European Respiratory Society
Tuberculosis

Tuberculosis (TB) remains a leading cause of morbidity and mortality in many areas, ranking as the eighth highest cause of death worldwide. TB control has been complicated by the emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis complex, particularly in Eastern Europe, sub-Saharan Africa and Asia. In the past decade, we have achieved important advances in TB diagnosis, whilst the development of new anti-TB drugs has been unsuccessful for almost half a century. New anti-TB drugs are now in clinical evaluation and will soon become available for the treatment of patients.

  • European Respiratory Society Monographs
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  2. Page vi
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  4. Page 1
    Abstract
    Correspondence: D.M. Cirillo, Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy. Email: cirillo.daniela@hsr.it

    Tuberculosis (TB) has been one of the most important human diseases for centuries now. It is mainly caused by Mycobacterium tuberculosis, a highly elusive bacillus. This intracellular pathogen does not possess the classic bacterial virulence factors. However, M. tuberculosis efficiently evades the immune response by complex and manipulative mechanisms, which enable survival for as long as decades. The fight with such a smart rival gives rise to the necessity for early diagnosis and appropriate treatment. The ability to rapidly detect M. tuberculosis in clinical specimens, as well as drug resistance, is essential for the appropriate treatment of TB patients and the prevention of spread of drug-resistant strains. New molecular tools are now used in many countries as part of a standard laboratory diagnosis. It is clear that important advances in TB diagnosis have recently been made and potentially useful new tools are emerging. Nevertheless, there is still a lot to be done, especially in high-burden countries where fast identification and early treatment are needed.

  5. Page 14
    Abstract
    Correspondence: R. Centis, World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Via Roncaccio 16, 21049, Tradate, Italy. Email: rosella.centis@fsm.it

    Although Mycobacterium tuberculosis was discovered over a century ago, and different generations of effective tuberculosis (TB) drugs and regimens have been discovered and are widely used within TB control programmes, TB still represents a first-class health priority at the global level in terms of death and disability.

    Several determinants, in addition to drugs, contributed to modify TB trends in different parts of the world, leading to the overall decline we have observed in the last few years. Among them, multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB, the HIV pandemic, and other social determinants have influenced the epidemiological features of the disease.

    In this chapter, we will discuss how TB transmission occurs in humans (through a separate description of exposure, infection, disease and death) and how to measure its core steps by means of ad hoc specific indicators.

  6. Page 25
    Abstract
    Correspondence: D. Wagner, Center of Infectious Diseases and Travel Medicine, and Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Email: Dirk.Wagner@uniklinik-freiburg.de

    Pulmonary disease due to non-tuberculous mycobacteria (NTM) is an emerging infection, mainly in regions with a decreasing prevalence of tuberculosis (TB). Patients with existing pulmonary diseases (e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD) and/or bronchiectasis), or patients with local or systemic immunosuppression are at risk of developing NTM lung disease. Disease manifestations can be: fibrocavitary, resembling TB; nodular/bronchiectatic, usually in elderly lean, nonsmoking female patients; or hypersensitivity-like after exposure to contaminated water. Since the clinical relevance of pulmonary NTM isolates differs significantly between NTM species, correct laboratory identification of NTM isolates is important to guide treatment decisions and drug-susceptibility testing (DST) efforts. Diagnosis requires the application of clinical and microbiological criteria according to published American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines. Treatment decisions need to be individualised; long-term antibiotic therapy may be combined with surgical resection of affected portions of the lung.

  7. Page 38
    Abstract
    Correspondence: C.G. Meyer, Dept of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359 Hamburg, Germany. Email:c.g.meyer@bni-hamburg.de

    Over the last few decades, the observed impact of genetic variation on infectious disease phenotypes has contributed to the understanding of why individuals exist who, when infected with the same pathogen, may resist infections, while others experience severe disease or even may succumb to the infection. Since the early recognition of the protective effect that the sickle cell trait exerts on courses of Plasmodium falciparum malaria, studies of genetic susceptibility to infectious disease in humans have, through rapid technological advancements and the availability of analytical tools, made enormous progress. This also applies to investigations of host genetic factors in tuberculosis (TB), where considerable efforts have been undertaken. The methodologies for the identification of genetic variants comprise a variety of techniques for genotyping. In addition to genome-wide linkage and candidate gene studies, whole-genome and high-throughput DNA sequencing and appropriate appliances for genome-wide association studies, such as high-density single-nucleotide polymorphism arrays, are now available. In this chapter, we provide a brief overview of the genetic epidemiology of pulmonary TB.

  8. Page 59
    Abstract
    Correspondence: T.H.M. Ottenhoff, Dept of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Email: t.h.m.ottenhoff@lumc.nl

    Each year, more than 1.5 million people die of tuberculosis (TB) and over 9 million individuals newly develop active disease. The currently available tools are inadequate to control infection and combat TB. The only TB vaccine currently in use, Mycobacterium bovis bacille Calmette–Guérin (BCG), affords incomplete and highly variable protection against TB, and better TB vaccines are urgently needed. Here we discuss recent progress in developing, testing and clinically evaluating new TB vaccines. A dozen new TB vaccine candidates have been and are being evaluated in human clinical trials. Future perspectives and directions for new TB vaccines will also be discussed.

  9. Page 72
    Abstract
    Correspondence: R. Diel, Dept of Pulmonary Medicine, Medical School Hanover (MHH), Carl-Neuberg-Straβe 1, 30625 Hanover, Germany. Email: Diel.Roland@mh-hannover.de

    Identifying particular groups that are at high risk of developing tuberculosis (TB) is of major interest in low-incidence countries. In order to reach the phase of TB elimination, new challenges arising from the steadily declining TB prevalence in the native population but increasing importation of Mycobacterium tuberculosis strains from high-incidence countries and the growing emergence of hard-to-reach groups, must first be dealt with. Thus, in particular, the evidence of protection by bacille Calmette–Guérin (BCG) vaccination and screening of migrants has to be assessed. A newly recommended regime for preventive treatment of latent TB infection (LTBI) in HIV- and non-HIV-infected persons is promising. However, a rapid evaluation of possible strategies of preventive treatment for contacts of multidrug-resistant (MDR) source cases is still lacking.

    Prevention of TB in low-incidence countries is complex and no single action can lead to a lasting result but rather a bundle of properly balanced measures must be taken.

  10. Page 84
    Abstract
    Correspondence: B.J. Marais, Clinical School, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Sydney, Australia. Email: ben.marais@health.nsw.gov.au

    In areas where the tuberculosis (TB) epidemic is well controlled, most new cases are imported or result from endogenous re-activation of distant infection. In this scenario, the wide-scale use of preventive therapy could eliminate the pool of latent infection and facilitate TB eradication. However, in settings with poor epidemic control and ongoing Mycobacterium tuberculosis transmission, re-infection limits the ability to eradicate the pool of latent infection and reduces the duration of protection provided by preventive therapy. The provision of preventive therapy to vulnerable individuals following documented TB exposure and/or infection is universally accepted as the standard of care but multiple barriers result in a pronounced policy–practice gap, with near-absent implementation in many TB-endemic areas. This chapter provides a brief overview of the field with specific emphasis on common misperceptions, contentious issues and pragmatic strategies to improve implementation.

  11. Page 95
    Abstract
    Correspondence: K. Dheda, Dept of Medicine, H floor, Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa. Email: keertan.dheda@uct.ac.za

    The burgeoning epidemic of drug-resistant (DR)-TB threatens to destabilise TB control in high-burden settings, particularly in Africa. From a cost perspective, drug resistance consumes a disproportionate amount of national TB programme budgets in resource-poor settings and is not sustainable. With the roll-out of new technologies, such as the Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA) assay, there will need to be an appropriate scale-up of treatment services throughout high-burden settings. Compared with intermediate and low-burden settings, DR-TB in high-burden settings is characterised by an increase in the overall case burden, lack of access to first- and second-line susceptibility testing, limited or no access to second-line drugs, higher default rates and a poorer prognosis. Of concern is the increasing number of extensively drug-resistant (XDR)-TB cases, and therapeutically destitute XDR-TB treatment failures, which pose a major logistical and ethical dilemma in high-burden settings. In this chapter, we review the epidemiology, diagnosis, management and prognosis of DR-TB with a specific emphasis on high-burden settings.

  12. Page 111
    Abstract
    Correspondence: K. Kliiman, Dept of Pulmonary Medicine, Tartu University Hospital, Riia 167, 51014 Tartu, Estonia. Email: kai.kliiman@kliinikum.ee

    During the last few years, many low-incidence countries have reported a significant decrease in the incidence of tuberculosis (TB) among the local-born population, while the proportion of foreign-born TB patients is increasing. Multidrug-resistant (MDR)-TB is, in general, uncommon in low-incidence countries, although rates are higher in recent entrants, especially among immigrants from countries where prevalence of MDR-TB is high, in previously treated individuals and in HIV-infected patients. Improvements in awareness and management strategies in low-incidence countries are urgently required in order to prevent outbreaks of drug-resistant (DR)-TB in the local populations.

  13. Page 124
    Abstract
    Correspondence: M. Pai, McGill University, Dept of Epidemiology and Biostatistics, 1020 Pine Ave West, Montreal, QC H3A 1A2, Canada. Email: madhukar.pai@mcgill.ca

    Rapid, affordable and accurate tuberculosis (TB) diagnosis is key to effective patient management and global TB control. Effective clinical screening and optimised sample acquisition methods remain the first steps in the diagnostic process. Smear microscopy, despite optimisation, remains widely used even though its sensitivity is poor. Mycobacterial liquid culture is accurate but poorly accessible. The use of novel molecular tools, such as Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA) or GenoType® MTBDRplus (Hain Lifescience GmbH, Nehren, Germany) assays, which offer superior diagnostic accuracy and decreased time-to-diagnosis for drug-sensitive and/or -resistant TB, is increasing following World Health Organization (WHO) endorsement and, in some countries, national roll-out is underway. In contrast, both serology (antibody-detection tests) and interferon-γ release assays (IGRAs) have been found to offer little diagnostic utility for active TB diagnosis and have been discouraged by WHO. IGRAs and the tuberculin skin test (TST) remain important tools for latent TB infection (LTBI) diagnosis. Other novel, simple technologies, such as the point-of-care (POC) urine lipoarabinomannan strip test and the visually read loop isothermal amplification PCR nucleic acid amplification technique (NAAT), although of uncertain and restricted clinical utility, highlight the progression toward an inexpensive, instrument-free, laboratory-free POC diagnostic technology for TB in the future.

  14. Page 144
    Abstract
    Correspondence: G.H. Bothamley, Dept of Respiratory Medicine, Homerton University Hospital, Homerton Row, London, E9 6SR, UK. Email: graham.bothamley@homerton.nhs.uk

    The diagnosis of tuberculosis (TB) depends on sputum-smear examination, mycobacterial culture and tuberculin skin testing (TST). Future diagnosis requires near-patient tests and early recognition of drug-resistant (DR) TB. Nucleic acid amplification techniques (NAAT) can detect approximately 100 bacilli·mL−1 and have moved from the laboratory into the field. Sensitivity can be improved by detecting proteins, using mass spectrometry, and their function, using reporter enzymes. Ultimately, microfluidics will permit reactions in restricted spaces with the potential to measure single molecules or sequence strains of Mycobacterium tuberculosis directly. Metabolic products released by TB and the human response to infection can be described by a characteristic metabolome and volatome of exhaled air. Interferon-γ release assays (IGRA) are blood tests that indicate the immune response to the few bacilli responsible for latent TB infection (LTBI). Their sensitivity may be improved by cytokines released by activated macrophages (inducible protein-10). The pattern of the immune response to many or all TB antigens, the immunome, may in future distinguish between active disease and latent infection.

  15. Page 154
    Abstract
    Correspondence: J.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. Email: jcamlun@gobiernodecanarias.org

    The treatment of all forms of tuberculosis (TB) is based on two principles: 1) the combination of drugs (at least four) to avoid the selection of anti-TB drug resistances; and 2) the need for prolonged treatment in order to ensure that all bacteria in their different phases of metabolic growth are effectively killed. The selection of drugs to be included in the combination is based on their bactericidal and sterilising capacity, and their ability to prevent drug resistance. Following extensive research in the field in the second part of the last century, the optimal regimen of initial treatment of all forms of drug-sensitive TB, both pulmonary and extrapulmonary, is 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 4 months of treatment with H and R (2HRZE/4HR). The impossibility of using R, the most powerful of all anti-TB drugs, substantially complicates the treatment of TB.

    In this chapter, we discuss the fundamental basis of anti-TB therapy, demonstrating that with proper clinical and operational management, patients with TB have a high probability of being cured, even though this probability is reduced with increasing levels of Mycobacterium tuberculosis drug resistance.

  16. Page 167
    Abstract
    Correspondence: C.C. Leung, Wanchai Chest Clinic, 99 Kennedy Road, Wanchai, Hong Kong, China. Email: cc_leung@dh.gov.hk

    Adverse drug events are encountered frequently during treatment of tuberculosis (TB). Current recommendations for their management are primarily based on clinical experiences rather than systematic clinical trials. A pragmatic approach is generally adopted, usually including pre-treatment evaluation, monitoring, treatment interruption or symptomatic management, and careful re-introduction of appropriate treatment. Proper pre-treatment evaluation, notably of liver and renal function, other drugs and psychiatric disorders, with the appropriate choice of regimens and suitable dosing, minimises the risk of drug toxicities and interactions. Patient education and close clinical or laboratory monitoring facilitate early recognition. It is desirable to avoid unnecessary drug interruption, but timely removal of the offending drug causing a major reaction is crucial for patient safety. After a drug reaction subsides, careful re-establishment of an effective treatment within a reasonably short period is essential to avoid treatment failure and drug resistance. Optimal balance of benefits and risks is required, especially when treatment options are limited by drug resistance or unfavourable clinical and social factors.

  17. Page 194
    Abstract
    Correspondence: E. Pontali, Dept of Infectious Diseases, Galliera Hospital, Mura delle Cappuccine 14, 16128 Genoa, Italy. Email: pontals@yahoo.com

    Internal and international human migration has increased worldwide in recent years. Migrants are generally people travelling from less to more economically developed geographical areas in search of jobs and better living conditions. The epidemiological profile of tuberculosis (TB) has dramatically changed in some high-income countries, partly because of migration.

    In many nations, a screening system for TB disease or latent TB infection (LTBI) has been set up in order to prevent the increase of TB prevalence, dissemination of Mycobacterium tuberculosis strains in the local community, or new incident TB cases. Nevertheless, several reports from different developed countries with well-performing screening and treatment systems have shown in the last few years that foreign-born TB patients do not significantly contribute to M. tuberculosis transmission in the native population.

  18. Page 206
    Abstract
    Correspondence: E. Whittaker, Dept of Paediatrics, St. Mary's Campus, Imperial College of Science, Technology and Medicine, Norfolk Place, London W2 1PG, UK. Email: e.whittaker@imperial.ac.uk

    Tuberculosis (TB) in childhood is under reported but represents a sentinel event of transmission in the community. Susceptibility to TB is age-dependent with young children at highest risk of disseminated disease. Age-related differences in immune responses to mycobacteria underlie this phenomenon. Since childhood TB tends to be paucibacillary, bacteriological confirmation is more difficult to achieve and accurate diagnosis remains a challenge. Diagnostics include measures of host sensitisation, such as the tuberculin skin test (TST) and interferon-γ release assay (IGRA), but their performance varies between children and adults and in the context of bacille Calmette-Guérin (BCG) vaccination. Therapeutic regimens are based on adult studies but increased doses have recently been recommended by the World Health Organization (WHO), following pharmacokinetic studies in children. TB/HIV co-infection adds complexity to diagnosis and management, much like in adults. The BCG vaccine is not fully protective and is not recommended for HIV-infected children. New vaccines are currently under investigation, with trials including infants and adolescents.

  19. Page 219
    Abstract
    Correspondence: A. Nienhaus, University Medical Center Hamburg-Eppendorf, Institute for Health Services Research in Dermatology and Nursing (IVDP), Martinistrasse 52, 20246 Hamburg, Germany. Email: a.nienhaus@uke.uni-hamburg.de

    Tuberculosis (TB) in healthcare workers (HCWs) and TB in combination with silicosis are considered occupational diseases. Improved hygiene in the workplace has led to a reduction of exposure to mineral dust. Therefore, the incidence of silicosis, as well as silicotuberculosis, in high-income countries has declined. However, silicotuberculosis remains a significant and frequently occurring occupational disease in low- and middle-income countries. Recent studies have reported mortality ratios of between 2.2 and 27. Even in high-income countries the risk of TB in HCWs is increased for a wide range of tasks in healthcare, and the prevention of nosocomial infection of HCWs remains a challenge. Interferon-γ release assays (IGRAs) facilitate the screening of HCWs. In comparison with the tuberculin skin test (TST), the IGRAs reduce the number of radiographs and the amount of chemoprevention needed. However, a grey zone should be introduced for the interpretation of IGRA results in the serial testing of HCWs.

  20. Page 230
    Abstract
    Correspondence: M. Sester, Dept of Transplant and Infection Immunology, Saarland University, D-66421 Homburg, Germany. Email: martina.sester@uks.eu

    Tuberculosis (TB) remains one of the most serious infectious complications among immunocompromised patients, such as individuals infected with HIV, solid organ or stem cell transplantation patients, patients with end-stage renal disease or individuals after tumour necrosis factor (TNF) antagonist treatment. The incidence of TB in these patient groups is in general higher compared with that of the general population and disease manifestations frequently differ from those typically found in immunocompetent patients with TB. Despite immunodeficiency as the common underlying principle, immunocompromised patient groups differ with respect to TB pathogenesis, risk of TB progression and results of immune-based testing for evidence of latent infection with Mycobacterium tuberculosis.

    This chapter will summarise current knowledge on epidemiology, pathogenesis, diagnosis and treatment of TB in immunocompromised patients and will highlight areas in which increased knowledge is needed to improve management of TB in this vulnerable patient group.

  21. Page 242
    Abstract
    Correspondence: G.B. Migliori, World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Via Roncaccio 16, 21049, Tradate, Italy. Email: giovannibattista.migliori@fsm.it

    Tuberculosis (TB) remains among the leading causes of death among treatable infectious diseases after HIV/AIDS, despite the existence of a cost-effective strategy for its prevention and control.

    This chapter will discuss the existing strategies developed to achieve the projected goals of TB control by 2015 and elimination by the year 2050, as advocated by the Millennium Development Goals (MDGs) and the Stop TB Partnership, as well as the major threats the international community is presently facing in this respect.

    After introducing the key definitions and concepts relevant to TB control and elimination, the history and content of the five core pillars of the DOTS (directly observed therapy, short course) strategy and the six elements of the Stop TB Strategy will be described, as they represent the World Health Organization (WHO)-recommended strategy endorsed by Member States. At present, as the main priorities are represented by control of multidrug-resistant (MDR)-TB and TB/HIV co-infection, the chapter will discuss the core public health interventions available on this domain, based on the available evidence. Finally, the perspective of TB elimination will be critically discussed.