Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

Cecilia K Andersson,Alexandra Adams,Prasad Nagakumar,Cara Bossley,Atul Gupta,Daphne De Vries,Afiqah Adnan,Andrew Bush,Sejal Saglani,Clare M Lloyd

doi:10.1016/j.jaci.2016.09.022

Abstract

BackgroundNeutrophils 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.ObjectivesWe sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).MethodsChildren 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.ResultsChildren with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients 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.ConclusionsA 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.

Highlights

Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity
A subgroup of severe therapyresistant asthma (STRA) is characterized by increased intraepithelial neutrophils Previous findings from our group[5] that showed increased bronchoalveolar lavage (BAL) and submucosal eosinophils in children with STRA compared with controls were confirmed in the present study (Fig 1, A and B and D and E)
We have shown that a subgroup of children with STRA have increased intraepithelial neutrophils compared with younger controls without asthma, which, surprisingly and contrary to our hypothesis, was associated with better FEV1 %predicted, symptom score, and lower maintenance inhaled steroids

Summary

Introduction

Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. Their role in pediatric asthma is unknown. Methods: Children with STRA (n 5 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n 5 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. 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. There were significantly more IL17RA–positive cells in the submucosa and epithelium in

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