Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma
- PMID: 40592388
- DOI: 10.1016/j.jaci.2025.05.031
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma
Abstract
Background: Targeted type 2 (T2) biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.
Objective: We sought to assess airways inflammation in T2-high asthmatic patients treated with anti-IL-5 biologics to investigate whether differential mechanism of airway inflammation explains varied response to biologics.
Methods: Proteomic analysis (Olink, 1463 protein panel) and high-sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high severe asthmatic patients in the UK multicenter Mepolizumab EXacerbation study. Samples included were pre-mepolizumab (n = 28), stable on mepolizumab (n = 43), and at first exacerbation (n = 26).
Results: Clustering of sputum proteins while stable on mepolizumab identified 2 clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab, and at exacerbation. Patients in cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1%, and higher 5-Question Asthma Control Questionnaire score on mepolizumab. Cluster 1 had increased expression of proinflammatory cytokines (IL-1β, IL-6, and soluble IL-6R), epithelial alarmins (thymic stromal lymphopoietin [TSLP] and IL-33), and neutrophil activation (myeloperoxidase [MPO], neutrophil elastase [NE], and neutrophil extracellular trap concentration [NET]). All patients were T2-high with no difference in fractional exhaled nitric oxide, eosinophil number, or activity (eosinophil-derived neurotoxin, EDN) across the 2 clusters.
Conclusions: In a cohort of T2-high severe asthmatic patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines, and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2 biologics, which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
Keywords: Severe asthma; airway inflammation; clinical remission; epithelial activation; neutrophil activation; proteobacteria; vicious vortex.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure statement The MEX study was funded jointly by the Medical Research Council UK (MR/M016579/1) and industrial partners within the Refractory Asthma Stratification Program Consortium. The presented analysis, including Olink proteomics and high-sensitivity cytokine analysis, was funded by an investigator study grant from GlaxoSmithKline. Disclosure of potential conflict of interest: P. J. McDowell received speaker’s honoraria from GlaxoSmithKline (GSK); and received support for attending educational meetings from AstraZeneca (AZ) and GSK. A. Azim works as a paid employee for AZ. J. Busby reports a grant from AZ paid to the institution. S. Diver reports speaker’s honoraria from AZ. F. Yang received speaker’s honoraria from GSK and AZ; and received support for attending educational meetings from AZ. R. Shrimanker has received speaker’s honoraria from GSK, Chiesi, and AZ; and received support for attending educational meetings from AZ. R. Chaudhuri has received a grant from AZ paid to her institution; received speaker’s honoraria from GSK, AZ, Teva, Chiesi, and Sanofi; received support for attending conferences from Chiesi, Sanofi, and GSK; and has participated on advisory boards for GSK, AZ, and Celltrion. C. E. Brightling has received grants and consultancy fees from 4D Pharma, Areteia, AZ, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi paid to his institution. I. D. Pavord received consulting fees and speaker’s honoraria from GSK, Sanofi/Regeneron, and AZ; received speaker’s honoraria from Circassia; and received support for attending meetings from Sanofi/Regeneron. P. Howarth is a paid employee of GSK and has stock options in it. J. Chalmers has received grants from AZ, Boehringer Ingelheim, Insmed, Gilead Sciences, Genentech, GSK, Grifols, and Trudell; and received consultancy fees from AZ, Chiesi, GSK, Boehringer Ingelheim, Insmed, Grifols, Novartis, Pfizer, Janssen, Antabio, and Zambon. L. G. Heaney reports grants from GSK, AZ, and Roche/Genentech; reports consulting fees from AZ, Sanofi, Circassia, GSK, and Teva; reports support to attend meetings from AZ, Sanofi, Teva, and GSK; and has participated on advisory boards for GSK, AZ, and Celltrion. The rest of the authors declare that they have no relevant conflicts of interest.
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