TY - JOUR

T1 - Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients

AU - Silkoff, Philip E

AU - Laviolette, Michel

AU - Singh, Dave

AU - FitzGerald, J Mark

AU - Kelsen, Steven

AU - Backer, Vibeke

AU - Porsbjerg, Celeste M

AU - Girodet, Pierre-Olivier

AU - Berger, Patrick

AU - Kline, Joel N

AU - Chupp, Geoffrey

AU - Susulic, Vedrana S

AU - Barnathan, Elliot S

AU - Baribaud, Frédéric

AU - Loza, Matthew J

AU - Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study investigators

N1 - Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

PY - 2017

Y1 - 2017

N2 - 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.CONCLUSION: 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.

AB - 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.CONCLUSION: 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.

KW - Adolescent

KW - Adult

KW - Asthma/blood

KW - Biomarkers/blood

KW - Cell Adhesion Molecules/immunology

KW - Cell Line

KW - Chemokine CCL17/blood

KW - Chemokine CCL26

KW - Chemokines, CC/blood

KW - Eosinophils/immunology

KW - Female

KW - Gene Expression

KW - Humans

KW - Interleukin-13/genetics

KW - Leukocyte Count

KW - Male

KW - Middle Aged

KW - Nitric Oxide/metabolism

KW - Respiratory Function Tests

KW - Respiratory Mucosa/immunology

KW - Severity of Illness Index

KW - Young Adult

U2 - 10.1016/j.jaci.2016.11.038

DO - 10.1016/j.jaci.2016.11.038

M3 - Journal article

C2 - 28089872

VL - 140

SP - 710

EP - 719

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 3

ER -