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.

Objectives: 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.

FIG 1

Flow diagram illustrating the number of children with problematic severe asthma who were assessed and how many patients with STRA underwent invasive investigations to assess airway pathology. Feno₅₀, Fraction of exhaled nitric oxide at 50 mL/s.

FIG 2

A and B, Increased BAL fluid eosinophil (Fig 2, A) and submucosal eosinophil (Fig 2, B) counts in children with STRA compared with those seen in control subjects. C, A 5-μm paraffin section stained with Congo red dye showing positively stained eosinophils (black arrows) in the submucosa of a patient with STRA compared with an absence of submucosal eosinophils in a control subject (D; original magnification ×400).

FIG 3

Submucosal IL-5⁺ (A) and IL-13⁺ (B) cell counts in biopsy specimens from children with STRA compared with control subjects. Submucosal IL-5⁺ cell counts were higher in control subjects compared with those seen in patients with STRA, and levels of IL-13⁺ cells were similar in both groups. Analyses were performed with the Mann-Whitney U test. ns, Not significant.

FIG 4

Markers of airway remodeling showing increased RBM thickness in patients with STRA compared with control subjects (A), similar epithelial shedding in patients with STRA and control subjects (B), increased volume of ASM indexed to subepithelium in patients with STRA compared with control subjects (C), and increased volume of ASM indexed to RBM in patients with STRA compared with control subjects (D). ns, Not significant.