Inflammatory and transcriptional profiles associated with structural and functional recovery in pre-XDR/XDR tuberculosis

Background In drug-resistant TB, bacteriology-based monitoring often fails to capture recovery. We aimed to identify baseline host inflammatory and transcriptional features associated with multidomain treatment recovery in pre-XDR/XDR-TB. Methods We conducted an ancillary analysis of a pilot clinical trial in patients with pre-XDR/XDR-TB (NCT02781909). Participants were assessed at baseline and during treatment using clinical, radiological, microbiological, and health-related quality-of-life measures, plasma biomarkers, and whole-blood transcriptomic profiling, analyzed in relation to treatment outcomes. Results Microbiological and symptomatic improvement occurred earlier than radiological and functional recovery. Baseline elevated NLR, SII, and IL-6, and an increased expression of interferon-related genes as CD274 and GBP5, were associated with poorer radiological and HRQoL outcomes. IL-8 consistently correlated with symptom severity, radiological and functional outcomes. Previously published blood transcriptomic signatures were more strongly associated with radiological and HRQoL recovery than with early bacterial clearance. Conclusions Bacteriological cure precedes but does not ensure structural and functional recovery in pre-XDR/XDR-TB. Baseline inflammation identifies patients at risk of incomplete recovery, and IL-8 emerges as a candidate cross-domain monitoring biomarker. These findings support multidimensional treatment monitoring and a biological rationale for host-directed interventions targeting persistent inflammation.