title: Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function.
abstract: BACKGROUND
  Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.
  
  
  OBJECTIVE
  We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).
  
  
  METHODS
  Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.
  
  
  RESULTS
  Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1%predicted (r = 0.43; P = .008). Neutrophilhighpatients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.
  
  
  CONCLUSIONS
  A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Cecilia K
authors.initials: CK
authors.lastname: Andersson
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom; Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Adams
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom; Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom.
authors.forename: Prasad
authors.initials: P
authors.lastname: Nagakumar
authors.affiliation: Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom.
authors.forename: Cara
authors.initials: C
authors.lastname: Bossley
authors.affiliation: Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom.
authors.forename: Atul
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Daphne
authors.initials: D
authors.lastname: De Vries
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Afiqah
authors.initials: A
authors.lastname: Adnan
authors.affiliation: Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom; Respiratory Paediatrics, the Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom. Electronic address: s.saglani@imperial.ac.uk.
authors.forename: Sejal
authors.initials: S
authors.lastname: Saglani
authors.affiliation: Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: c.lloyd@imperial.ac.uk.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D001706:Biopsy; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D001999:Bronchoscopy; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D053722:Receptors, Interleukin-17; D000097043:Interleukin-22; C508717:IL17A protein, human; C109985:IL17RA protein, human
keywords: IL-17A; IL-17A receptor; Pediatric asthma; neutrophils; severe therapy-resistant asthma