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.