The peripheral airwaves in Asthma : assessment of clinical significance and response to targeted therapy

Abstract

There is a growing body of evidence highlighting the role of peripheral airway dysfunction in asthma. This thesis presents two studies using multi-breath nitrogen washout and oscillometry, that assess ventilation heterogeneity, respiratory impedance, and airway closure, to examine the role of peripheral airway function in asthma. The first study assessed the relationship between peripheral airway function and acute exacerbations with 3 groups; subjects with stable asthma, subjects who were prone to exacerbations based on history, and subjects who had experienced a recent exacerbation of asthma. Results showed elevated acinar ventilation heterogeneity and dynamic airway closure in the exacerbation prone group, whereas subjects within one month of exacerbation had peripheral airway function similar to the stable group. These findings implicate peripheral airway dysfunction in the mechanisms behind asthma exacerbations. In addition to physiological techniques, the second study used ventilation MR imaging techniques (Specific Ventilation Imaging, SVI, and Phase-REsolved FUnctional Lung imaging, PREFUL) to assess spatial ventilation to evaluate the efficacy of small (2.6μm) and large (6.2μm) particle short-acting bronchodilator. Overall, the small particle bronchodilator led to improvements in more physiological parameters compared to large particle bronchodilator. Reversal of airway dysfunction was reflected in reduction in spatial ventilation heterogeneity from SVI, in response to small particle bronchodilator. However, quantitative PREFUL parameters failed to detect a superiority of small particle bronchodilator. Subjects who showed a physiological response on spirometry or oscillometry displayed a greater reversal of airflow limitation and reduction in airway closure, with the small particle bronchodilator. This demonstrated that particle size of inhaled bronchodilator is an important determinant of response and suggests the potential benefit of targeting small airways in individuals with peripheral dysfunction. This work highlights the utility of sophisticated physiological assessments in clinical practice and asthma research, with the potential to enable asthma management tailored to individual patient characteristics.