title: Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis.
abstract: BACKGROUND
  Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management.
  
  
  OBJECTIVE
  To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB.
  
  
  METHODS
  A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays.
  
  
  RESULTS
  IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively.
  
  
  CONCLUSIONS
  We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.
authors.affiliation: 1 Department of Paediatrics and.|2 Infectious Diseases Unit and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.|4 Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Tebruegge
authors.affiliation: 3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Binita
authors.initials: B
authors.lastname: Dutta
authors.affiliation: 1 Department of Paediatrics and.|5 Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Donath
authors.affiliation: 1 Department of Paediatrics and.|2 Infectious Diseases Unit and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.|6 Infectious Diseases Unit, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ritz
authors.affiliation: 3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Forbes
authors.affiliation: 2 Infectious Diseases Unit and.
authors.forename: Kattia
authors.initials: K
authors.lastname: Camacho-Badilla
authors.affiliation: 1 Department of Paediatrics and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Clifford
authors.affiliation: 3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Christel
authors.initials: C
authors.lastname: Zufferey
authors.affiliation: 1 Department of Paediatrics and.|7 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Roy
authors.initials: R
authors.lastname: Robins-Browne
authors.affiliation: 8 Institute of Infectious Diseases and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa; and.
authors.forename: Willem
authors.initials: W
authors.lastname: Hanekom
authors.affiliation: 1 Department of Paediatrics and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.|9 Centre for International Child Health, Parkville, Victoria, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Graham
authors.affiliation: 1 Department of Paediatrics and.|2 Infectious Diseases Unit and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Tom
authors.initials: T
authors.lastname: Connell
authors.affiliation: 1 Department of Paediatrics and.|2 Infectious Diseases Unit and.|3 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Curtis
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood*; D054357:Chemokine CXCL10 / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D007378:Interleukins / Q000097:blood*; D055985:Latent Tuberculosis / Q000097:blood / Q000175:diagnosis*; D008297:Male; D011237:Predictive Value of Tests; D012372:ROC Curve; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D015415:Biomarkers; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: biomarker; child; cytokines; diagnosis; tuberculosis