Asthma and lower airway disease
Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33

https://doi.org/10.1016/j.jaci.2015.01.016Get rights and content
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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 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.

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, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.

Key words

Severe asthma
fungal sensitization
pediatric
IL-33
innate immunity
steroid resistance

Abbreviations used

ABPA
Allergic bronchopulmonary aspergillosis
AHR
Airway hyperresponsiveness
BAL
Bronchoalveolar lavage
HDM
House dust mite
ICOS
Inducible costimulator
ILC
Innate lymphoid cell
MMP-9
Matrix metalloproteinase 9
SAFS
Severe asthma with fungal sensitization
sIgE
Specific IgE
SPT
Skin prick test
STRA
Severe therapy-resistant asthma

Cited by (0)

C.M.L. and R.J.S. were funded by the Wellcome Trust UK (grants 086718/Z/08/Z and 095707/Z/11/Z). S.S. was funded by the MRC New Investigator Research Grant (grant MR/J010529/1). A.B. is an NIHR Senior Investigator and was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. S.S., C.M.L., and A.B. are investigators in the MRC Asthma UK Centre for Allergic Mechanisms of Disease. R.G. was funded by the German Research Foundation (GR 4379/1 1).

Disclosure of potential conflict of interest: S. Walker has received research support from the MRC/Asthma UK Centre for Asthma and Allergic Mechanisms. J. Buckley has received research support from the Wellcome Trust. R. Grychtol has received research support from the German Research Foundation. L. Fleming has received consultancy fees from Chiesi, is employed by Imperial College, London, has received research support from the Royal Brompton and Harefield NHS Trust (Biomedical Research Unit), and has received lecture fees from Novartis. R. J. Snelgrove has received research support from the Wellcome Trust. C. M. Lloyd has received research support from the Wellcome Trust, MedImmune, and Johnson & Johnson. S. Saglani has received research support from the MRC. The rest of the authors declare that they have no relevant conflicts of interest.

These authors contributed equally to this work.