Fungal Sensitisation, Remodelling and the Mycobiome In Asthma

Fungal sensitisation and Allergic Bronchopulmonary Aspergillosis (ABPA) are seen more commonly in severe asthma. Asthmatics with ABPA / SAFS have differing disease trajectories and degrees of disease severity. In view of this uncertainty, this thesis has focused on the role that fungal allergy and the fungal microbiome (mycobiome) have on aspects of airway physiology, inflammation and remodelling. This thesis suggests that asthmatics with neutrophilic airway inflammation and sensitisation to A. fumigatus are at greater risk of a reduction in lung function and the development of radiological abnormalities, whether they fulfil the diagnostic classification for ABPA or not. IgE sensitisation to thermotolerant filamentous fungi, but not total IgE, was associated with a reduction in post bronchodilator FEV1 (independent of atopic status), bronchiectasis, tree-in-bud and collapse ± consolidation in moderate to severe asthma. This suggests that current diagnostic classifications do not capture all of those at risk of adverse outcomes due to fungal sensitisation. No features of airway remodelling were found in asthmatics sensitised to fungi. An association was however found between intraepithelial mast cell infiltration, an increase in fungal load and fungal sensitisation. A ‘core’ mycobiome of 12 species, belonging to the Ascomycota and Basidomycota phyla, were identified in all compartments of the lung. A. fumigatus was the most abundant fungus, present in healthy controls and asthmatics. Certain fungi were seen to have a protective effect with a reduction in reticular basement membrane thickness and epithelial integrity associated with Cryptococcus pseudolongus, whilst others such as Aspergillus striatus was associated with increased airway smooth muscle mass. A new phenotypic group could not be accurately described. This thesis does, however, show that asthmatics sensitised to thermotolerant filamentous fungi are at a greater risk of adverse outcomes and are characterised by neutrophilic airway inflammation and a high fungal load.