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It is one hundred and thirty years since Franz Ziehl and Friedrich Neelsen developed the rapid stain for acid-fast bacilli;1 ,2 accurate point-of-care diagnosis of active tuberculosis (TB) remains a major unmet clinical need. With the sensitivity of the Ziehl–Neelsen stain in sputum less than 50% and more than 20% of TB cases negative on both acid-fast stain and culture for Mycobacterium tuberculosis, there has long been a yawning gap in the diagnostic toolkit for TB. New rapid molecular methods have recently improved detection of M tuberculosis nucleic acids in sputum providing diagnostic sensitivity that is much higher than sputum-smear microscopy but lower than culture.3
The longstanding diagnostic gap has stimulated decades of research into immunodiagnosis, mostly serological. Although serological tests for TB are point-of-care, they lack diagnostic accuracy and are devoid of clinical utility. After thorough review of the evidence, and on account of their continued widespread misuse in many high-burden countries, WHO recently tried to bury current commercial serological test kits with a negative endorsement warning against their use.4
Research into cellular immunodiagnosis has been more fruitful, delivering a tangible advance in clinical practice in the form of interferon-gamma release-assays (IGRA).5 IGRA detect M tuberculosis infection, providing a new standard-of-care for diagnosis of latent TB infection (LTBI), but they cannot distinguish active TB from LTBI. Hence, their potential role in evaluation of patients with suspected active TB is limited to that of a possible rule-out test of TB, yet currently available IGRA lack sufficient diagnostic sensitivity for this indication, as discussed elsewhere in this issue of Thorax.6 ,7
Are there immune responses that differ sufficiently between active TB and LTBI to enable development of an immunodiagnostic test that is specific for active TB? Quantifying genome-wide host gene-expression yielded a …
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