{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T02:49:50Z","timestamp":1771037390667,"version":"3.50.1"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T00:00:00Z","timestamp":1704153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Previous meta-analysis regarding the performance of QuantiFERON Gold-In-Tube in children have yielded contrasting results. Emerging data in children younger than 5 years of age necessitates a new analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Systematic searches were conducted of MedLINE, EMBASE and Cochrane databases between 1998\u20132023. Pooled estimates of sensitivities and specificities of QFT-GIT compared to tuberculin skin test (TST) were calculated. The Kappa (k) coefficient was calculated for each study to determine the degree of congruence between TST and QFT-GIT results. Studies including patients co-infected with HIV or other immune compromising conditions or those treated with anti-tubercular treatment were excluded.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Seventeen studies (4335 patients) were included in quantitative analysis. All studies were conducted in middle to high income countries. They were conducted across 14 countries and 4 studies in countries with high TB incidence. The pooled sensitivity, specificity and DOR were 0.45 (0.42\u20130.48), 0.96 (0.96\u20130.97) and 18.84 (7.33\u201348.41) respectively. The ability of QFT-GIT to discriminate with disease and no disease was \u201cgood\u201d as demonstrated by a summary receiver operating characteristic curve with area under curve of 0.7812. The average Kappa (k) co-efficient was 0.501 with a wide variety of values between studies (0.167 to 0.800).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The findings of this meta-analysis support the judicious use of QFT-GIT in children 5 years and under, with caution as a sole test to exclude Tuberculosis in this age group. The heterogeneity and methodological quality of diagnostic studies limits the generalisability of results.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0295913","type":"journal-article","created":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T19:49:27Z","timestamp":1704224967000},"page":"e0295913","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["QuantiFERON Gold-In-Tube for the diagnosis of mycobacterial tuberculosis infection in children under 5 years of age: A systematic review and meta-analysis"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6422-7712","authenticated-orcid":true,"given":"Thomas","family":"Volkman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Visai","family":"Muruganandah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2461-0463","authenticated-orcid":true,"given":"Hamish","family":"Graham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shidan","family":"Tosif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Stokes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarath","family":"Ranganathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,1,2]]},"reference":[{"key":"pone.0295913.ref001","unstructured":"World Health Organization (WHO) collaborators. Global Tuberculosis Report 2021. Available from: https:\/\/www.who.int\/publications\/i\/item\/9789240037021."},{"key":"pone.0295913.ref002","unstructured":"World Health Organization (WHO). WHO consolidated guidelines on tuberculosis. Geneva, World Health Organization, 2022. Available from: https:\/\/www.who.int\/publications\/i\/item\/9789240056084."},{"key":"pone.0295913.ref003","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S0140-6736(20)30166-5","article-title":"The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis., on behalf of the Pediatric TB Contact Studies Consortium","volume":"395","author":"L Martinez","year":"2020","journal-title":"Lancet"},{"key":"pone.0295913.ref004","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1136\/adc.2006.104976","article-title":"Pai, Recent advances in the diagnosis of childhood tuberculosis","volume":"92","author":"M. Marais BJ and","year":"2007","journal-title":"Arch Dis Child"},{"key":"pone.0295913.ref005","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1164\/rccm.200511-1809SO","article-title":"R Starke. Children pulmonary tuberculosis: old wisdom and new challenges","volume":"173","author":"BJ Marais","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"pone.0295913.ref006","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1164\/ajrccm.163.4.ed0201c","article-title":"Diagnosing latent tuberculosis infection: the 100-year upgrade","volume":"163","author":"PF Barnes","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"pone.0295913.ref007","doi-asserted-by":"crossref","first-page":"e1763","DOI":"10.1542\/peds.2014-2983","article-title":"Committee on Infectious Diseases. Interferon-\u03b3 release assays for diagnosis of tuberculosis infection and disease in children","volume":"134","author":"JR Starke","year":"2014","journal-title":"Pediatrics"},{"key":"pone.0295913.ref008","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.ccm.2009.08.012","article-title":"Godfrey-Faussett. Screening and preventive therapy for tuberculosis","volume":"30","author":"BJ Marais","year":"2009","journal-title":"Clin. Chest Med"},{"issue":"1","key":"pone.0295913.ref009","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1164\/rccm.201006-0974OC","article-title":"Negative and positive predictive value of a whole-blood interferon-\u03b3 release assay for developing active tuberculosis: an update","volume":"183","author":"R Diel","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"issue":"suppl 3","key":"pone.0295913.ref010","doi-asserted-by":"crossref","first-page":"S164","DOI":"10.1093\/cid\/civ613","article-title":"A blueprint to address research gaps in the development of biomarkers for pediatric TB","volume":"61","author":"MP Nicol","year":"2015","journal-title":"Clin Infect Dis"},{"issue":"6","key":"pone.0295913.ref011","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.jinf.2020.09.032","article-title":"Mycobacterium tuberculosis-specific cytokine biomarkers to differentiate active TB and LTBI: A systematic review","volume":"81","author":"EL Sudbury","year":"2020","journal-title":"J Infect"},{"issue":"3","key":"pone.0295913.ref012","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1177\/039463201202500301","article-title":"Interferon-\u03b3 release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a systematic review and meta-analysis","volume":"25","author":"E Chiappini","year":"2012","journal-title":"Int J Immunopathol Pharmacol"},{"key":"pone.0295913.ref013","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1097\/INF.0b013e318214b915","article-title":"The utility of an interferon gamma release assay for diagnosis of latent tuberculosis infection and disease in children: a systematic review and meta-analysis","volume":"30","author":"S Machingaidze","year":"2011","journal-title":"Pediatr Infect Dis J"},{"key":"pone.0295913.ref014","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.5588\/ijtld.10.0631","article-title":"Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis","volume":"15","author":"AM Mandalakas","year":"2011","journal-title":"Int J Tuberc Lung Dis"},{"issue":"Suppl 1","key":"pone.0295913.ref015","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1186\/1471-2334-14-S1-S6","article-title":". Systematic review and meta-analysis on the utility of Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a 2013 update","volume":"14","author":"S Sollai","year":"2014","journal-title":"BMC Infect Dis"},{"issue":"13","key":"pone.0295913.ref016","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1177\/0009922814540040","article-title":"Interferon-\u03b3 release assay for the diagnosis of latent Mycobacterium tuberculosis infection in children younger than 5 years: a meta-analysis","volume":"53","author":"L Ge","year":"2014","journal-title":"Clin Pediatr"},{"key":"pone.0295913.ref017","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1471-2288-3-25","article-title":"The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews","volume":"3","author":"P Whiting","year":"2003","journal-title":"BMC Med Res Methodol"},{"issue":"1","key":"pone.0295913.ref018","article-title":"Interferon-\u03b3 Release Assays in Children <15 Years of Age","volume":"145","author":"TUBERCULOSIS EPIDEMIOLOGIC STUDIES CONSORTIUM","year":"2020","journal-title":"Pediatrics"},{"key":"pone.0295913.ref019","first-page":"1","article-title":"Is secretion of IFN-gamma in response to Mycobacterium tuberculosis antigens in youngest children sufficient to play a role in TB diagnostics?","author":"T Bielecka","year":"2017","journal-title":"Pediatric Pulmonology"},{"key":"pone.0295913.ref020","first-page":"67","article-title":"QuantiFERON to diagnose infection by Mycobacterium tuberculosis: Performance in infants and older children","author":"A Blandinieres","year":"2013","journal-title":"Journal of Infection"},{"issue":"12","key":"pone.0295913.ref021","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1097\/INF.0000000000000432","article-title":"Interferon-Gamma release assay sensitivity in children younger than 5 years is insufficient to replace the use of tuberculin skin tests in western countries","volume":"33","author":"E Chiappini","year":"2014","journal-title":"Pediatr Infect Dis J"},{"key":"pone.0295913.ref022","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3389\/fped.2019.00291","article-title":"Contribution of QuantiFERON-TB Gold-in-Tube to the Diagnosis of Mycobacterium tuberculosis Infection in Young Children in a Low TB Prevalence Country","volume":"7","author":"S Debulpaep","year":"2019","journal-title":"Front Pediatr"},{"issue":"12","key":"pone.0295913.ref023","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.5588\/ijtld.16.0382","article-title":"Utility of the QuantiFERON-TB Gold In-Tube assay for the diagnosis of tuberculosis in Moroccan children","volume":"20","author":"S El Azbaoui","year":"2016","journal-title":"International Journal of Tuberculosis and Lung Disease"},{"issue":"8","key":"pone.0295913.ref024","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/jpc.13865","article-title":"Tuberculin skin test versus interferon-gamma release assay in refugee children: A retrospective cohort study","volume":"54","author":"C Elliot","year":"2018","journal-title":"J Paediatr Child Health"},{"issue":"9","key":"pone.0295913.ref025","doi-asserted-by":"crossref","first-page":"E226","DOI":"10.1097\/INF.0000000000000353","article-title":"Performance of interferon-gamma release assay for the diagnosis of active or latent tuberculosis in children in the first 2 years of age: A multicenter study of the Italian society of pediatric infectious diseases","volume":"33","author":"S Garazzino","year":"2014","journal-title":"Pediatric Infectious Disease Journal"},{"key":"pone.0295913.ref026","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.tmaid.2018.07.009","article-title":"Utility of tuberculin skin test and IGRA for tuberculosis screening in internationally adopted children: Retrospective analysis from a single center in Florence, Italy","volume":"28","author":"MV Mastrolia","year":"2019","journal-title":"Travel Med Infect Dis"},{"issue":"9","key":"pone.0295913.ref027","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.5588\/ijtld.10.0770","article-title":"Tuberculin skin test and QuantiFERON assay in young children investigated for tuberculosis in South Africa","volume":"15","author":"S Moyo","year":"2011","journal-title":"International Journal of Tuberculosis and Lung Disease"},{"key":"pone.0295913.ref028","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1017\/S0950268807009831","article-title":"Performance of an interferon-gamma release assay for diagnosing latent tuberculosis infection in children","volume":"36","author":"K Okada","year":"2008","journal-title":"Epidemiol. Infect"},{"issue":"4","key":"pone.0295913.ref029","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1007\/s10753-012-9466-1","article-title":"Comparison of quantiferon test with tuberculin skin test for the detection of tuberculosis infection in children","volume":"35","author":"H. Onur","year":"2012","journal-title":"Inflammation"},{"issue":"10","key":"pone.0295913.ref030","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1097\/INF.0b013e318220c52a","article-title":"Interferon-gamma release assay for the diagnosis of latent tuberculosis in children younger than 5 years of age","volume":"30","author":"I Pavic","year":"2011","journal-title":"Pediatric Infectious Disease Journal"},{"issue":"3","key":"pone.0295913.ref031","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1309\/LMCQLO8PG0IZ5APX","article-title":"Discordance between tuberculin skin test and interferon-gamma release assay in children younger than 5 years who have been vaccinated with bacillus Calmette-Guerin","volume":"46","author":"I Pavic","year":"2015","journal-title":"Laboratory Medicine"},{"issue":"2","key":"pone.0295913.ref032","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/jpids\/piu024","article-title":"Relating Tuberculosis (TB) Contact Characteristics to QuantiFERON-TB-Gold and Tuberculin Skin Test Results in the Toronto Pediatric TB Clinic","volume":"4","author":"W Rose","year":"2015","journal-title":"J Pediatric Infect Dis Soc"},{"issue":"12","key":"pone.0295913.ref033","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1097\/INF.0000000000002015","article-title":"Performance of Tuberculin Skin Tests and Interferon-\u03b3 Release Assays in Children Younger Than 5 Years","volume":"37","author":"E Velasco-Arnaiz","year":"2018","journal-title":"Pediatr Infect Dis J"},{"issue":"4","key":"pone.0295913.ref034","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/jpc.14687","article-title":"Evaluation of QuantiFERON tuberculosis Gold In-Tube assay for diagnosis of active tuberculosis in children","volume":"56","author":"T Zubarioglu","year":"2020","journal-title":"J Paediatr Child Health"},{"issue":"6","key":"pone.0295913.ref035","article-title":"Interferon-\u03b3 Release Assay Performance for Tuberculosis in Childhood","volume":"141","author":"AW Kay","year":"2018","journal-title":"Pediatrics"},{"key":"pone.0295913.ref036","unstructured":"World Health Organization (WHO) Guidelines on the Management of Latent Tuberculosis Infection. Geneva; (2015). Available from: https:\/\/www.who.int\/publications\/i\/item\/9789241548908."},{"issue":"2","key":"pone.0295913.ref037","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/cid\/ciw778","article-title":"Official American Thoracic Society\/Infectious Diseases Society of America\/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children","volume":"64","author":"DM Lewinsohn","year":"2017","journal-title":"Clin Infect Dis"},{"key":"pone.0295913.ref038","unstructured":"European Centre for Disease Prevention and Control (2011) Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC; 2011; Available from: ecdc.europa.eu\/en\/publications\/Publications\/1103_GUI_IGRA.pdf."},{"key":"pone.0295913.ref039","unstructured":"NICE CG 117: tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. Available from: https:\/\/www.nice.org.uk\/guidance\/ng33."},{"key":"pone.0295913.ref040","unstructured":"National Tuberculosis Advisory Committee (2018). Position statement on interferon-g release immunoassays in the detection of latent tuberculosis infection. Published by Commonwealth Department of Health and Ageing. December 2017. Updated March 2018. Available from: https:\/\/www1.health.gov.au\/internet\/main\/publishing.nsf\/Content\/cdi4104-c."},{"key":"pone.0295913.ref041","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0022-3476(97)70120-3","article-title":"Immunobiology of childhood tuberculosis: a window on the ontogeny of cellular immunity","volume":"131","author":"S Smith","year":"1997","journal-title":"J Pediatr"},{"issue":"4","key":"pone.0295913.ref042","doi-asserted-by":"crossref","DOI":"10.1086\/422532","article-title":"Increased Interleukin-4 production by CD8 and gamma delta T cells in health-care workers is associated with the subsequent development of active tuberculosis","volume":"190","author":"DJ Ordway","year":"2004","journal-title":"J Infect Dis"},{"issue":"6","key":"pone.0295913.ref043","doi-asserted-by":"crossref","DOI":"10.1016\/j.vaccine.2009.11.004","article-title":"Complex cytokine profiles induced by BCG vaccination in UK infants","volume":"28","author":"MK Lalor","year":"2010","journal-title":"Vaccine"},{"issue":"11","key":"pone.0295913.ref044","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.puhe.2007.12.007","article-title":"Use of QuantiFERON-TB Gold test in the investigation of unexplained positive tuberculin skin tests","volume":"122","author":"E Nsutebu","year":"2008","journal-title":"Public Health"},{"issue":"1","key":"pone.0295913.ref045","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.prrv.2010.09.009","article-title":"Immune-based diagnostics for TB in children: what is the evidence?","volume":"12","author":"DI Ling","year":"2011","journal-title":"Paediatr Respir Rev"},{"issue":"1","key":"pone.0295913.ref046","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s12879-017-2301-4","article-title":"Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis","volume":"17","author":"P Auguste","year":"2017","journal-title":"BMC Infect Dis"},{"issue":"8","key":"pone.0295913.ref047","doi-asserted-by":"crossref","first-page":"625","DOI":"10.3855\/jidc.9601","article-title":"Mantoux test revisited: Variability in reading tuberculin test in pediatric population","volume":"12","author":"D Goel","year":"2018","journal-title":"Journal of infection in developing countries"},{"issue":"6","key":"pone.0295913.ref048","doi-asserted-by":"crossref","DOI":"10.1093\/tropej\/fmab103","article-title":"Discordance between TST and QFT-TBGold Plus for Latent Tuberculosis Screening among Under-Five Children: An Interim Analysis","volume":"67","author":"S Surve","year":"2021","journal-title":"J Trop Pediatr"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295913","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T19:49:53Z","timestamp":1704224993000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295913"}},"subtitle":[],"editor":[{"given":"Mao-Shui","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,2]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0295913","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,2]]}}}