Increase in Alveolar Septal Width Is a Histological Predictor of Chronic Lung Allograft Dysfunction and Survival in Lung Transplant Recipients—A Longitudinal Study

<b>Background:</b> Chronic lung allograft dysfunction (CLAD) occurs in up to 50% of patients within the first five years after lung transplantation (LuTX) and represents the main complication and cause of death regarding this surgery. Alveolar septal widening in transbronchial biopsies has shown an association with acute humoral allograft rejection. We aimed to explore histological markers that could predict the development of CLAD before its clinical manifestation. <b>Methods:</b> We retrospectively analyzed transbronchial biopsies taken at three time points from 57 patients who underwent LuTX between February 2010 and July 2019, 26 of whom developed CLAD up to November 2022. The biopsies were analyzed by microscopic morphometry and quantitative reverse transcription PCR to identify predictors of CLAD. <b>Results:</b> CLAD development was associated with increased alveolar septal width (ASW) as early as the first year post-LuTX (5.46 ± 0.76 µm versus 4.59 ± 0.44 µm; <i>p</i> < 0.001). The ASW in later biopsy timepoints predicted survival in multivariate models (last timepoint: hazard ratio 1.885, 95% confidence interval 1.086-3.269). Collagen (COL1A1 and COL3A1) expression was significantly increased in samples from patients who developed CLAD compared with those who did not. The increase in ASW was paralleled by interstitial deposition of COL1A1 and COL3A1 and a decrease in both the carbon monoxide (DLCO) diffusing capacity of the lung and the DLCO/alveolar volume. <b>Conclusions:</b> We report a new histologic approach for early assessment of risk of CLAD in patients who have undergone LuTX. The ASW represents a pre-symptomatic, continuous, and widely distributed change within the lung parenchyma that is accessible to transbronchial biopsy.