Identification of Airway-Mucosal Type-2 inflammation by Clinical Biomarkers in Asthma

BACKGROUND AND OBJECTIVE: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled mild, moderate and severe asthma, and non-atopic healthy controls. We explored this dataset 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 mild, 29 moderate, and 26 severe asthmatics, based on airway-mucosal expression of 1) CC-motif chemokine ligand (CCL)-26, (the most differentially expressed gene), 2) periostin, or 3) a multi-gene IL-13 in-vitro signature (IVS). Clinically accessible biomarkers included fractional exhaled nitric oxide (FENO), blood eosinophils (bEOS), serum CCL26, and serum CCL17.

RESULTS: Expression of airway-mucosal-CCL26, periostin, and IL-13-IVS all provided segregation into Type-2-high and -low asthmatics, but in the ADEPT population, CCL26 was optimal. All airway-mucosal-CCL26-high subjects with moderate-severe asthma were FENO-high (≥35 ppb) and/or blood eosinophils-high (≥300cells/mm(3)), compared to a minority (36%) of airway-mucosal- CCL26-low subjects. A combination of FENO, blood eosinophils, serum CCL17 and CCL26 had 100% positive-predictive-value and 87% negative-predictive-value for airway-mucosal-CCL26-high status. Clinical variables did not differ between Type-2 high and -low subjects. 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-mucosa CCL26, perisotin or IL-13-IVS gene expression. Use of FENO, blood eosinophils and serum markers e.g. CCL26, CCL17 in combination may allow patient selection for novel Type-2 therapeutics.