Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma

TY - JOUR

T1 - Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma

AU - McDowell, P. Jane

AU - Azim, Adnan

AU - Busby, John

AU - Diver, Sarah

AU - Yang, Freda

AU - Borg, Catherine

AU - Brown, Vanessa

AU - Shrimanker, Rahul

AU - Haldar, Koirobi

AU - Chaudhuri, Rekha

AU - Brightling, Christopher E.

AU - Pavord, Ian D.

AU - Howarth, Peter

AU - Chalmers, James D.

AU - Heaney, Liam G.

AU - Medical Research Council UK Refractory Asthma Stratification Programme (RASP-UK Consortium)

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/10

Y1 - 2025/10

N2 - 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.

AB - 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.

KW - airway inflammation

KW - clinical remission

KW - epithelial activation

KW - neutrophil activation

KW - proteobacteria

KW - Severe asthma

KW - vicious vortex

UR - https://www.scopus.com/pages/publications/105011623618

U2 - 10.1016/j.jaci.2025.05.031

DO - 10.1016/j.jaci.2025.05.031

M3 - Article

C2 - 40592388

AN - SCOPUS:105011623618

SN - 0091-6749

VL - 156

SP - 911

EP - 922

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 4

ER -