Tuberculosis

Abstract

Although the worldwide incidence of tuberculosis has been slowly decreasing, the global disease burden remains substantial (∼9 million cases and ∼1·5 million deaths in 2013), and tuberculosis incidence and drug resistance are rising in some parts of the world such as Africa. The modest gains achieved thus far are threatened by high prevalence of HIV, persisting global poverty, and emergence of highly drug-resistant forms of tuberculosis. Tuberculosis is also a major problem in health-care workers in both low-burden and high-burden settings. Although the ideal preventive agent, an effective vaccine, is still some time away, several new diagnostic technologies have emerged, and two new tuberculosis drugs have been licensed after almost 50 years of no tuberculosis drugs being registered. Efforts towards an effective vaccine have been thwarted by poor understanding of what constitutes protective immunity. Although new interventions and investment in control programmes will enable control, eradication will only be possible through substantial reductions in poverty and overcrowding, political will and stability, and containing co-drivers of tuberculosis, such as HIV, smoking, and diabetes.

Figure 1:. Outcomes of infection with Mycobacterium tuberculosis

M tuberculosis infection has variable outcomes in different hosts. The individual (A) has been exposed but, through innate or adaptive immune function, has cleared the invading bacilli completely. Immunodiagnostic tests might be positive or negative in such people. This individual was interferon gamma release assay (IGRA) positive but is at no risk of relapse disease, and this outcome occurs in about 90% of infected individuals. We speculate that such individuals have sterilising immunity with no viable organisms in their tissues. Infected cells containing live M tuberculosis bacteria can also migrate to the draining lymph nodes (B; marked with an arrow); in non-human primates and human beings, this might often be accompanied by very small parenchymal lesions or infiltrates that are not visible by chest radiograph but might be visible on chest CT. The infection has progressed (C), but disease is fairly minimal, restricted to the right-lower lobe. Individuals with minor disease can report with variable symptoms or be asymptomatic and this state has been referred to as subclinical disease; non-human primates can similarly show acid-fast bacilli in gastric aspirates but seem clinically healthy, and are referred to as percolators. An individual has extensive consolidative disease throughout the right posterior and apical segments and lower lobe (D). Some individuals have recurrent active tuberculosis, but mechanisms underlying this susceptibility are unclear. Immunodiagnostic tests at any stage of disease might be negative because both tuberculin skin test (TST) and IGRA have suboptimum sensitivity for diagnosis of latent and active tuberculosis. Even for active tuberculosis, TST and IGRA sensitivity is around 80%.

Figure 2:. Summary of diagnostic tests in various phases of development

Phases of development include early prototype stage, locked in design phase, commercially available, and on the pathway to WHO evaluation. Drugs are classified according to assay complexity. DST=drug susceptibility testing. MDR=multidrug-resistant. TB=tuberculosis. MTB=Mycobacterium tuberculosis. XDR=extensively drug-resistant. Coproduced with the Foundation for Innovative New Diagnostics (FIND).