Airway infection and Pseudomonas aeruginosa in bronchiectasis (cystic fibrosis and non-cystic fibrosis bronchiectasis)

Overview Bronchiectasis is a term used to refer to dilatation of the bronchi that is often permanent and associated a chronic productive cough and recurrent respiratory infections. It is caused by a wide range of clinical disorders, both inherited and acquired [1]. Bronchiectasis is not itself a disease, but rather the result of various processes that often share aspects of management. A traditional distinction has been made between Cystic Fibrosis (CF) and non-cystic fibrosis bronchiectasis. CF is a genetic disease found in northern Europe and North America with a carrier frequency of 1 in 25 [2]. CF represents a more well-defined population of patients whom respiratory disease is the main predictor of mortality (2). It has subsequently been subject to more research and commercial activity than what has been undertaken in non-CF bronchiectasis. Non-CF bronchiectasis in contrast, affects a diverse heterogeneous population with many aetiologies, including idiopathic or unknown causes. The real incidence and prevalence of non-CF bronchiectasis in the general population is difficult to estimate as it is often underdiagnosed and shares many symptoms and disease characteristics with other respiratory illnesses. However, it is estimated 212,000 individuals have the disease in the UK [3]. Pulmonary exacerbations are defined as a deterioration in local symptoms such as cough, sputum production or purulence and breathlessness, with or without systemic upset, necessitating antibiotics [4]. Pulmonary exacerbations in CF and non-CF bronchiectasis are primarily driven by pulmonary infection and neutrophilic airway inflammation, which leads to progressive lung damage. However, evidence suggests other key factors can influence pulmonary exacerbations, disease progression and outcomes in both CF and non-CF bronchiectasis such as social deprivation, gender and environmental factors such as pollution [5]. Nevertheless, the treatment of pulmonary exacerbations and the management of respiratory infections in both CF and bronchiectasis present some of the greatest challenges in the modern age. Severe exacerbations requiring hospital admissions and intravenous antibiotics have a greater impact in terms of healthcare costs as well as long term prognosis as these are associated with increased mortality, significant lung decline and reduced quality of life [6]. The true economic burden of bronchiectasis is not known, with only 5 published studies providing concrete figures. A study in 2013 of 456 bronchiectatic patients in Spain showed the mean annual cost per patient was €4671.9. Chronic bronchial infection with P. aeruginosa was the subgroup with the greatest impact on overall cost at 69.1% with an overall expenditure of €1,471,248 [7]. Many of the statistics we report both for CF and non-CF bronchiectasis are based on small studies and are unlikely to be representative or generalisable to the populations as a whole. Nevertheless, it is clear that both non-CF bronchiectasis and CF are placing an increasing burden on the healthcare systems internationally. Medical advances mean patients are living longer with chronic illnesses and the impact of recently approved therapies treating both the defect; as in the case with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy in CF, or the underlying cause such as immunomodulatory therapy in asthma, is improving survival [8, 9]. P. aeruginosa is both an important and prevalent pathogen in both CF and bronchiectasis and is intrinsically resistant to many antibiotics. Persistent P. aeruginosa infection has been linked to poorer outcomes in non-CF bronchiectasis such as lung function decline and mortality similar to that reported in CF [10]. Nevertheless, there are a number of unknowns that span across the basic biology and pathogenesis of P. aeruginosa such as the interactions with other micro-organisms and the host defence at a cellular level, which cannot be answered with conventional microbiological techniques. There is a need to develop greater understanding of the clinical impact of P. aeruginosa and other micro-organisms present in CF and non-CF bronchiectasis to define and develop optimal management strategies that is personalised to both the patient and to their current microbiological status. A lack of high quality clinical data may be aided with better phenotyping of patient cohorts utilising severity scores, adverse outcomes such as lung function decline and mortality coupled with longitudinal studies exploring the whole pulmonary microbial community; termed microbiome, and intercellular signalling molecules [11] as biomarkers. This thesis is divided into two parts. In the first part, clinical data from a cystic fibrosis observational cohort was obtained over an 8 year follow up period. Long term clinical outcomes such lung function decline, frequency of pulmonary exacerbations, mortality or lung transplantation were explored with P. aeruginosa quorum sensing (QS) molecules and anaerobic bacteria present in the sputum microbiota. In addition, the potential of QS molecules as biomarkers of P. aeruginosa burden were investigated by comparing QS molecules in sputum, blood, urine and saliva with pulmonary P. aeruginosa bacterial load measured by polymerase chain reaction (PCR). In the second part, 50 participants with non-CF bronchiectasis who were experiencing a pulmonary exacerbation and requiring administration of intravenous antibiotics were recruited into a prospective observational study. The primary objective of this study was to explore the feasibility of collecting and analysing samples for P. aeruginosa quorum sensing (QS) molecules in this cohort. In addition, clinical data such as lung function, quality of life questionnaires, time to next exacerbation and mortality were obtained. However, due to the COVID-19 pandemic, data on quorum sensing molecules in non-CF bronchiectasis were unable to be analysed. Instead, sputum, blood and urine samples were used to explore the role of novel urinary inflammatory molecules and pro-inflammatory cytokines with pulmonary exacerbation status in individuals with non-CF bronchiectasis. It was my aim in this thesis to explore both the clinical and microbiological factors that may influence our understanding of disease progression in CF and non-CF bronchiectasis. In summary, this thesis explores several novel non-microbiological strategies such as biomarkers as a non-invasive approach to better define treatment responses in pulmonary exacerbations, predict adverse clinical outcomes and quantify the P. aeruginosa bacterial burden