Proteomic signatures of eosinophilic and neutrophilic asthma from serum and sputum.

Background: Eosinophilic and neutrophilic asthma defined by high levels of blood and sputum eosinophils and neutrophils exemplifies the inflammatory heterogeneity of asthma, particularly severe asthma. We analysed the serum and sputum proteome to identify biomarkers jointly associated with these different phenotypes.
Methods: Proteomic profiles (N = 1129 proteins) were assayed in sputum (n = 182) and serum (n = 574) from two cohorts (U-BIOPRED and ADEPT) of mild-moderate and severe asthma by SOMAscan. Using least absolute shrinkage and selection operator (LASSO)-penalised logistic regression in a stability selection framework, we sought sparse sets of proteins associated with either eosinophilic or neutrophilic asthma with and without adjustment for established clinical factors including oral corticosteroid use and forced expiratory volume.
Findings: We identified 13 serum proteins associated with eosinophilic asthma, including 7 (PAPP-A, TARC/CCL17, ALT/GPT, IgE, CCL28, CO8A1, and IL5-Rα) that were stably selected while adjusting for clinical factors yielding an AUC of 0.84 (95% CI: 0.83-0.84) compared to 0.62 (95% CI: 0.61-0.63) for clinical factors only. Sputum protein analysis selected only PAPP-A (AUC = 0.81 [95% CI: 0.80-0.81]). 12 serum proteins were associated with neutrophilic asthma, of which 5 (MMP-9, EDAR, GIIE/PLA2G2E, IL-1-R4/IL1RL1, and Elafin) complemented clinical factors increasing the AUC from 0.63 (95% CI: 0.58-0.67) for the model with clinical factors only to 0.89 (95% CI: 0.89-0.90). Our model did not select any sputum proteins associated with neutrophilic status.
Interpretation: Targeted serum proteomic profiles are a non-invasive and scalable approach for subtyping of neutrophilic and eosinophilic asthma and for future functional understanding of these phenotypes.
Funding: U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contributions (www.imi.europa.eu). ADEPT was funded by Johnson & Johnson/Janssen pharmaceutical Company.
Competing Interests: Declaration of interests Prof M Chadeau-Hyam holds shares in the O-SMOSE company; consulting activities conducted by the company are independent of the present work. Prof Adcock reports consulting fees from GSK, Sanofi, Chiesi and Kinaset; speaker fees from AZ, Sanofi, Eurodrug and Sunovion; travel support from AZ; grants from GSK, MRC, EPSRC, Sanofi and NIEHS, which were independent of the present work. Dr. Dahlén reports consulting fees from Affiboby, AZ, Cayman Chemicals, GSK and Regeneron, and speaker fees from AZ, GSK and Sanofi, outside the submitted work. Prof Chung has received speaker fees from Novartis, AZ and Merck; honoraria for participating in Advisory Board meetings of GSK, Novartis, Roche, Merck, Trevi, Rickett-Beckinson, Nocion and Shionogi; and has received grants from MRC, EPSRC and GSK. Prof Chung is a member of the Scientific Advisory Board of the Clean Breathing Institute supported by Haleon. Dr Djukanovic declares consulting fees from Synairgen plc and lecture fees from GSK, ZenasBio and Celltrion. He holds shares from Synairgen and is Chair of the European Respiratory Society's Clinical collaboration on severe asthma (SHARP). The other authors have no conflict of interest to disclose.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)