Airway Impedance, Heterogeneity and Variability in Adult Asthma

Abstract

While bronchodilator (BD) reversibility is a feature of asthma, the relative contributions of small and large airways to BD is unclear, and the effect of small-airway heterogeneity on respiratory system impedance, Zrs has not been directly quantified. Furthermore while short-term variability in Zrs has been contentiously ascribed to asthma, how it may relate to airway pathology is unclear. This thesis addresses these questions, and contributes a novel method to remove transient artifacts. I found that while respiratory system resistance Rrs decreased due to BD in both health and asthma, elastance, Ers derived from the reactance (Xrs) decreased only in asthma. Using a multi-branch airway tree model, the large airway response in Rrs to BD was nearly identical in both healthy and asthmatic subjects, while the small airways accounted for nearly all the differences in Rrs and Xrs in asthma, suggesting that Xrs may be a sensitive measure of small-airway function in asthma. When comparing Ers to the frequency dependence of Rrs in graded heterogeneity, I found as expected the frequency dependence of Rrs increased with heterogeneity, but depended largely on the frequency range, while Ers also increased with heterogeneity, but independent of frequency. Thus, Ers may be a more useful measure of small-airway dysfunction and asthma. I also developed an automated technique based on the discrete wavelet transform to eliminate transient artifacts in Zrs which achieved sensitivity and specificity greater than 95%. While Rrs and Xrs responded significantly to bronchonstriction and BD in both health and asthma, variation in Rrs and Xrs were altered only in asthma, but the changes in variation did not exceed the changes in Rrs and Xrs, and variability was not associated with lack of asthma control. Thus, confirming that while variability in Rrs and Xrs may be distinguishing features of asthma, they may not have much more clinical significance than Rrs and Xrs. This thesis has shown that while Rrs, its variability, and the frequency dependence of Rrs, and its responses to agonists are altered in asthma, Ers may be a better distinguishing measure of asthma because it can be mechanistically related to small-airway dysfunction.