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A distinct inflammatory profile marked by neutrophil activity and cytokine elevation may underline poor biological response in T2-high severe asthma.  

A study published in June 2025 issue of Journal of Allergy and Clinical Immunology emphasized the impact of targeted T2 biologics on transforming asthma care, while noting persistent differences in treatment response among individuals.  

Researchers conducted a retrospective study to assess airway inflammation in individuals with T2-high asthma treated with anti-interleukin (IL)-5 (IL-5) biologics and to explore whether distinct inflammatory mechanisms accounted for varied treatment responses.  

They performed proteomic profiling using the Olink ^®  panel targeting 1,463 proteins and carried out high-sensitivity cytokine analysis with enzyme-linked immunosorbent assays (ELISAs) on induced sputum samples. The samples were obtained from individuals with T2-high, severe asthma enrolled in the UK multicentre Mepolizumab EXacerbation (MEX) study. A total of 97 samples were analyzed, including 28 pre-mepolizumab, 43 during stable treatment, and 26 at the first exacerbation.  

The results showed that sputum protein clustering during stable mepolizumab treatment revealed 2 distinct clusters. Cluster 1 displayed elevated differentially expressed sputum proteins at all 3-time points—pre-mepolizumab, stable treatment, and exacerbation. Individuals in Cluster 1 had an earlier age at diagnosis, longer asthma duration, reduced forced expiratory volume in 1 second (FEV₁), and higher Asthma Control Questionnaire-5 (ACQ5) scores during treatment. This cluster also showed increased levels of pro-inflammatory cytokines IL1β, IL6, sIL6R, epithelial alarmins (thymic stromal lymphopoietin [TSLP], IL33), and neutrophil activation markers (myeloperoxidase [MPO], neutrophil elastase [NE], and neutrophil extracellular traps [NET]). All participants remained T2-high, with no significant differences in fractional exhaled nitric oxide (FeNO), eosinophil counts, or eosinophil-derived neurotoxin (EDN) levels between clusters.  

Investigators concluded that a subgroup of individuals with T2-high severe asthma and long-standing disease exhibited persistent airway inflammation and poor clinical outcomes despite mepolizumab. 

Source: jacionline.org/article/S0091-6749(25)00696-7/abstract