Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33

Background The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. Objective We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Methods Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus , Alternaria alternata , or Cladosporium herbarum . Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Results Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P  = .006), higher total IgE levels (637 vs 177 IU/mL, P  = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P  = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13 + innate lymphoid cell (ILC) and T H 2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13 + ILC numbers, T H 2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2 −/− mice lacking a functional receptor for IL-33. Conclusion Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, T H 2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.