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Tuberculosis remains the leading cause of death from an infectious disease worldwide. Early and accurate diagnosis and detection of drug-sensitive and drug-resistant tuberculosis is essential for achieving global tuberculosis control. Despite the introduction of the Xpert MTB/RIF assay as the first-line rapid tuberculosis diagnostic test, the gap between global estimates of incidence and new case notifications is 4·1 million people. More accurate, rapid, and cost-effective screening tests are needed to improve case detection. Diagnosis of extrapulmonary tuberculosis and tuberculosis in children, people living with HIV, and pregnant women remains particularly problematic. The diagnostic molecular technology landscape has continued to expand, including the development of tests for resistance to several antituberculosis drugs. Biomarkers are urgently needed to indicate progression from latent infection to clinical disease, to predict risk of reactivation after cure, and to provide accurate endpoints for drug and vaccine trials. Sophisticated bioinformatic computational tools and systems biology approaches are being applied to the discovery and validation of biomarkers, with substantial progress taking place. New data have been generated from the study of T-cell responses and T-cell function, serological studies, flow cytometric-based assays, and protein and gene expression studies. Alternative diagnostic strategies under investigation as potential screening and triaging tools include nonsputum- based detection with breath-based tests and automated digital radiography. We review developments and key achievements in the search for new tuberculosis diagnostics and biomarkers. We highlight gaps and challenges in evaluation and rollout of new diagnostics and biomarkers, and prioritise areas needing further investment, including impact assessment and cost–benefit studies.
During 2016, incidence of tuberculosis was estimated to be 10·4 million cases, with 1·7 million deaths. Rapid and accurate detection of tuberculosis is essential for guiding treatment, yet case detection and reporting rates remain low, with 40% of estimated incident cases failing to be identified and reported. Underdiagnosis remains a problem, particularly in countries where patients face substantial geographical and socioeconomic barriers when accessing health care. In most countries with a high burden of tuberculosis, case detection relies on patients reporting symptoms to a health-care facility. Delays in accessing effective treatment provides increased opportunity for transmission and continuation of the epidemic. Detection of extrapulmonary forms of the disease and tuberculosis in children is particularly problematic. Access to tests for drug resistance remains inadequate. In 2016, only 33% of patients with bacteriologically confirmed tuberculosis that was not previously treated were tested for resistance to rifampicin, whereas 60% of patients who had previously received antituberculosis treatment for at least 1 month, and who were considered at higher risk of resistance, were tested. Treatment success rates during 2016 were 83% but outcomes were considerably worse for drug-resistant disease. In 2014, treatment success rates were 54% for multidrug-resistant (MDR) tuberculosis (resistance to at least isoniazid and rifampicin) and 30% for extensively drug-resistant (XDR) tuberculosis (additional resistance to the fluoroquinolones and second line injectable drugs). The rapid diagnostic test for detection of tuberculosis and rifampicin resistance recommended by WHO is an automated PCR assay, with an integrated semiautomated device for sample extraction. The GeneXpert MTB/RIF assay (Cepheid Inc, Sunnyvale, CA, USA) was endorsed by WHO in 2010.