Whole Blood Mycobacterial Growth Assays for Assessing Human Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis

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Barrenechea V.
Milón P.
Quiliano M.
Vargas-Reyes M.
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Background Whole blood mycobacterial growth assays (WBMGA) quantify mycobacterial growth in fresh blood samples and may have potential for assessing tuberculosis vaccines and identifying individuals at risk of tuberculosis. We evaluated the evidence for the underlying assumption that in vitro WBMGA results can predict in vivo tuberculosis susceptibility. Methods A systematic search was done for studies assessing associations between WBMGA results and tuberculosis susceptibility. Meta-analyses were performed for eligible studies by calculating population-weighted averages. Results No studies directly assessed whether WBMGA results predicted tuberculosis susceptibility. 15 studies assessed associations between WBMGA results and proven correlates of tuberculosis susceptibility, which we divided in two categories. Firstly, WBMGA associations with factors believed to reduce tuberculosis susceptibility were statistically significant in all eight studies of: BCG vaccination; vitamin D supplementation; altitude; and HIV-negativity/therapy. Secondly, WBMGA associations with probable correlates of tuberculosis susceptibility were statistically significant in three studies of tuberculosis disease, in a parasitism study and in two of the five studies of latent tuberculosis infection. Meta-analyses for associations between WBMGA results and BCG vaccination, tuberculosis infection, tuberculosis disease and HIV infection revealed consistent effects. There was considerable methodological heterogeneity. Conclusions The study results generally showed significant associations between WBMGA results and correlates of tuberculosis susceptibility. However, no study directly assessed whether WBMGA results predicted actual susceptibility to tuberculosis infection or disease. We recommend optimization and standardization of WBMGA methodology and prospective studies to determine whether WBMGA predict susceptibility to tuberculosis disease.
Funding is gratefully acknowledged from: the Wellcome Trust (awards 057434/Z/99/Z, 070005/Z/02/Z, 078340/Z/05/Z, 105788/Z/14/Z, and 201251/Z/16/Z); UK-AID DFID-CSCF; the Joint Global Health Trials Scheme (award MR/K007467/1) with funding from the UK Foreign, Commonwealth and Development Office, the UK Medical Research Council, the UK Department of Health and Social Care through the National Institute of Health Research (NIHR) and Wellcome; the STOP TB partnership's TB REACH initiative funded by the Government of Canada and the Bill & Melinda Gates Foundation (awards W5_PER_CDT1_PRISMA and OPP1118545); CONCYTEC/FONDECYT award code E067-2020-02-01 number 083-2020; and the charity IFHAD: Innovation For Health And Development.
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