European Respiratory Society

Tuberculosis

Edited by Giovanni Battista Migliori, Graham Bothamley, Raquel Duarte and Adrian Rendon
Tuberculosis

With over 10 million new TB cases and 1.6 million deaths, TB is a global health priority. Multidrug-resistant TB is of particular concern to both clinicians and national TB programmes: in 2017, there were 558 000 new rifampicin-resistant cases and 460 000 confirmed multidrug-resistant TB cases. Despite extensive investigation over the years, there is still a great deal to learn about the prevention, diagnosis and treatment of TB. This Monograph brings together chapters from global TB experts and begins with a patients' perspective that sets the tone. The following chapters cover: the history of TB; epidemiology; strategies for control and elimination; clinical and laboratory diagnosis; imaging; treatment and drugs; TB in children and different patient populations; comorbidities; clinical cases; and much more.

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  4. Page 1
    Abstract
    Pippa Powell, European Lung Foundation, 442 Glossop Road, Sheffield S10 2PX, UK. E-mail: pippa.powell@europeanlung.org

    This chapter looks at TB and MDR-TB from the patients’ perspective by posing three questions: how does TB and MDR-TB affect the daily lives of patients, how can the care of TB be improved, and where should we go with TB care in the next 10 years? The answers draw on the authors’ experience and knowledge, and on published literature and case studies.

    Cite as: Spita G, Clegg H, Dumitru M, et al. The patients’ perspective. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 1–7 [https://doi.org/10.1183/2312508X.10020517].

  5. Page 8
    Abstract
    Robert Loddenkemper, German Central Committee against Tuberculosis, Hertastr. 3, 14169 Berlin, Germany. E-mail: robert.loddenkemper@pneumologie.de

    This chapter begins with the supposition that Mycobacterium tuberculosis and humans co-evolved during their greater than 70 000-year partnership, but how and where are still not fully understood. During the Neolithic revolution the size of the population and its farming and animal domestication activities contributed to the maintenance and transmission of M. tuberculosis. TB continued its increase beginning around 1750 owing to the deplorable conditions prevailing during the first half of the Industrial revolution (overcrowding, malnutrition and absent sanitation), but then began to decline. Even after Robert Koch's seminal discovery of M. tuberculosis in 1882, methods of diagnosis, treatment and prevention advanced slowly. But then TB mortality again increased sharply in many countries during world war I and II. In 1944, effective TB antibiotics first appeared and even better ones followed. Major impediments to TB eradication or elimination remain HIV infection and drug resistance. The WHO created the End TB Strategy in 2014, but achieving its goals appears unlikely by 2035. Possible solutions include widespread treatment for LTBI and an effective vaccine.

    Cite as: Loddenkemper R, Murray JF, Gradmann C, et al. History of tuberculosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 8–27 [https://doi.org/10.1183/2312508X.10020617].

  6. Page 28
    Abstract
    Raquel Duarte, ISPUP-EPIUnit, Faculdade de Medicina, Universidade do Porto, Rua das Taipas No. 135, 4050-600 Porto, Portugal. E-mail: rdmelo@med.up.pt

    The incidence rate of TB has declined worldwide but remains unacceptably high. TB is currently the ninth leading cause of death and the leading cause of death among infectious diseases worldwide. Several behavioural and biological factors are associated with TB, such as HIV infection, tobacco smoking, DM, alcohol abuse and poor nutrition. Socioeconomic factors, such as poor housing, crowded living conditions, migration, low income and advanced age, are also associated with TB. There is an established link between poverty and TB, and increasing evidence suggests that actions or policies that target the socioeconomic determinants of TB can reduce its incidence. In addition, the costs of treatment faced by patients, which can be significant in countries without universal health coverage, must be assessed so that interventions can be implemented at the clinical, public health and socioeconomic levels to reduce the burden of TB.

    Cite as: Duarte R, Santos JV, Santos Silva A, et al. Epidemiology and socioeconomic determinants. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 28–35 [https://doi.org/10.1183/2312508X.10020717].

  7. Page 36
    Abstract
    Mario C. Raviglione, 415F Route des Alpes, 01280 Prévessin-Moëns, France. E-mail: mario.raviglione@unimi.it

    TB still affects millions of people every year, causing 1.6 million deaths annually. Attempts to control this disease intensified after the discovery of its infectious nature over the past century, when both diagnosis and treatment became widely available. After a period of neglect, linked with the conviction that TB was declining, new information about global burden and major outbreaks in rich countries in the early 1990s prompted a renewed effort. The first WHO global strategy, DOTS, was widely implemented in countries from the mid-1990s and contributed towards standardising control activities and reverting TB incidence. However, emerging challenges, including HIV-associated TB, MDR-TB, how to engage the private sector and communities, and the need for new tools, have required a revisiting of the strategy in the form of the new WHO Stop TB Strategy launched in 2006. Lately, multiple actors have become prominent in the global fight against TB, and the new framework of the SDGs has prompted innovations in the global approach, with more emphasis placed on patient-centred care, policies addressing the social and economic determinants of TB, and the role of research. The new WHO End TB Strategy is currently the approach universally recommended in the SDG era, while TB enjoys growing political attention thanks to two unprecedented events in 2017–2018 that should transform the global struggle against this disease.

    Cite as: Raviglione MC. Evolution of the strategies for control and elimination. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 36–61 [https://doi.org/10.1183/2312508X.10020817].

  8. Page 62
    Abstract
    Margarida Correia-Neves, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal. E-mail: mcorreianeves@med.uminho.pt

    The interaction of Mycobacterium tuberculosis with a host may result in a number of distinct outcomes: the host can either eliminate the micro-organisms immediately or allow the establishment of an infection, which in turn can progress to active TB or remain as LTBI. The nature of this outcome depends on a number of factors, most of which are related to the immune response developed by the host and the particularities of the bacterial genetics. Here, we summarise the major concepts and unanswered questions on the host response to infection and M. tuberculosis strain-related differences associated with distinct outcomes. In addition, detection of infection before individuals develop clear signs of active disease is challenging, as is the recognition of those who are at a higher risk of progressing towards active TB. Thus, new biomarkers for active and latent TB are presented.

    Cite as: Barreira-Silva P, Torrado E, Nebenzahl-Guimaraes H, et al. Aetiopathogenesis, immunology and microbiology. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 62–82 [https://doi.org/10.1183/2312508X.10020917].

  9. Page 83
    Abstract
    Jean-Pierre Zellweger, Swiss Lung Association, Chutzenstrasse 10, 3007 Berne, Switzerland. E-mail zellwegerjp@swissonline.ch

    Clinical symptoms and signs of TB are very diverse, and depend on the localisation and extent of the disease as well as the age and immunological status of the affected patient. For each localisation, a differential diagnosis has to be considered. Symptoms are generally not specific enough to allow a diagnosis; however, they are indicators of the necessity to perform further diagnostic tests, usually radiographic and bacteriological examinations, in order to obtain a definitive diagnosis and start treatment. Due to the slowly progressive nature of TB, the nonspecific character of symptoms, the difficulty in access to healthcare in many settings or the lack of experience of primary healthcare clinicians, there may be a long delay between the onset of symptoms and the implementation of an appropriate treatment. During this interval, some patients with transmissible forms of TB may infect their contacts and caregivers. Reduction of the diagnostic delay may contribute to the decrease in transmission of TB in the population.

    Cite as: Zellweger J-P, Sousa P, Heyckendorf J. Clinical diagnosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 83–98 [https://doi.org/10.1183/2312508X.10021017].

  10. Page 99
    Abstract
    Daniela Maria Cirillo, Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. E-mail: cirillo.daniela@hsr.it

    Laboratory diagnosis of TB needs to be accurate, rapid and able to provide sufficient data to start patients on proper treatment. While culture and phenotypic DST remain pillars in the diagnostic process, molecular methods have the advantage of providing key data in a very short time. Worldwide roll-out of automated platforms able to detect TB and rifampicin resistance have substantially contributed to the increase of detection and treatment of MDR-TB cases. New, more comprehensive platforms are under development or have just started commercialisation, where the main advantage will be the capacity to detect resistance to isoniazid in addition to rifampicin. Some of the platforms are designed to be placed at a more centralised and high workload level. Whole-genome sequencing (WGS) and WGS-based technologies are the promise for the future. These tests will provide a very comprehensive range of information, from extensive resistance prediction to data on transmission in the population.

    Cite as: Tagliani E, Nikolayevskyy V, Tortoli E, et al. Laboratory diagnosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 99–115 [https://doi.org/10.1183/2312508X.10021318].

  11. Page 116
    Abstract
    Dumitru Chesov, Division of Pneumology and Allergology, “Nicolae Testemitanu” State University of Medicine and Pharmacy, 165 Stefan cel Mare, 2004 Chisinau, Republic of Moldova. E-mail: dumitru.chesov@usmf.md

    The importance of imaging in the diagnosis and management of TB has varied over time. Chest radiography, in particular, has moved from its role as a key diagnostic test in all cases to one where it is now recognised as an efficient method of early TB detection. This has arisen in part due to the introduction of new digital radiographic approaches (both in performance and reading) as well as changes in global TB policies to detect all TB cases irrespective of their infectiousness. Combined with clinical and microbiological data, radiography remains helpful in both TB diagnosis and follow-up in a large number of patients. However, in some cases imaging tools with a higher specificity are required, e.g. computed tomography or magnetic resonance imaging. These may be particularly useful in EPTB, paucibacillary and immunocompromised patients. The relatively high cost of modern imaging diagnostics remains a barrier to their wider adoption in high-burden TB settings.

    Cite as: Chesov D, Botnaru V. Imaging for diagnosis and management. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 116–136 [https://doi.org/10.1183/2312508X.10021217].

  12. Page 137
    Abstract
    Angshu Bhowmik, Dept of Respiratory Medicine, Homerton University Hospital NHS Foundation Trust, Homerton Row, London, E9 6SR, UK. E-mail: a.bhowmik@nhs.net

    Examination of the sputum, either spontaneous or induced, for acid- and alcohol-fast bacilli smear and culture for Mycobacterium remains the first choice for diagnosing TB. If sputum cannot be obtained, bronchoscopic procedures such as bronchoalveolar lavage may be required, targeting areas of radiographic abnormality. If endobronchial lesions are seen, biopsies are helpful. Endobronchial ultrasound (EBUS)-guided needle aspiration is recommended for the diagnosis of paratracheal, subcarinal and hilar lymphadenopathy. Endoscopic ultrasound helps to diagnose lower mediastinal lymphadenopathy, left adrenal disease, and accessible parts of the mesentery and omentum. Transbronchial lung biopsy, bronchial brushings and blind transbronchial needle aspiration are less useful nowadays, unless EBUS is not available. Image-guided biopsy, thoracoscopy and surgical biopsy have a role in undiagnosed lesions, particularly when peripheral. Pleural aspiration is required for pleural effusion but thoracoscopy with pleural biopsy may increase yield. Closed pleural biopsy may improve yield in resource-poor areas. Gastric lavage may be useful for diagnosis in children.

    Cite as: Bhowmik A, Herth FJF. Bronchoscopy and other invasive procedures for diagnosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 137–151 [https://doi.org/10.1183/2312508X.10020518].

  13. Page 152
    Abstract
    José A. Caminero, Dept of Pneumology, University Hospital of Gran Canaria “Dr Negrín”, Barranco de la Ballena s/n, 35010 Las Palmas de Gran Canaria, Spain. E-mail: jcamlun@gobiernodecanarias.org

    The treatment of TB, both drug-susceptible and drug-resistant forms, should be based on two principles: 1) the combination of drugs (at least four) to avoid selection pressure resulting in the emergence of DR-TB strains and 2) the need for prolonged treatment in order to sterilise all infectious sites and thus 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. Based on these principles, and on the mode of action of the different drugs, this chapter describes in detail anti-TB treatment, the most appropriate choice of drugs based on in vitro susceptibility testing, starting with drug-susceptible TB (DS-TB), and a proposal to standardise as much as possible the difficult-to-manage patients with DR-TB. The chapter delineates the recommended treatment for DS-TB, mono- and polyresistant TB, MDR-TB, XDR-TB and forms of TB beyond XDR-TB. Special attention is given to the 2018 WHO guidelines regarding the revised grouping of second-line TB drugs recommended for use in longer MDR-TB regimens, the shorter MDR-TB regimens, the possibility of designing a standardised pre-XDR and XDR-TB regimen adapted to the country, and some relevant management issues.

    Cite as: Caminero JA, Scardigli A, van der Werf T, et al. Treatment of drug-susceptible and drug-resistant tuberculosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 152–178 [https://doi.org/10.1183/2312508X.10021417].

  14. Page 179
    Abstract
    Simon Tiberi, Division of Infection, Royal London Hospital, Barts Health NHS Trust, 80 Newark Street, London E1 2ES, UK. E-mail: simon.tiberi@bartshealth.nhs.uk

    Rates of resistance to antimicrobial agents that are used to treat Mycobacterium tuberculosis infection have risen in recent years and account for a growing number of TB deaths worldwide. DR-TB often necessitates long treatment times with toxic drug combinations that are poorly tolerated. Research is focusing on repurposing existing agents for use in TB treatment and on the discovery of new compounds. There are many new agents in the TB drug development pipeline that have shown great promise. Bedaquiline is the first new drug to be licensed for treatment of TB in 40 years. Trials are researching different drug combinations in order to shorten treatment duration and reduce toxicity. This chapter will summarise the evidence around these new and repurposed agents, and their action and adverse effects, and will discuss new potential drug combinations that may soon be recommended.

    Cite as: Krutikov M, Bruchfeld J, Migliori GB, et al. New and repurposed drugs. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 179–204 [https://doi.org/10.1183/2312508X.10021517].

  15. Page 205
    Abstract
    José A. Caminero, Dept of Pneumology, University Hospital of Gran Canaria “Dr Negrín”, Barranco de la Ballena s/n, 35010 Las Palmas de Gran Canaria, Spain. E-mail: jcamlun@gobiernodecanarias.org

    It is currently possible to cure TB, but multiple drugs are required over a long term, and both of these factors produce adverse drug reactions (ADRs). ADRs can be caused by all anti-TB drugs but are much more frequent with second-line drugs. Fortunately, most anti-TB ADRs are mild or moderate and do not always require removal of the offending drug. However, some ADRs can be severe or potentially life-threatening, requiring urgent clinical interventions, including removal of the suspected drug(s). Early detection and adequate management of ADRs is essential for a good TB treatment outcome. This chapter reviews the majority of the possible ADRs to anti-TB drugs. In addition, practical recommendations to identify the possible drug(s) involved in the different reactions and the most adequate management in each situation are outlined.

    Cite as: Caminero JA, Lasserra P, Piubello A, et al. Adverse anti-tuberculosis drug events and their management. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 205–227 [https://doi.org/10.1183/2312508X.10021617].

  16. Page 228
    Abstract
    Gilbert Massard, Hôpitaux Universitaires de Strasbourg, Thoracic Surgery Dept, Nouvel Hôpital Civil, 1 place de l'Hôpital, Strasbourg 67000, France. E-mail: gilbert.massard@chru-strasbourg.fr

    To date, well conducted chemotherapy will cure up to 85% of all pulmonary TB cases. In this vast majority of patients, surgery will be limited to a diagnostic tool. Video-assisted thoracic surgery and other elective mini-invasive approaches (mediastinoscopy) will help biopsy small lung nodules and/or diseased lymph nodes. But, in the case of MDR-/XDR-TB patients, anatomical lung resections (lobectomy and pneumonectomy) will help eradicate tuberculous cavitations still hosting mycobacterias, despite well-conducted chemotherapy. The strategy for lung resection in MDR-/XDR-TB patients will be determined by a multidisciplinary team taking into account the medical history of the patient, comorbidities, the recent history and evolution of the TB under appropriate chemotherapy, and a complete pre-operative work up of the patient, including nutritional status, and respiratory and cardiovascular functional status. High rates of favourable outcomes (over 90%) have been described provided surgery was applied during the first year of newly diagnosed MDR-/XDR-TB. In the meantime, reporting results of collapse therapy (pneumothorax/ pneumoperitoneum) during the first year of a newly diagnosed destructive TB, studies demonstrate clinical recovery in 93.9% of patients. Surgery provides excellent results for curing MDR-/XDR-TB insisting on the need for performing surgery following the actual guidelines, and during the first year of TB diagnose without neglecting the true efficiency of collapse therapy despite its old-fashioned appearance.

    Cite as: Olland A, Falcoz P-E, Guinard S, et al. Surgery as a treatment. In: Migliori GB, Bothamley G, Duarte R, et al, eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 228–233 [https://doi.org/10.1183/2312508X.10021717].

  17. Page 234
    Abstract
    H. Simon Schaaf, Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa. E-mail: hss@sun.ac.za

    TB in children has been the invisible part of the global TB epidemic; however, it is responsible for high morbidity and mortality, especially in TB-endemic settings where most children remain undiagnosed and untreated. Added to this are the challenges of diagnosing DR-TB in children. In the face of these diagnostic challenges, it is even more important to prioritise prevention efforts. TB in children is mainly paucibacillary, which means that fewer drugs and/or shorter treatment regimens may be used, but severe forms of TB such as tuberculous meningitis need special consideration. In general, outcomes of both drug-susceptible and drug-resistant disease in children are good if diagnosed early and treated appropriately, but challenges remain regarding optimal drug dosing, availability of child-friendly formulations and child-appropriate regimens. HIV infection is decreasing due to prevention of mother-to-child transmission roll-out, but antiretroviral and anti-TB drug–drug interactions remain a challenge. Optimal prevention strategies, diagnostic tools, treatment regimens and practical operational issues remain key research questions.

    Cite as: Schaaf HS, Marais BJ, Carvalho I, et al. Challenges in childhood tuberculosis. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 234–262 [https://doi.org/10.1183/2312508X.10021817].

  18. Page 263
    Abstract
    Graham Bothamley, Dept of Respiratory Medicine, Homerton University Hospital, London E9 6SR, UK. E-mail: g.bothamley@nhs.net

    TB in both pregnancy and the elderly may occur more frequently and with more EPTB than in the general population, possibly due to immunological changes relevant to these conditions. They both share complexities in the difficulty of clinical diagnosis, related to the nature of nonspecific symptoms in TB disease. New molecular tests are especially helpful in diagnosing paucibacillary disease. Treatment of TB disease in pregnancy is complicated by adverse effects, especially of second-line drugs, affecting both mother and fetus, and in the elderly by a high rate of DILI with increasing age. Screening for TB has been suggested in both populations as part of the plan to eliminate TB. Treatment of LTBI is possible in both populations, but clinicians are concerned by adverse effects, which may be less than they fear.

    Cite as: Repossi A, Bothamley G. Pregnancy and the elderly. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 263–275 [https://doi.org/10.1183/2312508X.10021917].

  19. Page 276
    Abstract
    Cecile Magis-Escurra, Radboud UMC-Dekkerswald, Pulmonology, Nijmeegsebaan 31, Nijmegen, Gelderland, 6561KE, The Netherlands E-mail: cecile.magis-escurra@radboudumc.nl

    In this chapter, we provide practical treatment advice for physicians to treat patients with TB and different comorbidities (HIV, diabetes, renal failure and liver cirrhosis), and TB patients post-solid organ transplant, based on the recommendations of different (inter)national guidelines, publications and expert opinions.

    Cite as: Magis-Escurra C, Carvalho ACC, Kritski AL, et al. Comorbidities. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 276–290 [https://doi.org/10.1183/2312508X.10022017].

  20. Page 291
    Abstract
    Kerri Viney, Dept of Public Health Sciences, Karolinska Institutet, Centre of Global Health, Widerströmska Huset, Tomtebodavägen 18 A, 171 77 Stockholm, Sweden. E-mail: kerri.viney@ki.se

    In this chapter, we discuss two key concepts of TB prevention and care: access and adherence. We discuss these in the context of “hard-to-reach” groups, defined as groups of people who are under-represented or underserved. By definition, these groups may experience particular difficulties in accessing TB care (including preventative, diagnostic and care services) and remaining in care once it has been accessed. As TB often affects hard-to-reach groups, healthcare services should be designed with such groups in mind, aiming for equitable and affordable access to people-centred TB care. We also describe barriers to healthcare access and adherence, and provide some solutions to overcoming these barriers, based on current evidence. Ensuring that access and adherence are addressed, with the most disadvantaged groups in mind, is a necessary step towards achieving the ambitious goals of the WHO End TB Strategy and SDGs, which aim to eliminate TB by 2030.

    Cite as: Viney K, Wingfield T, Kuksa L, et al. Access and adherence to prevention and care for hard-to-reach groups. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 291–307 [https://doi.org/10.1183/2312508X.10022117].

  21. Page 308
    Abstract
    Jan-Willem C. Alffenaar, University of Groningen, University Medical Center Groningen, Dept of Clinical Pharmacy and Pharmacology, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: j.w.c.alffenaar@umcg.nl

    TB treatment is long and often complicated by adverse reactions. Baseline assessment can reduce the likelihood of adverse reactions, especially DILI. Regular monitoring can ensure treatment efficacy and prevent serious complications. A slow response to treatment may indicate poor adherence, an inadequate treatment regimen or acquired drug resistance. Adherence can be addressed by the use of directly observed therapy in a supportive environment. To avoid under- and overdosing, plasma drug concentrations can be measured to tailor the dose to the individual needs of a patient (i.e. TDM). To assess treatment response, the 2-month sputum test is an important time-point for decision making during treatment. Confirmation of treatment response at the end of treatment and the absence of relapse over at least the ensuing 12 months is essential to determine cure. To conclude, monitoring at the start, during and after TB treatment is a simple but necessary task for the TB team to ensure the optimal course and outcome of TB treatment.

    Cite as: Alffenaar J-WC, Akkerman OW, Bothamley G. Monitoring during and after treatment. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 308–325 [https://doi.org/10.1183/2312508X.10022217].

  22. Page 326
    Abstract
    Marcela Muñoz-Torrico, Tuberculosis Clinic, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Colonia Seccion XVI, Tlalpan, Mexico City, Mexico. E-mail: dra_munoz@iner.gob.mx

    Despite multiple WHO strategies aimed at reducing TB burden, it remains a major cause of death worldwide. However, dyspnoea and disability caused by PTB sequelae are often neglected when managing TB.

    Investigating TB sequelae with pulmonary function tests is mandatory after treatment completion. Pulmonary function tests allow the clinician to evaluate the residual lung function, and determine the mechanism of lung damage involved and the severity of pulmonary impairment. The tests also allow prediction of the patients at risk of surgical complications and death.

    Pulmonary rehabilitation plays a key role in the treatment of PTB sequelae. Pulmonary rehabilitation is an individualised and multidisciplinary approach (consisting of muscle training, education, behavioural change, respiratory physiotherapy and nutritional support) aimed at improving quality of life and reducing surgical complications in candidates for surgery. Due to the enormous impact this intervention has on the physical and psychological wellbeing, it is recommended in all patients with pulmonary impairment after TB treatment.

    Cite as: Muñoz-Torrico M, Cid-Juárez S, Galicia-Amor S, et al. Sequelae assessment and rehabilitation. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERSMonograph). Sheffield, European Respiratory Society, 2018; pp. 326–342 [https://doi.org/10.1183/2312508X.10022317].

  23. Page 343
    Abstract
    Morten Ruhwald, Human Immunology, Center for Vaccine Research, Statens Serum Institut, Artillerivej 5, 2300 S, Denmark. E-mail moru@ssi.dk

    Despite extensive administration of the BCG vaccine to infants throughout the world, the global TB epidemic continues, with TB representing the world's leading infectious cause of death. Developing a TB vaccine capable of preventing TB disease, primarily in adolescents and adults, the most important sources of Mycobacterium tuberculosis spread, represents a critical need in efforts to stem the global TB epidemic, including the spread of M.tuberculosis strains resistant to multiple TB drugs. 13 TB vaccine candidates are currently in clinical trials. Results from two recently completed trials have demonstrated protective efficacy, and new broader strategies to TB vaccine development, including the diversification of M.tuberculosis antigens, vaccine platforms and routes of vaccine administration are being pursued. In this chapter, we review the current status of the TB vaccine pipeline as well as the future directions in the critically important effort to develop new TB vaccines.

    Cite as: Ruhwald M, Andersen PL, Schrager L. Towards a new vaccine. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 343–363 [https://doi.org/10.1183/2312508X.10022417].

  24. Page 364
    Abstract
    Edward Nardell, Division of Global Health Equity, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. E-mail: enardell@gmail.com

    Ongoing transmission, infection and reinfection, in both community and congregate settings, is fuelling the global TB epidemic. This is despite longstanding comprehensive WHO TB transmission control policies and training, suggesting generally ineffective implementation strategies. Traditional transmission control efforts in institutions tend to focus on known TB patients; many already on effective therapy and not the source of most transmission. Longstanding evidence suggests that TB patients on effective therapy become rapidly noninfectious, and that unsuspected, untreated cases (and unsuspected drug resistance) account for most transmission. In this chapter we argue for a refocused TB transmission control strategy based on active case finding (community and institutional), rapid molecular diagnosis and DST, followed by prompt, fully supervised effective treatment, in the community rather than the hospital or clinic. In Eastern Europe and Central Asia, prolonged hospitalisation combined with delayed diagnosis of drug resistance and poor ventilation in cold climates has resulted in hyper-transmission, resulting in rates of MDR-TB of ≥25% among new cases, compared with <7% in most other countries. Despite screening, some infectious cases will be missed, especially in crowded ambulatory settings. We discuss the pros and cons of natural ventilation, mechanical ventilation systems, upper room germicidal ultraviolet air disinfection, fit-tested respirators on healthcare workers, and short-term use of masks on coughing patients before effective treatment is initiated. We discourage the use of portable room air cleaners.

    Cite as: Nardell E, Volchenkov G. Transmission control: a refocused approach. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 364–380 [https://doi.org/10.1183/2312508X.10022517].

  25. Page 381
    Abstract
    Adrian Rendon, Pulmonary services, Hospital Universitario de Nuevo Leon, CIPTIR AV. Madero y Gonzalitos Mitras Centro, Monterrey, Nuevo Leon, 64460 Mexico. E-mail: adrianrendon@hotmail.com

    Current concepts of diagnosis and treatment of LTBI will be reviewed in detail and the rationality to use IGRA for diagnosis will be explained. The new regimens that include rifampicin or rifapentine and the main groups to be considered for treatment are fully described.

    Cite as: Rendon A, Goletti D, Matteelli A. Diagnosis and treatment of latent tuberculosis infection. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 381–398 [https://doi.org/10.1183/2312508X.10022617].

  26. Page 399
    Abstract
    Jakko van Ingen, Dept of Medical Microbiology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: jakko.vaningen@radboudumc.nl

    NTM can cause chronic severe infections, particularly of the lungs. The incidence and prevalence of these infections is increasing in most settings, particularly those where TB incidence is in decline. Owing to their ubiquity in nature, the diagnosis of NTM pulmonary disease is based on symptoms, radiology and repeated isolation of the same NTM species. NTM are intrinsically resistant to most classes of antibiotics. Treatment is multidrug, long, species specific and cumbersome. DST can help streamline these treatment regimens. In the past two decades, a lot of new knowledge on epidemiology, risk factors, microbiology, and treatment and outcome has been gathered. This chapter provides a review of the new insights in these fields, to support clinicians in the diagnosis and treatment of these severe infections.

    Cite as: Zweijpfenning S, Hoefsloot W, van Ingen J. Nontuberculous mycobacteria. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 399–413 [https://doi.org/10.1183/2312508X.10022717].

  27. Page 414
    Abstract
    Graham Bothamley, Dept of Respiratory Medicine, Homerton University Hospital, London E9 6SR, UK. E-mail: g.bothamley@nhs.net

    The End TB Strategy presents an ambitious target to reduce TB by 90% compared to 2015 levels over a 20-year period, ending in 2035. Already, there are developments that will revolutionise the diagnosis of TB and of drug resistance. Entirely new treatments for TB are on the horizon. Patient involvement, not only in near-patient tests but also in active case finding, data input for research and adherence, and TB support clubs will be crucial. For the longer term future, there are exciting developments in understanding the host and pathogen responses to each other, which will lead to important advances, provided clinical aspects of TB are not forgotten.

    Cite as: Bothamley G. What next? Basic research, new treatments and a patient-centred approach. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 414–429 [https://doi.org/10.1183/2312508X.10026118].

  28. Page 430
    Abstract
    Caterina Casalini, Jhpiego Tanzania, Plot 72, Block 45B, Victoria Area, New Bagamoyo Road, PO Box 9170, Dar es Salaam, Tanzania. E-mail: caterina.casalini@jhpiego.org

    This chapter discusses the key global learning platforms in TB, and describes findings from published studies about TB training and how such training has been evaluated. Key findings from our literature review show that training can be strengthened by: an understanding of the audience; conducting a needs assessment; designing an interactive course with specific learning objectives; including exercises and activities into the curriculum that allow trainees to practice their skills; performing onsite clinical mentoring and monitoring afterwards; and ensuring that healthcare providers and managers work collaboratively towards common outcomes. A favourable environment is also essential to motivate participants to transfer their knowledge to other colleagues at work and to apply their knowledge to service delivery. An evaluation of training provided is essential to understand the power of such investment and to guide future programming. However, evaluations need to be structured in a way that minimises bias and focuses on clinical outcomes.

    Cite as: Casalini C, Matteelli A, Komba A, et al. Opportunities for training and learning. In: Migliori GB, Bothamley G, Duarte R, et al., eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 430–445 [https://doi.org/10.1183/2312508X.10022917].

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