The Clinical Implications of Eosinophilic Inflammation in Asthma

Asthma is a complex and heterogeneous disorder, comprising domains of pathology (airway inflammation), physiology (disordered airway function) and clinical expression (symptoms and exacerbations) that are variably related. Within this network, the role of eosinophils remains uncertain. This thesis explores further the relationship between eosinophilic inflammation and clinical asthma by: 1. using multivariate statistical techniques to characterise and classify relationships between individual domains in the asthma population; 2. investigating clinical outcomes with mepolizumab (anti-IL 5) in a randomised placebo controlled trial for 12 months, in subjects with refractory eosinophilic asthma. In the first study I have used factor analysis techniques to formulate statistically independent domains of the clinical phenotype. These have been entered into a cluster analysis algorithm to identify subgroups that define a classification model based on expression patterns and composite relationships across the asthma domains. By applying this independently to populations of Primary and Secondary Care asthma, I have identified two secondary care predominant clusters, characterised by discordance between asthma symptoms and eosinophilic airway inflammation. I have shown that discordant clusters derive greatest clinical benefit with a management strategy directed at maintaining a normal sputum eosinophil count, supporting its implementation in secondary care. More specifically, I report a 10-fold reduction in severe exacerbations with inflammation guided therapy in discordant eosinophil-predominant asthma, supporting a specific role for eosinophils in these events. In the second study, I report a significant reduction in severe exacerbations with mepolizumab therapy, but no effect on other clinical outcome measures. These findings support a specific effector role for eosinophils in the pathogenesis of severe exacerbations; and dissociation of this endpoint and other clinical outcome measures. Finally, I report a 12 month washout analysis of mepolizumab treated subjects in which a significant increase in severe exacerbation frequency is observed that is temporally preceded by rising sputum eosinophils.