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

S. Castanhinha, R. Sherburn, S. Walker, A. Gupta, C. J. Bossley, James Buckley, N. Ullmann, R. Grychtol, G. Campbell, M. Maglione, S. Koo, L. Fleming, L. Gregory, R. J. Snelgrove, A. Bush, C. M. Lloyd, S. Saglani

    Research output: Contribution to journalArticle

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    Abstract

    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.
    Original languageEnglish
    Pages (from-to)312.322
    JournalJournal of Allergy and Clinical Immunology
    Volume136
    Issue number2
    DOIs
    Publication statusPublished - 5 Mar 2015

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    Asthma
    Steroids
    Pediatrics
    Immunoglobulin E
    Interleukin-13
    Cell Count
    Pyroglyphidae
    Interleukin-33
    Lymphocytes
    Cladosporium
    Budesonide
    Alternaria
    Lung
    Aspergillus fumigatus
    Therapeutics
    Skin Tests
    Allergens
    Fungi
    Maintenance
    Serum

    Bibliographical note

    The full text is also available from: http://dx.doi.org/10.1016/j.jaci.2015.01.016
    Under a Creative Commons license

    Keywords

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

    Cite this

    Castanhinha, S., Sherburn, R., Walker, S., Gupta, A., Bossley, C. J., Buckley, J., ... Saglani, S. (2015). Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. Journal of Allergy and Clinical Immunology, 136(2), 312.322. https://doi.org/10.1016/j.jaci.2015.01.016

    Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. / Castanhinha, S.; Sherburn, R.; Walker, S.; Gupta, A.; Bossley, C. J.; Buckley, James; Ullmann, N.; Grychtol, R.; Campbell, G.; Maglione, M.; Koo, S.; Fleming, L.; Gregory, L.; Snelgrove, R. J.; Bush, A.; Lloyd, C. M.; Saglani, S.

    In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 2, 05.03.2015, p. 312.322.

    Research output: Contribution to journalArticle

    Castanhinha, S, Sherburn, R, Walker, S, Gupta, A, Bossley, CJ, Buckley, J, Ullmann, N, Grychtol, R, Campbell, G, Maglione, M, Koo, S, Fleming, L, Gregory, L, Snelgrove, RJ, Bush, A, Lloyd, CM & Saglani, S 2015, 'Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33' Journal of Allergy and Clinical Immunology, vol. 136, no. 2, pp. 312.322. https://doi.org/10.1016/j.jaci.2015.01.016
    Castanhinha, S. ; Sherburn, R. ; Walker, S. ; Gupta, A. ; Bossley, C. J. ; Buckley, James ; Ullmann, N. ; Grychtol, R. ; Campbell, G. ; Maglione, M. ; Koo, S. ; Fleming, L. ; Gregory, L. ; Snelgrove, R. J. ; Bush, A. ; Lloyd, C. M. ; Saglani, S. / Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, No. 2. pp. 312.322.
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    abstract = "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.",
    keywords = "Severe asthma, fungal sensitization, pediatric, IL-33, innate immunity, steroid resistance",
    author = "S. Castanhinha and R. Sherburn and S. Walker and A. Gupta and Bossley, {C. J.} and James Buckley and N. Ullmann and R. Grychtol and G. Campbell and M. Maglione and S. Koo and L. Fleming and L. Gregory and Snelgrove, {R. J.} and A. Bush and Lloyd, {C. M.} and S. Saglani",
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    TY - JOUR

    T1 - Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33

    AU - Castanhinha, S.

    AU - Sherburn, R.

    AU - Walker, S.

    AU - Gupta, A.

    AU - Bossley, C. J.

    AU - Buckley, James

    AU - Ullmann, N.

    AU - Grychtol, R.

    AU - Campbell, G.

    AU - Maglione, M.

    AU - Koo, S.

    AU - Fleming, L.

    AU - Gregory, L.

    AU - Snelgrove, R. J.

    AU - Bush, A.

    AU - Lloyd, C. M.

    AU - Saglani, S.

    N1 - The full text is also available from: http://dx.doi.org/10.1016/j.jaci.2015.01.016 Under a Creative Commons license

    PY - 2015/3/5

    Y1 - 2015/3/5

    N2 - 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.

    AB - 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.

    KW - Severe asthma

    KW - fungal sensitization

    KW - pediatric

    KW - IL-33

    KW - innate immunity

    KW - steroid resistance

    U2 - 10.1016/j.jaci.2015.01.016

    DO - 10.1016/j.jaci.2015.01.016

    M3 - Article

    VL - 136

    SP - 312.322

    JO - Journal of Allergy and Clinical Immunology

    JF - Journal of Allergy and Clinical Immunology

    SN - 0091-6749

    IS - 2

    ER -