Sputum mediator profiling in severe asthma: relationships with clinical phenotypes, airway inflammation and morphometry in stable disease and at exacerbations

Asthma is characterised by typical symptoms or cough, breathlessness and wheeze with variable airflow obstruction. It is severe in about 10% of asthmatics with persistent symptoms and frequent exacerbations. There is increasing recognition that asthma, and to a greater extent severe asthma, is a heterogeneous disease with respect to its aetiology, inflammatory profile, and clinical expression and treatment responses. However, our understanding of the relationship between cellular and cytokine profiles in severe asthma with symptoms, physiology, airway morphometry and environmental exposure to pathogens in stable disease and at exacerbations is poorly understood. I hypothesized that sputum mediator profiling in severe asthma would identify clinically important biological phenotypes in stable disease and provide insights into relationships with airway remodelling and reveal key dynamic changes in airway inflammation at exacerbation. I undertook a multivariate analysis of sputum mediators from severe asthmatics in stable state and found distinct biological phenotypes associated with clinical features and moreover differential sputum cell counts. Interestingly, in obese asthmatics sputum IL-5 was elevated in spite of a low sputum eosinophil count whereas bronchial submucosal eosinophils were increased suggesting eosinophil trafficking is altered in obese asthmatics. Sputum mediator profiles were weakly associated with airway morphometry. At exacerbation there were marked differences in sputum mediator profiles with upregulation of Th1 cytokines, TNF-R1 and IL-1β in those with evidence of bacterial colonisation and with IL-6R most strongly associated with severe exacerbations of asthma. In summary, this thesis has explored sputum mediator profiles in severe asthma; informed our understanding of the mechanisms underpinning the heterogeneity of disease and identified biomarkers of exacerbations.