{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T20:57:07Z","timestamp":1781211427788,"version":"3.54.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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<jats:italic>in vitro<\/jats:italic>WBMGA results can predict<jats:italic>in vivo<\/jats:italic>tuberculosis susceptibility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.641082","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T07:42:17Z","timestamp":1620718937000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Whole Blood Mycobacterial Growth Assays for Assessing Human Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Jeroen","family":"Bok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina W.","family":"Hofland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlton A.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"B1","unstructured":"World Health OrganizationGlobal Tuberculosis Report 2020"},{"key":"B2","unstructured":"Risk factors for tuberculosis828939 NarasimhanP WoodJ MacintyreCR MathaiD 10.1155\/2013\/828939Pulm Med20132013"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nri2960","article-title":"Immunological biomarkers of tuberculosis","volume":"11","author":"Walzl","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30447-4","article-title":"A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort study","volume":"17","author":"Saunders","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30753-9","article-title":"Active and passive case-finding in tuberculosis-affected households in Peru: a 10-year prospective cohort study","volume":"19","author":"Saunders","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.07.058","article-title":"In vitro mycobacterial growth inhibition assays: A tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy","volume":"34","author":"Tanner","year":"2016","journal-title":"Vaccine"},{"key":"B7","doi-asserted-by":"publisher","first-page":"14480","DOI":"10.1038\/s41598-018-32755-x","article-title":"Immunological correlates of mycobacterial growth inhibition describe a spectrum of tuberculosis infection","volume":"8","author":"O\u2019Shea","year":"2018","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e74220","DOI":"10.1371\/journal.pone.0074220","article-title":"Effects of Ascent to High Altitude on Human Antimycobacterial Immunity","volume":"8","author":"Eisen","year":"2013","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31097","article-title":"Neutrophil-mediated innate immune resistance to mycobacteria","volume":"117","author":"Martineau","year":"2007","journal-title":"J\u00a0Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/srep43478","article-title":"The influence of haemoglobin and iron on in vitro mycobacterial growth inhibition assays","volume":"7","author":"Tanner","year":"2017","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1086\/315766","article-title":"Evaluation of Human Antimycobacterial Immunity Using Recombinant Reporter Mycobacteria","volume":"182","author":"Kampmann","year":"2000","journal-title":"J Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1086\/319679","article-title":"A Whole Blood Bactericidal Assay for Tuberculosis","volume":"183","author":"Wallis","year":"2001","journal-title":"J Infect Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1000097","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"6","author":"Moher","year":"2009","journal-title":"PLoS Med"},{"key":"B14","volume-title":"Quality assessment tool for observational cohort and cross-sectional studies","year":"2014"},{"key":"B15","author":"Harrell","year":"2014","journal-title":"Hmisc: A package of miscellaneous R functions"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/CDLI.9.4.901-907.2002","article-title":"Surrogate Marker of Immunity after Vaccination against Tuberculosis","volume":"9","author":"Cheon","year":"2002","journal-title":"Clin Vaccine Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1086\/344359","article-title":"Investigation of the Relationships between Immune-Mediated Inhibition of Mycobacterial Growth and Other Potential Surrogate Markers of Protective Mycobacterium tuberculosis Immunity","volume":"186","author":"Hoft","year":"2002","journal-title":"J Infect Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.11.6401-6407.2004","article-title":"Novel Human In Vitro System for Evaluating Antimycobacterial Vaccines","volume":"72","author":"Kampmann","year":"2004","journal-title":"Infect Immun"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00427-13","article-title":"Inhibition of Mycobacterial Growth In Vitro following Primary but Not Secondary Vaccination with Mycobacterium bovis BCG","volume":"20","author":"Fletcher","year":"2013","journal-title":"Clin Vaccine Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200701-007OC","article-title":"A single dose of vitamin D enhances immunity to mycobacteria","volume":"176","author":"Martineau","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000222073.45372.ce","article-title":"Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART","volume":"20","author":"Kampmann","year":"2006","journal-title":"AIDS"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1086\/374799","article-title":"Failure to control growth of mycobacteria in blood from children infected with human immunodeficiency virus and its relationship to T cell function","volume":"187","author":"Tena","year":"2003","journal-title":"J Infect Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g4643","article-title":"Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis","volume":"349","author":"Roy","year":"2014","journal-title":"BMJ"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dym247","article-title":"Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis","volume":"37","author":"Nnoaham","year":"2008","journal-title":"Int J Epidemiol"},{"key":"B25","first-page":"4","article-title":"Effect of altitude on the frequency of pulmonary tuberculosis","author":"Vargas","year":"2004","journal-title":"Int J Tuberc Lung Dis"},{"key":"B26","doi-asserted-by":"publisher","first-page":"49","DOI":"10.4269\/ajtmh.2006.75.49","article-title":"Comparison of altitude effect on Mycobacterium tuberculosis infection between rural and urban communities in Peru","volume":"75","author":"Saito","year":"2006","journal-title":"Am J Trop Med Hygiene"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.163.9.1009","article-title":"The growing burden of tuberculosis: global trends and interactions with the HIV epidemic","volume":"163","author":"Corbett","year":"2003","journal-title":"Arch Intern Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0184563","DOI":"10.1371\/journal.pone.0184563","article-title":"Application of a whole blood mycobacterial growth inhibition assay to study immunity against Mycobacterium tuberculosis in a high tuberculosis burden population","volume":"12","author":"Baguma","year":"2017","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2009.02.001","article-title":"Strain specificity of antimycobacterial immunity in whole blood culture after cure of tuberculosis","volume":"89","author":"Wallis","year":"2009","journal-title":"Tuberculosis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700845","article-title":"Enhanced Anti-Mycobacterial Immunity in Children with Erythema Nodosum and a Positive Tuberculin Skin Test","volume":"127","author":"Nicol","year":"2007","journal-title":"J Invest Dermatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02893","article-title":"Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection","volume":"9","author":"O\u2019Shea","year":"2018","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/978-1-4939-1489-0_3","article-title":"Helminth-M. Tb Co-Infection","volume-title":"How Helminths Alter Immunity to Infection","author":"du Plessis","year":"2014"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.2.605-613.2003","article-title":"Human Eosinophil Peroxidase Induces Surface Alteration, Killing, and Lysis of Mycobacterium tuberculosis","volume":"71","author":"Borelli","year":"2003","journal-title":"Infect Immun"},{"key":"B34","first-page":"286\u201398","article-title":"The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals","author":"Cegielski","year":"2004","journal-title":"Int J Tuberc Lung Dis"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3156.2006.01578.x","article-title":"Are intestinal helminths risk factors for developing active tuberculosis","volume":"11","author":"Elias","year":"2006","journal-title":"Trop Med Int Health"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)01316-1","article-title":"A blood RNA signature for tuberculosis disease risk: a prospective cohort study","volume":"387","author":"Zak","year":"2016","journal-title":"Lancet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5208","DOI":"10.1038\/s41467-018-07635-7","article-title":"Metabolite changes in blood predict the onset of tuberculosis","volume":"9","author":"Weiner","year":"2018","journal-title":"Nat Commun"},{"key":"B38","unstructured":"Well-quantified tuberculosis exposure is a reliable surrogate measure of tuberculosis infection MandalakasAM KirchnerHL LombardC WalzlG GrewalHMS GieRP The International journal of tuberculosis and lung disease162012"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.06190-11","article-title":"Plasmodium falciparum line-dependent association of in vitro growth-inhibitory activity and risk of malaria","volume":"80","author":"Rono","year":"2012","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92348-9","article-title":"Variation in protection by BCG: implications of and for heterologous immunity","volume":"346","author":"Fine","year":"1995","journal-title":"Lancet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97508","article-title":"Mycobacterial growth inhibition is associated with trained innate immunity","volume":"128","author":"Joosten","year":"2018","journal-title":"J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","first-page":"20130437","DOI":"10.1098\/rstb.2013.0437","article-title":"The ongoing challenge of latent tuberculosis","volume":"369","author":"Esmail","year":"2014","journal-title":"Philos Trans R Soc B: Biol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1378\/chest.11-3157","article-title":"Predictive value of interferon-\u03b3 release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis","volume":"142","author":"Diel","year":"2012","journal-title":"Chest"},{"key":"B44","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S1473-3099(11)70210-9","article-title":"Predictive value of interferon-\u03b3 release assays for incident active tuberculosis: a systematic review and meta-analysis","volume":"12","author":"Rangaka","year":"2012","journal-title":"Lancet Infect Dis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir951","article-title":"Risk of Progression to Active Tuberculosis Following Reinfection With Mycobacterium tuberculosis","volume":"54","author":"Andrews","year":"2012","journal-title":"Clin Infect Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2236","article-title":"The spectrum of latent tuberculosis: rethinking the biology and intervention strategies","volume":"7","author":"Barry","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e1007305","DOI":"10.1371\/journal.ppat.1007305","article-title":"Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques","volume":"14","author":"Cadena","year":"2018","journal-title":"PLoS Pathog"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2001.01446.x","article-title":"Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette\u2013Gu\u00e9rin (BCG) vaccination","volume":"123","author":"Elias","year":"2001","journal-title":"Clin Exp Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e38556","DOI":"10.1371\/journal.pone.0038556","article-title":"Factors Associated with the Performance of a Blood-Based Interferon-\u03b3 Release Assay in Diagnosing Tuberculosis","volume":"7","author":"Banfield","year":"2012","journal-title":"PLoS One"},{"key":"B50","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.it.2016.07.005","article-title":"Helminth-Tuberculosis Co-Infection: an Immunologic Perspective","volume":"37","author":"Babu","year":"2016","journal-title":"Trends Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102891","article-title":"Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure","volume":"59","author":"Basu Roy","year":"2020","journal-title":"EBioMedicine"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jim.2019.01.006","article-title":"Optimisation, harmonisation and standardisation of the direct mycobacterial growth inhibition assay using cryopreserved human peripheral blood mononuclear cells","volume":"469","author":"Tanner","year":"2019","journal-title":"J Immunol Methods"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.641082\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T15:26:04Z","timestamp":1699025164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.641082\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,11]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2021.641082"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.641082","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,11]]},"article-number":"641082"}}