title: Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines.
abstract: BACKGROUND
  The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.
  
  
  OBJECTIVE
  We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T(H)2 cytokines IL-4, IL-5, and IL-13.
  
  
  METHODS
  Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T(H)2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation.
  
  
  RESULTS
  Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5(+) and IL-13(+) cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T(H)2 cytokines had significantly lower lung function than those with undetectable BAL fluid T(H)2 cytokines.
  
  
  CONCLUSIONS
  STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T(H)2 mediators that are thought to drive allergic asthma were mostly absent.
authors.affiliation: the Royal Brompton and Harefield NHS Trust, London, UK.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Bossley
authors.forename: Louise
authors.initials: L
authors.lastname: Fleming
authors.forename: Atul
authors.initials: A
authors.lastname: Gupta
authors.forename: Nicolas
authors.initials: N
authors.lastname: Regamey
authors.forename: Jennifer
authors.initials: J
authors.lastname: Frith
authors.forename: Timothy
authors.initials: T
authors.lastname: Oates
authors.forename: Lemonia
authors.initials: L
authors.lastname: Tsartsali
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.forename: Sejal
authors.initials: S
authors.lastname: Saglani
mesh_terms: D000293:Adolescent; D056151:Airway Remodeling / Q000187:drug effects; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology*; D004802:Eosinophilia / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008297:Male; D013183:Sputum / Q000737:chemistry; D013256:Steroids / Q000008:administration & dosage / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: D018927:Anti-Asthmatic Agents; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D013256:Steroids