Recent years have witnessed key developments in the diagnosis and treatment of tuberculosis. Alongside this, and running in direct opposition to this progress, was the COVID-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.
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- Page 1AbstractCorresponding author: Guy B. Marks (g.marks@unsw.edu.au)
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.
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].
- Page 18AbstractCorresponding author: Alberto L. García-Basteiro (alberto.garcia-basteiro@isglobal.org)
Ending TB has been a global struggle for decades. Despite numerous efforts to accelerate the reduction in incidence and mortality, TB continues to be one of the top infectious killers worldwide. Global advances in reducing TB burden have been halted or reversed by the impact of the COVID-19 pandemic, with major effects on TB diagnosis and treatment. This chapter summarises evidence on the current burden of disease and on the different risk factors for TB, as well as their implications for past and current TB burden. There is an urgent need to strengthen our efforts and get back on track to achieve global TB targets, while taking into account risk factors and social determinants to help optimise intervention targets.
Cite as: 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 [https://doi.org/10.1183/2312508X.10023922].
- Page 34AbstractCorresponding author: Delia Goletti (delia.goletti@inmi.it)
Almost 2 billion people worldwide are infected with Mycobacterium tuberculosis. Most individuals are likely to clear infection, whereas only a minority might still contain dormant M. tuberculosis in granulomas that could resuscitate during their lifetime. This high proportion of contained infections implies a long coevolution between the bacterium and its human hosts, with the pathogen developing several immune evasion strategies. A shift in the host–pathogen balance due to decreased host immunity (e.g. through HIV-mediated CD4 depletion), or increased bacterial virulence, will cause disease progression. Over 10 million new TB disease cases occur per year. The only available vaccine, BCG, does not protect against adult PTB and attempts to develop a more protective vaccine are hampered by the complex life-cycle of M. tuberculosis, disparities in protective versus pathogenic host immune responses, pathogen strain diversity, and our lack of understanding of what constitutes natural protective immunity to M. tuberculosis. Host-directed therapies can represent an important clinical approach in addition to standard therapies. This chapter explores factors affecting the host–pathogen interaction and clinical outcome in TB.
Cite as: Goletti D, Aiello A, Tientcheu LD, et al. Host–pathogen interactions in the context of tuberculosis infection and disease. 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. 34–50 [https://doi.org/10.1183/2312508X.10024022].
- Page 51AbstractCorresponding author: Onno W. Akkerman (o.w.akkerman@umcg.nl)
This chapter presents an overview of the clinical presentation of PTB and EPTB. The signs and syptoms of PTB are discussed, as well as several forms of EPTB, including disseminated TB, central nervous system TB, spinal TB, pleural TB, lymph node TB, abdominal TB, joint and extraspinal TB, urogenital TB, cutaneous TB, ocular TB, airway TB and pericardial TB. Diagnostic delay is considered, and the extra transmission risk this causes. No symptom or sign is specific for TB; it therefore remains important that symptoms and signs are examined carefully.
Cite as: Akkerman OW, Guenther G, Munoz-Torrico M, et al. Clinical presentation of pulmonary and extrapulmonary tuberculosis. 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. 51–63 [https://doi.org/10.1183/2312508X.10025523].
- Page 64AbstractCorresponding author: Daniela Maria Cirillo (cirillo.daniela@hsr.it)
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.
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].
- Page 78AbstractCorresponding author: Madhukar Pai (madhukar.pai@mcgill.ca)
Imaging has a long history as an aid to the diagnosis of TB. In recent years, the pace of technological development in the imaging of TB has been rapid, with the arrival of ultra-portable CXR and point-of-care ultrasound (POCUS) devices, as well as substantial advances made in computer-aided detection (CAD) of CXRs, leading to the WHO's landmark 2021 recommendation of CAD as an alternative to human interpretation of digital CXRs for the screening of TB. However, the evidence is currently limited and of low quality for the use of POCUS as a diagnostic aid for TB. In this chapter, we review the current status of these imaging tools to aid TB diagnosis.
Cite as: Bigio J, Denkinger CM, Kadam R, et al. The evolution of imaging and portable imaging tools to aid tuberculosis diagnosis. 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. 78–89 [https://doi.org/10.1183/2312508X.10024322].
- Page 90AbstractCorresponding author: Graham Bothamley (g.bothamley@nhs.net)
The diagnosis of TB depends on a collation of clinical history, examination, radiology, general investigations, and microbiology. Consequently, the differential diagnosis of TB is huge. However, a systematic approach to clinical diagnosis will avoid mistakes. As the incidence of TB falls, more effort is required to keep the possibility of TB in mind. Confirmation bias can lead to prioritising more common diagnoses, such as COPD, pneumonia, and lung cancer, despite clinical information suggesting TB. Persistence with a failing treatment is often the first step to misdiagnosis, reassessment of the diagnostic possibilities is an important safety measure. In high-risk populations or in high incidence areas, there is a tendency to trial TB treatment without ensuring adequate investigations beforehand. A retrospective audit of TB notifications can assist in recognising your local pattern of disease. The successful management of TB is a measure of the general quality of standard clinical care.
Cite as: Bothamley GH, Adeoye G, Heyckendorf J, et al. The differential diagnosis of thoracic tuberculosis: a guide to under- and over-diagnosis. 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. 90–103 [https://doi.org/10.1183/2312508X.10024422].
- Page 104AbstractCorresponding author: Jose A. Caminero (jcamlun@alosatb.org)
The treatment of both drug-susceptible TB and DR-TB should be based on two principles: 1) the combination of potentially effective drugs (at least three to four) to avoid selection pressure resulting in the emergence of strains resistant to anti-TB drugs, and 2) the need for prolonged treatment in order to sterilise all infectious sites and thereby cure the patient and prevent relapses. The selection of drugs should be based on their bactericidal and sterilising properties, their ability to prevent drug resistance and their safety profile. In this chapter, we describe the basis of TB treatment and the fundamental concepts that should be considered before treating a patient with TB, and address important topics such as the minimum number of drugs needed to treat all patients with TB and DR-TB, the treatment duration, the ideal combination of anti-TB drugs and other essential aspects of TB treatment.
Cite as: Caminero JA, Singla R, Scardigli A, et al. The basis of tuberculosis treatment: fundamental concepts before treating a patient. 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. 104–116 [https://doi.org/10.1183/2312508X.10024522].
- Page 117AbstractCorresponding author: Christoph Lange (clange@fz-borstel.de)
Recent advances have enabled the use of shorter TB treatment regimens. Key changes in the management of TB are: 1-month preventive treatment with rifapentine and isoniazid; 4-month treatment for paucibacillary TB in children; 4-month treatment for PTB in adults based on rifapentine; and 6-month treatment for MDR/RR-TB with bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM). However, the history of TB drug resistance, and limited capacity worldwide for DST, are cause for caution.
Cite as: Lange C, Brehm TT, Chesov D, et al. Treatment of drug-susceptible and drug-resistant tuberculosis. 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. 117–138 [https://doi.org/10.1183/2312508X.10024622].
- Page 139AbstractCorresponding author: Catherine Ong (catherine.ong@nus.edu.sg)
TBI may afflict up to a quarter of the world's population. Although no gold-standard test exists at present, strategies to improve diagnostics in TBI are important. There are populations at significantly elevated risk of progression from TBI to TB disease, particularly the immunocompromised and those with comorbidities such as end-stage kidney disease. The rising scourge of DR-TBI further complicates the screening and management of this important clinical condition.
Cite as: Chhabra S, Wu S, Ngiam JN, et al. Diagnosis of tuberculosis infection. 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. 139–150 [https://doi.org/10.1183/2312508X.10024722].
- Page 151AbstractCorresponding author: Alberto Matteelli (alberto.matteelli@unibs.it)
In 2015, the WHO recognised TBI as a public health concern and defined the essential role of programmatic management of TPT (PMTPT) in the End TB Strategy. PMTPT consists of a cascade of activities starting with the selection of target populations up to the completion of treatment in those in need. Treatment of TBI became a public health intervention, and in the latest 2020 guidelines, the WHO recommended five different regimens and provided advice on their use considering TB burden, HIV status, age and pregnancy. The major problems related to TPT are duration of treatment, toxicity and tolerability, completion rates, and interactions between rifamycins and other drugs. To date, we are still far from reaching the 2022 milestone set by the United Nations High-Level Meeting in 2018 and therefore the End TB Strategy goal of treating 1.7 billion people seems out of reach. Future research and funding should focus on discovering shorter and better-tolerated regimens that could widen the target population for PMTPT.
Cite as: Matteelli A, Rossi L, Lovatti S, et al. Preventive therapies for tuberculosis infection. 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. 151–163 [https://doi.org/10.1183/2312508X.10024822].
- Page 164AbstractCorresponding author: Mark Hatherill (Mark.Hatherill@uct.ac.za)
Fourteen candidate TB vaccines are in clinical development, including eight in phase 2b–3 trials, although there is a paucity of new candidates advancing from preclinical testing. Live mycobacterial vaccines, including recombinant Mycobacterium bovis BCG and live-attenuated Mycobacterium tuberculosis candidates, are entering prevention of disease efficacy trials in infants and adolescents/adults. Several candidates are in nontraditional efficacy trials to prevent M. tuberculosis infection, treatment failure or recurrent disease. The most promising protein-subunit vaccine, M72/AS01E, is expected to enter a large, multicountry, licensure trial in adolescents/adults, including PLHIV and those with/without prior M. tuberculosis sensitisation. Findings are expected by 2028. Efforts to discover immune correlates of vaccine-mediated protection are ongoing. Accelerated global TB vaccine advocacy, community sensitisation to reduce vaccine hesitancy, modelling of impact and development of the investment case, evidence considerations for policy and a framework for country-level introduction will be critical to drive demand, release funding and promote uptake of a new, effective TB vaccine.
Cite as: Luabeya AKK, Tameris M, Shenje J, et al. How close are we to a new, effective tuberculosis vaccine? Recent advances in the field. 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. 164–177 [https://doi.org/10.1183/2312508X.10024922].
- Page 178AbstractCorresponding author: Iñaki Comas (icomas@ibv.csic.es)
Recent improvements in WGS are transforming how we use genomics for TB epidemiology and diagnosis. The increased precision of new techniques allows us to identify transmission with unprecedented resolution and design tailored strategies to reduce the incidence of TB at a local and global scale. In addition, compared with limited commercial molecular tests, diagnosis of drug resistance using the complete genome can interrogate all drug-resistance targets through the use of catalogues of resistance-associated variants, including a catalogue sponsored by the WHO. All these advances are making their way into the clinical setting and will eventually allow us to slow the spread of TB and offer personalised care to all patients.
Cite as: Comas I, López MG, Chiner-Oms Á, et al. Genomic approaches to tuberculosis management and control. 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. 178–190 [https://doi.org/10.1183/2312508X.10025022].
- Page 191AbstractCorresponding author: Andrea Rachow (rachow@lrz.uni-muenchen.de)
About half of microbiologically cured TB patients experience TB-related persistent respiratory health problems or residual lung pathology, which are summarised under the term post-TB lung disease (PTLD). The development of PTLD is complex and moderated by a multitude of host, pathogen and environmental risk factors. With regards to pathogenesis, two processes are likely to be important: 1) Mycobacterium tuberculosis infection-driven tissue damage, and 2) pathological tissue remodelling following active disease. The PTLD phenotype that is currently best described in the data is obstructive airways disease in adults. Other patterns of PTLD including bronchiectasis, other (non-obstructive) lung function abnormalities, such as low forced vital capacity or impaired diffusion capacity, and patterns of secondary morbidity, such as chronic pulmonary aspergillosis and pulmonary arterial hypertension, are less well described. In the absence of robust, evidence-based management guidelines for PTLD, clinical statements suggest a set of diagnostic and therapeutic “toolboxes” which must be adapted to the local and clinical context of PTLD patients.
Cite as: Rachow A, Walker NF, Allwood B, et al. The challenge of post-tuberculosis lung disease. 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. 191–209 [https://doi.org/10.1183/2312508X.10025122].
- Page 210AbstractCorresponding author: Elisa López-Varela (elisa.lopez@isglobal.org)
Despite being both treatable and preventable, TB in children and adolescents continues to cause substantial mortality and morbidity in high-incidence settings. Major challenges include missed opportunities for TB prevention and poor case detection, particularly in young children. Although historically neglected, recent developments, including the 2022 WHO child and adolescent TB guidelines, represent important milestones in improving TB prevention and care in this population. The guidelines include the use of treatment decision algorithms, shorter treatment regimens, and TPT for both drug-susceptible and DR-TB, as well as steps to address the unique needs of adolescents. Closing persistent policy-practice gaps will be necessary to ensure that these new developments are implemented effectively. This chapter emphasises the need for continued efforts to prevent and control TB in children and adolescents, which will require a multifaceted approach involving governments, health systems and communities.
Cite as: López-Varela E, Munyangaju I, Chabala C, et al. Tuberculosis in children and adolescents: a forgotten group in a forgotten disease. 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. 210–234 [https://doi.org/10.1183/2312508X.10025322].
- Page 235AbstractCorresponding author: Raquel Duarte (raquelafduarte@gmail.com)
The interaction of Mycobacterium tuberculosis with components of the innate and acquired immune system has significant implications for the clinical outcome of infection (clearance, latency or progression to active disease). Thus, the risk of progressing from LTBI to active TB is greater in some populations. Understanding which populations are at increased risk of TBI and of TB disease is essential to understand who we should screen and treat for TBI. In the past decades, much new knowledge on epidemiology, risk factors and treatment of TBI has been gathered, which is summarised in this chapter.
Cite as: Torrado E, vanCrevel R, Afonso AR, et al. Protecting the most vulnerable: tuberculosis in immunocompromised individuals. 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. 235–250 [https://doi.org/10.1183/2312508X.10025422].
- Page 251AbstractCorresponding author: Guillermo Sequera (guillesequera@gmail.com)
In this chapter, we review data related to TB and prisons, including the relationship between TB epidemics in prisons and surrounding communities, diagnostic strategies for TBI and TB disease, and TPT. Focusing primarily on low–middle-income country settings, we discuss considerations concerning the implementation of prevention and control strategies in these contexts, with their unique challenges. We refer to “prisons” for convenience throughout this chapter, recognising that carceral settings are diverse and include jails, police stations, correctional facilities and other forms of detention, and to “people deprived of liberty” (PDL) for any person who is in judicial retention in one of these places. Although prison staff, visitors, and religious or health staff are also more exposed to TB in prisons and could spread it in the community, this chapter is focused on PDL, who represent the major part of the problem. The general findings presented here are applicable to most prison settings; however, specific implementation will always depend on the unique conditions of each country's confinement context. TB affects vulnerable populations disproportionately, and prisons are a setting where multiple forms of vulnerability converge. The epidemiological rationale for focusing TB control efforts on prisons aligns with the moral obligation to address inequalities and injustices.
Cite as: Sequera G, Estigarribia G, Walter KS, et al. Tuberculosis in prisons: a growing global health concern. 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. 251–266 [https://doi.org/10.1183/2312508X.10025522].
- Page 267AbstractCorresponding author: Heinke Kunst (h.kunst@qmul.ac.uk)
Global migration has increased in recent decades due to war, conflict, persecution, human rights violations and natural disasters, but also because of work opportunities or study. Migrants’ risk of TB differs by reasons for migration, socioeconomic status, mode of travel and TB risk in transit, healthcare provision in the country of origin, and host country. TB control programmes include migrant TB screening strategies for TB and LTBI before and after entry of a host country. The risk of TB is increased in migrant populations, especially refugees and undocumented migrants, who often face difficulties accessing healthcare. Delay in TB diagnosis may be due to patient-related factors such as language, cultural and socioeconomic barriers, or healthcare provider-related factors such as lack of training on migrant health issues. Migrant health promotion, accessible health systems and migrant-sensitive TB strategies are essential at all migration stages to succeed in TB control.
Cite as: Kunst H, Zenner D, Sotgiu G. How do migrations affect tuberculosis burden? Tuberculosis control among migrant populations. 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. 267–279 [https://doi.org/10.1183/2312508X.10025622].
- Page 280AbstractCorresponding author: Melisa Mei Jin Tan (melisatanmj@u.nus.edu)
TB is one of the world's leading causes of death, with 10.6 million new cases of TB and a total of 1.6 million deaths reported in 2021. This chapter analyses the TB prevention, control and management efforts globally in countries with a high TB burden and in those with a low incidence rate by bringing together systems thinking and collaborative approaches in health systems research. The key findings highlight important insights to align TB needs with pandemic preparedness and response. These include having a trusted leadership to help countries steer through the pandemic quicker and better; adopting service delivery processes that can be adapted to restriction measures in times of crisis; continuing the delivery of quality services and routine care; and management of TB and co-infections during a crisis. Countries must reflect on the COVID-19 response and ensure that services are integrated and coordinated for TB detection and control, forming a key part of a better-prepared and more resilient health system.
Cite as: Tan MMJ, Legido-Quigley H. Preparedness for successful TB control: lessons from the COVID-19 pandemic. 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. 280–291 [https://doi.org/10.1183/2312508X.10025722].