The role of gastro-oesophageal reflux in airway inflammation and symptoms of asthma

Abstract

Gastro-oesophageal acidic reflux disease (GORD) is associated with treatment-resistant asthma and recurring asthma exacerbations. Trials of acid suppressants have not shown benefit in asthma management. This could imply that: 1) GORD plays no role in asthma, 2) reflux may be relevant only in some subsets asthmatics or 3) weakly/non-acid reflux, that continues unabated by PPIs, is an important factor in asthma. I undertook a detailed assessment of clinical and pathobiological changes in patients with severe asthma in relation to GORD applying novel, objective techniques for better patient stratification to identify those in whom GOR is clinically relevant. My work was in 3 parts. In Part 1, I performed a retrospective analysis of clinical data and sputum samples from the UBIOPRED programme, to seek associations between GOR (established by history) and a host of novel potential biomarkers identified by state-of-the-art ‘omics technologies. The study showed that severe asthmatics have a higher prevalence of GORD and suffer from worse asthma control and quality of life. This is associated with the finding of proteomic biomarkers in patients with active GORD symptoms, including increased levels of Lipocalin-1 which has role in mucosal defence, the role of which requires further elucidation.
In part 2, I designed a prospective, cross-sectional study, followed by an open label sequential medicine intervention study. First, I characterized GORD in detail using 24hr pH/impedance monitoring. I used a validated cough meter, full clinical and pathobiological assessments in healthy individuals and severe asthmatics with and without GORD. At baseline, all participants were assessed by standard asthma and GORD questionnaires, pulmonary function, sputum analysis for diff. cell counts, lipid-laden macrophages (LLM), and pepsin in both throat clearate and saliva (to detect GOR). These were then repeated with each trial of anti-reflux treatments. I performed bronchoscopy for stigmata of reflux, with laryngeal and bronchial biopsies and BAL for additional comparisons of pathology in patients with and without GOR. I showed a significant improvement in asthma control and symptoms with treatment of GORD. Treatment of GORD in severe asthmatics does control acid reflux but has little or no impact on the weakly acidic and non-acid reflux or the proximal extent of the refluxate as detected by 24-hour pH/impedance. I also observed that Pepsin measured in throat clearates, is a good predictor of GORD in asthma but does not respond to GORD treatment. This also suggests a role of weakly acid and non-acid reflux as well as proximal reflux, and whether this requires further treatment, remains to be elucidated. Sputum and BAL diff. cell counts and immunohistochemical analysis of laryngeal and bronchial biopsies between severe asthmatics with and without GORD did not show any differences. I concluded that these biomarkers lack the sensitivity to show any changes that may have occurred as a result of GORD.
In part 3, my study enabled collaboration with Dr Jeanne-Marie Perotin Collard who developed an in vitro model of GORD using differentiated BECs from healthy and severe asthmatics exposed to a combination of pepsin, low pH and bile acids using a multiple challenge protocol. The clinical data bronchial brushings, biopsies and BAL samples from part 2 were used in this study. RNA-sequencing of bronchial brushings from controls and severe asthmatics with and without GORD was done. Exposure of BECs to the refluxate (as part of the MCP) caused structural disruption, increased permeability, IL-33 expression, inflammatory mediator release and changes in gene expression. The cultures from severe asthmatics were significantly more affected than those from healthy donors. IL-33 expression was increased in bronchial mucosa in severe asthmatics with GORD. RNA-sequencing of bronchial brushings from this group identified 15 of the top 37 dysregulated genes found in MCP treated BECs, including genes involved in oxidative stress responses. These results suggest the need for research into alternative therapeutic management of GORD in severe asthma.

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Identifiers

ORCID for Benjamin Nicholas: orcid.org/0000-0003-1467-9643

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