Scanning the Asthmatic Airway: Defining Relationship between Physiology, Inflammation and Airway Structure in Severe Asthma using Computed Tomography
thesisposted on 16.11.2012, 12:28 by Sumit Gupta
Severe asthma is a complex and heterogeneous disease characterised by chronic airway inflammation, disordered airway physiology and airway remodelling. Computed tomography (CT) has emerged as a non-invasive tool for assessment of airway structural changes. A critical gap in our understanding of severe asthma is the ability to relate structural changes to important clinical outcomes. This thesis examines the relationship between CT assessed airway structure, airway inflammation and airway physiology in severe asthma patients. I first present the largest qualitative study of CT findings in severe asthma patients. I have shown that airway structural changes such as bronchiectasis and bronchial wall thickening are common and demonstrate association with disease duration and airflow obstruction. I then present a study describing airway and densitometry phantom models that were developed to study errors associated with quantitative airway morphometry and lung densitometry and device validation and standardisation methods for quantitative CT indices. In the next quantitative cross-sectional study, I report for the first time that right upper lobe apical bronchus (RB1) percent wall area (%WA) was associated with the preceding burden of neutrophilic inflammation over time measured by repeated sputum analysis. RB1 dimensions were not significantly different in four severe asthma phenotypes determined based on clinical and physiological indices. I also present a study demonstrating a decrease in RB1 wall dimensions after 1 year of treatment with mepolizumab (anti-IL-5) compared to placebo providing strong evidence in favour of the eosinophils playing a key role in airway remodelling determined by CT. Finally, I report for the first time three distinct asthma phenotypes identified based on CT assessed proximal and distal airway remodelling. Temporal assessment in severe asthma subjects demonstrates increase in RB1 wall dimensions over time but no change in RB1 lumen dimensions. These findings underpin the role of CT in multi-dimensional phenotyping of severe asthma.