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

Publication date: Available online 13 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Philip E. Silkoff, Michel Laviolette, Dave Singh, J Mark FitzGerald, Steven Kelsen, Vibeke Backer, Celeste M. Porsbjerg, Pierre-Olivier Girodet, Patrick Berger, Joel N. Kline, Geoffrey Chupp, Vedrana S. Susulic, Elliot S. Barnathan, Frédéric Baribaud, Matthew J. Loza
Background and ObjectiveThe 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.MethodsIL-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.ResultsExpression 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/mm³), 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.ConclusionA 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.

Teaser

A panel of clinically-accessible biomarkers (FENO, blood eosinophils, serum CCL17 and CCL26) identified asthma patients with an airway 'Type-2-high' or 'Type-2-low' phenotype based on expression of airway-mucosal-CCL26, periostin, or an IL-13 multigene signature. This combination may prove useful in selecting patients for novel therapies targeting Type-2 inflammation.


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