Role of gastro-oesophageal reflux in the development and severity of bronchiectasis
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Background: Bronchiectasis is a chronic lung disease associated with significant morbidity and mortality, escalating public health costs and profound reductions in health-related quality of life (QoL). Comorbidity is a frequent finding in these patients, often with synergistic effects on disease severity and resultant poorer clinical outcomes. The relationship between gastro-oesophageal reflux and bronchiectasis is difficult to elucidate. This thesis aims to explore the contribution and mechanism of gastro-oesophageal reflux disease (GORD), airway reflux and duodeno-gastro-oesophageal microaspiration to the development and severity of lung injury in patients with bronchiectasis using multiple methodologies. Methods: A qualitative systematic review exploring the association between GORD, airway reflux and pulmonary microaspiration with bronchiectasis in terms of disease prevalence, disease outcomes and potential available treatment strategies was performed. Several large prospective multicentre cohort analyses to derive, validate and compare bronchiectasis-specific disease severity and comorbidity indices were conducted to better define the effect of GORD on bronchiectasis outcomes. A single centre cross-sectional analysis of the associations of the prevalence of hiatal hernias and bronchiectasis severity was also performed. Exploration of the relationship between GORD, proton pump inhibitor use and bronchiectasis outcomes of disease severity, mortality, chronic infection and exacerbations was performed using pan-European multicentre data from the FRIENDS and EMBARC bronchiectasis patient registries. Subsequently, a bicentric parallel prospective observational case-control study assessing the prevalence, mechanism and functional impact of GORD on bronchiectasis patients, utilising a multi-modal diagnostic approach incorporating questionnaires, pH-impedance and biomarkers of duodeno-gastro-oesophageal reflux, was also performed, comparing findings to age, sex, ethnicity and BMI-matched chronic bronchitis patients and healthy volunteer controls. Finally in vitro and ex-vivo primary bronchial epithelial cell studies were conducted to investigate the cytotoxic, inflammatory and remodelling effects of physiologically achievable individual and combined bile acids and to determine a potential role for azithromycin in attenuating bile acid-mediated neutrophilic inflammation and remodelling in bronchiectasis with validation of the role of azithromycin in GORD in the EMBARC bronchiectasis patient registry. Results: The systematic review highlighted GORD prevalence rates of 11-75% in bronchiectasis depending on methodology used. Derivation, validation and comparison of bronchiectasis-specific disease severity and comorbidity indices showed the BSI and BACI to be superior to other scores with both scores combined having the highest prognostic potential in terms of predicting mortality, exacerbations, hospitalisations and health-related quality of life (QoL). Hiatal hernia presence was associated with worse bronchiectasis disease severity. GORD was associated with a 2.5 fold increase in mortality in the FRIENDS cohort and a 20-30% increased risk of moderate and severe exacerbations requiring hospitalisation but no observed increased mortality risk in the EMBARC cohort; proton pump inhibitor (PPI) use was not associated with an increased hospitalisation rate. In the case control study, bronchiectasis patients were clearly shown to have a dysregulated immune response at baseline compared with chronic bronchitis patients and healthy volunteers, largely driven by neutrophil extracellular trap (NET)-related proteins, immunoglobulins and anti-oxidative stress proteins on proteomic analysis. GORD, airway reflux and pulmonary microaspiration were highly prevalent among bronchiectasis patients (22-91%) and associated with increased bronchiectasis severity manifest by increased exacerbations, reduced functional status, increased chronic infection, increased airways inflammation, and worse QoL. Bile acids caused direct inflammation and injury in both in vitro and ex-vivo primary cell culture models with neutrophilic inflammation, epithelial to mesenchymal transition and airways remodelling. Azithromycin attenuated bile acid-mediated injury in cellular studies with macrolides demonstrating a significant effect in reducing GORD-associated exacerbation frequency and hospitalisations in the EMBARC international database. Interpretation: These studies provide novel observational clinical and translational evidence of bronchiectasis disease severity and the associations of GORD, airway reflux and pulmonary microaspiration with increased airways inflammation, epithelial injury, increased disease severity and reduced QoL. We report a novel link between macrolides and the attenuation of GORD-mediated inflammation and exacerbations which may have relevance to other chronic neutrophilic airway conditions. These findings have contributed to recent British and European Clinical Guidelines on Bronchiectasis and have further highlighted future research priorities towards improving our understanding of the disease and quality of care for patients with bronchiectasis.
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