Functional CT imaging for identification of the spatial determinants of small-airways disease in adults with asthma

Background: Asthma is a disease characterized by ventilation heterogeneity (VH). A number of studies have demonstrated that VH markers derived by using impulse oscillometry (IOS) or multiple-breath washout (MBW) are associated with key asthmatic patient related outcome measures and airways hyperresponsiveness. However, the topographical mechanisms of VH in the lung remain poorly understood. Objectives: We hypothesized that specific regionalization of topographical small-airway disease would best account for IOS- and MBW-measured indices in patients. Methods: We evaluated the results of paired expiratory/inspiratory computed tomography in a cohort of asthmatic (n = 41) and healthy (n = 11) volunteers to understand the determinants of clinical VH indices commonly reported by using IOS and MBW. Parametric response mapping (PRM) was used to calculate the functional small-airways disease marker PRMfSAD and Hounsfield unit (HU)-based density changes from total lung capacity to functional residual capacity (Delta HU); gradients of Delta HU in gravitationally perpendicular (parallel) inferior-superior (anterior-posterior) axes were quantified. Results: The Delta HU gradient in the inferior-superior axis provided the highest level of discrimination of both acinar VH (measured by using phase 3 slope analysis of multiple-breath washout data) and resistance at 5 Hz minus resistance at 20 Hz measured by using impulse oscillometry (R5-R20) values. Patients with a high inferior-superior Delta HU gradient demonstrated evidence of reduced specific ventilation in the lower lobes of the lungs and high levels of PRMfSAD. A computational small-airway tree model confirmed that constriction of gravitationally dependent, lower-zone, small airway branches would promote the largest increases in R5-R20 values. Ventilation gradients correlated with asthma control and quality of life but not with exacerbation frequency. Conclusions: Lower lobe predominant small-airways disease is a major driver of clinically measured VH in adults with asthma.