Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation

Benjamin Renaud-Picard; Gregory Berra; David Hwang; Ella Huszti; Ei Miyamoto; Gerald J Berry; Prodipto Pal; Stephen Juvet; Shaf Keshavjee; Tereza Martinu

doi:10.1016/j.healun.2024.04.002

Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation

J Heart Lung Transplant. 2024 Apr 23:S1053-2498(24)01563-8. doi: 10.1016/j.healun.2024.04.002. Online ahead of print.

Authors

Affiliations

¹ Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; INSERM Unité mixte de recherche 1260, Regenerative nanomedicine, University of Strasbourg, Strasbourg, France.
² Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Service de pneumologie, Département de Médecine, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
³ Department of Pathology, Sunnybrook Hospital, Toronto, Ontario, Canada.
⁴ Biostatistics Research Unit, University Health Network, Toronto, ON, Canada.
⁵ Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
⁸ Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
⁹ Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada. Electronic address: Tereza.Martinu@uhn.ca.

PMID: 38663465
DOI: 10.1016/j.healun.2024.04.002

Abstract

Background: Long-term survival after lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types.

Methods: Peripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, as well as epithelial and vascular abnormalities.

Results: CLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in pathological scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p=0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes and airway fibrosis. Immunofluorescence staining demonstrated a trend towards a lower frequency of club cells in CLAD, and a higher frequency of apoptotic club cells in BOS samples (p=0.01).

Conclusions: CLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathological changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD pathological assessments.

Keywords: chronic rejection; lung transplantation/pulmonology; pathology; translational research/science.