title: Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum.
abstract: The World Health Organization (WHO) calls for an accurate, rapid, and simple point-of-care (POC) test for the diagnosis of pediatric tuberculosis (TB) in order to make progress "Towards Zero Deaths". Whereas the sensitivity of a POC test based on detection of Mycobacterium tuberculosis (MTB) is likely to have poor sensitivity (70-80% of children have culture-negative disease), host biomarkers reflecting the on-going pathological processes across the spectrum of MTB infection and disease may hold greater promise for this purpose. We analyzed transcriptional immune biomarkers direct ex-vivo and translational biomarkers in MTB-antigen stimulated whole blood in 88 Indian children with intra-thoracic TB aged 6 months to 15 years, and 39 asymptomatic siblings. We identified 12 biomarkers consistently associated with either clinical groups "upstream" towards culture-positive TB on the TB disease spectrum (CD14, FCGR1A, FPR1, MMP9, RAB24, SEC14L1, and TIMP2) or "downstream" towards a decreased likelihood of TB disease (BLR1, CD3E, CD8A, IL7R, and TGFBR2), suggesting a correlation with MTB-related pathology and high relevance to a future POC test for pediatric TB. A biomarker signature consisting of BPI, CD3E, CD14, FPR1, IL4, TGFBR2, TIMP2 and TNFRSF1B separated children with TB from asymptomatic siblings (AUC of 88%).
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, and Department of Medical Microbiology, Vestre Viken Hospital Trust, Drammen, Norway.
authors.forename: Synne
authors.initials: S
authors.lastname: Jenum
authors.affiliation: Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, N-5021, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Dhanasekaran
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Lodha
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar Saini
authors.affiliation: Division of Clinical Microbiology &Molecular Medicine, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sarman
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Kalawati Saran Children Hospital, New Delhi, India.
authors.forename: Varinder
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Guruprasad
authors.initials: G
authors.lastname: Medigeshi
authors.affiliation: Department of Infectious Diseases Group, Immunology and Immunogenetics of Bacterial Infectious Disease, Leiden University Medical Center, The Netherland.
authors.forename: Marielle C
authors.initials: MC
authors.lastname: Haks
authors.affiliation: Department of Infectious Diseases Group, Immunology and Immunogenetics of Bacterial Infectious Disease, Leiden University Medical Center, The Netherland.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: GlaxoSmithKline Pharma, Vaccines, Brøndby, Denmark.
authors.forename: Timothy Mark
authors.initials: TM
authors.lastname: Doherty
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Kabra
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Ritz
authors.affiliation: Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, N-5021, Norway.|Department of Microbiology, Haukeland university hospital, University of Bergen,N-5021, Norway.
authors.forename: Harleen M S
authors.initials: HM
authors.lastname: Grewal
mesh_terms: D015415:Biomarkers / Q000097:blood; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019095:Point-of-Care Systems; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis* / Q000276:immunology
chemical_list: D015415:Biomarkers