Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR

We tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.