title: Concordant or discordant results by the tuberculin skin test and the quantiFERON-TB test in children reflect immune biomarker profiles.
abstract: The tuberculin skin test (TST) and QuantiFERON-TB-Gold-In-tube (QFTGIT) are adjunctive tests used in the diagnosis of pediatric tuberculosis (TB). Neither test can rule out TB; however, a positive test usually triggers preventive treatment in TB contacts aged <5 years. TST and QFTGIT can give divergent results and it is unclear how discordant results should be interpreted in terms of TB risk and preventive treatment. To understand the immune processes underlying concordant or discordant TST and QFTGIT results, we analyzed immune responses in children from Palamaner Taluk in India (a TB-endemic region with routine neonatal BCG vaccination) who were referred to a TB case verification ward on suspicion of TB. Two hundred and ten children aged <3 years were classified according to their TST and QFTGIT results, and their immune responses analyzed by dual-colour-Reverse-Transcriptase-Multiple-Ligation-dependent-Probe-Amplification, using a panel of 45 genes and a 10-plex antigen-specific enzyme-linked immunosorbent assay. We show that immune biomarkers FPR1, TNFRSF1A and interferon (IFN)-γ are upregulated (all P<0.05) in concordant test-positive children, whereas BPI is downregulated (P<0.05). In contrast, SEC14L1 (P=0.034) and Interferon gamma-induced protein 10 (IP-10) (P=0.001) are differentially expressed between the TST+QFTGIT- /TST-QFTGIT+ groups. Known TB exposure was more frequent in concordant positive children and results were consistent with elevated expression of genes associated with inflammatory responses. Children with discordant test results displayed a mixed profile with activation of both pro- and anti-inflammatory markers. TST and/or QFTGIT positivity appears to reflect distinct but overlapping aspects of host immunity.
authors.affiliation: Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Dhanasekaran
authors.affiliation: Center for Immune Regulation, Rikshospitalet-Radium Hospitalet Medical Centre, University of Oslo, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Jenum
authors.affiliation: Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Stavrum
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Ritz
authors.affiliation: Division of Infectious Diseases, St John's Research Institute, Bangalore, India.
authors.forename: J
authors.initials: J
authors.lastname: Kenneth
authors.affiliation: Division of Health and Humanities, St John's Research Institute, Bangalore, India.
authors.forename: M
authors.initials: M
authors.lastname: Vaz
authors.affiliation: 1] Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway [2] Vaccines, GlaxoSmithKline Pharma, Brøndby, Denmark.
authors.forename: T M
authors.initials: TM
authors.lastname: Doherty
authors.affiliation: 1] Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway [2] Department of Microbiology, Haukeland University Hospital, University of Bergen, Bergen, Norway.
authors.forename: H M S
authors.initials: HM
authors.lastname: Grewal
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000097:blood; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D060885:Multiplex Polymerase Chain Reaction / Q000592:standards; D011446:Prospective Studies; D044042:Receptors, Formyl Peptide / Q000097:blood; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D012680:Sensitivity and Specificity; D014374:Tuberculin Test / Q000592:standards*; D014376:Tuberculosis / Q000175:diagnosis* / Q000276:immunology; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; C469986:FPR1 protein, human; D044042:Receptors, Formyl Peptide; D047888:Receptors, Tumor Necrosis Factor, Type I; C100642:SEC14L1 protein, human; C506235:TNFRSF1A protein, human; D007371:Interferon-gamma
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