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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the German Center for Infection Research (DZIF) [TTU 02.812] funding indicator 8029802812. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This publication is a systematic review of existing published literature. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript