Peripheral airways type 2 inflammation, neutrophilia and microbial dysbiosis in severe asthma.

Adnan Azim,Hitasha Rupani,Kenneth Bruce,Laurie Lau,Nivenka Jayasekera,Peter Howarth,Ben Green

doi:10.1111/all.14732

Abstract

BackgroundIL‐13 is considered an archetypal T2 cytokine central to the clinical disease expression of asthma. The IL‐13 response genes, which are upregulated in central airway bronchial epithelial of asthma patients, can be normalized by high‐dose inhaled steroid therapy in severe asthma. However, this is not the case within the peripheral airways. We have sought to further understand IL‐13 in the peripheral airways in severe asthma through bronchoalveolar analysis.MethodsBronchoalveolar lavage samples were collected from 203 asthmatic and healthy volunteers, including 78 with severe asthma. Inflammatory mediators were measured using a multiple cytokine immunoassay platform. This analysis was replicated in a further 59 volunteers, in whom 16S rRNA analysis of BAL samples was undertaken by terminal restriction fragment length polymorphism.ResultsSevere asthma patients with high BAL IL‐13, despite treatment with high‐dose inhaled corticosteroids, had more severe lung function and significantly higher BAL neutrophil percentages, but not BAL eosinophils than those with normal BAL‐13 concentrations. This finding was replicated in the second cohort, which further associated BAL IL‐13 and neutrophilia with a greater abundance of potentially pathogenic bacteria in the peripheral airways.ConclusionOur findings demonstrate a steroid unresponsive source of IL‐13 that is associated with BAL neutrophilia and bacterial dysbiosis in severe asthma. Our findings highlight the biological complexity of severe asthma and the importance of a greater understanding of the innate and adaptive immune responses in the peripheral airways in this disease.

Highlights

Asthma is a highly prevalent airway disease that affects more than 300 million people across the world.[1]
We have extended our bronchial brush findings of persistent IL-13 gene expression in the peripheral airways of patients with severe asthma,[12] by demonstrating elevated levels of Bronchoalveolar lavage (BAL) IL-13 in patients with severe asthma compared to healthy volunteers and those with mild asthma
Interleukin-13 is commonly associated with T2 disease processes that are linked to eosinophilia and are corticosteroid sensitive 10,16; it might be anticipated that both BAL

Summary

| INTRODUCTION

Asthma is a highly prevalent airway disease that affects more than 300 million people across the world.[1]. Approximately 10% of patients with asthma continue to struggle, despite treatment with high-dosage inhaled corticosteroids (ICS) plus a second controller and/or systemic corticosteroids 2: these patients with persistent uncontrolled asthma suffer from high rates of morbidity 3 and account for a disproportionate use of asthma healthcare resources.[4]. In this difficult to control asthma population, the phenotypic heterogeneity 5,6 and varied response to currently available treatments 7-9 testify to the complexity and variability in the underlying disease-related biology. We have sought to gain insight into persistent IL-13 activity in the peripheral airways of severe asthma through bronchoalveolar lavage analysis

| METHODS

| RESULTS

Findings

| DISCUSSION