The challenge of tuberculosis in the 21st century 9781849841696, 9781849841702

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Recent years have witnessed key developments in the Pantone PASTEL 9081 CMJN 200 CMJN (darker) Pantone 647 CMJN diagnosis Pantone and tuberculosis. Alongside this, and Cyan 0 Cyan 0 treatment of Cyan 100 Magenta 0 Magenta 100 Magenta 56 Yellowwas 6 70 0 running inYellow direct oppositionYellow to this progress, the COVIDBlack 8 Black 14 Black 24 19 pandemic, which had an unprecedented detrimental effect on tuberculosis control and the achievement of targets set by the End TB Strategy. This timely and important Monograph provides a crucial update on recent changes, developments and setbacks in the field, and calls for a re-commitment to the achievement of the End TB Strategy and Sustainable Development Goals. Written by authors from across the world, the Monograph covers: diagnosis; advances in treatment; prevention; and tuberculosis control challenges in different populations and contexts.

Print ISBN: 978-1-84984-169-6 Online ISBN: 978-1-84984-170-2 September 2023 €60.00

ERS monograph 101

Print ISSN: 2312-508X Online ISSN: 2312-5098

The Challenge of Tuberculosis in the 21st Century

ERS monograph

ERS monograph

Pantone 200 CMJN (darker) Cyan 0 Magenta 100 Yellow 70 Black 14

The Challenge of Tuberculosis in the 21st Century

Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Alberto L. García-Basteiro, Füsun Öner Eyüboğlu and Molebogeng X. Rangaka

The Challenge of Tuberculosis in the 21st Century Edited by Alberto L. García-Basteiro, Füsun Öner Eyüboğlu and Molebogeng X. Rangaka Editor in Chief Peter M.A. Calverley This book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specific clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientific detail, drawing on specific case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph. ERS Monographs are available online at books.ersjournals.com and print copies are available from www.ersbookshop.com

Editorial Board: Christian B. Laursen (Deputy Chief Editor; Odense, Denmark), Francesco Bonella (Essen, Germany), Daniela Gompelmann (Vienna, Austria), David S. Hui (Hong Kong), Holly R. Keir (Dundee, UK) and Maria Molina Molina (Catalunya, Spain). Managing Editor: Rachel Gozzard European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK Tel: 44 114 2672860 | E-mail: [email protected] Production and editing: Caroline Ashford-Bentley, Alice Bartlett, Matt Broadhead, Clarissa Charles, Jonathan Hansen, Claire Marchant, Catherine Pumphrey and Kay Sharpe Published by European Respiratory Society ©2023 September 2023 Print ISBN: 978-1-84984-169-6 Online ISBN: 978-1-84984-170-2 Print ISSN: 2312-508X Online ISSN: 2312-5098 Typesetting by Nova Techset Private Limited Printed by Page Bros Group Ltd, Norwich, UK All material is copyright to ­European Respiratory Society. It may not be reproduced in any way including electronic means ­without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

ERS monograph

Contents The Challenge of Tuberculosis in the 21st Century

Number 101 September 2023

Foreword

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Preface Guest Editors

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Introduction

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List of abbreviations xviii 1. International efforts to reverse and end the tuberculosis pandemic: past, present and future global strategies Guy B. Marks, Alvin Kuo Jing Teo, Emily B. Wong, Greg J. Fox and Thu Anh Nguyen

1

2. Epidemiology: the current burden of tuberculosis and its determinants Rita Verstraeten, Marta Cossa, Leonardo Martinez, Kristin Nelson, Dinis Nguenha

18

3. Host–pathogen interactions in the context of tuberculosis infection and disease Delia Goletti, Alessandra Aiello, Leopold D. Tientcheu, Caleb Muefong,

34





and Alberto L. García-Basteiro

Ting Huey Hu, Paula Niewold, Simone A. Joosten, Catherine W.M. Ong and Jayne S. Sutherland

Diagnosis of tuberculosis 4. Clinical presentation of pulmonary and extrapulmonary tuberculosis Onno W. Akkerman, Gunar Guenther, Marcela Munoz-Torrico, Aylin Babalik,

51

Jan Heyckendorf, Antonia Morita Iswari Saktiawati, Jean-Pierre Zellweger, Pedro Sousa and Füsun Öner Eyúboğlu

5. Microbiological tests and laboratory tests: the value of point-of-care testing Elisa Tagliani, Francesca Saluzzo and Daniela Maria Cirillo

64

6. The evolution of imaging and portable imaging tools to aid tuberculosis diagnosis Jacob Bigio, Claudia M. Denkinger, Rigveda Kadam, Mikashmi Kohli, Giorgia Sulis,

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César Ugarte-Gil, Seda Yerlikaya and Madhukar Pai

7. The differential diagnosis of thoracic tuberculosis: a guide to 90 under- and over-diagnosis Graham H. Bothamley, Grace Adeoye, Jan Heyckendorf, Joe Rowan and Abhinav Singla

Advances in tuberculosis treatment. Are we moving forward in the quest for shorter, safer, effective regimens? 8. The basis of tuberculosis treatment: fundamental concepts before treating 104 a patient Jose A. Caminero, Rupak Singla, Anna Scardigli, Amitesh Gupta, Guillermo Pérez-Mendoza

and Alberto Mendoza

9. Treatment of drug-susceptible and drug-resistant tuberculosis Christoph Lange, Thomas Theo Brehm, Dumitru Chesov, Yousra Kherabi

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and Lorenzo Guglielmetti

Prevention 10. Diagnosis of tuberculosis infection



Srishti Chhabra, Sean Wu, Jinghao Nicholas Ngiam, Giovanni Battista Migliori, Delia Goletti and Catherine W.M. Ong

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11. Preventive therapies for tuberculosis infection 151 Alberto Matteelli, Luca Rossi, Sofia Lovatti, Anna Cristina C. Carvalho and Anita Sforza 12. How close are we to a new, effective tuberculosis vaccine? Recent advances in the field Angelique Kany Kany Luabeya, Michele Tameris, Justin Shenje, Anele Gela,

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13. Genomic approaches to tuberculosis management and control Iñaki Comas, Mariana G. López, Álvaro Chiner-Oms, Maha R. Farhat,

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Elisa Nemes, Thomas J. Scriba and Mark Hatherill

Jean Claude Semuto Ngabonziza, Josefina Campos and Miguel Moreno-Molina

Tuberculosis in different populations and specific situations 14. The challenge of post-tuberculosis lung disease Andrea Rachow, Naomi F. Walker, Brian Allwood, Marieke M. van der Zalm,

Anthony Byrne and Jamilah Meghji

15. Tuberculosis in children and adolescents: a forgotten group in a forgotten disease Elisa López-Varela, Isabelle Munyangaju, Chishala Chabala, Moorine Sekadde

191

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and James A. Seddon

16. Protecting the most vulnerable: tuberculosis in immunocompromised 235 individuals Egídio Torrado, Reinout vanCrevel, Ana Raquel Afonso, Diana Amorim and Raquel Duarte 17. Tuberculosis in prisons: a growing global health concern Guillermo Sequera, Gladys Estigarribia, Katharine S. Walter, Rafael Lopez,

251

18. How do migrations affect tuberculosis burden? Tuberculosis control among migrant populations Heinke Kunst, Dominik Zenner and Giovanni Sotgiu

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Jason Andrews and Julio Croda

19. Preparedness for successful TB control: lessons from the COVID-19 pandemic Melisa Mei Jin Tan and Helena Legido-Quigley

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Epilogue: A view of tuberculosis care from tuberculosis survivors Phumeza Tisile and Goodman Makanda

Foreword Tereza Kasaeva We live in a world of global and local challenges: new threats, pandemics like COVID-19, climate change and natural disasters, armed conflicts and socioeconomic crises. These challenges affect many different regions and countries, and heavily impact on people’s life, health and wellbeing. However, the world today is also very dynamic, with many new opportunities and unprecedented advances in science and technology – and, of course, medicine. This is the backdrop that inspired world-renowned experts to come together as a team to develop this new issue of the ERS Monograph, The Challenge of Tuberculosis in the 21st Century. This Monograph is a consolidated, comprehensive guide to all key aspects of TB management and care, based on the latest data and WHO guidelines. It includes an overview of the progress made towards ending TB, and includes information on the latest evidence-based approaches to TB prevention, diagnosis and treatment. It also considers management of the TB response following the principles of people-centred care to address the specific needs of vulnerable groups and those with comorbidities. It places a spotlight on the importance for multisectoral engagement to address social determinants and drivers of the disease.

Tereza Kasaeva Director, WHO Global Tuberculosis Programme

In recent years, TB diagnosis has expanded considerably. Methods include: molecular tests for the detection of TB disease and drug resistance; IGRAs and new antigen-based skin tests for the detection of TB infection; computer-aided detection in TB screening using digital chest radiography. Clinical trials have evaluated: new drugs and regimens for TB treatment, including MDR-TB; management of TB in children and adolescents; and preventive treatment of TB infection. These advances have informed important updates of core WHO guidelines and have resulted in improved access to the latest diagnostic tests, treatment of both drug-susceptible TB and DR-TB, and development of TPT. It is now possible to achieve treatment with a shorter administration, that is fully oral and more effective.

Copyright ©World Health Organization 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098. https://doi.org/10.1183/2312508X.10027722

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Research and innovation, alongside use of the latest tools and guidelines, are essential in the mission to save millions of lives. These tools will help us realise the targets of reduced TB incidence and TB death outlined in the WHO’s End TB Strategy and the Global Strategy for TB Research and Innovation. This Monograph’s authors and Guest Editors highlight that, while being a preventable and curable disease, TB remains one of the world’s top infectious killers, affecting millions every year, especially in low- and middle-income countries. Progress towards achieving the global target of ending TB is lagging behind and has been pushed back by the impact of the COVID-19 pandemic. Access to WHO-recommended rapid molecular diagnostics, and new, effective and shorter TB regimens (including DR-TB treatment) remains limited. Only 60% of people with TB disease accessed treatment in 2021, according to the WHO’s Global Tuberculosis Report. We need to do better. This Monograph provides clear answers on what should be done to fast-track the TB response and reach targets, saving lives. I would like to specifically acknowledge the focus on accelerating the development of new, effective TB vaccines as a game changer in the fight against TB, and on strengthening the meaningful engagement of civil society and TB-affected communities in the TB response. I would also like to express my special appreciation of the international team of Guest Editors who brought this Monograph together – Alberto L. García-Basteiro from Spain, Füsun Öner Eyüboğlu from Turkey and Molebogeng X. Rangaka from South Africa. In September 2023, Heads of State will come together at the second United Nations high-level meeting on TB, to deliberate on and reinvigorate commitments to end TB. This presents a landmark opportunity to strengthen global cooperation and solidarity required to recover from the COVID-19 pandemic and accelerate efforts towards ending TB. The launch of this Monograph is timely and can help inform stakeholders on the challenges and priorities to end this ancient disease once and for all. We have the tools, and with commitment, unity and dedication we can end TB. T. Kasaeva is a staff member of the WHO. The author alone is responsible for the views expressed in this Foreword and they do not necessarily represent the views, decisions or policies of the WHO. This Foreword is published with the permission of the WHO. Disclosures: None declared.

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Preface Peter M.A. Calverley TB has variously been described as the “Captain of the Men of Death” and the “White Plague”. Although known to the ancient Egyptians, TB cases grew exponentially in the poverty-stricken, over-crowded conditions that characterised the Industrial Revolution of the 19th century. Sadly, it continues to cause death and suffering in developing economies across the Global South. TB is the foundational illness that respiratory medicine came into being to address by developing specialist treatments, accurate epidemiology and better systems for the delivery of care, ultimately leading to its eclipse in the Western world. One of the main reasons I became a pulmonary physician was because of the time I spent working for the late Sir John Crofton, the modest man who devised the triple therapy treatment regime that showed that TB could be cured rather than contained. Unsurprisingly, the ERS Monograph has visited the topic of TB before. In 2018, G.B. Migliori and colleagues presented a masterful summary of our knowledge of this condition. However, in the short time since then there have been important developments in the diagnosis and treatment of this old foe, and this merited a further volume that summaries the new approaches to the management of TB available in the 21st century. The present volume, ably edited by Alberto L. García-Basteiro, Füsun Öner Eyüboğlu and Molebogeng X. Rangaka, meets this need and provides a wider perspective on the impact and management of TB globally. Despite many challenges and setbacks, TB remains a disease that we can defeat, if we work together. This volume offers us important insights into how we can do that. Disclosures: P.M.A. Calverley reports receiving grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat respiratory disease. This includes reimbursement for educational activities and advisory work, and support to attend meetings.

Copyright ©ERS 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098. https://doi.org/10.1183/2312508X.10013123

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Guest Editors Alberto L. García-Basteiro Alberto L. García-Basteiro is Associate Research Professor at the Barcelona Institute for Global Health (ISGlobal) – Hospital Clínic in Barcelona (Spain) and coordinates the TB research area at the Centro de Investigação em Saúde de Manhiça (CISM) in Manhica (Mozambique). He trained as a physician at the University of Santiago de Compostela (USC) (Santiago, Spain), and finished his residency on preventive medicine and public health at Hospital Clínic in Barcelona. He completed an MSc in epidemiology at the London School of Hygiene and Tropical Medicine (LSHTM) (London, UK), and a PhD at the University of Amsterdam (Amsterdam, the Netherlands). Alberto currently leads research focused on the study of TB in high TB-burden and high HIV-burden settings in sub-Saharan Africa, including field epidemiological assessments, novel sputum-free diagnostic evaluations, and drug and vaccine clinical trials. His interests include the burden of TB disease in different vulnerable populations and the characterisation of TB at a clinical, microbiological and social level. Alberto has published over 170 manuscripts in peer-reviewed biomedical journals, and has attracted international funding from the European and Developing Countries Clinical Trial Partnership (EDCTP), the National Institute for Health (NIH), the Stop TB Partnership, the United States Agency for International Development (USAID), and the Bill & Melinda Gates Medical Research Institute, among others. His scientific contributions have been recognised by several international organisations. In 2017, he received the Young Investigator Prize, awarded by the International Union against Tuberculosis and Lung Disease (The Union). He also received the Early Career Member Award from the European Respiratory Society (ERS) in 2020, and the Stephen Lawn TB-HIV Research Leadership Prize from the LSHTM, the Desmond Tutu HIV Centre at the University of Cape Town (Cape Town, South Africa) and The Union in 2021.

Copyright ©ERS 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098. x

https://doi.org/10.1183/2312508X.10013223

Füsun Öner Eyüboğlu Füsun Öner Eyüboğlu currently practices at her private clinic and holds adjunct teaching positions at private medical schools. She trained as a physician at the Medical School of Ankara University (Ankara, Turkey) and completed her residency on pulmonolgy at the Atatürk Chest Diseases and Surgery Center (Ankara). She was a research fellow at the Hospital of the University of Pennsylvania (Philadelphia, PA, USA) and was involved in several projects and clinical trials relating to the immunology of TB. She started work as a specialist at the Başkent University Faculty of Medicine (Ankara) in 1997 and became a professor at the same division in 2007. During this time, she established the Pulmonary Division at Başkent University and was Chair of the division from 2000 to 2016. Füsun was a member of the Tuberculosis Advisory Board of the Turkish Ministry of Health National. Throughout her academic career, she has made a notable contribution to the education and training of medical students, as well as specialists in the field of pulmonology. Füsun’s research focuses on pulmonary infection in immunocompromised patients (solid organ transplant patients and other immunosuppressed conditions) and the immunology/diagnosis of TB. She also has expertise in the diagnosis and management of TB among immunocompromised patients. Füsun has participated in several national and international research projects and clinical trials as principal investigator or co-investigator of the diagnosis of latent TBI in renal failure and solid organ transplant patients. She has collaborated in several TB-NET/European Respiratory Society (ERS) research projects and produced a number of peer-reviewed publications. Füsun has been the Secretary of the ERS Group “Tuberculosis and non-tuberculosis mycobacterial diseases” since 2021.

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Molebogeng X. Rangaka Molebogeng X Rangaka is a Professor in Infectious Disease Epidemiology and Public Health at the Institute of Global Health and the MRC Clinical Trials Unit, University College London (London, UK). She holds the position of honorary Associate Professor at the University of Cape Town (Cape Town, South Africa) where she has contributed to global health research in infectious diseases within the School of Public Health and the Wellcome Centre for Clinical Infectious Disease Research Institute in Africa (CIDRIAFRICA) since 2005. She is the co-Director of the Clinical Research Platform of the Wellcome-funded Discovery Platform Award. Lele held a position at the WHO Global TB Programme as the consultant lead for TB prevention, responsible for policy development on the programmatic management of LTBI testing and treatment, with particular focus on under-resourced high-burden contexts. She is the Director of the WHO Collaborating Centre on TB Research and Innovation and the lead for the WHO global TBIPD platform for TB treatment and outcomes at University College London. Her research spans the epidemiology of poverty-related diseases, randomised assessment of public health technology, digital health innovation and implementation science. Her team conducts clinical trials into TB prevention across a range of multimorbidities, people at risk and world regions. Lele sits on a number of international working groups, including TB-LEAP, the Collaboration for TB Vaccine Discovery (CTVD), the Cross-Network TB Vaccine Working Group (TB Vaccine WG), the Maternal and Child Working Group of The Union (the International Union Against Tuberculosis and Lung Disease) and the LTBI Task Force of the Stop TB New Diagnostic Working Group. She is also a member of The Lancet Digital Health International Advisory Board and UCL-TB Leadership.

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Introduction Alberto L. García-Basteiro1,2,3, Füsun Öner Eyüboğlu and Molebogeng X. Rangaka 5,6,7

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1

ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain. 2Centro de Investigação em Saude de Manhiça (CISM), Maputo, Mozambique. 3Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain. 4Department of Pulmonary Diseases, Başkent University Hospital, Ankara, Turkiye. 5 Institute for Global Health, University College London, London, UK. 6CIDRI-AFRICA, University of Cape Town, Cape Town, South Africa. 7School of Public Health, University of Cape Town, Cape Town, South Africa. Corresponding author: Molebogeng X. Rangaka ([email protected]) @ERSpublications This timely and important Monograph provides a crucial update on recent changes, developments and setbacks in the field, and calls for a re-commitment to the achievement of the End TB Strategy and Sustainable Development Goals https://bit.ly/ERSM101intro Copyright ©ERS 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

Priorities to bend the TB epidemic curve towards elimination The WHO Global End TB Strategy, launched in 2015, sets priorities and specific targets aimed at reducing TB incidence and mortality to end the TB epidemic and eliminate disease-associated economic hardship worldwide by 2030 [1]. Its three main pillars are: integrated patient-centred care and prevention; bold policies and supportive systems; and intensified research and innovation [1]. Regional and national elimination strategies have been developed to set targets and achieve these priorities. These enable region-specific TB control activities based on the local epidemiology and contextual factors. For example, the WHO TB action plan for the WHO European Region, provides strategies to allow Europe to reach the global End TB Strategy targets to reduce TB incidence by 80% and TB deaths by 90% by 2030 [2]. Resolutions adopted by member states at the first ever United Nations (UN) high level meeting (UNHLM) political declaration on TB in 2018 set the scene for bold policies and further sharpened the global focus on the priorities of the End TB Strategy, to accelerate adoption of specific strategies. Member states endorsed a declaration on TB that included targets to treat 40 million people with TB between 2018 and 2022, 3.5 million children with TB and 1.5 million people with DR-TB, and for ⩾30 million put on TPT during that period [3].

Recent advances in TB research Innovative research is required to develop and assess new tools for the diagnosis, treatment and prevention of TB. To realise reductions in the burden of disease and reach the targets set by the international community (reduction in mortality, incidence and no households facing catastrophic costs), there is an urgent need to innovate. Specifically, we need acceleration of research and development in new effective TB vaccines, rapid and easy-to-use point-of-care diagnostics for TB, new drugs and shorter treatment regimens for both infection and disease, as https://doi.org/10.1183/2312508X.10025822

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well as new tools to support prevention, care and implementation, including digital health technologies [4, 5]. Although there have been considerable challenges and shortcomings in the available funding for TB research and development (US$915 million in 2020, less than half of the intended target set by the international community) [6], the last decade has witnessed unprecedented efforts in the development of novel diagnostics, promising vaccine candidates, and medicines. In the field of prevention, several milestones have been achieved. The development and roll out of short and ultra-short regimens for TB prevention, including weekly high-dose rifapentine and isoniazid for 3 months [6] and 1 month of daily rifapentine plus isoniazid to prevent HIV-related TB [7] have represented relevant advances, which have quickly translated into national and international policies [8]. In addition, several TB drug preventive trials for both drug-susceptible (DS)-TB and DR-TB are currently in progress, with the hope of increasing the preventive efficacy, improving safety in vulnerable populations, such as children or PLHIV, or further shortening the duration of these regimens [9]. Similarly, the field of TB vaccine development is experiencing a period of unprecedented optimism, mostly based on the promising results of two recent efficacy studies into prevention of disease and infection [10, 11]. The protein-subunit vaccine candidate M72/AS01E has shown an efficacy of ∼50% against progression from infection to disease in a large phase 2B study conducted in Kenya, South Africa and Zambia [10]. A large phase 3 registration trial is now in preparation and is expected to start enrolment during 2024. In addition, a study in South African adolescents has shown that BCG revaccination provides ∼45% protection against sustained IGRA conversion [11]. These findings are currently being followed-up with a further trial whose results are also expected in 2024. There has never been a time in history with more TB vaccine candidates being tested in large phase 3 trials (currently four at phase 3 and 17 in clinical development) [12]. Novel successful platforms used in the development of COVID-19 vaccines (using mRNA for TB antigen delivery) are already being tested in humans for TB [13]. We might be very close to adding a game-changing element to our tool kit in fight against TB. The quest for improved point-of-care diagnostics continues to be a priority for TB research [5]. Importantly, novel, rapid molecular assays have been developed and recommended by the WHO for different levels of care [14]. Promising research is being conducted to develop sputum-free TB diagnostics, which are especially relevant for populations in whom TB laboratory confirmation continues to be suboptimal, such as children, PLHIV or in cases of EPTB [15]. Unfortunately, the only true point-of-care non-sputum-based TB diagnostic test continues to be TB-LAM, which is recommended for PLHIV under specific criteria [16]. Disappointingly, its uptake is low despite having evidence of its positive impact in reducing TB mortality [17, 18]. Thus, the quest for novel point-of-care tests that can accelerate TB diagnosis at decentralised levels of care remains. Although the WHO recently included novel tools as part of the new TB-screening recommendations, such as C-reactive protein or artificial intelligence-based computer-aided detection to analyse digital CXR, there is a need for more specific assays for both screening or triage. New diagnostics capable of identifying individuals that are at high risk of TB progression are a priority target product profile in the field of TB diagnostics [19]. Despite decades of limited progress in global efforts to establish shorter treatment regimens for DS-TB (including several unsuccessful phase 3 treatment-shortening trials) [20–22], the field has been invigorated by exciting results demonstrating the effectiveness of a 4-month regimen against xiv

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DS-TB (including high-dose rifapentine and moxifloxacin) [23]. 8 weeks of daily treatment with high-dose rifapentine (1200 mg), isoniazid, pyrazinamide and moxifloxacin, followed by 9 weeks of daily treatment with high-dose rifapentine, isoniazid and moxifloxacin was shown to be non-inferior to the standard 6-month regimen [23]. These results show that shorter, efficacious and safe treatments are possible and thus, further late-stage trials, including new and repurposed drugs, are warranted. Similarly, recent studies have shown that shorter MDR-TB oral regimens can achieve high cure rates. Combinations of 6 weeks of bedaquiline, pretomanid and linezolid (with or without moxifloxacin) have shown favourable outcomes and an improved safety profile compared with the previous standard of care [24, 25]. Importantly, results have immediately translated into policy and the new 6-month MDR-TB treatment regimens are already recommended by the WHO [26]. Shorter regimens are likely to improve patient adherence and reduce adverse events; they may also decrease overall treatment costs in the long term. Current priorities of TB research focus not only on the development of new tools but also on the factors associated with their successful implementation and on improving our understanding of the natural history of TB, especially the early stages of the spectrum infection–disease. Several studies suggest that asymptomatic TB disease, also referred to as subclinical TB, might be associated with a large proportion of global TB transmission [27, 28]. (See chapter 2 of this Monograph [29]). Large prevalence surveys in both African and Asian countries report that ∼50% of TB patients in whom Mycobacterium tuberculosis was isolated in sputum, were subclinical [30]. There is therefore a need to understand and measure its contribution to global TB transmission, given its immediate implications for control and research.

Re-prioritisation of control strategies Globally, challenges remain in reducing the burden of disease. Specifically, DR-TB and TB-associated HIV co-infection continue to cause premature mortality in many world regions. Future threats include emerging and re-emerging pandemics, and disruption as a result of war and climate change. The recent COVID-19 pandemic eroded gains toward TB control and target achievement. The shift in focus towards public health interventions to control COVID-19 contributed to service disruptions and barriers in accessing TB care, significantly reducing both the number of people notified with TB, those enrolled to treatment – especially for MDR/RR-TB – and those put on TPT, worldwide. Wars (such as those ongoing in the Middle East, Africa and Europe in 2023) can trigger humanitarian crises, worsen the broader determinants of TB, and have a damaging impact on TB control, thereby reducing progress towards TB targets. Re-prioritisation is essential for future impact on the TB epidemic. On the eve of the second UNHLM political declaration on TB in 2023, it is hoped that member states will steady and increase their resolve to eliminate TB by re-committing to the End TB Strategy pillars, setting bold disease burden targets and closing the funding gap. Patient and provider-centred care is crucial to realising the desired declines in TB incidence, which can only be achieved if both patients and providers are made central to policies. This involves early diagnosis of TB with relevant tests, prompt treatment (for both DS-TB and DR-TB), investigation and appropriate evaluation, treatment of contacts of people with infectious TB disease, and prevention of further transmission through infection control. https://doi.org/10.1183/2312508X.10025822

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Everyone, regardless of socioeconomic or geographical context, should receive appropriate and effective care. All people diagnosed with TB should have an equal opportunity to access standard diagnostic tools and treatment options, and should benefit from new modalities. New treatment options provide an opportunity for personalised and patient-centred care that considers individual factors such as drug resistance, comorbidities and treatment preferences – this should be prioritised. Moreover, success in TB control is not realistic without preventive treatment of those at high risk, vaccination against TB, and management of comorbidities and TB-associated impairment and disability. BCG vaccination offers protective effects against TB. Priorities for the future should not only expand BCG vaccination to wider populations and strengthen vaccination programmes, they should also invest in research for new and effective vaccines against TB. Decisive and accountable global, regional and national leadership is important, and this should include regular UN reporting and review. Following the 2018 UNHLM on TB, WHO developed the Multisectoral Accountability Framework for Tuberculosis [4], as a monitoring and accountability tool to track progress in the fight against TB in global, regional and country profiles. Member states declared that they would strengthen collaborations between global and national public health authorities, patient groups, researchers and the private sector, providing a framework for action and a roadmap for accelerating efforts to end the TB epidemic [4]. National TB programmes and synergies with other strategies would improve TB control. The UNHLM on TB 2023 [3] will provide an opportunity for all stakeholders to contribute to the ongoing preparatory process for the high-level meetings, with a focus on current efforts and requirements to accelerate the response among TB survivors, people affected by TB, communities and civil society, and other TB stakeholders, including UN agencies, high-burden TB countries, donors and the private sector. References 1 Uplekar M, Weil D, Lonnroth K, et al. WHO’s new End TB Strategy. Lancet 2015; 385: 1799–1801. 2 World Health Organization. Tuberculosis Action Plan for the WHO European Region 2023–2030: Draft for the Seventy-second Regional Committee for Europe. https://apps.who.int/iris/bitstream/handle/10665/361921/ 72bg06e-AP-TB.pdf Date last updated: 14 September 2022. Date last accessed: 19 July 2023. 3 Stop TB Partnership. UNHLM on TB Key Targets and Commitments. https://www.stoptb.org/advocacy-andcommunications/unhlm-tb-key-targets-and-commitments Date last accessed 19 July 2023. 4 World Health Organization. Multisectoral Accountability Framework to Accelerate Progress to End Tuberculosis by 2030. Geneva, World Health Organization, 2019. 5 World Health Organization. The End TB Strategy. Geneva, World Health Organization, 2015. 6 World Health Organization. Global Tuberculosis Report 2022. Geneva, World Health Organization, 2022. 7 Swindells S, Ramchandani R, Gupta A, et al. One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med 2019; 380: 1001–1011. 8 World Health Organization. WHO Consolidated Guidelines on Tuberculosis: Module 1: Prevention: Tuberculosis Preventive Treatment. Geneva, World Health Organization, 2020. 9 World Health Organization. Research and development for tuberculosis. www.who.int/observatories/ global-observatory-on-health-research-and-development/analyses-and-syntheses/tuberculosis/analysis-of-tb-r-dpipeline Date last accessed: 19 June 2023. 10 Tait DR, Hatherill M, Van Der Meeren O, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med 2019; 381: 2429–2439. 11 Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med 2018; 379: 138–149. 12 Tuberculosis Vaccine Initiative. Pipeline of vaccines. www.tbvi.eu/what-we-do/pipeline-of-vaccines/ Date last accessed: 19 June 2023. 13 Bagcchi S. Can mRNA vaccine tech take on tuberculosis? www.gavi.org/vaccineswork/can-mrna-vaccinetech-take-tuberculosis Date last updated: 14 April 2022. xvi

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14 World Health Organization. WHO Consolidated Guidelines on Tuberculosis: Module 2: Screening: Systematic Screening for Tuberculosis Disease. Geneva, World Health Organization, 2021. 15 Nathavitharana RR, Garcia-Basteiro AL, Ruhwald M, et al. Reimagining the status quo: how close are we to rapid sputum-free tuberculosis diagnostics for all? EBioMedicine 2022; 78: 103939. 16 Broger T, Koeppel L, Huerga H, et al. Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data. Lancet Glob Heal 2023; 11: e903–e916. 17 World Health Organization. Global Tuberculosis Report 2021. Geneva, World Health Organization, 2021. 18 Peter JG, Zijenah LS, Chanda D, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet 2016; 387: 1187–1197. 19 World Health Organization. Consensus Meeting Report: Development of a Target Product Profile (TPP) and a Framework for Evaluation for a Test for Predicting Progression from Tuberculosis Infection to Active Disease. Geneva, World Health Organization, 2017. 20 Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med 2014; 371: 1599–1608. 21 Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med 2014; 371: 1588–1598. 22 Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 2014; 371: 1577–1587. 23 Dorman SE, Nahid P, Kurbatova EV, et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med 2021; 384: 1705–1718. 24 Nyang’wa B-T, Berry C, Kazounis E, et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med 2022; 387: 2331–2343. 25 Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. N Engl J Med 2022; 387: 810–823. 26 World Health Organization. WHO Consolidated Guidelines on Tuberculosis: Module 4: Treatment: Drug-resistant tuberculosis treatment. 2022 Update. Geneva, World Health Organization, 2022. 27 Ryckman TS, Dowdy DW, Kendall EA. Infectious and clinical tuberculosis trajectories: Bayesian modeling with case finding implications. Proc Natl Acad Sci USA 2022; 119: e2211045119. 28 Emery JC, Dodd PJ, Banu S, et al. Estimating the contribution of subclinical tuberculosis disease to transmission – an individual patient data analysis from prevalence surveys. medRxiv 2022; pre-print [DOI: https://doi.org/10.1101/2022.06.09.22276188]. 29 Verstraeten R, Cossa M, Martinez L, et al. Epidemiology: the current burden of tuberculosis and its determinants. In: García-Basteiro AL, Öner Eyüboğlu F, Rangaka MX, eds. The Challenge of Tuberculosis in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 18–33. 30 Frascella B, Richards AS, Sossen B, et al. Subclinical tuberculosis disease - a review and analysis of prevalence surveys to inform definitions, burden, associations, and screening methodology. Clin Infect Dis 2021; 73: e830–e841.

Disclosures: M.X. Rangaka holds a Wellcome Investigator Award for a project that is unrelated to this Monograph. The remaining authors have nothing to disclose.

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List of abbreviations ART antiretroviral therapy BCG bacille Calmette–Guérin COVID-19 coronavirus disease 2019 CXR chest X-ray DOTS directly observed treatment, short course DR-TB drug-resistant tuberculosis DST drug-susceptibility testing EPTB extrapulmonary tuberculosis IFN interferon IGRA interferon-γγ release assay IL interleukin LTBI latent tuberculosis infection MDR-TB multidrug-resistant tuberculosis PLHIV people living with HIV PTB pulmonary tuberculosis RR-TB rifampicin-resistant tuberculosis TB tuberculosis TBI tuberculosis infection TNF tumour necrosis factor TPT tuberculosis preventive treatment TST tuberculin skin test WGS whole-genome sequencing WHO World Health Organization XDR-TB extensively drug-resistant tuberculosis

Chapter 1

International efforts to reverse and end the tuberculosis pandemic: past, present and future global strategies Guy B. Marks 1,2,3, Alvin Kuo Jing Teo4,5, Emily B. Wong6,7, Greg J. Fox2,4 and Thu Anh Nguyen2,4 1

University of New South Wales, Sydney, Australia. 2Woolcock Institute of Medical Research, Glebe, Australia. International Union Against Tuberculosis and Lung Disease (The Union), Paris, France. 4Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. 5Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore. 6Africa Health Research Institute, Durban, South Africa. 7Division of Infectious Diseases, Heersink School of Medicine, University of Alabama Birmingham, Birmingham, AL, USA.

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Corresponding author: Guy B. Marks ([email protected]) Cite as: Marks GB, Teo AKJ, Wong EB, et al. International efforts to reverse and end the tuberculosis pandemic: past, present and future global strategies. In: García-Basteiro AL, Öner Eyüboğlu F, Rangaka MX, eds. The Challenge of Tuberculosis in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 1–17 [https://doi.org/10.1183/2312508X.10023822]. @ERSpublications We are persisting with approaches to TB that are “affordable” but are not working. We have known how to prevent TB for 150 years. We must break the chain of transmission by finding and treating all people with TB. https://bit.ly/ERSM101 Copyright ©ERS 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

TB is an ancient disease. Substantial advances in knowledge about the disease and tools for diagnosis and treatment developed in the late 19th and early 20th centuries led to its virtual ending as a public health problem in the third and fourth quarters of the 20th century in several countries. This demonstrates that the very high burden of disease still seen in most of the world is neither inevitable nor immutable. Several ambitious global targets and strategies have been implemented since the 1990s. However, progress has been disappointing. Some new tools (for both diagnosis and treatment) and new approaches have been developed. This chapter reviews the opportunities for accelerating progress towards finally ending TB.

Introduction: the goal of ending TB The TB pandemic has afflicted humanity for millennia [1]. Causing an estimated 1 billion deaths throughout human history [2], TB remains a leading infectious cause of death globally [3]. The burden of TB varies enormously between settings. Annual incidence per 100 000 people ranges from less than one in those born in the USA, up to more than 1000 in parts of sub-Saharan Africa [3, 4]. The incidence of TB is also highly variable and dynamic. In the 18th and 19th centuries, the incidence of TB in much of Western Europe and North America was comparable to that of many high-burden countries today [5]. The successful control of TB in many high-income countries demonstrates that the TB pandemic is neither inevitable nor immutable. It is possible for countries to substantially decrease the prevalence of TB and its public health impacts. Ending TB is now the goal of global TB public health management [6], building upon national strategies dating back to the 1980s [7]. https://doi.org/10.1183/2312508X.10023822

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In this chapter, we explore the historical experience of strategies to end TB in low-incidence settings. We will also present the evidence for effective interventions that can be employed to chart a course towards ending TB in both low- and high-burden settings. A brief history of TB prevention and care The modern history of efforts to prevent and treat TB probably begins with Robert Koch’s announcement on 24 March 1882 [8] (available in English translation in [9]) that he had identified Mycobacterium tuberculosis and had proven its causal association with the disease we know as TB. Contemporaneous developments in microbiology, enabling acid-fast staining for direct microscopic detection of M. tuberculosis in expectorated sputum [10], and developments in the physics of radiographic imaging that emerged soon afterwards [11], meant that the essential elements for modern diagnosis of TB were available from beginning of the 20th century. Although a vaccine was first administered to humans in 1921 [12] and this remains widely used as a neonatal vaccination due to its benefits in preventing disseminated and fatal TB in infants, its effectiveness in preventing TB in adults has been disappointing [13]. In the middle of the 20th century, effective chemotherapy for TB became available, initially with streptomycin [14] and subsequently with multidrug therapy. By 1970, all the modern drugs that are still used to effectively treat most cases of TB were available [15]. The modern toolbox for TB diagnosis and treatment was complete. These fundamental biological, physical and chemical developments provided the tools needed to diagnose and treat TB. However, effective control of the disease at massive scale, particularly the ability to find, diagnose and deliver therapy to all or most people with TB, continues to prove elusive, as evidenced by the very high burden of TB disease still present throughout the world. This will be discussed further in the next chapter of this Monograph [16]. In this section, we briefly review several of the strategies implemented to utilise these tools to prevent and cure the disease and hence reduce suffering due to TB. Sanatorium movement, institutional care, and the decline in TB incidence in the pre-chemotherapy era Sanatoria as facilities for treatment for people with TB emerged in the southern German Alps in the 1850s [17], probably in the tradition of cure-taking spas (see page 54 in [18]), and soon developed in other European alpine areas, such as Switzerland and Austria. In New York, Edward Livingston Trudeau, a physician who had suffered from TB, created a sanatorium in the mountains in upstate New York [19]. In Edinburgh, in the 1880s, Robert Philip recognised the potential for dispensaries to mitigate transmission of the disease by removing infectious people with TB from their households and communities. In founding the Victoria Dispensary for Consumption, he sought to make the facility available to the poor, who were severely affected by TB. This “Edinburgh scheme” had a substantial influence on European, North American, South African and Australian public health approaches to TB in the early 20th century [18]. Most poor people did not have access to the better conditions available in sanatoria. However, many were placed in Poor Law infirmaries or workhouses, in which they were segregated from the general population and from other inmates without TB [20]. Hence, institutional care of people with TB contributed to the reduction in transmission of TB in the places where this was implemented [5]. The rationale for its implementation was not always clearly articulated but it seems likely that awareness of the nature of airborne transmission and the need for segregation was appreciated by some of the architects of these measures. WILSON [5] has challenged the conventional and widely held view that declines in TB mortality during the 19th and early 20th century were due to improved nutrition, sanitation and living 2

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conditions and, instead, highlighted the role of segregation of the sick, either deliberately or otherwise, as a more plausible explanation. Modelling by VYNNYCKY and FINE [21] supports this contention by demonstrating that the decline in TB morbidity during the 20th century in developed countries has been associated with a decline in the extent of effective contact with infectious individuals: from 22 effective contacts per person with TB in 1900 to 10 in 1950 and one in 1990. Segregation of people with TB seems the most plausible explanation for this change. Early experience with mass miniature radiology and national TB campaigns Population screening by CXR was implemented, to a varying extent, in several countries in Northern and Western Europe, the Americas (including Cuba), and elsewhere [22–24]. Here we report on two case studies for illustration: Australia and Japan. In Australia, the National Tuberculosis Campaign was launched in October 1945 (see page 152 and following pages in [18]). The campaign included, among other initiatives, population-wide screening using mass miniature radiology. From the 1950s, the Australian states began to enact and enforce compulsory CXR examinations. In New South Wales, a fine was levied for non-compliance. This action led to the expected substantial increase in participation and continued until 1979 (see pages 158–162 in [18]). This 30-year campaign was associated with huge decline in TB notifications (from 40 per 100 000 in 1960 to 1 month [37, 39, 42]. On physical examination, peripheral lymphadenopathy and hepatosplenomegaly are more frequent in children. Cutaneous lesions can be seen, including erythematous macules and papules (tuberculosis miliaria cutis). Ophthalmoscopic examination may reveal choroidal tubercles, which are suggestive of miliary TB. It is important to assess for meningeal involvement, as TB meningitis (TBM) is found in 10–30% of adult patients [43, 44]. Disseminated TB can progress to septic shock and multiple organ failure with a high rate of mortality [45, 46]. Central nervous system TB The most common presentation of central nervous system TB is TBM, followed by tuberculoma and tuberculous brain abscess. The most common complication of central nervous system TB is hydrocephalus, accompanied by infarct and ventriculitis [47]. 54

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Diagnosing TBM is a clinical challenge due to the nonspecific characteristics of the signs and symptoms. In adults, the most frequent symptom is the gradual onset of headache over 1–2 weeks, followed by fever, nausea, or vomiting and confusion, which may quickly evolve into stupor, coma and death if untreated [48, 49]. Clinical signs include neck stiffness, cranial nerve palsies, plegia/paresis, movement disorders and seizures [48, 49]. Cranial nerve palsy can be detected in 24% of TBM cases, most commonly the abducens nerve followed by the oculomotor nerve [50]. Atypical presentations include slowly progressive dementia over many months, marked by personality change, social withdrawal, memory deficit, acute meningitis similar to pyogenic bacterial infection and TB encephalopathy with neither meningitis signs nor prominent cerebrospinal fluid abnormalities [48, 50]. Focal neurological deficits (i.e. central nervous palsies, hemiparesis and seizures) or symptoms of hydrocephalus (headache, papilloedema, diplopia and visual disturbance) sometimes precede signs of meningitis [49]. Young children and immunosuppressed adults have the highest risk of developing TBM [48, 51]. In children, clinical features include apathy, irritability, decreased levels of consciousness, anorexia, poor weight gain, headache, fever, vomiting (without diarrhoea), malaise, signs of increased intracranial pressure, such as a bulging fontanelle, cranial nerve palsy, and focal neurological signs and seizures [48, 49]. Headache is less common, while irritability, restlessness, anorexia and protracted vomiting are prominent symptoms, especially in the very young [52]. Cerebral tuberculomas without meningitis are often asymptomatic but may either present signs and symptoms of focal brain lesions or increased intracranial pressure [51, 53]. Tubercular brain abscess is a focal collection of pus, containing viable tubercular bacilli without evidence of cerebral tuberculoma. Patients may present with features of raised intracranial pressure and focal neurological deficit corresponding to the site of the abscess [54]. Spinal tuberculosis TB spondylitis’ clinical presentation depends on the vertebrae involved. Characteristic symptoms include fever, weight loss, night sweats, neck pain and stiffness. Manifestation might not show any neurological symptoms; alternatively, it might show single nerve root compression to quadriplegia [55]. The most common areas of TB spondylitis are the lower thoracic and upper lumbar regions. Involvement of the cervical and upper thoracic regions is less common [56]. Symptom onset is usually insidious, and the disease progresses slowly [57]. The diagnostic period from the appearance of symptoms can range 2 weeks to several months [58]. Long delays in diagnosis are significantly associated with the presence of severe disease [59]. 40–70% of patients present with signs and symptoms of cord compression at diagnosis [60, 61]. The most common symptom is back pain, which increases over weeks and months, and is associated with muscle spasm and stiffness. Systemic symptoms, fever and weight loss may occur in up to 40% of cases [57, 58, 62, 63]. At physical examination, restricted motion is the most common feature, followed by painful percussion and kyphosis [64]. Neurological deficits, cold abscesses and draining skin sinus tracts can also be found in patients with spinal TB [63, 65]. Hip flexion may cause pain in the groin when a paraspinal abscess develops within the psoas muscle [66]. https://doi.org/10.1183/2312508X.10005523

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Pleural TB Pleural TB is most frequently characterised by unilateral pleural effusion. Typical symptoms are fever, pleuritic chest pain and dry cough [67]. Other symptoms are breathlessness (in cases of large effusions), night sweats, weight loss and malaise. 20–80% of patient with pleural TB have involvement of the lung parenchyma [67]. In the early stages of the infection, neutrophils are the dominant cell in the effusion. Pleural TB can be complicated by loculated effusion, empyema and fibrothorax, broncho-pleural fistulas and trapped lung [67, 68]. TB empyema is characterised by aspiration of pus from the pleural cavity, while empyema necessitans is characterised by subcutaneous swelling of the chest wall due to continuation of the pleural empyema into the soft tissues [69]. Physical examination is similar to that seen in other causes of pleural effusion, with the most frequent findings being dullness to percussion, absent breath sounds on auscultation, reduced chest expansion and decreased vocal resonance [70]. Lymph node TB Lymph nodes, particularly cervical and thoracic lymph nodes, are a common site of EPTB [71]. Typically, tuberculous lymphadenitis is described as unilateral, multiple, matted, hard to fluctuant with draining sinuses [72]. However, in stages 1 and 2 these may be firm and fixed, as described by JONES and CAMPBELL [73] in their five clinicopathological stages: • Stage 1: enlarged, firm, mobile, discrete nodes showing nonspecific reactive hyperplasia. • Stage 2: lymph nodes became larger, rubbery and fixed to surrounding tissue due to periadenitis. • Stage 3: central softening due to abscess formation. • Stage 4: a purplish thin skin covers a fluctuant swelling and a deeper induration is palpable beneath the deep fascia, known as collar-stud abscess. • Stage 5: nonhealing fistulas to the skin; sinus formation stage. Patients may also present with nonspecific symptoms, such as fatigue, low-grade fever, night sweats and weight loss [74]. Intrathoracic lymph nodes can cause symptoms due to compression, such as dysphagia, dyspnoea and even tracheo-oesophageal fistulas [75]. Chylothorax due to thoracic duct obstruction, pyopericardium and cardiac tamponade have also been described [76, 77]. Tuberculous lymphadenitis usually resolves after 2 months of effective anti-TB treatment; however, paradoxical reaction can be seen in ∼12–23% of cases, with new lymph node enlargement with or without inflammatory signs, which can progress to spontaneous rupture and draining sinuses [78]. Abdominal TB Abdominal TB consists of gastrointestinal and peritoneal TB, and has nonspecific symptoms. Regardless of the gastrointestinal portion involved, abdominal pain and systemic symptoms, such as weight loss, fever and anorexia, are frequent [79]. Gastrointestinal TB most commonly 56

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affects the ileocaecal region, followed by the jejunum and colon [80]. Small intestinal TB usually manifests features of obstruction, most frequently at the ileocaecal valve, such as colicky abdominal pain, nausea, vomiting and abdominal distension [79, 80]. In addition to abdominal pain and systemic features, colorectal TB may follow the same course, with diarrhoea, altered bowel habits and haematochezia [79]. When colonic TB involves the appendix, presentation can be similar to classical appendicitis [79]. Oesophageal TB may present with retrosternal pain, dysphagia and odynophagia [79, 80]. Gastric TB may present with vague epigastric discomfort or pain, features of gastric outlet obstruction, or a palpable mass [79, 80]. Peritoneal TB generally develops over a period of several weeks to months [81]. Abdominal pain is the most common symptom; the most frequent clinical sign is ascites [81]. Other clinical features include fever, weight loss, diarrhoea, constipation, abdominal tenderness, abdominal distension, hepatomegaly and splenomegaly [82, 83].

Joint and extraspinal bone TB Joint/articular TB generally occurs in weight-bearing joints, such as the hips and knees, usually as monoarthritis [65], which may result in destruction of the joint and surrounding bones [84]. Occasionally it may present as typical oligoarticular juvenile idiopathic arthritis in the absence of PTB [84]. The earliest symptom is pain, which may precede swelling and other signs of inflammation, for weeks or months. Systemic symptoms are usually absent [65]. There may also be the presence of cold abscesses, sinus tracts and cartilage destruction [65, 84, 85]. Extraspinal bone TB can affect virtually any bone. The onset is often insidious, and usually presents as a cold abscess with swelling and mild erythema and pain.

Urogenital TB Urogenital (UG) TB includes kidney TB, urinary tract TB, and both male and female genital TB [86]. Young children are rarely affected due to the long latency period after primary TBI [87–89]. Renal TB is the most common form of UG TB. Symptoms, appearances and imaging features are nonspecific. Treatment delay leads to destruction of the parenchyma and obstructive nephropathy with end-stage permanent destruction [90–92]. In TB of the ureters, the lower third of the ureter is the most frequently affected site [90]. Symptoms of ureteral TB are nonspecific, including haematuria and abdominal colic-like pain. Bladder TB symptoms are nonspecific and include urinary frequency and urgency to micturate, dysuria and haematuria [86, 90]. Sterile pyuria, with or without haematuria, is a classic finding [91, 92]. Other clinical features of urinary tract TB include back, flank and suprapubic pain [93]. Systemic symptoms are unusual [94]. The fallopian tubes are the most common site involved in female genital TB [95]. Female genital TB usually presents with infertility, pelvic pain and abnormal uterine bleeding [95]. Physical examination may reveal a pelvic mass, uterine enlargement, fistulas, and ulcerative and hypertrophic lesions in the cervix, vagina or vulva [95]. https://doi.org/10.1183/2312508X.10005523

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The epididymis is the most commonly affected site in male genital TB [87]. Patients may present with complaints of scrotal mass (usually painless, but can be painful), urinary frequency, nocturia, dysuria, haematuria, haemospermia and infertility [87]. Physical assessment may reveal prostatic indurations and nodules on rectal examination, hydrocele, sinus tracts discharging pus, ulcerative penile lesions and a nodular enlargement of the epididymis [87]. Cutaneous TB Skin TB can be exogenous or endogenous. The patient’s history may describe a variety of symptoms. If patients have PTB along with cutaneous TB, they may show pulmonary and cutaneous symptoms. About one-third of skin TB is associated with systemic involvement. On examination, one can find inflammatory papules, ulcers, nodules, pustules, verrucous plaques, and any other type of lesion [96]. Diagnosis is challenging and microbiological confirmation is often not possible [97]. Ocular TB M. tuberculosis can compromise the eyes either as a result of direct inoculation or because of a hypersensitivity reaction [98]. Ocular TB has a wide spectrum of presentations, from the involvement of the external components of the eye such as the eyelids, cornea, sclera and conjunctiva, to the development of panophthamitis, endophthalmitis and uveitis [99, 100]. Posterior uveitis is the most common presentation, with the presence of choroidal tuberculomas, which can be bilateral or unilateral [100, 101]. Clinical diagnosis of ocular TB is difficult as manifestations are nonspecific and do not require pulmonary or systemic involvement – a high index of suspicion is therefore required. Ocular TB is usually a presumptive diagnosis, once other causes of infectious (e.g. toxoplasmosis, syphilis, histoplasmosis) and non-infectious (e.g. sarcoidosis, rheumatological diseases) uveitis have been excluded, usually via TST or in IGRA-positive cases. Airways TB Airways TB affects the larynx, trachea or bronchi. It develops as a result of direct invasion by inhaled bacilli or due to haematogenous or lymphatic dissemination [102]. The most common symptom is hoarseness. Other symptoms include cough, wheezing, haemoptysis, dysphagia, odynophagia and otalgia due to the painful ulcers of the epiglottis, pharynx, tonsils and mouth, and involvement of the middle ear. Lesions vary from erythema to ulceration and masses, and from nodular to exophytic resembling carcinomas [103]. The most frequently affected part is the vocal cords, while the least affected is the epiglottis [104]. In those with endobronchial TB, the incidence of tracheal involvement is 4% [105]. In some cases, it only affects the greater part of the trachea and the bronchi; in others, it affects a small segment of the trachea or one bronchus [106]. In most cases, patients with tracheobronchial TB present with a productive cough, haemoptysis, chest pain, generalised weakness, fever, dyspnoea, stridor and bronchorrhea [107]. In more severe cases, there may be acute tracheal obstruction [107]. The main complications are fibrotic scarring and tracheobronchial stenosis [107]. Tuberculous pericarditis Morbidity associated with tuberculous pericarditis occurs as a result of the immune response to the bacilli penetrating the pericardium (in HIV-negative hosts) or due to bacilli infection itself (in HIV-positive individuals) [108]. The bacilli result from haematogenous or lymphatic spread [109]. Patients with active TB may have asymptomatic pericardial involvement with 58

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incidental pericarditis, or they may be symptomatic, compatible with pericardial effusion and constrictive pericarditis [110, 111]. The clinical symptoms correspond with the following four pathological phases. 1) Dry stage: fibrinous exudation and early granuloma formation. Patients present with acute pericarditis – chest pain, pericardial friction rub and widespread ST elevation without effusion. 2) Effusive stage: lymphocytic exudation and serosanguineous effusion. Patients show signs of heart failure and/or cardiac tamponade, or effusive constrictive pericarditis. 3) Adsorptive stage: absorption of effusion and forming of fibrosis. Patients show symptoms and signs of constrictive pericarditis, but radiology and echocardiography examination show evidence of thick fibrinous fluid around the heart. 4) Constrictive stage: contraction of the fibrosing visceral and parietal pericardium. The patient’s symptoms, signs and echocardiography are consistent with constrictive pericarditis with no residual fluid in the pericardium [108].

Diagnostic delay As TB is an insidious chronic infection and no symptom is specific to the disease, a long time can pass between the appearance of symptoms and diagnosis. Diagnostic delay not only relates to nonspecific symptoms but also to the patient’s comorbidities, living conditions and accessibility to the health system. In terms of living conditions, migrations due to different reasons (war, socioeconomic conditions, etc.) around the world have caused an increasing number of undocumented people with no health insurance. As TB patients in these groups have limited access to health services, diagnosis is delayed, resulting in disease spread. Healthcare provider knowledge and awareness is decisive in diagnosing TB during the patient’s first visit, particularly if they are from an underserved population. Diagnostic delay is shorter in countries with a high incidence of TB than in those with a low incidence of TB due to physician awareness about and experience of the disease [112, 113]. Diagnostic delay varies in different populations and regions. A total delay of 4 weeks, 2 weeks each due to the patient and the health system delays, is reported as acceptable [113, 114]. Most studies report an average total delay of of 2–3 months, including diagnostic and treatment delays. Routine use of WHO-recommended rapid diagnostic nucleic acid amplification tests significantly reduces the diagnostic delay of TB. In a meta-analysis, LEE et al. [115] reported that the use of NAATs with good diagnostic accuracy reduced diagnostic delay of DS-TB and DR-TB by 1, and 7–40 days, respectively.

Conclusion No symptom or sign is specific to TB and any symptom frequently seen in TB may be caused by another disease. The diagnosis of TB should not be made solely on the basis of clinical symptoms and signs, but symptoms are usually the first reason for a patient to seek medical attention and care, and thus should prompt further examination. Diagnostic delay is a problem in clinical practice as patients may continue to actively transmit TB to their close contacts and caregivers during the period before the initiation of adequate therapy. https://doi.org/10.1183/2312508X.10005523

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Chapter 5

Microbiological tests and laboratory tests: the value of point-of-care testing Elisa Tagliani

, Francesca Saluzzo

and Daniela Maria Cirillo

Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Corresponding author: Daniela Maria Cirillo ([email protected]) Cite as: Tagliani E, Saluzzo F, Cirillo DM. Microbiological tests and laboratory tests: the value of point-of-care testing. In: García-Basteiro AL, Öner Eyüboğlu F, Rangaka MX, eds. The Challenge of Tuberculosis in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2023; pp. 64–77 [https://doi.org/10.1183/2312508X.10024222]. @ERSpublications After many years of stagnation, the TB diagnostic pipeline now has many new tests with the potential to speed up diagnosis of TB and drug-resistant TB. Some of the new tests need to be decentralised to be close to the point of need. https://bit.ly/ERSM101 Copyright ©ERS 2023. Print ISBN: 978-1-84984-169-6. Online ISBN: 978-1-84984-170-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

Accurate and rapid laboratory diagnosis of TB is one of the key actions in the fight against the disease. Rapid and accurate diagnosis allows the initiation of an appropriate treatment, leading to an improved outcome for the person affected by the disease and to the reduction of transmission in the community. We discuss here the different tools in use today and those that are now close to the market. Particular attention is devoted to the potential of rapid tests based on next-generation sequencing (NGS) technology for their potential to be used to diagnose and monitor at the population level the emerging resistance to new drugs. We discuss the different diagnostic algorithms and their challenges for implementation in the different settings, including high and low TB incidence settings.

Introduction After many years of stagnation, we now have several rapid diagnostic tests able to detect TB and drug resistance. Designing algorithms including the most suitable diagnostic tests for each contest can highly contribute to decrease the burden of TB at the global level. This chapter reviews the different tests available and discusses how they can best be positioned in different settings to maximise their impact. In addition, the main achievements and challenges in the implementation of new diagnostics are discussed. Decentralised versus centralised tests for TB diagnosis After many years of stagnation, we have now several molecular WHO-recommended rapid diagnostic tests (mWRDs) already endorsed [1] (table 1) and many under trial evaluation. These tests have different characteristics and, in general, are able to perform diagnosis of TB and of resistance to rifampicin (and some to isoniazid) simultaneously or as reflex test [1]. Detecting missing TB cases is one of the main priorities of the global TB programme, increasing accessibility to diagnostics is key to achieve this goal [2]. Accessibility can be increased by 64

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TABLE 1 WHO-endorsed molecular tests for TB and DR-TB testing Molecular assay

Xpert MTB/RIF Ultra (Cepheid)

Xpert MTB/XDR (Cepheid)

FL-LPA (e.g. GenoType MTBDRplus, Bruker-Hain Diagnostics) SL-LPA (e.g. GenoType MTBDRsl version 2, Bruker-Hain Diagnostics) Abbott RealTime MTB (Abbott) Abbott RealTime MTB RIF/INH (Abbott)

Method

Target region

Test accuracy [1]

IS6110/IS1081 Se 0.90, Sp 0.96 (M. tuberculosis Initial test for qPCR/melting (M. tuberculosis detection); detection); Se 0.94, Sp 0.99 TB detection temperature rpoB (RIF resistance) (RIF resistance) with drug analysis (RIF resistance (RIF) resistance) Se 0.94, Sp 0.98 (INH resistance); Follow-on test for Melting temperature inhA promoter, katG, INH, FQ, ETH, SLID analysis fabG1, oxyR–ahpC intergenic Se 0.93, Sp 0.98 (FQ resistance) resistance region (INH resistance); detection gyrA, gyrB (FQ resistance); inhA promoter (ETH resistance); rrs; eis promoter (SLID resistance) Initial test for TB Micro RT-PCR nrdZ and IS6110 Se 0.80, Sp 0.96 detection (M. tuberculosis detection) (M. tuberculosis detection) Follow-on test for Micro RT-PCR rpoB (RIF resistance) Se 0.84, Sp 0.97 RIF resistance (RIF resistance) detection inhA promoter, katG Se 0.89, Sp 0.98 (INH resistance); Follow-on test for PCR, hybridisation RIF and INH (INH resistance); Se 0.96, Sp 0.98 (RIF resistance) resistance rpoB (RIF resistance) detection Follow-on test for PCR, hybridisation gyrA, gyrB (FQ resistance); Se 0.86, Sp 0.99 FQ and SLID rrs, eis promoter (FQ resistance) resistance (SLID resistance) detection Initial test for TB RT-PCR IS6110 and pab Se 0.96, Sp 0.98 detection (M. tuberculosis detection) (M. tuberculosis detection) Follow-on test for RIF and INH resistance detection

RT-PCR

inhA promoter, katG (INH resistance), rpoB (RIF resistance)

Se 0.89, Sp 0.98 (INH resistance); Se 0.94, Sp 0.99 (RIF resistance)

Level of complexity

Setting of use

Turnaround time, h

NA

District or subdistrict laboratory

2 cm across on a CXR than the pretracheal, left paratracheal, subcarinal and paracardiac nodes. A false-positive diagnosis of lymph node enlargement is commonly due to an azygos vein, a persistent left superior vena cava or azygos continuation of the inferior vena cava. The most common differential diagnoses are TB, sarcoidosis and lymphoma (tables 3 and 4). Sarcoidosis is often problematic if only the MLNs are enlarged. However, these three diagnoses (table 4) are readily distinguished by histological examination and are highly suitable for endobronchial biopsy under ultrasound at bronchoscopy. As with all samples that are difficult to obtain, material should be sent for TB tests (PCR and mycobacterial culture) noting that formalin for histological samples will invalidate such tests. Most sarcoidosis is revealed during investigations for extrapulmonary features, such as uveitis, skin nodules or erythema nodosum, or by a CXR taken for another reason.

TABLE 4 Symptoms in TB, sarcoidosis and lymphoma TB

Sarcoidosis

Lymphoma

None (7–46%) Cough with phlegm Haemoptysis Fever Night sweats Weight loss Malaise Extrathoracic lymph nodes

None (80%) Dry cough Breathlessness Red eyes Skin lesions Thirst, polyuria (hypercalcaemia) Arthritis and erythema nodosum Neurological features

None (40%, A#) Breathlessness Fever (B#) Night sweats (B) Weight loss (B) Malaise Itching Extrathoracic lymph nodes

#

94

: A and B features are used in the staging of lymphoma.

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DIFFERENTIAL DIAGNOSIS OF THORACIC TB | G.H. BOTHAMLEY ET AL.

Pleural effusions Pleural effusions are thought to be the most common form of EPTB visible on the CXR. The greater adjusted odds ratio in children for TB pleural effusions, reported in European Union data [33], confirms that many TB pleural effusions occur shortly after initial infection, but it is likely that as many occurred with pulmonary involvement in adults and so were classified as PTB. Diagnosis requires aspiration of pleural fluid. TB diagnosis is aided by a concurrent pleural biopsy [34–36]. A tuberculous empyema occurs when a cavity breaks into the pleural space. Thoracoscopy is often undertaken to obtain material for histology, especially where the diagnosis remains in doubt. The multiple yellow nodules on the parietal pleura are characteristic of TB, whereas other causes have a less definitive appearance (table 5). Solitary lung nodules Solitary nodules are more commonly a feature of lung cancer, metastases, lymphoma or benign hamartomas. In TB, a “primary focus” is an inflammatory response surrounding an inhaled tubercle bacillus, usually found in the lower lobes. These may heal spontaneously or occasionally calcify. Increasingly, TB nodules are being identified by lung cancer screening. The Brock criteria for calculating malignancy (spiculation, female preponderance, upper lobe location and partly solid) mean that many are removed, and a few prove to be due to TB [40–42]. The local incidence of TB affects the likelihood of finding TB, especially if positron emission tomography (PET)/CT is used in the diagnostic evaluation [43, 44]. However, PET scanning cannot differentiate TB nodules from lung cancer [38] (also discussed in another chapter in this Monograph [26]). Although caseation on histology usually leads to treatment for TB, if no treatment is given (on the basis that the single nodule has been removed) active TB disease can still develop, irrespective of any radiological risk factors [45, 46]. Difficulties in distinguishing TB from fungal infections In the Americas, histoplasmosis, blastomycosis, and occasionally coccidiomycosis and nocardiosis can be difficult to distinguish from TB, the last of these having sputum or biopsy

TABLE 5 Causes of a pleural effusion (combined data from hospitals in the UK, Spain and Australia) Diagnosis Cancer (35% of total aspirated) Lung cancer, breast cancer and mesothelioma together account for 62% of this group Infection (27% of total aspirated) TB accounts for 32% of this group¶

Transudates (29% of total aspirated) Exudates not included above (10%) Included association with abdominal pathology, pulmonary embolism and connective tissue/immunological conditions

Diagnostic test

Cytology; adenosine deaminase# [38]

Microscopy, culture and sensitivities pH lower in non-TB infections Mycobacterial culture ± detection of TB DNA [39] Lymphocytic effusion Albumin: pleural to plasma ratio Associated clinical picture

Diagnosis information from [37]. #: note that this reference required the lymphocyte percentage to be >50% and was better at ruling out malignancy than diagnosing TB. ¶: diagnosis of TB defined as positive Ziehl– Neelsen stain or Mycobacterium tuberculosis cultures from pleural fluid or biopsies; necrotising granulomas on pleural biopsy; or a lymphocytic effusion where other causes were excluded and there was a good response with anti-TB treatment.

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material which give a positive Ziehl–Neelsen stain. Parenchymal changes can seem like TB and MLN enlargement is also common. Serological tests may be falsely positive in TB and urine antigen tests may also cross-react with those for lipoarabinomannan, but sputum staining and microscopy or bronchoalveolar cytology are often diagnostic, although occasionally tissue biopsies are required. An aspergilloma is most commonly found in the context of previous cavitary TB disease and a clinical history of massive haemoptysis. NTM Clinical presentation Nontuberculous mycobacterial pulmonary disease (NTM-PD) requires isolation of the same species on at least two occasions (one occasion if from bronchoalveolar lavage) and symptomatic lung parenchymal changes [47]. Although there are >180 NTM species, few are pathogenic [48]. In clinical practice, M. kansasii most resembles PTB: two-thirds are sputum smear-positive, radiological cavities occur in the upper zones and underlying lung disease is unusual. In older women, nodular bronchiectasis due to the M. avium complex (MAC) can arise in normal lung. HIV co-infection is common in PTB, while MAC occurs especially if CD4 cell counts are 28), low (22–28), medium (16–22) and high (streptomycin Isoniazid+streptomycin+PAS Isoniazid+rifampicin+ethambutol Isoniazid+rifampicin+pyrazinamide +ethambutol Isoniazid+rifapentin+moxifloxacin +pyrazinamide

First anti-TB antibiotic therapy Monotherapy leads to drug resistance and relapses Drug combination prevents drug resistance First anti-TB regimen: 18 months’ treatment Treatment length divided by 2: 9 months Current treatment of drug-susceptible TB: 6 months 4-month regimen

PAS: para-aminosalicylic acid.

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Drugs with multiple targets Pyrazinamide leads to intracellular acidification and disrupts plasma membrane

Drugs inhibiting cell wall synthesis

Clofazimine targets the outer membrane, respiratory chain and ion transport

Para-aminosalicyclic acid inhibits folate metabolism

DNA

Ethambutol inhibits arabinosyltransferases embA, embB, embC Isoniazid and thionamid drugs (ethionamide and prothionamide) inhibit inhA

Terizidone and cycloserine inhibit L-alanine racemase and D-alanine ligase Carbapenems (meropenem and imipenemcilastin) + clavulanic acid inhibit transpeptidase

Rifamycins (rifampicin, rifabutin and rifapentin) inhibit transcription

RNA polymerase mRNA Ribosome

ATP synthase

Peptide

Oxazolidinones (linezolid) and aminoglycosides (aminkacin, kanamycin, capreomycin and streptomycin) inhibit protein synthesis

Bedaquiline inhibits ATP synthesis

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FIGURE 2 Mechanisms of action of the currently used anti-TB medicines. ATP: adenosine 5’-triphosphate; mRNA: messenger ribonucleic acid. Created with BioRender.com. Reproduced and modified from [28] with permission.

TREATMENT OF DS-TB AND DR-TB | C. LANGE ET AL.

Delamanid and pretomanid inhibit some mycolic acids synthesis

Quinolones (levofloxacin and moxifloxacin) inhibit DNA synthesis

DNA gyrase

ERS MONOGRAPH | THE CHALLENGE OF TB IN THE 21ST CENTURY

Treatment against DS-TB in children and adults The traditional regimen for treating adults with TB caused by organisms that are not known or that are suspected to be drug-resistant consists of a 2-month intensive phase with isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase with isoniazid and rifampicin (table 2) [46–48]. However, it is advised to continue the quadruple therapy if acid-fast bacilli are still detectable from sputum at the end of the second month until drug susceptibility to isoniazid and rifampicin is confirmed or until acid-fast bacilli are no longer detectable in a sputum specimen. Patients with extensively advanced or cavitary disease and/or those with a delayed culture conversion may benefit from prolongation of the continuation phase to reduce the chance of a relapse. It has been recommended to extend the continuation phase of treatment for at least 4 months beyond the time when acid-fast bacilli become undetectable from sputum specimen [49]. Approximately 85% of patients achieve a successful treatment outcome with this regimen, which has been widely used worldwide for decades [1]. These recommendations also apply to patients with EPTB, except for central nervous system disease and bone and joint disease, for which longer treatment durations are recommended by some expert groups. Whenever feasible, fixed-drug combination tablets are preferred over separate drug formulations [50]. Daily therapy is favoured over intermittent therapy since it provides higher cure rates and a lower risk of disease relapse and drug-acquired resistance than thrice-weekly or twice-weekly dosing regimens [51–57]. Dosagesof different medicines are shown in table 3. An open-label, randomised controlled trial in 2021 indicated that a 4-month regimen with rifapentine, moxifloxacin, isoniazid, and pyrazinamide was non-inferior to the standard 6-month regimen in terms of efficacy and safety [58]. Consequently, the WHO endorsed this 4-month regimen as a treatment option for nonpregnant patients aged ⩾12 years with body weight ⩾40 kg, with drug-susceptible PTB [5]. This shorter treatment regimen has the potential to reduce the burden on healthcare systems, increase treatment adherence and allow faster cure. However, implementation and uptake are hampered by the limited availability of rifapentine. As of March 2020, rifapentine has been registered only in 13 countries worldwide [59]. A recent survey within the TB Network European Trials group (TBnet) showed that by October 2021,

TABLE 2 Treatment regimens for drug-susceptible PTB Regimen

Intensive phase

Continuation phase

Drugs

Duration, months

Drugs

Duration, months

Regimen 1 Regimen 2

HRZE H Rpt Z Mfx

2 4

HR

4

Regimen 3

H R Z (E)

2

HR

2

Comment

Traditional regimen Endorsed for nonpregnant patients aged ⩾12 years with body weight ⩾40 kg with drug-susceptible PTB by the WHO Endorsed for children and adolescents between 3 months and 16 years of age with presumed drug-susceptible non-severe disease by the WHO

H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; Rpt: rifapentine; Mfx: moxifloxacin.

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TABLE 3 Dosage for drugs used in TB regimens for adults and children Drug

Age

Daily dose

Comments

Amikacin may be included in the treatment of MDR-/RR-TB patients aged ⩾18 years on longer regimens when susceptibility has been demonstrated and adequate measures to monitor for adverse reactions can be ensured. If amikacin is not available, streptomycin may replace amikacin under the same conditions. Bedaquiline should be included in longer MDR-TB regimens for patients aged ⩾18 years. (Strong recommendation, moderate certainty of evidence.) Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6–17 years. (Conditional recommendation, very low certainty of evidence.) In children with MDR-/RR-TB aged