The end of the road for blood RNA biomarkers as triage tests for symptomatic pulmonary tuberculosis among spontaneous sputum producers?

<title>Extract</title> In 2022, an estimated 3.1 million people with tuberculosis (TB) remained undiagnosed [1] despite the global roll-out of rapid molecular tests for <italic>Mycobacterium tuberculosis</italic>, such as Xpert Ultra and Truenat MTB plus [2]. In pulmonary TB, these tests rely on the availability of a respiratory sample. Sputum induction or invasive sampling are required in sputum-scarce individuals, but often unavailable in resource-limited settings. Moreover, even among spontaneous sputum producers, resource constraints may limit the number of rapid molecular tests for <italic>M. tuberculosis</italic> that can be performed programmatically. Detecting host immune perturbations in response to <italic>M. tuberculosis</italic> infection, for example with blood RNA biomarkers, has been proposed as a triage approach to guide further confirmatory testing. Such an approach seeks to reduce the number of confirmatory tests performed, and direct these tests to higher risk individuals. Numerous RNA signatures, comprising quantitation of the expression of one or more genes, have been described with excellent diagnostic performance in their discovery populations.