The Molecular and Clinical Characterisation of the Eosinophilic Endotype of Bronchiectasis

Bronchiectasis is a chronic lung disease characterised by the permanent dilatation of the bronchi with a clinical syndrome including a chronic productive cough. Inflammation, particularly neutrophilic inflammation, is central to bronchiectasis pathophysiology. However, an eosinophilic endotype of disease has recently been described in ~20% of bronchiectasis cases, where patients present with a blood eosinophil count >300cells/μL despite the absence of asthma and/or allergic bronchopulmonary aspergillosis. As a newly recognised disease endotype, little research has been conducted into understanding the role of eosinophils in bronchiectasis, with contradictory evidence being reported regarding the link between eosinophilic inflammation and bronchiectasis severity. In addition, literature aiming to characterise eosinophilic disease at both the molecular and clinical level and identify drivers of eosinophilia in bronchiectasis, of which P. aeruginosa and Aspergillus species have been hypothesised to play a role but have not thus far been confirmed, is largely non-existent. In general, bronchiectasis is a disease with very limited treatment options, specifically those targeting the profound inflammatory responses driving disease. As such, there is an urgent need to identify/develop therapies that can modulate these inflammatory responses. With the therapeutic success of various eosinophil-targeting therapies in other respiratory diseases where eosinophilic inflammation is apparent, whether there is a place for such therapies in the management of those with eosinophilic bronchiectasis is of major interest. Likewise, with the challenges associated with novel drug discovery and development, whether there is potential to repurpose non-respiratory medications for their anti-inflammatory actions for use in bronchiectasis is also an important question. This thesis describes a molecular and clinical investigation into the eosinophilic endotype of bronchiectasis. This work first investigates the relationship between eosinophilic inflammation and bronchiectasis disease severity using a novel sputum proteomic assay and a series of UK and international bronchiectasis patient cohorts, with investigations into identifying characteristic inflammatory, microbial, and clinical features of eosinophilic disease by comparing those with eosinophilic and non-eosinophilic disease. This thesis goes on to explore Aspergillus-related diseases in those with bronchiectasis using the large, multicentre European Bronchiectasis Registry, to gain insights into the frequency of Aspergillus serology testing, the incidence of Aspergillus-related diseases in a large bronchiectasis patient cohort and the clinical significance of Aspergillus-related diseases in those with bronchiectasis, in relation to those with eosinophilic disease without serological evidence of Aspergillus disease. Lastly, this thesis assesses the influence of the current mainstay treatment for bronchiectasis, antibiotics, on eosinophilic inflammation to emphasise the need for more effective, inflammation-targeting therapies in those with bronchiectasis, and explores the use of inhaled corticosteroids in those with bronchiectasis to assess whether there is therapeutic potential for this eosinophil-targeting therapy in those with eosinophilic bronchiectasis. Finally, an in vitro investigation into the neutrophil- and eosinophil-targeting capabilities of the non-respiratory medication Disulfiram to identify whether there is therapeutic potential for this drug as a novel anti-inflammatory therapy in those with bronchiectasis.