Blood transcriptomic signatures predict poor outcomes in drug-susceptible pulmonary TB in Brazil

Background Non-sputum biomarkers to monitor tuberculosis treatment and predict poor outcomes are lacking. We evaluated host-blood transcriptomic signatures for treatment monitoring and prognosis (death, treatment failure, recurrence) in adults with pulmonary tuberculosis. Methods Adults with culture-confirmed, drug-susceptible pulmonary tuberculosis were enrolled at five Brazilian sites. Whole-blood PAXgene samples were collected at baseline, month 2 (M2), and end of treatment (EoT). Treatment failure was defined as sputum culture positivity at month 5 or later. Participants were followed for 24 months from treatment initiation for clinical or microbiological tuberculosis recurrence. Unfavourable outcomes were matched ∼1:3 to recurrence-free cure. Twenty-two published blood transcriptomic signatures were measured by microfluidic RT-qPCR and benchmarked against the WHO Target Product Profile (TPP) criteria. Main results We matched 263 participants with recurrence-free cure to 33 with treatment failure, 24 who died (tuberculosis/unknown cause), and 9 with recurrence. Signature scores generally declined from baseline to EoT. Multiple signatures measured at baseline and M2 predicted recurrence (AUC range 0.71-0.91), with waning performance when measured at EoT (AUC range 0.42-0.89). Against the WHO TPP, 2/22 signatures met minimum criteria at baseline, 13/22 at M2, and none at EoT. Prediction of treatment failure was poor across timepoints (AUC Conclusions Blood transcriptomic signatures tracked treatment response and predicted recurrence and death, meeting WHO TPP benchmarks at baseline and M2. These findings support prospective, biomarker-guided trials to individualise tuberculosis therapy-shortening regimens for early responders and intensifying care for high-risk patients.