Asthma and lower airway disease
Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines

https://doi.org/10.1016/j.jaci.2012.01.059Get rights and content

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 TH2 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 TH2 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 TH2 cytokines had significantly lower lung function than those with undetectable BAL fluid TH2 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 TH2 mediators that are thought to drive allergic asthma were mostly absent.

Section snippets

Subjects

Children aged 5 to 16 years referred to Royal Brompton Hospital with problematic severe asthma between April 2005 and June 2009 were included.6 Definitions of poor control and entry criteria were as follows:

  • 1.

    persistent (most days for ≥3 months) chronic symptoms (which prompt use of short-acting β2-agonists ≥3 times per week) of airway obstruction despite high doses of inhaled corticosteroids (ICSs; ≥800 μg/d budesonide equivalent) and/or regular oral corticosteroids, long-acting β2-agonists, and

Demographics

Of 104 patients referred with problematic severe asthma, 51 were classified as having difficult asthma (Fig 1). Fifty-three (51%) of 104 patients with true STRA were further investigated. The clinical characteristics of subjects are shown in Table I. Forty-five (85%) of 53 patients with STRA were atopic compared with 7 (47%) of 15 control subjects (P < .01). The median baseline FEV1 in patients with STRA was 68.5% (interquartile range [IQR], 54.8% to 86.5%) of predicted value compared with 94%

Discussion

In this large pediatric bronchoscopic study, an important novel facet is the use of prior detailed evaluation to exclude as far as possible all those who were nonadherent or had other confounding issues. We have shown that, unlike in adults,28, 29, 30 STRA in children is characterized by eosinophilic and not neutrophilic airway inflammation, there is no mast cell myositis,31 and the eosinophilic inflammation is not driven by signature TH2 cytokines in most patients.9

Quantification of BAL fluid

References (40)

  • A. Barbato et al.

    Epithelial damage and angiogenesis in the airways of children with asthma

    Am J Respir Crit Care Med

    (2006)
  • M. Bracken et al.

    The importance of nurse-led home visits in the assessment of children with problematic asthma

    Arch Dis Child

    (2009)
  • I. Tillie-Leblond et al.

    Airway remodeling is correlated with obstruction in children with severe asthma

    Allergy

    (2008)
  • S.J. Levine et al.

    Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes

    Ann Intern Med

    (2010)
  • T.R. Mosmann et al.

    Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins

    J Immunol

    (2005)
  • P.J. Barnes

    Th2 cytokines and asthma: an introduction

    Respir Res

    (2001)
  • C.J. Bossley et al.

    Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma

    Eur Respir J

    (2009)
  • N. Regamey et al.

    Time required to obtain endobronchial biopsies in children during fiberoptic bronchoscopy

    Pediatr Pulmonol

    (2009)
  • M.R. Miller et al.

    Standardisation of spirometry

    Eur Respir J

    (2005)
  • R. Pellegrino et al.

    Interpretative strategies for lung function tests

    Eur Respir J

    (2005)
  • Cited by (0)

    J.F. was funded by an Asthma UK Foundation Grant and a grant from the Royal Brompton & Harefield Biomedical Research Unit. S.S. is funded by the Wellcome Trust, UK, grant no. 083586/Z/07/Z. N.R. is the recipient of a European Respiratory Society Fellowship (no. 64) and a grant of the Swiss National Science Foundation (no. 1172/05b). The project was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

    Disclosure of potential conflict of interest: A. Gupta receives research support from the British Medical Association. N. Regamey is on advisory boards for Merck-Sharp and Dome and Novartis. C. M. Lloyd is a consultant for MedImmune. The rest of the authors declare that they have no relevant conflicts of interest.

    View full text