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 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.


CONCLUSIONS
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.
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom.
Susana
S
Castanhinha
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Rebekah
R
Sherburn
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Simone
S
Walker
Department of Respiratory Paediatrics, Kings College Hospital, London, United Kingdom.
Atul
A
Gupta
Department of Respiratory Paediatrics, Kings College Hospital, London, United Kingdom.
Cara J
CJ
Bossley
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
James
J
Buckley
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom.
Nicola
N
Ullmann
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Ruth
R
Grychtol
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Gaynor
G
Campbell
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom.
Marco
M
Maglione
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom.
Sergio
S
Koo
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom; Airways Disease, NHLI, Imperial College London, London, United Kingdom.
Louise
L
Fleming
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Lisa
L
Gregory
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Robert J
RJ
Snelgrove
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom; Airways Disease, NHLI, Imperial College London, London, United Kingdom.
Andrew
A
Bush
Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom.
Clare M
CM
Lloyd
Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom; Leukocyte Biology, NHLI, Imperial College London, London, United Kingdom. Electronic address: s.saglani@imperial.ac.uk.
Sejal
S
Saglani
D000293:Adolescent; D000528:Alternaria / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000276:immunology; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D019819:Budesonide / Q000627:therapeutic use*; D002648:Child; D002963:Cladosporium / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D009181:Mycoses / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000069444:Omalizumab; D039981:Pyroglyphidae / Q000737:chemistry / Q000276:immunology; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D012882:Skin Tests; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
D018927:Anti-Asthmatic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D000069444:Omalizumab; D007073:Immunoglobulin E; D019819:Budesonide
IL-33; Severe asthma; fungal sensitization; innate immunity; pediatric; steroid resistance