Evaluating The Peripheral Airways In Asthma: Further Development Of Novel Non-Invasive Assessment Tools.

Asthma is characterised by inflammation, damage, ventilation inhomogeneity and dysfunction of the small airways (arbitrary defined < 2mm diameter) but no standardised non-invasive biomarkers are available, leading to a lack of well-established clinical evaluation and treatment pathways. In this thesis, novel approaches and candidate biomarkers to probe the periphery are further developed, using forced oscillation techniques (FOT), particles in exhaled air (PExA) and oxygen enhanced MR imaging (OE-MRI). FOT techniques are explored using clinical population, comparative device studies and a 3-D printed model. These studies provide further evidence to support resistance at 5 Hz minus resistance at 20 Hz (R5-R20) parameter as small airways dysfunction detection tool. Furthermore, clinical and printed airway models show that two different FOT devices generate dissimilar measurements of airways impedance with evidence of proportional systematic bias. These results highlight the need for further standardisation across FOT measurement devices. Feasibility and repeatability of the PExA technique is explored further in adult asthma. Additionally, candidate biomarkers surfactant protein A (SPA) and albumin are evaluated in independent adult asthma cohorts. Proteins demonstrate good repeatability within and between-visits and strongly relate with spirometry but not decline over time. A clinically important phenotype of asthmatic patients with multiple markers of peripheral airway dysfunction is identified and demonstrates significantly lower levels of SPA and albumin. PExA is feasible across the spectrum of asthma severity and could be used to identify small airway disease phenotype in clinical trial settings. Preliminary results from imaging with OE-MRI and physiological parameters show that OE-MRI biomarkers are associated with exacerbations and eosinophilic airway inflammation. High fine particle fraction bronchodilator led to improvement of OE-MRI markers of ventilation inhomogeneity which appeared to track with improvements in the multiple breath washout measure of small airway conductive ventilation heterogeneity (Scond). The biomarkers developed further in this thesis are potentially suitable for exploration as endpoints in small airway targeted therapy trials.