Microbial biomarkers of tuberculosis infection and disease in blood: systematic review and meta-analysis.
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Authors
Chandran S.
Cervera E.C.
Jolliffe D.A.
Tiwari D.
Barr D.A.
Meintjes G.
Gupta R.K.
Catanzaro D.G.
Rodwell T.C.
Martineau, A. R.
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2026
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Background Numerous studies reporting utility of microbial blood biomarkers for diagnosis and treatment monitoring of M. tuberculosis (Mtb) infection and tuberculosis disease have been conducted, but up-to-date systematic reviews and meta-analyses of these data are lacking. We aimed to evaluate diagnostic accuracy of microbial blood biomarkers for detection of tuberculosis disease and to characterise their responses to antimicrobial therapy. Methods For this aggregate data meta-analysis, we searched MEDLINE, EMBASE and Scopus from 1st January, 1990, to 22 October, 2025, using terms for "tuberculosis", "microbial biomarker", and "human blood" to identify studies in which participants underwent blood sampling for detection of cell-free Mtb DNA, cell-associated Mtb DNA, protein/peptide Mtb antigens and lipid/glycolipid Mtb antigens before +/- after initiation of antimicrobial therapy. For bivariate analyses we used hierarchical summary receiver operating characteristic (HSROC) models to calculate areas under HSROC curves (AUC) for each analyte class to evaluate diagnostic accuracy for tuberculosis disease. For longitudinal analyses, we calculated risk differences to evaluate changes in proportions of biomarker-positive individuals after vs. before initiation of antimicrobial therapy, and pooled them using random-effects meta-analysis. Findings 137 eligible articles were identified in the search, of which 109 vs. 13 contributed data to bivariate vs. longitudinal analyses, respectively. For cell-free Mtb DNA targets, AUC was 0.87 (95% CI 0.84 to 0.89), with sensitivity 61.5% (51.0 to 71.0) and specificity 93.0% (88.1 to 96.1); 4,878 samples from 34 unique study/setting/biomarker combinations (investigations). For cell-associated Mtb DNA targets, AUC was 0.93 (0.90 to 0.95), with sensitivity 43.9% (29.4 to 59.4) and specificity 97.1% (94.5 to 98.5); 3,589 samples, 32 investigations. For protein/peptide targets, AUC was 0.94 (0.92 to 0.96), with sensitivity 78.9% (73.2 to 83.6) and specificity 92.9% (90.7 to 94.5%); 10,260 samples, 61 investigations. For lipid/glycolipid targets, AUC was 0.96 (0.94 to 0.97), with sensitivity 68.6% (54.1 to 80.3) and specificity 97.0% (94.0 to 98.5); 3,287 samples, 22 investigations. Pooled risk differences for proportions of individuals biomarker-positive after vs. before initiation of antimicrobial therapy were -0.44 (-0.89 to 0.01; 68 samples, 5 investigations) for cell-free Mtb DNA; -0.46 (-0.88 to -0.03; 89 samples, 5 investigations) for cell-associated Mtb DNA, and -0.24 (-0.75 to 0.28; 160 samples, 4 investigations) for protein/peptide antigens. No studies investigating responses of lipid/glycolipid antigens to antimicrobial therapy were identified. Heterogeneity was moderate (I2 25-50%) for the majority of studies. 98/109 and 11/13 studies contributing data to bivariate vs. longitudinal analyses, respectively, were assessed as being at high risk of bias. Interpretation Molecular and biochemical microbial blood biomarkers exhibit similar accuracy for detection of tuberculosis disease, with specificity consistently exceeding sensitivity. Cell-associated Mtb DNA biomarkers exhibited a statistically significant response to antimicrobial therapy, with similar trends observed for cell-free Mtb DNA and protein/peptide antigens. These findings should be interpreted cautiously in the light of high risk of bias for many of the primary studies contributing data. Higher quality studies are needed to evaluate this emerging class of tuberculosis biomarkers. Funding Barts Charity, The Medical College of Saint Bartholomew's Hospital Trust, Wellcome HARP Doctoral Fellowship Scheme. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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