Airway Remodeling in Cystic Fibrosis Is Heterogeneous.

Rationale: Cystic fibrosis (CF) is characterized by bronchiectasis on imaging, while functionally evolving toward obstructive impairment. Despite its assumed importance in CF, small airway remodeling and its relation to bronchiectasis remains poorly understood. Objectives: The aim of our study was to explore both large and small airway disease morphometrically, by using detailed imaging techniques, such as ex vivo high-resolution computed tomography (HRCT) and micro-computed tomography (μCT), and histological analysis in advanced CF. Methods: On HRCT (600 μm; CF, n = 21; control, n = 6) and μCT (150 μm; CF, n = 3; control, n = 1) scans of inflated explanted lungs, the ratio of visible airway volume to total lung volume (AV%) was calculated as a marker of bronchiectasis, while airway segmentation was used for generation analysis. Clinical data were retrospectively collected. On μCT (8.5 μm) images of lung cores (±2.8 cm3), extracted randomly from each lobe (three per lobe), distal airway (DA) diameter, number of airway collapses, and number of open terminal bronchioles per milliliter were analyzed. Morphometric analysis was supplemented with histological analysis of DA collapse. Results: AV% on HRCT was heterogeneous among CF lungs (0.7-4.6%), overlapping with controls (0.4-1.2%). However, the pattern of airway loss on μCT was homogeneous among CF lungs and most pronounced from generations 9-16. AV% did not correlate with the number of open terminal bronchioles per milliliter or percentage predicted forced expiratory volume in 1 second, which correlated with each other. Open DAs in CF lungs were narrowed compared with DA in controls. On the other hand, collapsed DAs in CF lungs showed varying degrees of proximal dilation, with DA diameter correlating with AV%. On histology, collapsed CF DAs showed constrictive bronchiolitis. Conclusions: Airway remodeling in end-stage CF is heterogeneous, ranging from minimal bronchiectasis, overlapping with control lungs, to extensive bronchiectasis with small airway dilation. However, the degree of bronchiectasis is unrelated to functional impairment or the amount of small airway loss, underscoring the importance of small airway disease.