Optimization and validation of plasma protein signatures for identification of tuberculosis disease

Non-sputum-based biomarkers for early diagnosis of TB disease are urgently needed to control transmission and achieve the World Health Organizations goals of ending TB. We previously identified a 12-marker plasma protein signature associated with TB disease severity. In this study we assessed the signature’s performance in identifying TB disease in independent Swedish and Italian cohorts, including individuals with TB infection and other respiratory diseases (total n=317 samples from 273 donors). We condensed the 12 proteins to smaller 6 (CDCP1, VEGFA, IFN- γ , CXCL9, IL6 and MCP-3) and 4 (CDCP1, VEGFA, IFN- γ , CXCL9)-protein signatures which remained highly enriched and even improved accuracy when compared with ten other published protein signatures for TB disease. Sensitivity in TB disease compared with TB-infection was 89% in the entire cohort and 97% in the Italian cohort, with specificity fixed at 70%. These signatures merit further evaluation as clinically relevant markers for a non-sputum-based test for TB disease.