Non-invasive Assessment of Small Airway Obstruction in Asthma

Small airway inflammation and remodelling occurs in asthma and may underpin disease persistence, since conventional inhaled treatments do not penetrate to the small airway compartment. There is an important unmet need for reliable and non-invasive methods to measure small airway obstruction. This thesis describes the development and validation of such methods, with a particular focus on the multiple breath inert gas washout (MBW) technique. In vitro validation of the sulphur hexafluoride wash-in technique for performing MBW demonstrated that the method yields accurate and repeatable results. We developed novel methods for analysing inert gas washout curves, and showed that the parameters derived are repeatable, capture the full information content of the curve, and may be superior to standard parameters in distinguishing between subphenotypes of airway diseases. MBW and impulse oscillometry (IOS) parameters were found to be repeatable within-visit, but IOS parameters displayed greater stability over time. IOS parameters were independent predictors of asthma symptoms, quality of life and exacerbation frequency, suggesting that IOS may add value to spirometry in the assessment of patients with asthma. The response of small airway biomarkers to an intervention was assessed within a clinical trial of a novel anti-eosinophilic agent. Significant treatment effects were observed with respect to spirometric airflow obstruction and air trapping, as well as with a number of MBW parameters. The structural correlates of ventilation heterogeneity in asthma were examined using hyperpolarised 3helium magnetic resonance and quantitative computed tomography. There was evidence for a structural abnormality in the pulmonary acinus in patients with asthma causing subtle alterations in diffusion within this compartment. Future studies should seek to further understand the structural basis of IOS and MBW parameters through computational modelling and the coupling of physiological measurements and functional imaging. Longitudinal studies are also required to assess the long-term significance of small airway biomarkers.