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. 2021 Jul;76(7):2070-2078.
doi: 10.1111/all.14732. Epub 2021 Jan 26.

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

Adnan Azim  1   2 , Ben Green  3 , Laurie Lau  1   2 , Hitasha Rupani  1   2 , Nivenka Jayasekera  4 , Kenneth Bruce  5 , Peter Howarth  1   2
Affiliations

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

Adnan Azim et al. Allergy. 2021 Jul.

Abstract

Background: IL-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.

Methods: Bronchoalveolar 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.

Results: Severe 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.

Conclusion: Our 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.

Keywords: 16srRNA; IL-13; neutrophils; peripheral airways; severe asthma.

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Conflict of interest statement

Dr. Azim has nothing to disclose. Dr. Green has nothing to disclose. Dr. Lau has nothing to disclose. Dr. Rupani has nothing to disclose. Dr. Jayasekera has nothing to disclose. Dr. Bruce has nothing to disclose. Prof. Howarth reports employment by and has shares in GSK.

Figures

FIGURE 1
FIGURE 1
Type 2 cytokine concentrations in healthy volunteers, mild asthma and severe asthma patients. Between group comparisons by Kruskal‐Wallis with pairwise comparisons corrected for multiple comparisons by Dunn's Method. (A) Bronchoalveolar Lavage Interleukin 13, (B) Bronchoalveolar Lavage Interleukin 4, (C) Bronchoalveolar Lavage Interleukin 5. Between group comparison by Kruskal‐Wallis test, ***p < 0.001
FIGURE 2
FIGURE 2
Bronchoalveolar Inflammatory Cell counts and Type 2 cytokine concentrations in healthy volunteers, mild asthma and severe asthma patients from the top and bottom tertile of patients ranked by Interleukin 13 concentrations. Between group comparisons by Kruskal‐Wallis with pairwise comparisons corrected for multiple comparisons by Dunn's Method. (A) Bronchoalveolar Lavage Eosinophil Percentages, (B) Bronchoalveolar Lavage Neutrophil Percentages, (C) Bronchoalveolar Lavage Interleukin 4, (D) Bronchoalveolar Lavage Interleukin 5. Between group comparison by Kruskal‐Wallis test, **p <0.01, ***p < 0.001
FIGURE 3
FIGURE 3
Correlation between total abundance of potentially pathogenic bacteria and Bronchoalveolar Lavage concentrations in the replication cohort. (A) Interleukin 13, (B) Neutrophils (%)
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