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

BackgroundTargeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.ObjectiveAssess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics.MethodsProteomic analysis (Olink®, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n= 43) & at first exacerbation (n=26).ResultsClustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1β, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters.ConclusionIn a cohort of T2-high severe asthma 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.