Lung Computational Models and the Role of the Small Airways in Asthma.

RATIONALE Asthma is characterised by disease within the small airways. Several studies have suggested that forced oscillation technique derived resistance at 5Hz minus 20Hz (R5-R20) is measure of small airways disease, however there has been limited validation of this measurement to date. METHODS Patient based complete conducting airway models were generated from CT scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5-R20 (n=31). The computational models were coupled with regression models in an asthmatic cohort (n=177), to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomised placebo control biologic trials (n=137). RESULTS Simulations demonstrated that narrowing of the small airways had a greater impact on R5-R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5-R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. CONCLUSIONS We have demonstrated using computational modelling that forced oscillation R5-R20 is a direct measure of anatomical narrowing in the small airways, that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.