title: Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.
abstract: BACKGROUND
  The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects.
  
  
  OBJECTIVE
  We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers.
  
  
  METHODS
  IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression.
  
  
  RESULTS
  Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression.
  
  
  CONCLUSIONS
  A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.
authors.affiliation: Janssen Research & Development LLC, Spring House, Pa. Electronic address: philsilkoff@gmail.com.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Silkoff
authors.affiliation: Institut Universitaire de Cardiologie et Pneumologie de Québec (IUCPQ), Quebec City, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: Centre for Respiratory Medicine and Allergy, University of Manchester, and the Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Institute for Heart and Lung Health, Lung Centre, Gordon and Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada.
authors.forename: J Mark
authors.initials: JM
authors.lastname: FitzGerald
authors.affiliation: Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, Pa.
authors.forename: Steven
authors.initials: S
authors.lastname: Kelsen
authors.affiliation: Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Backer
authors.affiliation: Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Porsbjerg
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Girodet
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
authors.affiliation: Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Kline
authors.affiliation: Yale School of Medicine, New Haven, Conn.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chupp
authors.affiliation: Janssen Research & Development LLC, Spring House, Pa.
authors.forename: Vedrana S
authors.initials: VS
authors.lastname: Susulic
authors.affiliation: Janssen Research & Development LLC, Spring House, Pa.
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Barnathan
authors.affiliation: Janssen Research & Development LLC, Spring House, Pa.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baribaud
authors.affiliation: Janssen Research & Development LLC, Spring House, Pa.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Loza
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000097:blood* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology; D002460:Cell Line; D054414:Chemokine CCL17 / Q000097:blood* / Q000276:immunology; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000097:blood* / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000276:immunology; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D015415:Biomarkers; C106230:CCL17 protein, human; C120429:CCL26 protein, human; D015815:Cell Adhesion Molecules; D054414:Chemokine CCL17; D000075906:Chemokine CCL26; D019742:Chemokines, CC; C578095:IL13 protein, human; D018793:Interleukin-13; C512835:POSTN protein, human; D009569:Nitric Oxide
keywords: Asthma; airway mucosal gene expression; biomarkers; phenotypes; type 2 inflammation