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

Abstract

BackgroundThe 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.ObjectiveWe sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33.MethodsEighty-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.ResultsChildren 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 TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 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.ConclusionPediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

“…This was also shown in a model of sensitization to fungal allergens, in which IL-33 was shown to be high in mice exposed to Alternaria allergen (Castanhinha et al, 2015). In our hands, treatment with r-sST2 to block IL-33 at the time of sensitization completely abolished eosinophilic airway inflammation, Th2-cell-associated cytokine production, and GCM particularly when administered in the period of maximal lung alveolarization.…”

“…In our hands, treatment with r-sST2 to block IL-33 at the time of sensitization completely abolished eosinophilic airway inflammation, Th2-cell-associated cytokine production, and GCM particularly when administered in the period of maximal lung alveolarization. Consistently, polymorphisms in IL1RL1, coding for ST2 (IL-33R), as well as the IL33 gene itself have been found associated with asthma and blood eosinophil counts, particularly in childhood asthma (Bøn-nelykke et al, 2014;Castanhinha et al, 2015;Gordon et al, 2016;Moffatt et al, 2010;Saglani et al, 2013;Savenije et al, 2011;Torgerson et al, 2011;Traister et al, 2015). In asthmatics, polymorphisms in IL1RL1 also control the relative abundance of the cell-bound IL-33R (ST2L) versus the soluble IL-33 receptor (sST2), that acts as a decoy receptor and antagonist of the IL-33-IL-33R axis (Grotenboer et al, 2013;Traister et al, 2015).…”

Severe asthma in children

“…We have shown that these children have evidence of worse inflammation than STRA without SAFS, despite being prescribed more treatment. 79 The innate epithelial cytokine is increased in bronchoalveolar lavage (BAL), and immunohistochemistry of bronchial biopsies also show increased IL-33-positive cells in children with SAFS, and in a neonatal Alternaria-sensitized murine model. Management is avoidance of fungal exposure as far as possible (checking any nebulizer for contamination and avoiding stables) and consideration of antifungal therapy, although it has to be said that the evidence for antifungal therapy is not compelling.…”

Current and future biomarkers in allergic asthma

“…Environmental exposure to smoke increases IL-6, IL-7 and IL-12 and thus lacks a Th2 fingerprint (158). In contrast, fungal sensitization with Alternaria alternata or rhinovirus-triggered asthma exacerbations are reported to stimulate increases in IL-33-mediated ILC2 numbers and Th2 cell numbers (159,160). CCR4 and CXCR3 are up-regulated in Aspergillus fumigatus-specific T cells from non-ABPA-allergic asthmatics (161).…”