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

ABSTRACT 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 which diagnose childhood TB and to summarize biomarker accuracy. Methods Data sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, SCOPUS, ClinicalTrials.gov, and World Health Organization (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 prior to anti-TB therapy.Reference standards: 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), miRNA (n=4 studies), and other (n=11 studies). Twelve biosignatures (seven cytokine, four metalloproteinase, one miRNA) and two individual biomarkers (one cytokine, one metalloproteinase) met the WHO target product profile (TPP) for TB disease diagnosis (sensitivity ≥95%, specificity >98%). Meta-analysis was conducted for the cytokine interferon-γ-inducible protein 10 (IP-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 TPP. 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 IP-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.