Elsevier

The Lancet

Volume 375, Issue 9729, 29 May–4 June 2010, Pages 1920-1937
The Lancet

Series
Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice

https://doi.org/10.1016/S0140-6736(10)60359-5Get rights and content

Summary

Human infection with Mycobacterium tuberculosis can progress to active disease, be contained as latent infection, or be eradicated by the host response. Tuberculosis diagnostics classify a patient into one of these categories. These are not fixed distinct states, but rather are continua along which patients can move, and are affected by HIV infection, immunosuppressive therapies, antituberculosis treatments, and other poorly understood factors. Tuberculosis biomarkers—host or pathogen-specific—provide prognostic information, either for individual patients or study cohorts, about these outcomes. Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis. Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible—with political commitment, increased funding, and engagement of all stakeholders.

Introduction

Tuberculosis, although a curable disease, continues to be one of the most important infectious causes of death worldwide. Despite substantial investments and progress made in expansion of the directly observed therapy, short course (DOTS) strategy and improved treatment completion rates, inadequate case detection remains a major obstacle to global control of tuberculosis. Efforts during the past decade to consistently diagnose and treat the most infectious cases have slowed the rate of disease incidence, but have not yielded substantial progress towards elimination. This experience has refocused attention on research and development for improved diagnostics, therapeutics, and vaccines—areas in which progress has historically been slow. Human Mycobacterium tuberculosis infection is almost always acquired by inhalation of infected aerosol droplets, which are generated by people with active pulmonary disease coughing (figure 1). However, the infection infrequently progresses directly to active disease, and is more often contained—at least initially—by the host immune response. The resulting latent infection can be eradicated, or can persist and reactivate many years later. Tuberculosis chemotherapy can also contain the disease, but leave a latent infection that is capable of causing relapse. This dynamic process can be started anew at any time by exogenous reinfection.

Key messages

  • Diagnostics classify patients at one point in time, whereas biomarkers can provide prognostic information about future health status and can advance knowledge of disease pathogenesis.

  • Qualified tuberculosis biomarkers are most urgently needed as predictors of reactivation and cure, and indicators of vaccine-induced protection. The biomarker most closely approaching qualification is 2-month culture conversion as a predictor of relapse risk.

  • The tuberculosis diagnostics pipeline has rapidly grown, with development of several promising technologies.

  • The existing tuberculosis diagnostics pipeline still does not have a simple, rapid, inexpensive point-of-care test. Accurate, rapid tests are also needed for smear-negative and childhood tuberculosis, as are tests for latent tuberculosis with increased predictive value for reactivation.

  • Several diagnostics and diagnostic strategies have been endorsed by WHO and are being introduced into clinical use and national tuberculosis control programmes.

  • Governments in all countries, especially industrialised countries, have to increase funding for tuberculosis research and control.

Tuberculosis diagnostics form the basis of classification of patients in this system. As diagnostic accuracy has increased, it has become apparent that these are not entirely distinct states, but instead represent gradations along which patients might move. Even within individual patients, foci of latent infection can coexist alongside sites of active M tuberculosis replication. Medical treatment, vaccine and immune status, and concomitant illness all affect this balance between host and pathogen, favouring one or another clinical outcome and thus representing the interface between prognostics and diagnostics. In this overview, we describe the development of tuberculosis biomarkers and diagnostics, knowledge gaps and scientific obstacles, and limitations of the existing pipeline of biomarkers and diagnostics, and summarise the major challenges in translation of scientific progress into action.

Section snippets

Biomarkers for tuberculosis

Biomarkers provide prognostic information about future health status, either for individual patients or cohorts in clinical trials. Biomarkers can thus indicate normal or pathogenic processes, or pharmacological responses to therapeutic intervention.1 In clinical trials, biomarkers can form the basis of surrogate endpoints, which can substitute for a clinical endpoint based on epidemiological, therapeutic, pathophysiological, or other scientific evidence, thereby assisting candidate selection

Tuberculosis diagnostics

Progress towards elimination of tuberculosis has remained elusive despite intensified standard measures of control. After a period of global acceleration in 2001–05, the case detection rate worldwide decelerated in 2006 and 2007, reaching 63% in 2007.137 Thus, the target of a case detection rate of at least 70% by 2005 has not yet been achieved, and is unlikely to be met until 2014.137

Insufficient access to advanced diagnostic tests has contributed to this suboptimum performance. Even in 2010,

Conclusions

The need for a more accurate, inexpensive point-of-care tuberculosis diagnostic test that is applicable in tuberculosis and HIV endemic areas is greater nowadays than ever before, and will be crucial for achieving global tuberculosis control. Several modelling studies208, 209, 210, 211, 212, 213, 214, 215 suggest that new diagnostics for tuberculosis disease and MDR tuberculosis could have an important effect within populations, especially in disease-endemic countries, although improving

Search strategy and selection criteria

For the tuberculosis biomarker section, we searched publications in PubMed and Google Scholar (1995–2009), the Cochrane library (2001–09), and Embase (2001–06) with the terms “tuberculosis”, “Mycobacterium tuberculosis”, “biomarkers”, “diagnostics”, and “clinical trials”. For the section on tuberculosis diagnostics, the search strategy was a 10-year review of diagnostic studies in PubMed and Embase. This search was supplemented by searching the website Evidence-based TB Diagnosis by the

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