Ventilatory capacity in CLAD is driven by dysfunctional airway structure.

Area of Science:

• Pulmonary Medicine
• Transplantation Immunology
• Medical Imaging

Background:

• Chronic lung allograft dysfunction (CLAD) is a major cause of lung transplant failure.
• CLAD presents as bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), or a mixed phenotype.
• The impact of CLAD on overall airway structure and ventilation distribution remains unclear.

Purpose of the Study:

• To investigate airway morphometry and its relation to ventilation distribution in end-stage CLAD phenotypes.
• To analyze the location and causes of airway obstructions in BOS, RAS, and Mixed CLAD.

Main Methods:

• Ex vivo micro-CT scanning of explant lungs from control and CLAD patients (BOS, RAS, Mixed).
• Digital airway reconstruction to assess airway dimensions and luminal obstructions.
• Correlation of airway morphometry with ventilation distribution.

Main Results:

• BOS and Mixed CLAD showed proximal bronchiolar obstructions (generation 5+), while RAS had distal obstructions (generation 12+).
• Obstruction affected 76% (BOS) and 84% (Mixed) of bronchioles, versus 22% in RAS.
• Lymphocytic inflammation, fibrotic remodeling, proximal bronchiolectasis, and imbalanced distal ventilation were observed across all CLAD phenotypes.

Conclusions:

• CLAD alters conducting airway structure, leading to regional differences in alveolar ventilation distribution.
• Airway obstructions, including mucus impaction, significantly contribute to CLAD pathophysiology and poor lung function.