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

Asthma is an inflammatory disease that affects the entire airway. Although there is increasing recognition of the role that small airways play in asthma, measuring small airway inflammation has been challenging. Forced oscillation technique–derived resistance (FOT) at 5 Hz (R5) to 20 Hz (R20) has been shown to correlate with small airway inflammation. The purpose of this study is to further validate the use of forced oscillation R5–R20 as a measurement of small airway narrowing and investigate the impact of small airway narrowing on asthma control and quality of life.

A cohort of adult asthmatics (n = 177) was recruited from Glenfield Hospital in Leicester, United Kingdom. Current smokers and patients with history of 10-pack years or more were excluded. Participants had physician-diagnosed asthma according to British Thoracic Society guidelines, and severity was defined using Global Initiative for Asthma (GINA) treatment steps. A subset of 20 patients from this cohort were randomly selected + 11 healthy control subjects were recruited for participation in the CT imaging sub-study.

Study results originate from combined analysis of 3 data sources: the large asthmatic cohort, the small cohort of computational modeling, and pooled clinical trial cohorts. The 177 subjects in the large asthmatic cohort attended up to two visits where the following was collected: asthma control questionnaire (ACQ-6), asthma quality of life questionnaire (AQLQ), exacerbation frequency, post-bronchodilator impulse oscillometry, and spirometry. These data were used to create a statistical regression linking R5–R20 to ACQ and AQLQ. Inspiratory CT scans were obtained from a subset of 20 asthmatics + 11 healthy controls. From this, patient-based virtual airway models were created and used to simulate the impact of different degrees of airway narrowing at different levels of the bronchial tree on forced oscillation R5–R20. Finally, to gain insight related to therapeutic intervention, researchers used pooled data from two previously reported, similarly designed, randomized, placebo-controlled phase II biologic trials. Both trials had used FOT-measured R5–R20 as an exploratory outcome, along with ACQ. Computational models were then used to predict the impact of these biologic therapies on small airway narrowing.

Simulations showed small airway narrowing had a greater effect on R5–R20 compared with narrowing of the larger airways and was associated with significant reduction in asthma control and asthma quality of life. The treatment effect of biologic therapy on R5–R20 in the pooled clinical trials equated to approximately 40% predicted reversal of small airway narrowing.

This study supports that forced oscillation R5–R20 can provide a more direct measure of narrowing of small airways. Additionally, using statistical regression, this study supports the notion that small airway narrowing has a significant impact on asthma control and asthma-related quality of life.

The findings of this study are intriguing. With the use of complex computational modeling, this study provides further insight on how forced oscillation R5–R20 can reflect airway narrowing in various levels of the bronchial tree. Additionally, the results add to the previously established concept of the utility of FOT-measured R5–R20 in measuring small airway involvement in asthma. The CT-based airway models designed in this study may provide further insight into small airway disease asthma subtypes and further our knowledge on the impact of biological therapies within these subtypes.