Host blood biomarkers for the diagnosis of childhood tuberculosis disease: a systematic review and meta-analysis

BACKGROUND: Current tuberculosis (TB) diagnostics have limited sensitivity in children, resulting in undiagnosed and untreated cases; host blood biomarkers have the potential to narrow this diagnostic gap. OBJECTIVES: To conduct a systematic review to identify host blood biomarkers that diagnose childhood TB and to summarize biomarker accuracy. METHODS: DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, SCOPUS, ClinicalTrials.gov, and WHO Global Index Medicus. STUDY ELIGIBILITY CRITERIA: Original studies that reported biomarker concentration and/or diagnostic accuracy for childhood TB. PARTICIPANTS: Children <15 years undergoing evaluation for TB disease. TESTS: Any host blood biomarker measured before anti-TB therapy. REFERENCE STANDARD: Mycobacterial culture, nucleic acid amplification tests, and/or clinical diagnosis. ASSESSMENT OF RISK OF BIAS: Quality Assessment of Diagnostic Accuracy Studies-2. METHODS OF DATA SYNTHESIS: A hierarchical bivariate model was used for meta-analysis. RESULTS: Fifty-five studies were included, of which 42 (76.4%) studies were at high risk of bias and/or had applicability concerns. The following biomarker classes were reported: cytokine/protein (n = 39 studies), mRNA (n = 10 studies), microRNA (n = 4 studies), and other (n = 11 studies). Twelve biosignatures (seven cytokine, four metalloproteinase, one microRNA) and two individual biomarkers (one cytokine, one metalloproteinase) met the WHO target product profile for TB disease diagnosis (sensitivity ≥95%, specificity >98%). Meta-analysis was conducted for the cytokine interferon-γ-inducible protein 10 from seven studies; summary estimates of sensitivity (85.2%, 95% CI, 71.1-93.1%) and specificity (59.3%, 95% CI, 44.7-72.5%) did not meet WHO target product profile. DISCUSSION: Host blood biomarkers were identified that met WHO targets for childhood TB disease diagnosis; however, most were reported from a single centre. Meta-analysis did not support interferon-γ-inducible protein 10 as an accurate stand-alone biomarker. High-quality studies are needed to validate host blood biomarkers in larger cohorts, and future work should focus on the development of point-of-care tests suitable for low-resource settings.