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

Susana Castanhinha,Rebekah Sherburn,Simone Walker,Atul Gupta,Cara J Bossley,James Buckley,Nicola Ullmann,Ruth Grychtol,Gaynor Campbell,Marco Maglione,Sergio Koo,Louise Fleming,Lisa Gregory,Robert J Snelgrove,Andrew Bush,Clare M Lloyd,Sejal Saglani

doi:10.1016/j.jaci.2015.01.016

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.

Highlights

The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown
Because IL-33 is known to induce type 2 innate lymphoid cell (ILC) in the context of adult models of allergic airways disease[23] and levels of IL33 were significantly higher after A alternata compared with house dust mite (HDM), we investigated whether type 2 ILCs might represent the cellular source of IL-13 after A alternata exposure
We have shown that IL-33 is more steroid resistant than IL-13.21 Because A alternata exposure resulted in higher IL-33 levels in the murine model and significantly more children with SAFS were prescribed oral steroids to achieve similar symptom control and lung function (Table I), we investigated whether A alternata exposure induces a steroid-resistant phenotype of allergic airways disease

Summary

Introduction

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. 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 5 .006), higher total IgE levels (637 vs 177 IU/mL, P 5 .002), and nonfungal inhalant allergen-specific IgE. SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary

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Conclusion