Spectrum of Chronic Lung Allograft Pathology in Human Lung Transplantation

Abstract

The long-term survival after a lung transplantation remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS), characterized by airway fibrosis and obliteration, and restrictive allograft syndrome (RAS), presenting with parenchymal fibrosis (PF) and restriction (2019 ISHLT consensus). It has been noted that there can be overlap between these phenotypes. We aimed to detail and quantify pathological features of human CLAD sub-types. Peripheral and central paraffin-embedded explanted left upper lobe lung samples were obtained from 20 consecutive patients undergoing second lung transplantation for CLAD (phenotyped clinically at retransplant). Sections were stained with Hematoxylin & Eosin and Elastic-Trichrome. Blinded semi-quantitative grading was performed: percentage of evaluable lung tissue area affected by PF was estimated; Peri-airway fibrosis (P-AF) and bronchiolitis obliterans (BO) were graded 0-4 for each airway. Pleural fibrosis (PLF), epithelial flattening (EF) and hyperplasia (EH) were graded on a scale 0-4 (fig 1A-C). There was notable overlap in pathological scores between BOS (n=11) and RAS/Mixed (RAS n=8, Mixed n=1), although there was a trend towards higher PF, P-AF and EH scores in RAS (fig 1D, E). Samples with BO grades >=2 had higher EH grades (p=0.003) and tended to have lower EF grades (p=0.11). Samples with P-AF >=2 had higher EH grades (p=0.002) and lower EF grades (p=0.01). Also, 9 patients had a respiratory infection at the time of retransplantation (1 BO, 8 RAS): PF scores were higher in RAS infected patients (p=0.02). Our results confirm that BO and PF can coexist to different degrees of severity in both patients with RAS and BOS. Divergent epithelial changes are seen and may be important in CLAD phenotype evolution. Sampling heterogeneity may be confounding these results and we plan to confirm these by grading multiple samples across 4 lobes.