Tuberculosis (out of print)

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.

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.

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.

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.

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.

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.

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.

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.

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.