked to report any symptoms

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of palpitations or episodes of syncope. Any prolongation of QT interval (QTc >500 ms) should prompt a thorough investigation including correcting for electrolytes imbalances (potassium, magnesium) or severe anemia, and suspension of some QTc-prolonging medications (consider non-TB drugs first, then short-­acting TB drugs).

References 1. Guidelines for treatment of drug-susceptible tuberculosis and patient care (2017 update). Geneva: World Health Organization (WHO); 2017. 2. WHO Guidelines Approved by the Guidelines Review Committee. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization (WHO); 2019. 3. Borisov S, Danila E, Maryandyshev A, Dalcolmo M, Miliauskas S, Kuksa L, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report. Eur Respir J. 2019;54(6):1901522. 4. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et  al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–52. 5. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et  al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–e95. 6. Ezer N, Benedetti A, Darvish-Zargar M, Menzies D.  Incidence of ethambutol-related visual impairment during treatment of active tuberculosis. Int J Tuberculosis Lung Dis. 2013;17(4):447–55. 7. Gorelik E, Masarwa R, Perlman A, Rotshild V, Abbasi M, Muszkat M, et al. Fluoroquinolones and cardiovascular risk: a systematic review, meta-analysis and network meta-analysis. Drug Saf. 2019;42(4):529–38. 8. Khan F, Ismail M, Khan Q, Ali Z. Moxifloxacin-induced QT interval prolongation and torsades de pointes: a narrative review. Expert Opin Drug Saf. 2018;17(10):1029–39. 9. Pontali E, Sotgiu G, Tiberi S, D’Ambrosio L, Centis R, Migliori GB. Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. Eur Respir J. 2017;50(5). pii: 1701462. 10. Sotgiu G, Centis R, D’Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40(6):1430–42. 11. Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, et al. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med. 2015;191(8):943–53. 12. Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. Int J Tuberc Lung Dis. 2013;17(10):1257–66. 13. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et  al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366(23):2151–60. 14. Olayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis. Eur Respir J. 2020;55(1). pii: 1901181. 15. Monedero-Recuero I, Hernando-Marrupe L, Sanchez-Montalva A, Cox V, Tommasi M, Furin J, et al. QTc and anti-tuberculosis drugs: a perfect storm or a tempest in a teacup? Review of evidence and a risk assessment. Int J Tuberc Lung Dis. 2018;22(11):1411–21.

Treatment of Drug-Susceptible Tuberculosis

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Marcela Munoz-Torrico, Norma Téllez-Navarrete, Heinke Kunst, and Nguyen Nhat Linh

Abstract

The main goals of this chapter are to establish tuberculosis (TB) treatment goals, how and when to start anti-TB treatment, discuss the recommended regimens for drug sensitive TB. Establish recommended doses of the primary regimen, and finally recommended treatment adjustment in special situations. Effective and on time tuberculosis treatment is essential for TB control, as it stops the spread of the disease in the community, and reduces the risk of death. All TB regimens should include the combination of bactericidal and sterilizing drugs to prevent the development of resistance and to avoid relapse. The most widely studied and recommended regimen for drug-susceptible TB cases is the 4-drug regimen [Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E)]. In this chapter, recommendations regarding drug sensitive TB regimens are described, including recommendations about dosage, duration of treatent, and treatment on special situations. Keywords

Tuberculosis · Drug therapy · Antitubercular Agents The author (N.N.L.) is a staff member of the World Health Organization. The author alone is responsible for the views expressed in this publication and they do not necessarily represent the views, decisions or policies of the World Health Organization. M. Munoz-Torrico (*) · N. Téllez-Navarrete Tuberculosis Clinic, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico H. Kunst Department of Respiratory Medicine, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK e-mail: [email protected] N. N. Linh Global TB Programme, World Health Organization, Geneva, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_14

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14.1 Objectives of the Chapter The main goals of this chapter are to establish tuberculosis (TB) treatment goals, how and when to start anti-TB treatment, discuss the recommended regimens for drug sensitive TB, establish recommended doses of the primary regimen, and finally recommend treatment adjustment in special situations.

14.2 Objectives of Tuberculosis Therapy Early and effective anti-TB treatment has a positive impact on the patient and the community, since besides treating the disease, it cuts the chain of transmission [1]. The three main goals of TB treatment are [1, 2]: 1. To reduce rapidly the metabolically and actively growing bacilli in lung cavities and TB lesions in affected organs of active TB patients; reduce TB symptoms; reduce the risk of death due to TB; and stop TB transmission in the community. In order to achieve this goal, it is necessary to use drugs with bactericidal activity, which have effect on the exponential fall in colony-forming units of Mycobacterium tuberculosis during the first days of treatment [3]. Bactericidal activity can be evaluated by culture conversion at the end of the second month of treatment, or at the end of the intensive or bactericidal phase. TB drugs with bactericidal activity include: isoniazid and rifampicin; second-line drugs include: fluoroquinolones, amikacin, linezolid, bedaquiline, delamanid, carbapenems (meropenem or imipenem), and Amoxicillin-clavulanic acid [4]. 2. To achieve durable cure and prevent relapse after completion of anti-TB treatment (maintaining or sterilizing phase), drugs with sterilizing activity are required to kill persisting, dormant or intermittently active bacilli. The use of sterilizing drugs shortens treatment duration and determines rates of relapse [3, 5]. TB drugs with sterilizing activity include: rifampicin and pyrazinamide; second-­line drugs include: levofloxacin/moxifloxacin, linezolid, clofazimine, bedaquiline, and delamanid [4]. 3. To prevent acquisition of TB drug resistance, it is necessary to make an adequate selection of drugs for the treatment regimen. TB treatment should be started as soon as possible following confirmation of a diagnosis of active TB. However, in certain cases for example in human immunodeficiency virus (HIV)/TB co-­infected patients or in patients with advanced TB disease the initiation of anti-TB treatment may be needed even before microbiological confirmation due to the high risk of death.

14.3 Recommended Treatment Regimens for Drug-­Susceptible Tuberculosis Currently, there is an arsenal of drugs for the treatment of TB with proven efficacy, including new drugs such as bedaquiline and delamanid [4, 6–8] (Table  14.1). However, most TB cases, where there is no suspicion of drug-resistant TB, will

Clofazimine

Linezolid Bedaquiline Delamanid

Injectables Linezolid Bedaquiline Delamanid Carbapenems

Injectables Fluoroquinolones Ethionamide/Prothionamide Cycloserine PAS Linezolid (?) Pyrazinamide Ethionamide Pyrazinamide

Sterilizing activity Rifampicin Pyrazinamide Mfx/Lfx

Bactericidal activity Isoniazid Rifampicin Lfx/Mfx

Prevention of resistance Rifampicin Isoniazid Ethambutol

Injectablesb Others

Toxicity Ethambutol Rifampicin Isoniazid Fluoroquinolonesa Bedaquiline Delamanid Pyrazinamide Linezolid

HIGH

Moderate

Low

a

Fluoroquinolones includes: levofloxacin, and moxifloxacin; FQ fluoroquinolone. Reproduced from with permission. Caminero JA, Scardigli A, van der Werf T, et al. Treatment of drug-susceptible and drug-resistant tuberculosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 152–178 [https://doi.org/10.1183/2312508X.10021417] b Injectables, includes amikacin and streptomycin

LOW

Moderate

Activity High

Table 14.1  Anti-TB drug classification, according to the desirable characteristics

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require the primary regimen with combination of four first-line TB drugs [Isoniazid (H), Rifampicin (R), Ethambutol (E), and Pyrazinamide (Z)]. An adequate anti-TB regimen requires the combination of bactericidal and sterilizing drugs to prevent the development of resistance and to avoid relapse. At least four drugs are required for the intensive or bactericidal phase. For the continuation or maintenance phase, fewer drugs are required since the bacillary load is reduced, and the goal is to reach the bacilli in the sporadic multiplication status. The length of the treatment depends on the drugs used in the regimen and the bacillary load. The most widely studied and recommended regimen for drug-susceptible TB cases is the 4-drug regimen which includes the use of 2 months of R, H, E, and Z for the intensive phase and 4 months of H and R for the continuation phase [1, 2]. This regimen includes two bactericidal drugs (H and R) and two sterilizing ones (R and Z); the rationale, for adding E to the regimen, is due to programmatic and operational reasons, as the rate of primary resistance to isoniazid is high in most setting. Unless, in case drug-susceptibility testing (DST) are ready before treatment initiation and show no resistance to any primary drugs, the patient could receive a regimen with only three drugs (H, R, Z) in the intensive phase (as recommended by the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America TB guidelines) [2]. Different studies have demonstrated the efficacy of the 4-drug regimen to be up to 95% [9, 10]. However, success rate varies greatly according to the different local and programmatic conditions, the global treatment success rate reported is 85% for new TB cases, of which the 4-drug regimen is mostly used [11]. The primary 4-drug regimen is designed for a total duration of 6 months with a daily dosing in both intensive and maintenance phases. Intermittent treatment regimens during the intensive phase or continuation phase are no longer recommended due to high risk of treatment failure and relapse [1, 12, 13]. Nevertheless some programs continue intermittent treatment in the continuation phase (thrice-weekly using directly observed treatment (DOT)) due to operational reasons [2, 12]. HIV co-infected TB patients should receive the same 6-month daily treatment regimen if patients are on antiretroviral therapy (ART) [1, 2]. In the uncommon situation in which an HIV-infected patient does not receive ART, extension of treatment duration for additional 2–3 months (e.g., 2-month intensive phase and 7-month continuation phase) may be considered [2]. Different studies have shown a greater risk of relapse and acquired resistance in HIV-infected individuals if intermittent doses are administered or R is indicated for less than 8  months in patients not on ART [14, 15]. Besides chest radiography bacillary load can be evaluated monthly by means of smear microscopy and/or culture. Non-conversion of sputum smear and/or culture after the second month or end of intensive phase is not a good proxy for final treatment outcome, as both have low sensitivity and modest specificity for predicting failure and relapse [16]. However, some studies have related a positive culture at 2 months of treatment and cavitation on baseline chest radiography to a negative outcome and these patients may need a longer treatment duration. Therefore for these cases consideration by clinicians may be needed for an extension of treatment

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duration up to 9 months (2 months of intensive phase +7 months of maintenance phase) if treatment response suggests prolongation of treatment is necessary [2, 17]. Patients with diabetes mellitus (DM) and TB should be included in this group, as DM has been related to extensive and cavitary disease, delayed sputum conversion, and the risk of rifampicin resistance [18, 19].

14.4 Tuberculosis Drugs Dosage The formulations and combinations of TB drugs available in each country are based on the recommendations made by World Health Organization (WHO) guidelines [1]. Nowadays, the use of fixed-­doses combination (FDC) tablets is recommended based on patient’s preference to intake medications. Common FDCs pharmaceutical presentation include: four drugs (4FDC: R + H + Z+ E), three drugs (3FDC: R + H + Z), and two drugs (2FDC: R + H). The use of FDC has not been related to a better outcome but simplifies TB therapy, it has similar efficacy to single-drug formulations and increases patient satisfaction. Furthermore, FDC use makes programmatic management of TB easier, and facilitates weight-adjusted dose by weight band [1, 20, 21]. The dosage of the drugs used in the primary regimen is described in Table 14.2 [1, 2]. TB dosage adjustment may be required in different situations of patient’s condition. In the presence of advanced renal insufficiency (creatinine clearance of 119 MIC Pyrazinamide 20–30 mg/kg AUC0–24/ >209 MIC Second line (drug-resistant TB) Group A  Levofloxacin 1–1.5 g AUC0–24/ =146 MIC =360a  Moxifloxacin 400–800 mg AUC0–24/ =56a MIC  Bedaquiline 400 mg – –  Linezolid 600 mg AUC0–24/ >119 MIC Group B  Clofazimine 100 mg – –  Cycloserine 10–15 mg/kg %Time/ 30% MIC Group C  Delamanid 200 mg – –   4 g – – Imipenem-­ cilastatinb  Meropenemb 3–4 g – –  Amikacin 15–20 mg/kg Cmax/MIC 10.13 (max 1 g)  Ethionamide 15–20 mg/kg AUC0–24/ >56.2 MIC (max 1 g)   P-aminosalicylic 8–12 g – – acid

–

LSS limited sampling strategy, DBS dried blood spot For suppression of resistance b Carbapenems are to be used with clavulanic acid 125 mg twice daily c Yes, based on limited studies at the time of writing, with potential for more assays. Possible, based on drug characteristics such as saliva penetration, or preliminary studies a

regional/rural to central laboratories where these high analytical assays are available [13]. Urine and saliva could also be used as an alternative matrix to blood, to monitor drug concentrations, and offer benefits of non-invasiveness, low costs, potential point-of-care testing in community and quick turnaround time [11].

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18.5.1 Programmatic Approach of Treatment Monitoring The programmatic approach to treatment monitoring has been designed with two main objectives: (a) to ensure the core variables are monitored as to follow the patient’s clinical progress, identify timely the occurrence of adverse events and potential failures; (b) to assess the core variables (historically bacteriological, e.g. sputum smear and culture) at month 2/3 (for new and re-treatment cases, respectively) to evaluate the sputum and culture conversion rate (which predicts treatment success) and at month 5 to assess treatment failure [6, 14]. National TB programmes in their guidelines explain which examinations to perform and when under a programmatic approach. In the TB register, in the past paper-based and nowadays usually electronic, specific columns are reserved for the assessment of sputum smear and culture [6]. Some countries have implemented more sophisticated registers allowing to capture the results of other tests, particularly for MDR-TB patients, for which a more comprehensive register has been recommended by WHO, including monthly cultures [3, 6, 14]. The basic examinations recommended for treatment monitoring at the programmatic level have to be considered a minimum set; they need to be complemented by other examinations which are of clinical interest [14]. Due to the variety of possible situations and the absence of specific studies on this issue, expert opinion is generally behind the suggestion to perform additional examinations. For example, chest radiographies (or other imaging examinations) are recommended with different frequency, from once a month [3] to a less frequent schedule. For patients undergoing treatment with bedaquiline or other drugs increasing the QT interval, electrocardiographic monitoring is clearly necessary at baseline and with a frequency ranging from once weekly to once every 2–3 weeks [3]. The frequency of other examinations (e.g. full blood count, renal liver and thyroid function tests, visual acuity, audiometry and TDM among others) after baseline depends on the clinical situation of the patient, the regimen prescribed (e.g. audiometry if injectable drugs are included in the regimen) and the age of the patient (e.g. visual acuity if a child is administered ethambutol) [14]. In summary, there is no dualism between a programmatic and clinical approach to treatment monitoring. A basic set of examinations are necessary for all patients and need to be captured by the TB register, while other examinations will be prescribed by the treating physicians based on clinical needs; ideally, they should also be captured by the TB register, allowing implementation of aDSM [10].

18.6 Main Conclusions and Recommendations TB treatment is long and challenging due to management of adverse drug reactions and drug resistance. Monitoring of microbiological and clinical response and drug-­ related parameters during TB treatment will help to achieve successful treatment outcome. This chapter aimed to provide a brief overview on basic aspects of monitoring during TB treatment. The most important recommendations are:

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J.-W. C. Alffenaar et al.

• Microbiological monitoring is required to monitor response to treatment and bacterial resistance and needs to be performed at baseline and during treatment. • Clinical and radiological monitoring assures that both disease and drug-related adverse effects are adequately addressed. Routine monitoring is supplemented with patient and drug-specific test to guarantee patient safety, ideally within well-designed aDSM projects. • TDM is important to increase efficacy of the treatment and prevent adverse drug reactions for selected drugs. Drug monitoring is recommended for fluoroquinolones, linezolid and cycloserine. In specific patients (e.g. diabetes or HIV) or those not responding to treatment TDM can be of help. • Programmatic treatment does not exclude a personalized treatment approach but provides a framework to make personalized treatment feasible and capture its data and results for further analysis.

References 1. World Health Organization (WHO). Global TB report. Geneva: WHO; 2019. 2. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: WHO; 2019. https://apps.who.int/iris/bitstream/han dle/10665/311389/9789241550529-­eng.pdf?ua=1. 3. Nahid P, Mase SR, Migliori GB, et  al. Treatment of drug-resistant tuberculosis an official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med. 2019;200(10):E93–142. 4. Nahid P, Dorman SE, Alipanah N, et  al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2017;63(7):e147–95. 5. World Health Organization (WHO) Regional Office for Europe. Algorithm for laboratory diagnosis and treatment-monitoring of pulmonary tuberculosis and drug-resistant tuberculosis using state-of-the-art rapid molecular diagnostic technologies. Geneva: WHO; 2017. http:// www.euro.who.int/__data/assets/pdf_file/0006/333960/ELI-­Algorithm.pdf 6. World Health Organization (WHO). Definitions and reporting framework for tuberculosis – 2013 revision. Geneva: WHO; 2020. https://www.who.int/tb/publications/definitions/en/ 7. Piubello A, Souleymane MB, Hassane-Harouna S, et al. Management of multidrug-resistant tuberculosis with shorter treatment regimen in Niger: nationwide programmatic achievements. Respir Med. 2020;161:105844. 8. Migliori GB. Evolution of programmatic definitions used intuberculosis prevention and care. Clin Infect Dis. 2019;68(10):1787–9. 9. Nicol MP.  Xpert MTB/RIF: monitoring response to tuberculosis treatment. Lancet Respir Med. 2013;1(6):427–8. 10. Borisov S, Danila E, Maryandyshev A, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report. Eur Respir J. 2019;54(6):1901522. 11. Alffenaar J-WC, Gumbo T, Dooley KE, et al. Integrating pharmacokinetics and pharmacodynamics in operational research to end TB. Clin Infect Dis. 2019;2019:pii: ciz942. 12. Van Der Burgt EPM, Sturkenboom MGG, Bolhuis MS, et al. End TB with precision treatment! Eur Respir J. 2016;47(2):680–2. 13. Vu DH, Alffenaar JWC, Edelbroek PM, Brouwers JRBJ, DR a U. Dried blood spots: a new tool for tuberculosis treatment optimization. Curr Pharm Des. 2011;17(27):2931–9. 14. Migliori GB, Tiberi S, Zumla A, et al. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network. Int J Infect Dis. 2020;92S:S15–25.

Tuberculosis Treatment and Adherence

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Al Story

Abstract

This chapter will examine the critical clinical and public health importance of adherence to prescribed tuberculosis (TB) treatment and approaches and interventions which have been tested and scaled to reduce nonadherence. Despite adherence being central to achieving TB elimination, it remains under-researched and under-resourced internationally. Patient autonomy, ability and choice to take TB treatment raise important ethical and, in some countries, legislative challenges. New and emerging digital technologies provide opportunities to better assess adherence in real time and guide differentiated patient-centred care. Recommendations for policy, practice and future research are also presented. Keywords

Adherence · Autonomy · Differentiated care · Digital health · DOT · VOT

19.1 Aims This chapter will examine the critical role adherence plays in tuberculosis (TB) treatment and control, the wide range of approaches and interventions which have been tested and implemented to promote adherence and provide recommendations for policy, practice and future research.

A. Story (*) University College Hospitals NHS Foundation Trust, London, UK © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_19

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19.2 Introduction Adherence, in this case, simply fidelity to the prescribed TB drug regimen, is critical to achieving cure, preventing transmission and the emergence and amplification of drug resistance. Despite its central role, interventions to increase adherence remain an under-resourced and under-researched barrier to global elimination. Adherence is multifaceted, can be intentional or non-intentional and consequently is difficult to predict. Factors that influence taking treatment at the frequency and duration necessary to achieve cure encompass socio-economic status, health system quality, regimen complexity, duration and toxicity and individual beliefs and abilities. These factors commonly overlap and fluctuate on an individual level. The complexity of adherence also presents challenges to research, as evident in the range of relative benefits demonstrated for specific interventions. In recent years, a consensus has emerged that no one size fits all [1] approach exists to increase adherence, and support should, wherever possible, be tailored to the individual needs and changing circumstances of each patient [2], an approach termed differentiated care [3]. At the same time, the need to address the structural barriers to treatment adherence, principally poverty, equity and insecurity, is becoming increasingly apparent.

19.3 Background Tuberculosis was proven infectious prior to the advent of effective treatment making isolation the principle public health response to reduce onward transmission in the community. For the fortunate few, the Sanatoria movement offered hope of remission through a strict regime of diet, rest and recuperation, but for the most, patients were sequestered with their families to endure. Drug resistance to Streptomycin, the first effective therapeutic compound introduced in 1946, was reported to occur in treatment. High relapse rates led to the introduction of combination therapies, mostly administered through prolonged hospitalisation, a significant barrier to scaling treatment access. Later more affordable and tolerable combination regimens drove demand to expand treatment access internationally, but the costs to both patients and health systems of hospitalisation remained a major obstacle. The Madras Study of 1960 was the first to demonstrate that patients randomly allocated to domiciliary treatment could achieve equivalent outcomes to those who were hospitalised for the full treatment duration. While this study opened the door to scaling community-based treatment, it also highlighted the immense burden and challenges patients faced in completing treatment without intensive support. To remedy this, intermittent treatment regimens where introduced that could be more readily administered under supervision in the community, but duration of treatment, use of injectables and multiple medications remained major barriers. This was partially addressed by the introduction of six-month ‘short course’ oral combination therapy which remains the suboptimal standard today. Recent evidence has confirmed that standard combination therapy is highly unforgiving to poor adherence which remains the single most important factor associated with unfavourable treatment outcomes [4].

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While the critical importance of adherence is well understood, the mechanisms to achieve it are not. TB treatment is highly effective, if taken, but its duration and, for some, toxicity fundamentally undermine adherence. Therapeutic responses to the emergence of multiple drug resistance, in large part attributable to widespread non-adherence, present a tragic conundrum. Drug resistance necessitates the prolonged use of multiple and more toxic compounds, which in turn further amplify barriers to adherence and drive the emergence of drug-resistant strains.

19.4 Interventions to Promote Adherence 19.4.1 Support for All Patients Non-adherence to oral medications is extremely common; studies have shown that almost half of all medications are not taken as prescribed [5], and in a global survey, 22.3% of responders self-reported non-adherence to antibiotic therapy [6]. TB treatment is long, potentially stigmatising and detrimental to socio-­ economic standing. Moreover, while TB can affect anyone, the risk of disease is far greater among the poorest and most vulnerable. In most patients, TB symptoms resolve within a few weeks, yet treatment must continue for many months and in some cases years. The assumption that patients understand and, more importantly, believe the rationale for prolonged treatment with multiple drugs is questionable. Similarly, the expectation that adherence is a given is clearly wrong and risks setting patients up to fail. Globally, TB treatment success rates have increased but remain below the target of ≥90% and are highly varied between programmes. Among new cases, 85% of patients are estimated to successfully complete treatment but treatment outcome data for people with multidrug-resistant/rifampicinresistant tuberculosis (MDR/RR-TB) show a global treatment success rate of 56% [7]. These data reinforce the need for all patients to receive adherence support which should include as a minimum package; access to a high-quality health system; ongoing information and counselling from trained and expert health workers and, where appropriate, incentives and enablers. Globally, the focus on health systems is shifting from measuring the coverage of services to improving quality of care [8]. Care quality and user experience improve adherence [9]. Clear communication is the bedrock to successful TB treatment and control. Multiple studies have highlighted how clear and culturally appropriate ongoing information and counselling from trained health workers can improve treatment completion and adherence. The evidence on use of incentives and enablers to help patients offset treatment costs is more mixed but, as with physiological interventions, they likely play an important role among specific socially vulnerable populations. An important recent finding is the beneficial impact of using a package of interventions tailored to individual patient’s needs and values [10]. The challenge is now to optimise and scale the provision of different intensities and types of care based on each patient’s needs and level of medication adherence; this is a differentiated care approach.

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19.5 From DOT to Digitally Differentiated Care Poor adherence was identified early on as the principle reason why levels of cure seen in real-world programmatic conditions were invariably lower than those achieved in trials. Objectively measuring adherence and collecting reliable dosing histories remain a huge and resource intensive challenge. In the absence of direct measurement, health workers have relied on clinical responses such as prolonged infectiousness and treatment outcomes including default and relapse. These are obviously highly unsatisfactory proxy measures as they miss any opportunity for supportive interventions to improve adherence. The known risks of non-adherence combined with the inability to either predict or reliably measure adherence led many TB programmes and the World Health Organization (WHO) to endorse directly observed treatment (DOT) as a standard of care, either offered to all patients or selected groups with specific risk factors for nonadherence, such as homelessness, substance use or previous treatment default. Under current WHO recommendations, DOT is the direct supervision and documentation of patients taking their treatment, ideally by a trained lay provider or healthcare worker in a community or home-based setting in preference to a health facility [11]. While DOT has demonstrated improved clinical and programmatic outcomes overall when compared to Self-Administered Treatment (SAT) internationally, it has some significant limitations. Outcomes from both DOT randomised controlled trials and cohort studies have shown marked variations in effect, in most part attributable to significant differences in the design, delivery and quality of DOT programmes and treatment outcome definitions used. These variations in effect extend into programmatic conditions highlighting the fact that DOT is not a standardised or uniform intervention and is difficult and resource intensive to deliver in the real world. DOT has also raised justified concerns from patients, advocates, health workers and researchers alike. Concerns include that DOT is intrusive, incurs patient costs in travel and lost time and is disempowering. From a nursing and community health worker perspective especially, DOT can appear as the antithesis to accepted models of care that put patient autonomy, independence and right to self-­ determination at the heart of the therapeutic relationship. In short, DOT is far from optimal and is only ethically justifiable in the context of a patient-centred approach [12]. Evidence for the value of digital adherence technologies (DATs) is rapidly emerging [13]. This approach uses basic mobile phone- and smartphone-based technologies, digital pillboxes and, most recently, ingestible sensors [14]. DATs have multiple functions including medication reminders using smart pill boxes and SMS, video observation of pill-taking [15] (Video Observed Treatment—VOT) using smartphones. A major advance with DATs is the ability to compile real-time accurate dosing histories for each patient without the need for direct observation. This breakthrough underpins the provision of differentiated care by enabling providers to individually triage and tailor the nature and intensity of adherence support interventions based on actual level of adherence. Global access to smartphones is increasing

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exponentially and becoming more affordable. DATs are not a stand-alone intervention but show promising potential to improve adherence when integrated into a comprehensive package of patient-centred care.

19.6 Conclusions and Recommendations • Adherence is the single most important determinant of TB treatment outcome and central to the goal of global TB elimination. • High rates of non-adherence and drop out from treatment represent a healthcare system failure. • Despite new therapeutic compounds and shorter and less toxic regimens, duration of treatment and drug toxicity remain major barriers to adherence. • There is no single definitive intervention to address non-adherence. • All patients should receive adherence support to complete a recommended course of treatment. • TB is not clinically uniform. Patients vary in disease severity and ability to biologically utilise and tolerate specific compounds. Increased focus on the importance of individually tailored treatment needs to be accompanied by an equal focus and investment in individually tailored measures to support adherence. • More convenient, affordable and reliable means to both measure and achieve high levels of adherence are urgently needed. DATs can inform tailored differentiated care approaches and offer significant promise when used as an adjunct to effective patient-centred care.

References 1. Pradipta IS, Houtsma D, van Boven JFM, et al. Interventions to improve medication adherence in tuberculosis patients: a systematic review of randomized controlled studies. NPJ Prim Care Respir Med. 2020;30:21. https://doi.org/10.1038/s41533-­020-­0179-­x. 2. Garner P, Smith H, Munro S, Volmink J. Promoting adherence to tuberculosis treatment. Bull World Health Organ. 2007;85(5):404–6. https://doi.org/10.2471/blt.06.035568. 3. Duncombe C, Rosenbulm S, Hellmann N, Holmes C, Wilkinson L, Biot M, et al. Reframing HIV care: putting people at the centre of antiretroviral delivery. Tropical Med Int Health. 2015;20(4):430–47. 4. Imperial MZ, Nahid P, Phillips PPJ, Davies GR, Fielding K, Hanna D, Hermann D, Wallis RS, Johnson JL, Lienhardt C, Savic RM. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med. 2018;24(11):1708–15. 5. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2014;11:CD000011. 6. Pechère JC, Hughes D, Kardas P, Cornaglia G. Non-compliance with antibiotic therapy for acute community infections: a global survey. Int J Antimicrob Agents. 2007;29(3):245–53. https://doi.org/10.1016/j.ijantimicag.2006.09.026. 7. World Health Organization. Global tuberculosis report 2019. Licence: CC BY-NC-SA 3.0 IGO. Geneva: World Health Organization; 2019.

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8. Pai M, Temesgen Z.  Quality: the missing ingredient in TB care and control. J Clin Tuberc Other Mycobact Dis. 2018;14:12–3. https://doi.org/10.1016/j.jctube.2018.12.001. PMID: 31720411; PMCID: PMC6830165. 9. Kruk ME, Gage AD, Arsenault C, et al. High-quality health systems in the sustainable development goals era: time for a revolution. Lancet Glob Health. 2018;6(11):e1196–e252. 10. Alipanah N, Jarlsberg L, Miller C, Linh NN, Falzon D, Jaramillo E, Nahid P. Adherence interventions and outcomes of tuberculosis treatment: a systematic review and meta-analysis of trials and observational studies. PLoS Med. 2018;15(7):e1002595. https://doi.org/10.1371/ journal.pmed.1002595. PMID: 29969463; PMCID: PMC6029765. 11. World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. 12. Ethics guidance for the implementation of the End TB strategy 2017. 13. Subbaraman R, de Mondesert L, Musiimenta A, et al. Digital adherence technologies for the management of tuberculosis therapy: mapping the landscape and research priorities. BMJ Glob Health. 2018;3:e001018. 14. Browne SH, Umlauf A, Tucker AJ, Low J, Moser K, Gonzalez Garcia J, Peloquin CA, Blaschke T, Vaida F, Benson CA. Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: a randomized controlled trial. PLoS Med. 2019;16(10):e1002891. https://doi.org/10.1371/journal.pmed.1002891. PMID: 31584944; PMCID: PMC6777756. 15. Story A, Aldridge RW, Smith CM, Garber E, Hall J, Ferenando G, Possas L, Hemming S, Wurie F, Luchenski S, Abubakar I, McHugh TD, White PJ, Watson JM, Lipman M, Garfein R, Hayward AC. Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial. Lancet. 2019;393(10177):1216–24. https://doi.org/10.1016/S0140-­6736(18)32993-­3. Epub 2019 Feb 21. PMID: 30799062; PMCID: PMC6429626.

Tuberculosis Patient-Centred Care

20

Onno W. Akkerman and Tjip S. van der Werf

Abstract

Increasing complexity of tuberculosis (TB) is one of the causes that TB is still the leading cause of death by an infectious disease. Among the complicating factors are increasing drug resistance and comorbidities. Patient-centred care, and even more individualised treatment, would be the way forward. The different aspects of patient-centred care model, including medical, social and supportive care are discussed. Keywords

Patient-centred care · Holistic approach · Individualised treatment · Pharmacokinetics · Social care · Supportive care · Video-observed treatment

O. W. Akkerman (*) Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands TB Center Beatrixoord, University Medical Center Groningen, University of Groningen, Haren, The Netherlands e-mail: [email protected] T. S. van der Werf Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_20

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20.1 Introduction The British Medical Research Council (BMRC) trials in the seventies of the last century established a combination of anti-tuberculosis (TB) drugs for 6 months as the standard treatment to cure TB, with more than 97% of TB patients having successful outcome [1]. The strength for national TB programmes to use this combination of anti-TB drugs was its simplicity; the standard TB regimen is the principle of ‘one size fits all’ in relation to the dose of the drugs, and the duration of treatment. If active case finding would be added to this standardized, highly effective treatment, national programs would be enabled to reduce transmission and improve TB control [2]. Since 1994, the principle of directly observed therapy (DOT) was actively promoted to increase compliance with TB treatment, thereby enhancing the efforts to eradicate TB [3]. Based on these principles, national programs have prevented many new cases, including over 50 million TB-related deaths in the past five decades. TB has however not been eradicated; it still leads the cause of death by infection. The fact that TB is still the most prevalent and deadly infectious disease worldwide [4] can at least partly be explained by the increased complexity of TB; its comorbidities and the ever-increasing drug resistance are just two of several important complicating factors. Emerging drug resistance reflects failure of national TB programs and with increasing drug resistance worldwide, it calls for alternative approaches to improve TB control [2]. With increasing complexity, a programmatic approach falls short to address these new challenges. Patient-centred care would be the way forward [5], as a new strategy [6] adjusting or replacing the DOT strategy that does not necessarily tailor the approach to enhance compliance with therapy, and patient-centred care addresses specific needs of individuals patients to adhere to the scheduled TB treatment. It recognizes the basic rights of people affected with TB to be addressed as a unique human being, with unique needs; the need to be fully informed about the condition they suffer from, and the required medication to obtain cure; the side effects that are possibly met; their preferences with regard to time slots and practical challenges to follow their treatment; the timing, venues and practicalities involved in follow-up visits; financial and time constraints to report at planned follow-up visits; financial and logistic problems involved in the therapy; care in case of adverse events; challenges in disclosure toward family members, beloved ones, friends and acquaintances; issues related to disclosure, in relation to contact and source investigations; pharmaceutical care issues and issues related to school attendance and resuming of work. It starts with including the private sector, where many first contacts with TB patients happen, into the national TB programs [5]. This private sector is diverse, and it is underequipped to both diagnose and manage TB patients. In summary, there is a need to make patient-centred care a more individualized or holistic approach that pays respect to patients’ unique needs and unique (drug-­ susceptible, mono- or multi-drug resistant) M. tuberculosis isolate; comorbidities, like diabetes mellitus or malnourishment; and co-infections like human immunodeficiency virus (HIV), hepatitis B or C. For the medical challenges, the individual approach uses the principles of treatment guided by pharmacokinetic/

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pharmacodynamic (PK/PD) equations, with adequate attention for adverse events and necessary tailoring of treatment. A more holistic approach of the patient also includes attention to their social environment, their vulnerability but also their specific physical, nutritional, social, mental and spiritual needs [7].

20.2 Aim The aim of this chapter is to provide an overview of different aspects of patient-­ centred care or an even more holistic approach, including medical, social and supportive care.

20.3 Individualized Care 20.3.1 Medical Care Management of severe forms of TB, like drug-resistant tuberculosis (DRTB) and central nervous system tuberculosis (CNSTB), is challenging. Treatment of DRTB, compared to drug-susceptible tuberculosis (DSTB), lasts long (from 9 to 24  months), is more toxic, needs centralized care, with longer hospital stays and, due to adverse drug reactions that are more common, result in interruptions or complete cessation of therapy [8]. Starting an adequate treatment regimen with high efficacy and low toxicity is the first step. Although in designing an individualized initial treatment schedule, typically following the international guidelines [9], often, tailormade solutions are essential to enhance adherence, trust and effectiveness. Knowledge of PK/PD principles is important to improve outcome and it helps to reduce complications. Drug susceptibility testing, using molecular or phenotypical assays—the PD part in the equation—is important to tailor individual treatment regimens. To optimize efficacy and decrease toxicity, therapeutic drug monitoring is essential. Based on the PK/PD results, the treatment regimen can be adjusted, by tailoring the dose. Collaboration with a clinical pharmacologist and microbiologist helps optimizing the adjusted treatment regimen [7]. Monitoring of treatment and follow-up are essential; once the patient is responding to treatment, and no longer infectious, treatment can be continued in a decentralized setting. A shared care model can be used with a local doctor works with the experts in the central facility. Many patients with TB experience sequalae after the end of treatment. Individualized awareness for these sequelae helps minimizing the complications and tailor the design of individualized rehabilitation programmes [10]. Some patients treated for pulmonary TB benefit from pulmonary rehabilitation, evaluating their pulmonary status, including pulmonary function and exercise tests [10], at the end or after treatment. Severe forms of extrapulmonary TB (EPTB), like spinal and central nervous system TB, have a high morbidity and mortality as well. Optimizing treatment regimens using the PK/PD principle, including knowledge of, or assessment of drug

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penetration in tissues and body fluids like the cerebrospinal fluid may improve outcome [11]. Follow up during treatment and rehabilitation should all be teamwork, including neurologists and rehabilitation specialists, and can be decentralized after well-­tolerated, adequately dosed treatment is initiated. A decline in physical function during treatment can be due to treatment failure, but also the result of paradoxical worsening, and should be assessed carefully and managed accordingly.

20.3.2 Social Care Special attention for the social status is one of the keystones of patient-centred care. Long treatment and hospital stays can lead to stigmatization, family or social isolation and loss of income. To improve adherence and treatment outcome, these issues are important in the centralized as well as in the decentralized treatment centres or TB clinics. Furthermore, patients should be encouraged to take an active role in their treatment, with special attention to denial of disease, lack of hope and their sense of social isolation. Paternalism in healthcare systems can hinder patient’s active engagement [12]. Proper communication, including attention for language barriers, is part of the motivation, as is compensation for their economic losses. Specially trained social workers can help and motivate patients in their engagement to treatment [12]. Explaining TB, while taking into account the literacy level of patients, can be done by these social workers as well, but also dedicated TB nurses have an important role. Some patients experience loss of quality of life during their treatment, but in most patients, we see their overall well-being improve over time during treatment. Patients who do not improve need extra attention, as their treatment outcome may be poor [13]. In every setting, social workers should actively assess quality of life using questionnaires to monitor improvement over time. Extra attention by socializing and connecting with individuals, addressing specific needs, desires, preferences and problems may help, while specific problems may be detected that require specialized care by psychiatrists, psychologists or spiritual counsellors. In the different setting, including the centralized TB centres, decentralized TB hospitals and TB clinics, nurses play a pivotal role in the treatment of TB.  Nurses are trained to interact with patients with various different backgrounds, and their mindset and commitment creates opportunities to effectively interact with patients without barriers that may be present in interactions with medical staff. Therefore, nursing staff are literally the ears and eyes of the medical staff [14]. They can play an important role in education and follow up of video-observed therapy (VOT) at home, which is a preferable option compared to DOT [15]. The next step in patient-­centred care is to decide (in different frequencies) for either synchronous VOT, i.e. swallowing the medication in front of a camera while the health care worker watches remotely, or asynchronous, i.e. video record swallowing the medication so the healthcare worker can assess drug intake later [16].

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20.3.3 Supportive Care Nutritional and physical assessment and care are important parts of TB treatment [10]. Malnutrition can be disease related, which is characterized by a loss of free fat mass, resulting in impaired muscle function. Even normal weight, overweight and obese TB patients can have disease-related malnutrition. Loss of physical function leads to dependency and reduced participation in society. Regaining the physical function shortens the time needed for recovery and to resume work. Malnutrition is an important reversible risk factor for treatment failure and is associated with a twofold higher mortality risk. Malnutrition, next to other comorbidities like diabetes and HIV, can lead to malabsorption of anti-TB drugs, resulting in low drug exposure [10]. Although a gold standard for malnutrition is lacking, the Global Leadership Initiative on Malnutrition provides criteria for uniformity in nutritional assessment. These criteria include assessment of weight loss, low Body Mass Index, reduced muscle mass (phenotypic criteria) and reduced food intake and disease burden/ inflammation condition (etiological criteria). If malnutrition is diagnosed, a tailormade, individualized treatment plan needs to be developed that should consist of a combination of training with sufficient intake of proteins and energy. During and after treatment, when patients follow a rehabilitation program, physical and nutritional counselling and measurements should be repeated regularly [10].

20.4 Global and Country Experiences Different aspects of patient-centred care have been studied and some have been implemented in TB programs. Performing therapeutic drug monitoring is addressed in the American Thoracic Society (ATS) guidelines for specific groups of TB patients [17]. Furthermore, VOT has been implemented in the TB programme of Belarus, with high patient satisfaction, resulting in time and cost savings, and good appreciation of healthcare workers [18]. A study conducted in the United Kingdom showed higher success rates of VOT versus DOT in treatment completion after the first 2 months of treatment [15]. In a South African study, social workers were specially trained in motivating active engagement of patients in their treatment for DRTB-HIV.  Though with a small sample size, this study showed that adequate training for social workers can be a successful strategy for patient-centred care.

20.5 Main Conclusions and Recommendations To improve outcome and decrease absolute numbers of DRTB or severe EPTB cases, there is an urgent need for more individualized and patient-centred care. Clearly, an effective treatment regimen with the lowest possible toxicity and lowest possible duration is needed. Treatment should be continued at home as soon as

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possible using (a)synchronous VOT.  Social circumstances, like stigmatization, social isolation and loss of income by expert social workers or TB nurses, are important. Supportive care should be focussed on societal participation, with individual needs, while regaining physical function as fast as possible, by nutritional and physical care. All these aspects enhance treatment adherence and, eventually, improve treatment outcome.

References 1. Mitchinson DA, Davies G. The chemotherapy of tuberculosis: past, presence and future. Int J Tuberc Lung Dis. 2012;16(6):724–32. 2. Fox W, Ellard GA, Mitchinson DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999;3(S2):S231–79. 3. Chaisson RE, Coberly JS, De Cock KM. DOTS and drug resistance: a silver lining to a darkening cloud. Int J Tuberc Lung Dis. 1999 Jan;3(1):1–3. 4. https://www.who.int/health-topics/tuberculosis. 5. Jaramillo J, Yadav R, Herrera R. Why every word counts: towards patient- and people-centered tuberculosis care. Int J Tuberc Lung Dis. 2019;23(5):547–51. 6. O’Donnell MR, Daftary A, Frick M, Hirsch-Moverman Y, Amico KR, Senthilingam M, Wolf A, Metcalfe JZ, Isaakidis P, Davis JL, Zelnick JR, Brust JC, Naidu N, Garretson M, Bangsberg DR, Padayatchi N, Friedland G. Re-inventing adherence: toward a patient-centered model of care for drug-resistant tuberculosis and HIV. Int J Tuberc Lung Dis. 2016;20(4):430–4. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J. 2018;51(3):1702490. 8. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017; Ahmad N, Ahuja SD, Akkerman OW, Alffenaar JC, Anderson LF, Baghaei P, Bang D, Barry PM, Bastos ML, Behera D, Benedetti A, Bisson GP, Boeree MJ, Bonnet M, Brode SK, Brust JCM, Cai Y, Caumes E, Cegielski JP, Centis R, Chan PC, Chan ED, Chang KC, Charles M, Cirule A, Dalcolmo MP, D’Ambrosio L, de Vries G, Dheda K, Esmail A, Flood J, Fox GJ, Fréchet-Jachym M, Fregona G, Gayoso R, Gegia M, Gler MT, Gu S, Guglielmetti L, Holtz TH, Hughes J, Isaakidis P, Jarlsberg L, Kempker RR, Keshavjee S, Khan FA, Kipiani M, Koenig SP, Koh WJ, Kritski A, Kuksa L, Kvasnovsky CL, Kwak N, Lan Z, Lange C, Laniado-Laborín R, Lee M, Leimane V, Leung CC, Leung EC, Li PZ, Lowenthal P, Maciel EL, Marks SM, Mase S, Mbuagbaw L, Migliori GB, Milanov V, Miller AC, Mitnick CD, Modongo C, Mohr E, Monedero I, Nahid P, Ndjeka N, O’Donnell MR, Padayatchi N, Palmero D, Pape JW, Podewils LJ, Reynolds I, Riekstina V, Robert J, Rodriguez M, Seaworth B, Seung KJ, Schnippel K, Shim TS, Singla R, Smith SE, Sotgiu G, Sukhbaatar G, Tabarsi P, Tiberi S, Trajman A, Trieu L, Udwadia ZF, van der Werf TS, Veziris N, Viiklepp P, Vilbrun SC, Walsh K, Westenhouse J, Yew WW, Yim JJ, Zetola NM, Zignol M, Menzies D. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018;392(10150):821–34. 9. https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-­­ treatment/en/ 10. Akkerman OW, Ter Beek L, Centis R, Maeurer M, Visca D, Muñoz-Torrico M, Tiberi S, Migliori GB. Rehabilitation, optimized nutritional care, and boosting host internal milieu to improve long-term treatment outcomes in tuberculosis patients. Int J Infect Dis. 2020;92S:S10–4.

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11. Wilkinson RJ, Rohlwink U, Misra UK, van Crevel R, Mai NTH, Dooley KE, Caws M, Figaji A, Savic R, Solomons R, Thwaites GE. Tuberculous meningitis international research consortium. Tuberculous meningitis Nat Rev Neurol. 2017;13(10):581–98. 12. Zelnick JR, Seepamore B, Daftary A, Amico KR, Bhengu X, Friedland G, Padayatchi N, Naidoo K, O’Donnell MR. Training social workers to enhance patient-centered care for drug-­ resistant TB-HIV in South Africa. Public Health Action. 2018;8(1):25–7. 13. Dujaili JA, Sulaiman SA, Hassali MA, Awaisu A, Blebil AQ, Bredle JM. Health-related quality of life as a predictor of tuberculosis treatment outcomes in Iraq. Int J Infect Dis. 2015;31:4–8. 14. Newell S, Jordan Z. The patient experience of patient-centered communication with nurses in the hospital setting: a qualitative systematic review protocol. JBI Database System Rev Implement Rep. 2015;13(1):76–87. 15. Story A, Aldrigde RW, Smith CM, Garber E, Hall J, Ferenando G, Possas L, Hemming S, Wurie F, Luchenski S, Abubakar I, McHugh TD, White PJ, Watson JM, Lipman M, Garfein R, Hayward AC. Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial. Lancet. 2019;393(10177):1216–24. 16. Garfein RS, Doshi RP.  Synchronous and asynchronous video observed therapy (VOT) for tuberculosis treatment adherence monitoring and support. J Clin Tuberc Other Mycobact Dis. 2019;17:100098. 17. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O’Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A.  Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–95. 18. Sinkou H, Hurevich H, Rusovich V, Zhylevich L, Falzon D, de Colombani P, Dadu A, Dara M, Story A, Skrahina A. Video-observed treatment for tuberculosis patients in Belarus: findings from the first programmatic experience. Eur Respir J. 2017;49(3):1602049.

Part V Risk Factors, Risk Groups, Challenges

Tuberculosis, Alcohol, Smoking, Diabetes, Immune Deficiencies and Immunomodulating Drugs

21

Jean-Pierre Zellweger, Raquel Duarte, and Marcela Munoz Torrico

Abstract

A minority of persons infected with M. tuberculosis will develop tuberculosis (TB). The risk of progressing from infection to active disease is strongly influenced by several internal and external factors which have to be considered in the evaluation of any person with latent TB infection and in the indications and potential benefits of preventive treatment. Keywords

Tuberculosis · Risk factors · Smoking · Diabetes · Silicosis · Immune deficiencies

The vast majority of persons exposed to a case of transmissible tuberculosis (TB) do not develop the disease. Some of them eliminate the mycobacteria at the surface of the respiratory mucosa, others develop an immune reaction without any clinical sign of disease leading to the development of latent tuberculosis infection (LTBI). In a minority of persons (traditionally evaluated at 5–10%, probably less), progressive primary infection or reactivation of a latent focus can give rise to the full-blown active TB disease.

J.-P. Zellweger (*) TB Competence Center, Swiss Lung Association, Berne, Switzerland e-mail: [email protected] R. Duarte EpiUnit, Centro Hospitalar de Vila Nova de Gaia, Faculdade de Medicina da Universidade do Porto, Instituto da Universidade do Porto, Porto, Portugal M. M. Torrico Tuberculosis Clinic, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_21

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The key issue is the ability of the immune system to control the formation of granuloma and maintain their integrity, thereby preventing the escape, multiplication and dissemination of the mycobacteria. In subjects with a weakened immune system, the formation of granulomas is impaired, [1]. In some cases, an excessive inflammatory response may also foster the development of tissue lesions and the dissemination of mycobacteria [2]. Many factors influence the efficiency of the immune defense mechanisms and by consequence the type and quality of the response against the presence of mycobacteria. This may explain why only some individuals have a high risk of rapid dissemination of mycobacteria, others have an excessive immune response with inflammation, tissue destruction, and formation of cavities whereas others, with an optimal immune response, are able to eradicate the mycobacteria or maintain them under long-term control [2, 3]. Among the factors modulating the quality of the immune defenses against mycobacteria, some are present in the organism of the infected person (and difficult to control), whereas others are external and may be more amenable to an intervention.

21.1 Internal Factors Modulating the Immune Defenses 21.1.1 Diabetes Diabetes is one of the most important disease with an impact on the risk of TB.  Hyperglycemia induces several abnormalities at the level of the innate and adaptive immune responses to M. tuberculosis infection: bactericidal recognition and phagocytosis are defective, impaired antigen-presenting cell (APC) recruitment and function delays the activation of the adaptative immune response, and therefore impaired cellular immune response results in diminished production of chemokines and cytokines able to control the infection. The immunological consequences of hyperglycemia affect the susceptibility to infection, and the risk of progression from infection to active disease. Active TB is then associated with an increased rate of smear positivity, more extensive disease in both lungs and a greater number of cavities, unfavorable outcome (increase in failure and death), and the risk of relapse [4]. Globally, diabetes is associated with a slight but significant increase in latent infection [5] and with a two- to fourfold risk of active TB [6]. Some studies have shown that pharmacology of anti-TB drugs, particularly rifampicin, may be negatively influenced by diabetes with an increase in the risk of development of drug resistance. The global increase in the prevalence of diabetes worldwide, particularly in countries with a high burden of TB, could have an large impact on the expected achievements of the World Health Organization (WHO) End TB strategy [4]. Currently, there is no recommendation for a systematic screening for latent TB TB infection has been traditionally called “latent TB infection (LTBI)”. This terminology has been used to define a state of persistent immune response to stimulation by M. tuberculosis antigens through tests such as the tuberculin skin test or an interferon gamma release assay (IGRA) without clinically active TB. This chapter uses the term LTBI throughout. However, this term may be progressively replaced by the simpler term “TB infection”. For this chapter the authors have decided for the time being to maintain the traditional terminology.

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infection in patients with diabetes in regions with low TB prevalence, but in countries with TB prevalence >100 cases per 100,000 population, persons with newly diagnosed diabetes should be screened for tuberculosis and persons already in care for diabetes should be informed about the risk and symptoms of TB [7].

21.1.2 Primary Immune Deficiencies Innate and adaptative immune response is essential for the control of mycobacterial infections. Several primary immune deficiencies increase the risk of tuberculosis and a broad spectrum of other infections. Individuals with defect in the interleukin (IL)-12/ IL-23–interferon gamma (IFN-γ) axis, known as Mendelian susceptibility to mycobacterial disease (MSMD), have increased risk of tuberculosis infections, even from low-­virulence mycobacteria like M. bovis bacillus Calmette-Guérin (BCG) [8, 9]. Primary immune deficiencies require a high degree of suspicion. These patients may require the use of prolonged antibiotic therapy, IFN-g therapy, or hematopoietic stem cell transplantation (HSCT).

21.2 External Factors Modulating Immune Defenses 21.2.1 Smoking Among the external factors which may influence the risk of TB, smoking has long been recognized as very important. The association was suspected as early as 1918 by JH Kellogg, an anti-smoking activist and the promoter of corn flakes, demonstrated in 1956 by Lowe [10] and confirmed by many further studies [11– 13]. The relations between tobacco and smoking were reviewed in a joint publication by the WHO and the Union [14]. Tobacco smoking increases the risk of infection and progression to active disease. Patients with TB who are smokers have more extensive pulmonary disease, smear positivity, late conversion, relapse, and death from TB [15]. The tobacco smoke augments the risk of TB by an increase in the production of bronchial secretions, decrease of the mucociliary clearance, and impairment of the macrophage function (decreased bacterial adherence, phagocytic ability, release of cytokines, intracellular killing activities, and production of tumor necrosis factor alpha (TNFα) and nitric oxide). The increase in risk is associated with the duration and intensity of smoking [16]. The influence of smoking on the risk of TB may also explain the gender difference (male predominance) in the prevalence of TB in countries where mainly males are smokers [17]. Globally, the contribution of smoking to the TB prevalence and mortality in high-­TB burden countries is estimated to 17.6 and 15.2, respectively, peaking to 31.6% in Russia [18]. An increased risk of TB infection and disease also exists for nonsmoking children or family members exposed to environmental tobacco smoke [19–21]. Considering that tobacco smoking is an external risk factor for TB (and of many other diseases) and the most important avoidable cause of death and disease worldwide, it is now recommended that all health-care workers in charge of TB patients

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advise their patients to stop smoking and offer smoking cessation counseling [14]. Several studies have demonstrated that a smoking cessation counseling is feasible and can decrease the prevalence of smoking among patients with TB. The impact of this intervention on the TB treatment outcome has also been demonstrated [22, 23]. Unfortunately, there is still a gap in the implementation of efficient measures aimed at helping smokers with TB to become abstinent [24].

21.2.2 Air Pollution The impact of exposure to environmental air pollution on TB is more controversial [25]. Some reviews concluded that there is a statistically significant association between indoor air pollution (mainly exposure to biomass fuel cooking) and TB [26] whereas other reviews did not find such an association [27]. More recent studies tend to confirm the association between indoor air pollution and TB [28]. In vitro studies have demonstrated that exposure to airborne particulate matter impairs the human immune response to M. tuberculosis at lung and blood level [29]. Two recent studies from China conclude that there is an association between some air pollutants (PM2.5, SO2, O3, and CO) and TB [30, 31].

21.2.3 Alcohol Alcohol also has a significant impact on TB. Excessive alcohol consumption affects all components of the adaptative immune response thus increasing the risk of progressing from infection to TB [32] and the risk of poor treatment outcome [33]. The risk of poor outcome (failure, death, and lost to follow-up) is similar for drug-sensitive TB and multidrug-resistant TB (MDR-TB) and is independent of the proportion of lost to follow-up. This indicates that the interaction between alcohol and poor outcome is associated not only with the social and behavioral factors frequently observed among alcohol abusers, like unemployment, homelessness, smoking, and malnutrition, but also with a biologic background. The impact of alcohol on the risk and outcome of TB is dose-dependent and seems to be more pronounced in highincome countries and is particularly important in high-TB burden countries with economic growth [33, 34]. Besides the impact on TB treatment outcome, history of excessive alcohol consumption has been related to an increased risk of drug-related adverse events, particularly on the development of hepatotoxicity, which compromises the effectivity of treatment and adherence [35].

21.3 Acquired Immune Deficiencies Immune deficiencies, acquired as a consequence of disease or drug action, influence the risk of acquiring TB infection and the outcome of disease. The impact of human immunodeficiency virus (HIV) infection on TB is addressed in Chapter 24 and will not be discussed further. Apart from HIV, an important group of patients are those

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who receive immunomodulating drugs (biologicals) for the treatment of disorders like rheumatoid arthritis (RA), inflammatory bowel diseases, or psoriasis. Several immunomodulating drugs increase the risk of TB, especially anti-TNF therapy, since the neutralization of TNF interferes with the TB granuloma equilibrium, leading to TB reactivation. The risk of developing active TB disease is different with each drug, being higher with the use of infliximab and adalimumab. The increase in TB risk associated with the use of infliximab was documented soon after the introduction of the drug [36], and the screening for latent TB infection before the prescription of biological treatments is recommended [37]. The risk of developing TB associated with other immunomodulating drugs, such as anti-IL6 (tocilizumab) and antiCD20 (Rituximab), is very low or absent.

21.3.1 Corticosteroids Corticosteroids are also frequently used to treat patients with rheumatic diseases. The risk of tuberculosis infection has been well documented in such patients, especially in those receiving high doses and for prolonged periods. A retrospective case control study, conducted in the UK, reported that the adjusted odds ratios (ORs) for use of 500 cases/100,000), specific countries of origin or all countries of origin targeted [17] . Migrants who have tested positive for LTBI (and in whom active TB is excluded) should be offered LTBI treatment. A study from the UK demonstrated that LTBI treatment significantly reduced the risk of developing TB in migrants from high TB incidence areas with a positive IGRA (incidence rate ratio 0.17, 95% CI 0.05–0.60) [36]. Beyond the contribution to TB control in low-incidence settings, individual migrants generally stand to benefit from LTBI treatment [37]. There are different treatment options for LTBI treatment, but notably, rifampicincontaining regimens (using 4 months of daily rifampicin or 3 months of daily rifampicin and isoniazid) are associated with higher completion rates compared with 6 months of daily isoniazid [38, 39]. However, LTBI treatment with isoniazid is also feasible and generally safe [40]. An emphasis on facilitating treatment completion through the use of shorter regimens is particularly important in those who suffer socio-economic hardship, which disproportionally applies to migrants [41]. Physicians’ reluctance to prescribe LTBI treatment to migrants has been shown to pose a significant barrier to increasing LTBI treatment rates [42, 43]. Explaining the abstract concept of latency and disease activation in an intercultural and interlingual context can be very challenging [44], and efforts must be made to communicate in a culturally appropriate manner.

23.6 Conclusions In many countries with a low incidence of TB, foreign-born persons make up the majority of TB cases. Strategies to prevent and manage TB in international migrants are therefore important to meet TB elimination targets in low-incidence countries. These include pre-migration TB screening, post arrival follow-up of migrants at high risk of developing TB and special efforts to reach out to asylum seekers and refugees.

References 1. WHO.  Global tuberculosis report 2019. Geneva: World Health Organization; 2019. http:// www9.who.int/tb/publications/global_report/en/. Accessed 24 May 2020. 2. Dobler CC, Fox GJ, Douglas P, Viney KA, Ahmad Khan F, Temesgen Z, et al. Screening for tuberculosis in migrants and visitors from high incidence settings: present and future perspectives. Eur Respir J. 2018; https://doi.org/10.1183/13993003.00591-­2018. 3. Pareek M, Greenaway C, Noori T, Munoz J, Zenner D. The impact of migration on tuberculosis epidemiology and control in high-income countries: a review. BMC Med. 2016;14:48. https://doi.org/10.1186/s12916-­016-­0595-­5.

23  Tuberculosis and Migration

209

4. International Organization for Migration (IOM). World migration report 2020. Grand-­ Saconnex: IOM; 2020. 5. WHO Regional Office for Europe/European Centre for Disease Prevention and Control. Tuberculosis surveillance and monitoring in Europe 2019–2017 data. Copenhagen: WHO Regional Office for Europe; 2019. 6. Public Health England. Tuberculosis in England 2019 report: Executive summary. London: Public Health England; 2019. 7. Schwartz NG, Price SF, Pratt RH, Langer AJ. Tuberculosis – United States, 2019. MMWR Morb Mortal Wkly Rep. 2020;69(11):286–9. https://doi.org/10.15585/mmwr.mm6911a3. 8. NSW Tuberculosis Program, Communicable Diseases Branch. Tuberculosis in NSW – surveillance report 2018. Sydney: Health Protection NSW; 2019. 9. Aldridge RW, Zenner D, White PJ, Williamson EJ, Muzyamba MC, Dhavan P, et al. Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland. Lancet. 2016;388(10059):2510–8. https://doi.org/10.1016/s0140-­6736(16)31008-­x. 10. Sandgren A, Schepisi MS, Sotgiu G, Huitric E, Migliori GB, Manissero D, et al. Tuberculosis transmission between foreign- and native-born populations in the EU/EEA: a systematic review. Eur Respir J. 2014;43(4):1159–71. https://doi.org/10.1183/09031936.00117213. 11. Pareek M, Watson JP, Ormerod LP, Kon OM, Woltmann G, White PJ, et  al. Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis. Lancet Infect Dis. 2011;11(6):435–44. https://doi.org/10.1016/ s1473-­3099(11)70069-­x. 12. Campbell JR, Krot J, Elwood K, Cook V, Marra F. A systematic review on TST and IGRA tests used for diagnosis of LTBI in immigrants. Mol Diagn Ther. 2015;19(1):9–24. https://doi. org/10.1007/s40291-­014-­0125-­0. 13. Kaushik N, Lowbridge C, Scandurra G, Dobler CC. Post-migration follow-up programme for migrants at increased risk of developing tuberculosis: a cohort study. ERJ Open Res. 2018;4(3) https://doi.org/10.1183/23120541.00008-­2018. 14. Shea KM, Kammerer JS, Winston CA, Navin TR, Horsburgh CR Jr. Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol. 2014;179(2):216–25. https://doi.org/10.1093/aje/kwt246. 15. Dobler CC, Crawford AB, Jelfs PJ, Gilbert GL, Marks GB.  Recurrence of tuber culosis in a low-­ incidence setting. Eur Respir J. 2009;33(1):160–7. https://doi. org/10.1183/09031936.00104108. 16. Lönnroth K, Migliori GB, Abubakar I, D’Ambrosio L, de Vries G, Diel R, et  al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45(4):928–52. https://doi.org/10.1183/09031936.00214014. 17. Pareek M, Baussano I, Abubakar I, Dye C, Lalvani A.  Evaluation of immigrant tuberculosis screening in industrialized countries. Emerg Infect Dis. 2012;18(9):1422–9. https://doi. org/10.3201/eid1809.120128. 18. Alvarez GG, Gushulak B, Abu Rumman K, Altpeter E, Chemtob D, Douglas P, et al. A comparative examination of tuberculosis immigration medical screening programs from selected countries with high immigration and low tuberculosis incidence rates. BMC Infect Dis. 2011;11:3. https://doi.org/10.1186/1471-­2334-­11-­3. 19. Chan IHY, Kaushik N, Dobler CC.  Post-migration follow-up of migrants identified to be at increased risk of developing tuberculosis at pre-migration screening: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(7):770–9. https://doi.org/10.1016/ s1473-­3099(17)30194-­9. 20. Aldridge RW, Yates TA, Zenner D, White PJ, Abubakar I, Hayward AC.  Pre-entry screening programmes for tuberculosis in migrants to low-incidence countries: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(12):1240–9. https://doi.org/10.1016/ s1473-­3099(14)70966-­1. 21. Lowenthal P, Westenhouse J, Moore M, Posey DL, Watt JP, Flood J. Reduced importation of tuberculosis after the implementation of an enhanced pre-immigration screening protocol. Int J Tuberc Lung Dis. 2011;15(6):761–6. https://doi.org/10.5588/ijtld.10.0370.

210

C. C. Dobler and L. R. Codecasa

22. Kranzer K, Afnan-Holmes H, Tomlin K, Golub JE, Shapiro AE, Schaap A, et  al. The benefits to communities and individuals of screening for active tuberculosis disease: a systematic review. Int J Tuberc Lung Dis. 2013;17(4):432–46. https://doi.org/10.5588/ijtld.12.0743. 23. U.S. Department of Health and Human Services – Centers for Disease Control and Prevention. Technical instructions for TB screening and treatment using cultures and directly observed therapy. Washington, DC: Division of Global Migration and Quarantine; 2009. 24. Australian Government, Department of Immigration and Border Protection. What health examinations you need, Permanent and provisional visa applicants. https://immi.homeaffairs. gov.au/help-­support/meeting-­our-­requirements/health/what-­health-­examinations-­you-­need. Accessed May 29, 2020. 25. McBryde ES, Denholm JT. Risk of active tuberculosis in immigrants: effects of age, region of origin and time since arrival in a low-exposure setting. Med J Aust. 2012;197(8):458–61. https://doi.org/10.5694/mja12.10035. 26. Erkens C, Slump E, Kamphorst M, Keizer S, van Gerven PJ, Bwire R, et al. Coverage and yield of entry and follow-up screening for tuberculosis among new immigrants. Eur Respir J. 2008;32(1):153–61. https://doi.org/10.1183/09031936.00137907. 27. Liu Y, Posey DL, Cetron MS, Painter JA.  Effect of a culture-based screening algorithm on tuberculosis incidence in immigrants and refugees bound for the United States: a population-­ based cross-sectional study. Ann Intern Med. 2015;162(6):420–8. https://doi.org/10.7326/ m14-­2082. 28. Dobler CC. Screening strategies for active tuberculosis: focus on cost-effectiveness. Clin Econ Outcomes Res. 2016;8:335–47. https://doi.org/10.2147/ceor.s92244. 29. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM.  Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;(2):CD001363. https://doi. org/10.1002/14651858.CD001363. 30. Wieland ML, Weis JA, Yawn BP, Sullivan SM, Millington KL, Smith CM, et al. Perceptions of tuberculosis among immigrants and refugees at an adult education center: a community-­ based participatory research approach. J Immigr Minor Health. 2012;14(1):14–22. https://doi. org/10.1007/s10903-­010-­9391-­z. 31. Seedat F, Hargreaves S, Friedland JS. Engaging new migrants in infectious disease screening: a qualitative semi-structured interview study of UK migrant community health-care leads. PLoS One. 2014;9(10):e108261. https://doi.org/10.1371/journal.pone.0108261. 32. de Vries SG, Cremers AL, Heuvelings CC, Greve PF, Visser BJ, Bélard S, et al. Barriers and facilitators to the uptake of tuberculosis diagnostic and treatment services by hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review of qualitative literature. Lancet Infect Dis. 2017;17(5):e128–e43. https://doi.org/10.1016/ s1473-­3099(16)30531-­x. 33. Villa S, Codecasa LR, Faccini M, Pontello MM, Ferrarese M, Castellotti PF, et al. Tuberculosis among asylum seekers in Milan, Italy: epidemiological analysis and evaluation of interventions. Eur Respir J. 2019;54(4) https://doi.org/10.1183/13993003.00896-­2019. 34. Spruijt I, Tesfay Haile D, Suurmond J, van den Hof S, Koenders M, Kouw P, et al. Latent tuberculosis screening and treatment among asylum seekers: a mixed-methods study. Eur Respir J. 2019;54(5) https://doi.org/10.1183/13993003.00861-­2019. 35. Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J. 2015;46(6):1563–76. https://doi.org/10.1183/13993003.01245-­2015. 36. Zenner D, Loutet MG, Harris R, Wilson S, Ormerod LP. Evaluating 17 years of latent tuberculosis infection screening in north-west England: a retrospective cohort study of reactivation. Eur Respir J. 2017;50(1) https://doi.org/10.1183/13993003.02505-­2016. 37. Dobler CC, Martin A, Marks GB.  Benefit of treatment of latent tuberculosis infection in individual patients. Eur Respir J. 2015;46(5):1397–406. https://doi.org/10.1183/1399300 3.00577-­2015. 38. Villa S, Ferrarese M, Sotgiu G, Castellotti PF, Saderi L, Grecchi C, et  al. Latent tuberculosis infection treatment completion while shifting prescription from isoniazid-only to

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rifampicin-­ containing regimens: a two-decade experience in Milan, Italy. J Clin Med. 2019;9(1) https://doi.org/10.3390/jcm9010101. 39. Rosales-Klintz S, Bruchfeld J, Haas W, Heldal E, Houben R, van Kessel F, et al. Guidance for programmatic management of latent tuberculosis infection in the European Union/European Economic Area. Eur Respir J. 2019;53(1) https://doi.org/10.1183/13993003.02077-­2018. 40. Codecasa LR, Murgia N, Ferrarese M, Delmastro M, Repossi AC, Casali L, et al. Isoniazid preventive treatment: predictors of adverse events and treatment completion. Int J Tuberc Lung Dis. 2013;17(7):903–8. https://doi.org/10.5588/ijtld.12.0677. 41. Pittalis S, Piselli P, Contini S, Gualano G, Alma MG, Tadolini M, et al. Socioeconomic status and biomedical risk factors in migrants and native tuberculosis patients in Italy. PLoS One. 2017;12(12):e0189425. https://doi.org/10.1371/journal.pone.0189425. 42. Spruijt I, Erkens C, Suurmond J, Huisman E, Koenders M, Kouw P, et al. Implementation of latent tuberculosis infection screening and treatment among newly arriving immigrants in The Netherlands: a mixed methods pilot evaluation. PLoS One. 2019;14(7):e0219252. https://doi. org/10.1371/journal.pone.0219252. 43. Dobler CC, Luu Q, Marks GB. What patient factors predict physicians’ decision not to treat latent tuberculosis infection in tuberculosis contacts? PLoS One. 2013;8(9):e76552. https:// doi.org/10.1371/journal.pone.0076552. 44. Dobler CC, Bosnic-Anticevich S, Armour CL.  Physicians’ perspectives on communication and decision making in clinical encounters for treatment of latent tuberculosis infection. ERJ Open Res. 2018;4(1) https://doi.org/10.1183/23120541.00146-­2017.

Tuberculosis in People Living with HIV

24

Svetlana Degtyareva, Scott Heysell, Nashaba Matin, Zelalem Temesgen, and Marc Lipman

Abstract

Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection occurs throughout the world, and remains a significant challenge to TB control. Both HIV and TB cause immune dysregulation that can result in atypical clinical and radiological presentation, and accelerated disease progression. Outcomes with advanced HIV and TB, therefore, can be poor. Whilst antiretroviral drug therapy is crucial, drug-drug interactions and immune reconstitution disease make treatment difficult. The joint effort of healthcare programmes, non-governmental organisations and civil society are needed to ensure the necessary access to testing, prevention and treatment that can reduce the burden of TB/HIV co-infection. S. Degtyareva Infectious Diseases with Courses of Epidemiology and Phthisiology, RUDN University, Moscow, Russian Federation e-mail: [email protected] S. Heysell Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA e-mail: [email protected] N. Matin Barts Health NHS Trust, London, UK e-mail: [email protected] Z. Temesgen Mayo Clinic Center for Tuberculosis, Mayo Clinic, Rochester, MN, USA HIV Program, Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] M. Lipman (*) UCL Respiratory, University College London, London, UK Respiratory Medicine, Royal Free London NHS Foundation Trust, London, UK e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_24

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Keywords

HIV-associated tuberculosis · Co-infection · Immunosuppression · Mycobacteraemia · Diagnostic tests · Extra-pulmonary tuberculosis · LAM test · GeneXpert · Drug–drug interactions · IRIS · Latent TB infection

24.1 Introduction Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection presents a significant challenge to global TB prevention, management and control. In this chapter, we discuss the features of adult TB/HIV co-infection that differ from nonHIV related TB and highlight areas of clinical importance relevant to the patient and the delivery of high-quality care.

24.2 Epidemiology of Tuberculosis/HIV Co-infection TB/HIV co-infection occurs throughout the world. Of the ten million people who developed TB in 2018, 862,000 (8.6%) were estimated by the World Health Organization (WHO) to be living with HIV. While 71% were in the WHO Africa region, the incidence has continued to rise in Eastern Europe and Central Asia (Fig. 24.1). The number of deaths from TB in people living with HIV (PLWH) has fallen by 60% since 2000. Most of this reduction has occurred in Africa and is attributable to the expansion of HIV testing and antiretroviral therapy (ART) coverage. Even so, of

HIV prevalence in new and relapse TB cases, all ages (%) 0–4.9 5–9.9 10–19 20–49 ≥50 No data Not applicable

Fig. 24.1  Estimated HIV prevalence in new and relapsed TB cases, 2018 (Reproduced from Global Tuberculosis Report 2019. Geneva. World Health Organisation 2019. Licence: CC BY-NC-SA 3.0 IGO)

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the 1.5 million deaths due to TB in 2018, approximately 250,000 were in PLWH. This comprises an estimated one-third of all deaths due to HIV/acquired immunodeficiency syndrome (AIDS) [1]. It is not clear beyond a shared epidemiological exposure to drug-resistant infection whether PLWH have a specific-increased risk of multidrug resistant or extensively drug resistant TB [2].

24.3 I mpact of Tuberculosis/HIV Interaction on Clinical Presentation and Diagnosis Unlike typical opportunistic infections associated with HIV, TB can develop in PLWH at any stage of HIV disease. Untreated HIV dramatically increases the risk of progression to TB disease (up to 20 times background rates) from both primary TB infection and reactivation of latent TB. As the relative risk of TB increases when blood CD4 counts and immunity decline, CD4 T cell depletion has been considered central to this [3]. However, despite a reduction in progression to TB disease being associated with apparent immune reconstitution from antiretroviral therapy (ART), in high burden TB settings TB rates in PLWH remain above background levels— suggesting that HIV impairs host defences against TB via mechanisms beyond CD4 T cell depletion and/or that ART may not adequately reconstitute CD4 cells in some tissue compartments, such as the lung [4]. Depending on the degree of host immunocompromise, the clinical presentation of TB/HIV varies from typical to atypical. With lower CD4 cell counts (especially 14–25 kg: 450 mg/dose; >25–32 kg: 600 mg/dose; >32–50 kg: 750 mg/dose; >50 kg: 900 mg/dose Dose not established in children. 5 mg/kg daily to 3×/ week has been used (max 300 mg)

Rifampicin (R)

Rifapentine (Rpt)

15–20 mg/kg/day

10–15 mg/kg/day

>12 years and >30 kg body weight: Adult dose of 400 mg daily × 2 weeks followed by 200 mg M/W/F × 24 weeks >6 years and 15–30 kg: 200 mg daily × 2 weeks followed by 100 mg M/W/F for 24 weeks Data on dose in younger children not yet available

WHO Group A Levofloxacin (Lfx)

Moxifloxacin (Mfx)

Bedaquiline (Bdq)

Rifabutin (Rfb)

15–25 mg/kg/day 7–15 mg/kg/day; (neonates only 10 mg/kg/day) high-dose 15–20 mg/kg/day

30–40 mg/kg/day

First-line drugs Pyrazinamide (Z)

Ethambutol (E) Isoniazid (H)a

Dose

Drug name

Needs further evaluation in children

Pharmacokinetic data for children 12 years/≥35 kg: 100 mg twice daily 6–12 years/20–34 kg: 50 mg twice daily 3–5 years/10–20 kg: 25 mg twice daily Data in younger children not yet available 20–40 mg/kg 8 hourly (IV)

Amikacinb (Am) or Streptomycin (Sm)

Delamanid (Dlm)

200–300 mg/kg daily as single or divided dose

Pharmacokinetic studies in children ongoing

Pharmacokinetic studies in children ongoing

Sutezolid possible safer option. No data in children

Only to use if susceptibility confirmed Only to use if susceptibility confirmed Ototoxicity (irreversible), nephrotoxicity Higher doses only if therapeutic drug monitoring (TDM) is available. Kanamycin and capreomycin no longer recommended Nausea, vomiting, dizziness, paraesthesia, Dose-finding and safety studies ongoing anxiety, QTc prolongation Pretomanid (Ptm), a similar novel agent, no pharmacokinetic studies in children GI intolerance, hypersensitivity reactions, Always use with carbapenem seizures, liver and renal dysfunction GI intolerance, hypersensitivity reactions, Always combine with a carbapenem seizures, liver and renal dysfunction (not effective on its own) Gastrointestinal disturbance, metallic Co-resistance in inhA promoter region taste, hypothyroidism mutations conferring isoniazid resistance GI intolerance, hypothyroidism, hepatitis Pharmacokinetic studies ongoing. Tolerance with single daily dose good according to experience

Neurological and psychological effects

Skin discolouration, ichthyosis, QTc prolongation, abdominal pain

Diarrhoea, headache, nausea, myelosuppression, peripheral neuritis, optic neuritis, lactic acidosis and pancreatitis

IMI intramuscular injection, IVI intravenous infusion, EBA early bactericidal activity a If isoniazid is used, supplement with pyridoxine (Vitamin B6) in infants and adolescents, in all malnourished and HIV-positive children, and when high-dose isoniazid is used to prevent peripheral neuropathy b Can be given with lidocaine to reduce pain of IM injections

Amoxicillin-­ clavulanate (Amx-clv) Ethionamide (Eto) or Prothionamide (Pto) Para-­aminosalicylic acid (PAS)

75 mg/kg/day in 3 divided doses of amoxicillin component 15–20 mg/kg/day

See first-line drugs above

Pyrazinamide

Meropenem (Mpm)

See first-line drugs above

2–5 mg/kg/day. Because of current 50 or 100 mg gel capsule formulations, alternative day dosing may be necessary in young children 15–20 mg/kg/day

Children ≤15 kg body weight: 15 mg/kg once daily Children/adolescents >15 kg 10–12 mg/kg once daily

Cycloserine (Cs) or Terizidone (Trd) WHO Group C Ethambutol

WHO Group B Clofazimine (Cfz)

Linezolid (Lzd)

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Studies are ongoing for shorter, effective regimens for TB meningitis with higher rifampicin dosing, and with a fluoroquinolone in the regimen. On the other hand, optimal doses of first-line medications in neonates and young infants need more investigation; a recent study of isoniazid in low birthweight and premature infants found that a dose of 10 mg/kg/day is adequate for all acetylator types in these young patients.

26.3.5  Treatment of DR Tuberculosis Guidance for the treatment of DR-TB, especially MDR-TB, is changing rapidly. Recently, the addition of new and repurposed medications has been recommended for the treatment of MDR-TB, as well as removal of the injectable medications in almost all regimens. Shorter regimens for rifampicin mono-resistant (RMR) and MDR-TB have been advised, and new pharmacokinetic data is available to guide second-line medication dosing. Child-friendly medications have also been developed [2, 6, 7]. The principles of DR-TB treatment are similar to those of adults. It is important to try to confirm DR-TB in the child; however, presumptive DR-TB cases should be treated as DR-TB according to the DST results of the adult index case’s isolate. Treatment regimens should include at least four effective medications (i.e., confirmed susceptibility or medications not previously used) [6]. Treatment should be daily, and in children and adolescents, a reliable caregiver or supporter should be identified to observe and support treatment. Progress should be monitored clinically, radiologically and bacteriologically if the child has culture-confirmed disease. Adherence and adverse effects should be monitored and managed appropriately. Treatment regimens for DR-TB are summarised in Box 26.2, and the medications, doses and important adverse effects are summarised in Table 26.2. Suggested regimens for children with DR-TB of different ages and with different resistant profiles to the fluoroquinolones can also be found in the Sentinel Project Field Guide [8]. Duration of MDR-TB treatment in children is variable, and clinicians should consider severity of disease (non-severe vs. severe), extent of drug resistance, site of infection (e.g. TB meningitis or osteoarticular TB) and response to treatment when deciding how long to treat. Treatment duration may vary from 9 to 20  months. Studies are planned to evaluate 6-month treatment regimens in children with MDR-TB with and without fluoroquinolone resistance using a combination of new and repurposed medications.

26.3.6  Drug–Drug Interactions (DDIs) with Antiretroviral Therapy (ART) Medications DDIs are mainly caused through rifampicin induction of cytochrome P450 isoenzymes. This mainly affects the protease inhibitors, such as lopinavir/ritonavir (LPV/r), the serum concentration of which is significantly reduced (80–90%) when co-administered with rifampicin. In adults and older children, double-dosing LPV/r effectively overcomes this reduction, but trough concentrations with double-dosing LPV/r in young children (50% in adult studies, and doubling the dose to twice daily is recommended. No data are available in children [9].

26.3.7  Corticosteroids Corticosteroids are currently recommended in TB meningitis and intracranial tuberculomas, TB lymph node compression of large airways and in some cases of TB immune reconstitution inflammatory syndrome in HIV-positive children. Use of corticosteroids in pericardial effusions is controversial.

26.3.8  Cotrimoxazole Prophylactic dose cotrimoxazole is recommended in all HIV-positive children during TB treatment.

26.3.9  Hydrocephalus Due to Tuberculosis Meningitis Acetazolamide and furosemide are often used in communicating hydrocephalus, while insertion of an extraventricular drain or a ventriculoperitoneal shunt is indicated in acute progression of raised intracranial pressure or non-communicating hydrocephalus.

26.3.10  Surgical Intervention Surgery is rarely indicated in children. Young children with severe airway compression may need nodal decompression, and children with osteoarticular TB may need surgical intervention. It may be necessary to perform diagnostic procedures for children with abdominal TB and large abscesses (such as psoas abscesses) may require drainage.

26.4 Preventive Therapy Preventive therapy for children exposed to drug-susceptible TB is effective and has been recommended by the WHO and many countries for many years. It is an important part of the WHO End TB Strategy to eliminate TB globally [10]. Children exposed to MDR-TB have long been neglected. However, more recent WHO

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guidelines indicate that preventive therapy should be considered in high-risk household contacts of patients with MDR-TB, based on individualised risk/benefit assessment [11]. In an expert consensus Policy Brief, the provision of MDR-TB preventive therapy to all high-risk contacts, including children under 5 years and immunocompromised individuals, is recommended using a fluoroquinolone (either alone or in combination with another agent to which the strain from the source case is susceptible) for 6 months [12]. Two clinical trials comparing levofloxacin to placebo are ongoing (TB-CHAMP and VQUIN) [13]. Preventive therapy regimens for drug-­ susceptible and different patterns of DR-TB are summarised in Table 26.2.

26.5 Summary and Recommendations Diagnosing TB in children requires the synthesis and combination of varying sources of evidence. While the ultimate goal of a bacteriological confirmed diagnosis can be elusive, all efforts should be made to collect samples to identify M. tuberculosis. Treatment of drug-susceptible TB depends on the type and extent of disease. Dosing and regimen construction could still be improved. This includes the dosage of rifampicin and the ideal regimen for TB meningitis. TB/HIV co-infection is becoming less common, but DDIs are important to consider when dual therapy is indicated. Adverse effects are uncommon, but severe adverse effects such as hepatotoxicity need to be acted on urgently. The treatment of MDR-TB is rapidly changing. New and repurposed medications have almost eliminated the need for injectable agents and shorter treatment durations are possible with all-oral regimens. However, adverse effects should be carefully monitored. Much is still to be learned regarding the new medications and their combinations.

References 1. World Health Organization. Global Tuberculosis Report. WHO/CDS/TB/2019.15. Geneva, Switzerland. 2019. https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-­ eng.pdf?ua=1. Accessed 22 Oct 2019. 2. Schaaf HS, Marais BJ, Carvalho I, Seddon JA.  Challenges in childhood tuberculosis. In: Migliori GB, Bothamley G, Duarte R, Rendon A, editors. Tuberculosis (ERS monograph). Sheffield: European Respiratory Society; 2018. p. 234–62. 3. Sartoris G, Seddon JA, Rabie H, Nel ED, Schaaf HS.  Abdominal tuberculosis in children: challenges, uncertainty, and confusion. J Pediatr Infect Dis Soc. 2020. pii: piz093. [Epub ahead of print]. https://doi.org/10.1093/jpids/piz093. 4. Heuvelings CC, Belard S, Andronikou S, Lederman H, Moodley H, Grobusch MP, Zar HJ. Chest ultrasound compared to chest X-ray for pediatric pulmonary tuberculosis. Pediatr Pulmonol. 2019;54(12):1914–20. 5. Wiseman CA, Gie RP, Starke JR, Schaaf HS, Donald PR, Cotton MF, Hesseling AC. A proposed comprehensive classification of tuberculosis disease severity in children. Pediatr Infect Dis J. 2012;31(4):347–52.

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6. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva, Switzerland. 2019. https://apps.who.int/iris/bitstream/han dle/10665/311389/9789241550529-­eng.pdf?ua=1. Accessed 23 Feb 2020. 7. Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, Cattamanchi A, Cegielski JP, Chen L, Daley CL, Dalton TL, Duarte R, Fregonese F, Horsburgh CR Jr, Ahmad Khan F, Kheir F, Lan Z, Lardizabal A, Lauzardo M, Mangan JM, Marks SM, McKenna L, Menzies D, Mitnick CD, Nilsen DM, Parvez F, Peloquin CA, Raftery A, Schaaf HS, Shah NS, Starke JR, Wilson JW, Wortham JM, Chorba T, Seaworth B. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med. 2019;200(10):e93–e142. 8. The Sentinel Project for Pediatric Drug-Resistant Tuberculosis. Management of drug-­resistant tuberculosis in children: a field guide. 4th ed. Boston: The Sentinel Project for Pediatric Drug-Resistant Tuberculosis; 2018. http://sentinel-­project.org/wp-­content/uploads/2019/02/ Updated_DRTB-­Field-­Guide-­2019-­V3.pdf. Accessed 23 Feb 2020. 9. Rabie H, Decloedt EH, Garcia-Prats AJ, Cotton MF, Frigati L, Lallemant M, Hesseling A, Schaaf HS.  Antiretroviral treatment in HIV-infected children who require a rifamycin-­ containing regimen for tuberculosis. Expert Opin Pharmacother. 2017;18(6):589–98. 10. World Health Organization. The end TB strategy. Geneva, Switzerland. 2015. http://www.who. int/tb/strategy/End_TB_Strategy.pdf?ua=1. Accessed 23 Feb 2020. 11. World Health Organization. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva, Switzerland. 2018. http://www.who.int/tb/publications/2018/latent-­tuberculosis-­infection/en/. Accessed 23 Feb 2020. 12. Seddon JA, Fred D, Amanullah F, Schaaf HS, Starke JR, Keshavjee S, Burzynski J, Furin JJ, Swaminathan S, Becerra MC.  Post-exposure managment of multidrug-resistant tuberculosis contacts: evidence-based recommendations. Policy Brief No. 1 Dubai, United Arab Emirates: Harvard Medical School Centre for Global Health Delivery—Dubai. 2015. http:// sentinel-­project.org/wp-­content/uploads/2015/11/Harvard-­Policy-­Brief_revised-­10Nov2015. pdf. Accessed 11 Jun 2018. 13. Schaaf HS, Garcia-Prats AJ, McKenna L, Seddon JA.  Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children. Expert Rev Clin Pharmacol. 2018;11(3):233–44. 14. Fregonese F, Ahuja SD, Akkerman OW, Arakaki-Sanchez D, Ayakaka I, Baghaei P, Bang D, Bastos M, Benedetti A, Bonnet M, Cattamanchi A, Cegielski P, Chien JY, Cox H, Dedicoat M, Erkens C, Escalante P, Falzon D, Garcia-Prats AJ, Gegia M, Gillespie SH, Glynn JR, Goldberg S, Griffith D, Jacobson KR, Johnston JC, Jones-Lopez EC, Khan A, Koh WJ, Kritski A, Lan ZY, Lee JH, Li PZ, Maciel EL, Galliez RM, Merle CSC, Munang M, Narendran G, Nguyen VN, Nunn A, Ohkado A, Park JS, Phillips PPJ, Ponnuraja C, Reves R, Romanowski K, Seung K, Schaaf HS, Skrahina A, Soolingen DV, Tabarsi P, Trajman A, Trieu L, Banurekha VV, Viiklepp P, Wang JY, Yoshiyama T, Menzies D. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med. 2018;6(4):265–75.

Tuberculosis in Women

27

Paul P. Nunn, Araksya Hovhannesyan, and Aamna Rashid

Abstract

Over three million women currently develop tuberculosis (TB) annually. In 2018, 34% of TB notifications were in women, 58% in men and 8% in children. The global male:female (M:F) ratio for TB notifications was 1.7 (regional range 1.1–2.1). A few countries, with histories of recent unrest or emigration or both, notify more women than men. Prevalence surveys confirm that, in most countries, women do get TB less than men, but women with TB are more likely to be notified. TB is still a massive burden for women, who generally have a lower social, economic and cultural standing in many societies. Health infrastructures are often women-­unfriendly. More than TB in men, the consequences of a woman with TB spill over to families and children, even the unborn. Although longsuspected, TB was recently shown to be significantly more common in pregnancy and the post-­partum period, combined, and both TB-affected mothers and their infants suffer poor outcomes. TB in pregnant women with HIV significantly increases obstetric mortality and doubles the risk of vertical transmission of HIV to the unborn child. Recently, isoniazid has been associated with poor outcomes of pregnancy when used for treating latent TB infection in HIV-positive pregnant women, presenting a problem for clinicians. Recommendations focus on correcting the neglect of collaboration and coordination between national TB programmes and mother and child health services.

P. P. Nunn (*) Global Infectious Diseases Consulting, Ltd., London, UK A. Hovhannesyan Yerevan, Armenia A. Rashid Mercy Corps, Islamabad, Pakistan e-mail: [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_27

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Keywords

Tuberculosis · Women · Gender · Sex differences · Epidemiology · Male:female ratio

27.1 Introduction In 2018, an estimated 3.2 million women fell ill with tuberculosis (TB) and nearly half a million women died from it [1]. TB is thus within the top six killers of adult women aged 15–49 years. Twenty years ago, global male:female (M:F) notification ratios greater than two fuelled concerns that women with TB were being systematically overlooked [2]. Nowadays, it seems clear that, in fact, less women than men get TB each year, but women still have to contend with sex- and gender-specific barriers to diagnosis and treatment.

27.2 Epidemiology of Tuberculosis in Women 27.2.1 Latent Infection The majority of studies from high-burden countries shows that girls and boys have similar levels of TB infection, but starting around adolescence, females are less likely than males to be infected [3]. This difference may be intrinsic or biological, the result of the sex of the individual, implying that females are resistant to infection, or to social or behavioural factors (gender differences) that expose boys or men to infection more than girls or women, or both. Once infected, males and females may then have different rates of primary disease, re-activation or exogenous re-infection.

27.2.2 Notifications and Risk Factors In the early part of the twentieth century in some Western countries, and in the Inuit in Alaska and Greenland, notifications and mortality among women of child-­bearing age exceeded those of men of the same age [3], implying a greater risk of disease in infected women, compared to infected men. Over time, this difference has disappeared and even reversed. In 2018, globally, only 34% of notifications were in women, compared to 58% in men and 8% in children. The global M:F ratio for TB notifications was 1.7, although it varied across regions [1] (Fig. 27.1). The M:F notification ratio is usually close to 1 in children under 15 and in most countries it begins to increase (males>females) between 15 and 54 years of age, rising further with age. The likely explanation is that women are less exposed to risk factors for TB.  In Portugal, for example [4], women older than 20 years had lower odds than men of

27  Tuberculosis in Women Africa 200 150 100

247 The Americas

40

60

30

50

25

40

20

30

15 50

20

10

10

5 0

0

0 0-4

Eastern Mediterranean

35

05-14 15-24 25-34 35-44 45-54 55-64 65plus

0-4

Europe

0-4 05-14 15-24 25-34 35-44 45-54 55-64 65plus

05-14 15-24 25-34 35-44 45-54 55-64 65plus

South-East Asia

Western Pacific

40 400 350 300 250 200 150 100 50 0

35 30 25 20 15 10 5 0 0-4

05-14 15-24 25-34 35-44 45-54 55-64 65plus

250 200 150 100 50 0-4 05-14 15-24 25-34 35-44 45-54 55-64 65plus

Females

0 0-4 05-14 15-24 25-34 35-44 45-54 55-64 65plus

Males

Fig. 27.1  Notified number of new and relapse tuberculosis cases (thousand) by sex and age groups, by WHO Region, 2018 (WHO 2019)

having the known risk factors of silicosis, a history of imprisonment, alcohol abuse, drug use, socioeconomic deprivation, previous TB treatment, and human immunodeficiency virus (HIV), as well as evidence of lower rates of tobacco smoking. There are a few countries where women are consistently notified more than men: Afghanistan, Bhutan, Lebanon, Oman and United Arab Emirates. Jordan, Kuwait, Pakistan and Yemen have sometimes reported similarly, but not consistently. Two countries have reported a recent switch from a predominance of men to a majority of women among notifications, Iraq (from 2012) and Tunisia (from 2016). In the Islamic Republic of Iran, the reverse occurred around 2012. The reasons for these observations are not clear, but many of these countries have experienced high levels of unrest or emigration, or both. Recent census data are not always available. It may be that men have preferentially emigrated in times of unrest resulting in a skewed population structure. Men may also preferentially attend the private sector, from where notifications are unusual, or may avoid seeking medical care altogether. However, if the barriers to access to TB diagnosis and notification vary by sex, notification data might not reflect the true burden of disease.

27.2.3 Tuberculosis Prevalence Survey Data TB prevalence surveys provide more robust measures of the TB burden among men and women than notifications can, since they are, in theory, unaffected by the barriers of care-seeking or access to diagnostic services. Moreover, the comparison of prevalence results with notifications assesses the extent of under-notification and enables identification of groups that are being missed by healthcare systems. A series of reviews of TB prevalence surveys conducted in high-burden, low-­ income countries between 1953 and 2014, all showed that TB prevalence among

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males exceeded that among females [5–7] with M:F ratios of 2.2 for bacteriologically positive TB, and 2.5 for smear positive TB.  The M:F prevalence ratio was higher in South-East Asia than in Africa, and increased linearly with age. Data from only the most recent surveys confirmed the previous findings in spite of the fact that women participated in the surveys more than men. Surveys that required individuals to self-report signs or symptoms of TB in initial screening procedures yielded M:F ratios lower than those in surveys with more objective screening procedures, suggesting that men with TB are less likely to report symptoms. Alternatively, the subclinical phase of disease may be longer for men. The ratio of prevalence to notifications (P:N) is used to assess the gap in timely diagnosis and reporting of TB (Fig. 27.2). The median number of prevalent cases per notified case of TB was much higher among men (2.7) than women (1.7) [7]. This suggests that in many countries, a higher TB burden in men is compounded by a failure to seek care, and get a timely diagnosis. Women, in fact, are more likely than men to seek and/or access TB care in many settings. An alternative explanation is that men are more likely than women to go to the private sector, where, in many countries, especially in Asia, few cases are notified. However, there are no sex-­ disaggregated data from large-scale private settings to corroborate this.

27.3 Gender-Related Barriers for Women 27.3.1 Access to Diagnosis and Care The fact that overall, women get less TB than men, or are better at noticing their symptoms, or more successful than men in getting notified, does not preclude women having serious access barriers of their own to contend with. Women generally have lower social, economic and cultural standing and their economic dependence on men, and restrictions on their mobility, suggest they have more restricted access than men to health services [8]. Men often control household resources, so they take health-related decisions for women. Intra-household bias towards males in food distribution, early marriage of girls, excessive childbearing and a high level of illiteracy adversely affect women’s health—and increase their risk of TB. The role of women is to perform household duties and look after the children. However, it may be precisely the child-caring role that brings mothers into contact with health services, and thus enables diagnosis of their TB earlier than men. Gender-insensitive healthcare infrastructure and practices in low-income countries also have an impact on women’s access to services. Although women are less likely to delay seeking care, once they do access TB services, they generally wait longer than men for diagnosis and treatment and are less likely to have their sputum examined. Women who attend TB services complain about a lack of privacy when receiving directly observed treatment, and women with children may not be able to attend TB services regularly due to a lack of alternative childcare. Lack of an assured female medical attendant when they arrive at a health facility or long distances from home to health centre are further disincentives for women, especially in those countries where they need a man to accompany them. Richer

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Nigeria 2012 China 2010 Lao 2010-2011 Philippines 2016 Tanzania 2012 Pakistan 2010-11 Uganda 2014-2015 Philippines 2007 Kenya 2016 Zambia 2013-2014 DPR Korea 2016 Ghana 2013 Eritrea 2005 Myanmar 2009-2010 Vietnam 2006-2007 Thailand 2012 Cambodia 2011 Mongolia 2014 Cambodia, 2002 Ethiopia 2010-2011 Zimbabwe 2014 Namibia 2017

Male

Rwanda, 2012 Female

Bangladesh 2007-2009 Gambia 2012 0.0

2.0

4.0

6.0

8.0

P:N ratio

Fig. 27.2  The prevalence to notification (P:N) ratio by sex for adult TB cases in nationwide prevalence surveys with publicly available reports. For Bangladesh, Cambodia (2002 and 2011), Eritrea, Ethiopia, Gambia, Ghana, Lao PDR, Mongolia, Myanmar, Nigeria, Pakistan, Philippines (2007), Rwanda, Tanzania, Thailand, Vietnam, Zambia the P:N ratio is for smear-positive TB cases. Prevalence estimates are from the published reports and notification data are obtained from the notified new sputum smear positive TB cases for that year available in the World Health Organization (WHO) Global TB database. For China 2010, Uganda, Kenya, DPR Korea, Zimbabwe and Namibia, the P:N ratio is for bacteriologically confirmed TB cases. For Kenya, DPR Korea, Namibia and Zimbabwe notification data are obtained from the notified new and relapse TB cases available for that year in the Global TB database. The rest of the data are extracted from the original study reports. Annual population numbers by age and sex were obtained from the World Population Prospects—2019

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countries appear to provide more equitable services [9]. Women are less likely to die from TB, before or during treatment.

27.3.2 Impact of Tuberculosis Stigma Stigma and discrimination in some settings seem to hit women more than men and lead to women with TB being ostracized by their families and communities. A woman who develops TB may have difficulty in finding a husband, or, if married, may be divorced by him. In India [10], in spite of family members by and large being supportive to women with TB, 10% of their marriages ended in divorce (commoner among younger spouses), 25% reported being isolated and discriminated against in their homes, 18% were rejected by husbands and in-laws and 40% of single women taken off the “marriage market” altogether. While men with TB expected their wives to care for them, wives with TB rarely received care. Children, especially girls, had to stay home from school to care for their sick mothers. Higher stigma was associated with higher class.

27.4 Tuberculosis and Maternal and Neonatal Health Globally in 2011, there were about 216,500 pregnant women with active tuberculosis, the majority in Africa and South-East Asia [11]. Peri-partum women are likely to have an almost twofold increased risk of active TB [12], and maternal TB is associated with an increased risk of small-for-gestational age, preterm and low-­ birthweight neonates and high perinatal mortality [13]. Diagnosis of TB is often delayed during pregnancy, because of its non-specific symptoms, and overlapping presentation with other infectious diseases. Adverse perinatal outcomes are even more pronounced in women with advanced disease, late diagnosis and incomplete or irregular drug treatment. Many antenatal clinics are unprepared to diagnose TB [14]. Female genital TB, which is challenging to diagnose, is an important cause of infertility in high TB-incidence settings. HIV ramps up the risk of TB 10- to 100-fold. TB in pregnant women with HIV quadruples both maternal and infant mortality, doubles vertical transmission of HIV to the unborn child and increases the risk of vertical transmission of TB. In high HIV-burden settings, TB can account for 15–34% of indirect causes of obstetric mortality. Once active TB is excluded, WHO recommends providing TB preventive therapy (TPT) with isoniazid for people living with HIV, including pregnant women, to prevent TB disease [15]. This recommendation has been called into question since a recent study found isoniazid preventive therapy (IPT) during pregnancy among people living with HIV (PLHIV) was associated with an increased (but not statistically significant) risk of adverse pregnancy outcomes [16]. National programmes now face the dilemma of whether to administer IPT to PLHIV or to use one of the

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new isoniazid-sparing TPT regimens available, although pregnant women were largely excluded from the research that led to them being registered. Some programmes request a test for TB infection prior to treatment in pregnancy, but the reliability of both tuberculin skin tests and interferon gamma release assays (IGRA) is seriously reduced in pregnancy and worst around the time of delivery [17].

27.5 Recommendations Mother and child health services present a too-often-neglected, strategic entry point for increasing access to TB services, for both women and their families, which is particularly essential in high HIV prevalence settings. TB, HIV, maternal, neonatal and child health programmes and primary care services should collaborate more to maximize the entry points to TB care for women and their families at all levels. Gender-sensitive services for TB prevention, diagnosis, treatment, care and support are essential and require a female clinician at each health facility likely to treat women. TB preventive treatment should follow sound clinical judgement and assessment of risk and benefits.

References 1. World Health Organization. Global tuberculosis report. Geneva: WHO; 2019. 2. Holmes C, Hausler H, Nunn PP. A review of sex-differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis. 1998;2(2):96–104. 3. Styblo K.  Epidemiology of tuberculosis. Selected papers, vol. 24. The Hague: The Royal Netherlands Tuberculosis Association; 1991. 4. Marçôa R. Tuberculosis and gender—factors influencing the risk of tuberculosis among men and women by age group. Pulmonology. 2018;24(3):199–202. https://doi.org/10.1016/j. pulmoe.2018.03.004. 5. Borgdorff MW, Nagelkerke NJD, Dye C, Nunn PP. Gender and tuberculosis: a comparison of prevalence surveys with notification data to explore sex differences in case detection. Int J Tuberc Lung Dis. 2000;4(2):123–32. 6. Onozaki I, Law I, Sismanidis C, Zignol M, Glaziou P, Floyd K. National tuberculosis prevalence surveys in Asia, 1990–2012: an overview of results and lessons learned. Trop Med Int Health. 2015;20(9):1128–45. https://doi.org/10.1111/tmi.12534. 7. Horton KC, MacPherson P, Houben RMGJ, White RG, Corbett EL. Sex differences in tuberculosis burden and notifications in low- and middle-income countries: a systematic review and meta-analysis. PLoS Med. 2016;13(9):1–23. https://doi.org/10.1371/journal.pmed.1002119. 8. Asian Development Bank (ADB). Country Briefing Paper—women in Pakistan. 2000. https:// www.adb.org/sites/default/files/institutional-­document/32562/women-­pakistan.pdf 9. Dale K, Tay E, Trauer J, Trevan P, Denholm J.  Gender differences in tuberculosis diagnosis, treatment and outcomes in Victoria, Australia, 2002–2015. Int J Tuberc Lung Dis. 2017;21(12):1264–71. https://doi.org/10.5588/ijtld.17.0338. 10. Srivastava K, Kant S, Narain A, Bajpai J. Tuberculosis in women: a reflection of gender inequity. Eur Respir J. 2018;52(suppl 62). 11. Sugarman J, Colvin C, Moran AC, Oxlade O. Tuberculosis in pregnancy: an estimate of the global burden of diseases. Lancet Glob Health. 2014;2:e710–6.

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12. Zenner D, Kruijshaar ME, Andrews N, Abubakar I.  Risk of tuberculosis in pregnancy: a national, primary care-based cohort and self-controlled case series study. Am J Respir Crit Care Med. 2012;185:779–84. 13. Jana N, Barik S, Arora N, Singh AK. Tuberculosis in pregnancy: the challenges for south Asian countries. J Obstet Gynaecol Res. 2012;38(9):1125–36. https://doi.org/10.1111/j.1447-­0756 .2012.01856.x. 14. Sulis G, Gnanou S, Roggi A, Konseimbo A, Giorgetti PF, Castelli F, Matteelli A. Active tuberculosis case finding among pregnant women: a pilot project in Burkina Faso. Int J Tuberc Lung Dis. 2016;20(10):1306–8. 15. World Health Organization. Latent TB infection: updated and consolidated guidelines for programmatic management. 2018. http://www.who.int/tb/publications/2018/latent-­tuberculosis-­ infection/en/. Accessed 27 Mar 2020. 16. Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, et  al. Isoniazid preventive therapy in HIV-infected pregnant and postpartum women. N Engl J Med. 2019;381:1333–46. 17. Mathad J, LaCourse S, Gupta A. TB prevention strategies and unanswered questions for pregnant and postpartum women living with HIV: the need for improved evidence. J Int AIDS Soc. 2020;23:e25481. https://doi.org/10.1002/jia2.25481.

Tuberculosis in the Elderly

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Lisa Kawatsu, Takashi Yoshiyama, and Seiya Kato

Abstract

Tuberculosis (TB) is increasingly becoming a public health priority among the elderly population globally. In this chapter, we examined the case of TB in Japan, one of the most rapidly aging societies in the world, and the role of age-specific prevalence of TB infection in shaping the trend in the epidemiology of TB. We also reviewed the various issues in diagnosing and managing TB among elderly patients in general, and drew some recommendations and conclusions. Keywords

Tuberculosis · Elderly · Epidemiology · Diagnosis · Treatment · Japan

28.1 Introduction The global pace of population aging is accelerating than never before, with the world’s population aged 60 years above being expected to triple from 600 million in 2000 to two billion in 2050 [1]. The impact of aging on tuberculosis (TB) epidemiology varies among and within countries, but generally, higher TB incidence and mortality have been reported among the elderly population primarily in the developed countries, with low or intermediate TB burden [2–4]. However, in the recent years, an increasing number of developing countries, with higher TB burden, are facing similar challenges. TB is therefore rapidly becoming a public health priority among the elderly population globally.

L. Kawatsu · T. Yoshiyama · S. Kato (*) Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, Tokyo, Japan e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2021 G. B. Migliori, M. C. Raviglione (eds.), Essential Tuberculosis, https://doi.org/10.1007/978-3-030-66703-0_28

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28.2 Aims of the Chapter In this chapter, we examine some of the issues in TB control among the elderly, drawing especially on the experiences from Japan, one of the world’s most rapidly aging societies. From its TB epidemiology among the elderly population, and experiences in finding, diagnosing, and managing elderly TB patients, we hope to draw some lessons for countries that are to experience similar challenges in the not so far future.

28.3 T  rend in the Epidemiology of Tuberculosis in the Elderly: Case Study of Japan The demographic outlook of TB patients in Japan has dramatically changed over the past several decades. In 1950s, the age structure of TB patients in Japan closely resembled those that can be seen in today’s many TB high-burden countries, with high annual risk of infection in an expansive population pyramid, thus resulting in a large proportion of TB cases occurring among the younger and middle-aged population. Thus, while in 1963, those aged between 20 and 59 years old have contributed to 65% of all cases, the proportion has fallen to 55.7% in 1980, and 27.9% in 2018. On the other contrary, the proportion contributed by those aged 60 years and older has increased significantly, from just 16% in 1963 to 39.5% in 1980, and 70.8% in 2018 (Fig. 28.1). The mechanism through which aging affects TB epidemiology is complex and is well summarized by Mori et al.—they point to the higher prevalence of TB infection among the elderly when compared with the younger population, cohort effect, exogenous reinfection, and reactivation due to immunologic incompetence as well as various risk factors associated with aging, such as comorbidities [5]. As far as Japan is concerned, the shift of the burden of TB towards the elderly population is largely attributable to the changes in the pattern of age-specific prevalence of TB infection. A study by Ohmori et al. has estimated that, in 1940, more than 80% of people aged 30 years and above were infected. However, the prevalence of infection among the

1963

1980

2018

PROPORTION (%)

60.0 50.0 40.0 30.0 20.0 10.0 0.0

0-4

5-9

10-14

15-19

20-29 30-39 AGE GROUPS

Fig. 28.1  Changing age structure of TB patients in Japan

40-49

50-59

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younger age groups has declined drastically since then owing to the successful implementation of TB control programs—for example, the estimated prevalence among those aged 20 has declined to 7% in 1980, 3% in 1990, and 2% in 2020. On the other hand, the prevalence among those aged 80 has remained constantly high, at 93% in 1980, 90% in 1990, and 85% in 2000 [4]. This indicates that in Japan today, the majority in the younger age groups are noninfected, while TB among the elderly are mostly arising from past infections. The growing burden of TB among the elderly, to a certain extent, is therefore a reasonable and unavoidable consequence of declining TB incidence and aging population. However, for Japan, and any other countries at similar epidemiological stage, to become a TB low-burden country, a successful TB control among the elderly population is critical. Failure to effectively manage TB among the elderly population could have serious consequences, including reactivation among elderly themselves, and transmission of the disease to other age groups. This could result in slowing or even halting the decline of overall incidence, which, according to Mori et al., is what happened in Japan after the 1980s [5], and a substantial delay in reaching the goals of the End TB Strategy. There are several aspects of TB among the elderly, however, which make its control challenging.

28.4 Clinical Aspects and Difficulties in Diagnosis Majority of elderly pulmonary TB cases are detected by passive, and not active case finding in Japan, where opportunities for health checkups are routinely provided and contact investigation is systematically conducted by public health centers. This, on the other hand, indicates that case finding heavily relies on clinicians identifying suspicious TB.  Diagnosis of TB among elderly is more difficult than younger patients due to untypical presentation of symptoms, nonspecific X-ray findings, and difficulty in obtaining appropriate sputum specimen for diagnosis. Numerous studies have compared clinical and radiographical presentations of TB among elderly and non-elderly patients. A meta-analytical review, published in 1999, has concluded that generally symptoms such as cough, sputum production, weight loss, fatigue/malaise, and fever were common among both elderly and non-­ elderly patients with pulmonary TB, while sweating and hemoptysis were found to be less prevalent, and dyspnea and some concomitant conditions, such as cardiovascular disorders, chronic obstructive pulmonary disease (COPD), diabetes, gastrectomy history, and malignancies, more prevalent among elderly patients [6]. However, for some symptoms, studies have not always necessarily agreed with one another. For example, in Japan, one study that compared TB among the “elderly” (aged 75 years and above), the “middle-aged” (aged between 45 and 54 years), and the “young” (aged 35  years and younger) patients has found that while fever of higher than 38 °C was less prevalent among the elderly patients, fever of higher than 37 °C was similarly frequent among the middle-aged and young patients. Diabetes, on the other hand, was found to be more common among the middle-aged than the elderly and young patients [7]. Another study similarly concluded that elderly

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patients were often diagnosed without respiratory symptoms but with systemic symptoms such as fever, body weight loss, and deteriorated activity [8]. Chest X-ray findings are often similar to other bacterial diseases among elderly patients, making diagnosis again more difficult. The meta-analytical review mentioned above has concluded that there were no differences between elderly and younger TB patients with respect to radiographic upper lobes lesions and positive acid-fast bacilli in sputum, and pointed out to lower prevalence of cavitary disease among the former [6]. A more recent study from Korea compared the chest computed tomography scans of younger (aged between 20 and 64 years old) and older (aged 65 years and above) pulmonary TB patients and concluded that while consolidations were more common, nodule and mass were less frequently observed among older patients [9]. In Japan, the proportion of cavitary cases among sputum smear positive pulmonary TB was lower among elderly (37%, among those aged 70  years and above) than younger patients (57%, among those aged below 70 years) [10]. As for extrapulmonary tuberculosis, data from the Japan TB surveillance has indicated higher proportion of military, skin, pericardial, and peritoneal tuberculosis, and lower proportion of mediastinal and other lymph nodes, meningeal, ocular, and ear tuberculosis among elderly patients aged 70 years and older [11].

28.5 A  ppropriate Case Management and Treatment Outcomes The main challenges to successful treatment among the elderly patients include poor drug tolerance, adverse reactions, and poor treatment adherence which could all potentially lead to unfavorable treatment outcomes. In Japan too, proportions of died sharply increases with age—among active TB patients notified in 2017, the proportion of those who have died was 3.1% (174/55,558) among those aged between 0 and 64, while 15.3% (399/2614) among those aged between 65 and 74, 27.0% (1141/4222) among those aged between 75 and 84, and was as high as 47.4% (2040/4308) among those aged 85 years and older (Fig. 28.2). Among various adverse drug reactions, gastrointestinal upset and hepatitis have been reported to be particularly frequent among elderly patients [10, 11]. In Japan, among elderly patients aged above 80 years, the proportion of those developing hepatitis was higher among those receiving treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol than those receiving isoniazid, rifampin, and ethambutol. However, the overall treatment outcome, including mortality, was not different between the two treatment regimens [12]. Following expert opinions, a guideline from the United States now includes three drug regimen excluding pyrazinamide as an option for elderly patients aged above 80 years old [13]. Elderly patients are however not necessarily at an equal risk of poor treatment adherence. One study from Japan has identified that “being elderly and certified as

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Fig. 28.2  Treatment outcome of active TB patients notified in 2017, Japan

requiring nursing care” (but not necessarily receiving that needed care) may be a possible risk factor for treatment interruption. The authors have found that the proportion of those who have interrupted treatment was significantly higher among patients who were assessed as “being elderly and requiring nursing care” than those who were not (19.1% vs. 5.7%, p 6 days, in particular if originating from TB high endemic areas, comorbidity such as HIV or young/high age. About one-third of patients with miliary TB also have CNS involvement with TBM. A lumbar puncture (LP) with at least 5 up to 10 mL of CSF should be sampled for mycobacterial diagnosis with PCR and culture. Microscopy of CSF is not performed due to low yield. LP should always be performed in miliary TB to rule out CNS involvement as well as mycobacterial sampling from other organs if relevant. A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain should be performed initially and prior to LP if focal neurological symptoms occur [6, 15]. GeneXpert RIF on CSF, recommended by the WHO, has shown a sensitivity of 60% and close to 100% specificity in TBM and also detects rifampicin (RIF) resistance [16]. With the second-generation GeneXpert (GeneXpert Ultra), a sensitivity

Table 29.1 Typical symptoms and laboratory findings suggestive of TBM [13]

Symptom duration >6 days Moderate pleocytosis