Altman M, Bacharier L, Villarreal M, Gill M, Liu A, Gruchalla R, O G, Robison R, Hershey GK, Sherenian M, Rivera-Spoljaric K, Stokes J, Zoratti E, Teach S, Kattan M, Lovinsky-Desir S, Visness C, Becker P, Gergen P, Gern J, Sorkness C, Busse W, and Jackson D. Distinct Airway Inflammatory Pathways Associated with Asthma Exacerbations are Modulated by Mepolizumab Therapy in Children. J Allergy Clin Immunol 2022; 149(2):AB146.
J Allergy Clin Immunol
Rationale: Identification of specific airway inflammatory pathways can lead to effective personalized treatment with biologics in asthma and insights to mechanisms of action.
Methods: 290 urban children with exacerbation-prone asthma and ≥150/mm3 blood eosinophils were randomized (1:1) to placebo or mepolizumab added to guideline-based care. Nasal lavage samples were collected at randomization and during treatment for RNA-sequencing, and analyzed by cell-deconvolution modular analysis to assess genome-wide expression patterns associated with exacerbation number and effect of treatment.
Results: Mepolizumab significantly reduced the frequency of exacerbations compared to placebo. At randomization, there were no differences in expression between treatment groups; multiple modules were subsequently differentially expressed during mepolizumab but not placebo treatment. Furthermore, expression levels of multiple modules were associated with the exacerbation number during the study, with distinct relationships observed in the placebo and/or mepolizumab groups. Notably, higher expression at randomization of an eosinophil-associated module enriched for Type-2 genes including IL4, IL5, and IL13, was associated with increased exacerbations in placebo (β=0.19, p<0.001), but not mepolizumab-treated children (interaction p<0.01). Furthermore, mepolizumab treatment reduced expression of this module (Fold-change=0.62, p<0.001). In contrast, higher expression at randomization of an eosinophil-associated module enriched for eosinophil activation (e.g. CD9) and mucus hypersecretion (e.g. MUC5AC) genes was associated with exacerbation number in both groups throughout the study (β=0.18, p<0.01) and was unaltered by mepolizumab therapy.
Conclusions: Multiple distinct airway inflammation patterns were identified associated with exacerbation frequency. These findings identify inflammatory endotypes and indicate likelihood and potential mechanisms of a beneficial clinical response to mepolizumab therapy to prevent exacerbations.