The range of therapeutic options available for the clinical management of CF has increased significantly in recent years. The introduction of Ivacaftor for the G551D mutation marked the first CFTR corrective therapy, since joined by Orkambi for the F508Δ mutation. However, chronicity and lung function decline can already be established before these therapies become an option. Reduced lung function is a negative prognostic marker for the effectiveness of Orkambi. Therefore, early intervention to maintain health and lung function in paediatric patients remains paramount.
Over the last 5 years we have investigated the emerging bile aspiration hypothesis which provides a unifying model that integrates the diverse strands of research on chronic infection and inflammation. The translational outcome of our research is the suggestion that anti-BA therapies may be effective as an early intervention therapy to prevent or treat the onset of early pathogen colonisation and inflammation.
While several studies have reported positive outcomes of macrolide antibiotic treatments in the management of CF, the underlying mechanism is currently unknown. Anti-inflammatory macrolide antibiotics are known to exhibit pro-kinetic activities, thus reducing the transition of bile acids into the lungs. In this study, which integrates clinical expertise and samples from the COMBAT CF Phase III Clinical Trial in Australia, and the Paediatric CF clinic at Cork University Hospital, we will investigate the impact of azithromycin intervention on bile acid profiles and lung microbiology of paediatric patients with CF. Confirmation of (i) the suppression of bile acid accumulation in the lungs of azithromycin treated patients and (ii) associated reduction in chronic infection and inflammation would confirm the feasibility of early intervention therapies targeting bile acid accumulation in the paediatric lung. These outcomes would also underpin a new understanding of the outcomes of the ongoing COMBAT CF clinical trial relating to chronic pathogen microbiomes and inflammation.