Host blood protein biomarkers to screen for Tuberculosis disease: a systematic review and meta-analysis

Abstract Introduction Non-sputum tests are needed to improve TB diagnosis and close the diagnostic gap. The World Health Organization target product profile (TPP) for point-of-care (POC) screening tests requires minimum sensitivity 90% and specificity 70%. Our objective was to identify host blood protein biomarkers meeting TPP criteria. Methods A systematic review was conducted and reported following PRISMA guidelines. Data extraction and quality assessment with QUADAS-2 were completed for included studies. Heterogeneity was assessed. For biomarkers reporting sensitivity and specificity in at least four studies, a random-effects meta-analysis was performed for biomarkers with similar cut-offs. Results We screened 4,651 citations and included 65 studies that enrolled 16,010 participants and evaluated 156 host proteins. Most (47/65) studies enrolled adult pulmonary TB (PTB), with 15 studies in adult extra-pulmonary TB and 5 in children. Small early-stage discovery studies with case-control design were common (24/65) and had high risk of bias. For adult PTB, CRP, IP-10, NCAM-1, and SAA met TPP criteria in high-quality studies. There was a high degree of heterogeneity in biomarker cut-offs and study design. CRP at 10mg/L cut-off was meta-analyzed from 10 studies; pooled sensitivity 86% (95% CI: 80-95) and pooled specificity 67% (95% CI: 54-79). In people living with HIV (6 studies) CRP pooled sensitivity was 93% (95% CI: 90-95) and pooled specificity 59% (95% CI: 40-78). Discussion We identified promising biomarkers that performed well in high-quality studies. Data overall are limited and highly heterogenous. Further standardized validation across subgroups in prospective studies is needed before translating into POC assays.