Small airway disease as a driver of irreversible flow obstruction in COPD

At the breath lab of the KU Leuven, Yousry Khaled Mohamady and colleagues are investigating how small airway disease drives airflow limitation in chronic lung conditions using a unique biobank of over 600 explant lungs. By combining high-resolution micro-CT imaging with flow simulations, they were able to characterize structural and functional changes in airways that are not normally visible in clinical scans. 

A first of two presentation at ERS 2025 focused on small airway cores, which are cylindrical sections of lung tissue from both control and COPD patients. Three-dimensional reconstructions allowed the investigators to simulate expiratory flow and directly compare healthy-appearing and structurally deformed or occluded airways. They found that deformation and blockage significantly increased pressure, resistance, and wall shear stress. The elevated shear stress suggests harmful effects on the epithelial lining, potentially fuelling further structural damage and establishing a cycle of disease progression.1 These findings can be linked to the clinical observation that COPD patients develop airflow obstruction detectable in spirometry as reduced FEV1.

In a second step, Mohamady and colleagues scaled up to whole-lung micro-CT imaging of control, moderate, and end-stage COPD specimens. A structural analysis revealed profound airway loss in COPD lungs, with 22% fewer branches in moderate COPD and up to 71% fewer branches in end-stage disease. Simulations of inspiratory and expiratory flows under standardized pressure conditions showed increased resistance and decreased ventilation in diseased lungs, culminating in a 71% reduction in expiratory flow compared to controls. These results confirm that small airway disease is a critical, early driver of COPD progression. However, with our current diagnostic technologies, airway disease remains undetectable until it is substantial and irreversible damage has occurred. As such, this work underscores the importance of targeting small airway pathology in COPD to allow for an earlier diagnosis and more timely intervention.