Precision medicine in severe asthma

Although comprising a small portion of all asthmatics, patients with severe asthma utilise a disproportionate amount of healthcare resources, have significantly higher mortality and hospitalisation and reduced quality of life compared to those with milder disease. Advances in recent years have witnessed the introduction of biologic agents that have improved patient outcomes with regards to exacerbation reduction, asthma control, quality of life and lung function. At present, type 2 biomarkers, patient comorbidities and clinician and patient preference determine choice of biologic in those who are uncontrolled on optimal inhaled and oral therapies. The aim of this PhD is to further our knowledge regarding specific aspects of precision medicine in severe asthma including less well studied areas such as small airways dysfunction, mucus plugging, bronchial wall thickness and airway hyperresponsiveness in the context of decisions surrounding biologic therapy. The introduction of this thesis explores evidence from the currently available pivotal studies on biologic and anti-alarmin therapies in severe asthma. Chapter 3 summarises the current literature on the effect of biologics in small airways dysfunction (SAD) with the majority of the evidence base present from trials using spirometry defined SAD. This chapter also contains cohort studies demonstrating that oscillometry exhibits high repeatability over time and good sensitivity in detecting bronchodilator responses in severe asthma. Here, the effects of combining spirometry- with oscillometry-defined SAD are analysed to identify more severe asthma patients with worse disease control and more frequent severe exacerbations requiring oral corticosteroids. Chapter 4 summarises the current evidence on biologics in chronic rhinosinusitis with nasal polyps (CRSwNP), a common comorbidity in patients with severe asthma. It also details a study with the aim of delineating phenotypic differences in asthma patients according to the presence or absence of CRSwNP. In chapter 5, it is shown that mucus plugging, a common radiological feature of asthma, is associated with worse spirometry, greater type 2 inflammation, more frequent severe exacerbations, and higher Aspergillus fumigatus IgE titres. Furthermore, close associations 18 are demonstrated between bronchial wall thickening with severe exacerbations and lung compliance measured by oscillometry reactance area. The final chapter of this thesis embodies the benralizumab in severe asthma (BISA) clinical trial (Eudract No. 2019-003763-22). In this study, it was shown for the first time that the antiIL5Rα biologic benralizumab attenuates mannitol airway hyperresponsiveness, improves domiciliary peak flow and improves asthma control and quality of life in patients with severe eosinophilic asthma.