Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system

Abstract

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. METHODS: We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan−Meier and Cox proportional hazards models. RESULTS: Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17−3.93; p = 0.014) and similar survival to RAS or mixed phenotype.

Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation — a retrospective single‐center cohort study

“…Patients were excluded from CLAD analysis if they had < 4 PFT measurements post‐transplant, <90 days survival, or if they developed CLAD prior to detection of eosinophils in TBBx. CLAD phenotype was defined by the 2019 Consensus criteria [2,22,23].…”

Restrictive allograft syndrome after lung transplantation

“…In one cohort, the median survival after RAS diagnosis was 541 days, compared to 1421 days in the BOS group 6 . Other studies have found even less favorable outcomes, with the time to death or re‐transplantation being 372 days in RAS and 500 days in BOS 32 . Today, the average survival after the diagnosis of RAS is estimated to be between 6 and 18 months, compared to 3–5 years after BOS 9 …”

“…Finally, pediatric lung transplants occur less frequently compared to adults, making not only detection and recognition of complications, but also coordinating randomized control trials to investigate them difficult. 24,26,32 Most therapeutic and treatment strategies for RAS in the pediatric population are extrapolated from adult and animal literature.…”

“…6 Other studies have found even less favorable outcomes, with the time to death or re-transplantation being 372 days in RAS and 500 days in BOS. 32 Today, the average survival after the diagnosis of RAS is estimated to be between 6 and 18 months, compared to 3-5 years after BOS. 9 In a case series of 53 patients with RAS, predictors of decreased survival included lower lobe or diffuse infiltrates on chest computed tomography (CT), increased BALF neutrophilia or eosinophilia, and a discernible trigger such as lymphocytic bronchiolitis.…”

“…Providers also must weigh the risk/benefit of radiation from repetitive chest imaging, and the potential neurodevelopment complications from repeat anesthesia. Finally, pediatric lung transplants occur less frequently compared to adults, making not only detection and recognition of complications, but also coordinating randomized control trials to investigate them difficult 24,26,32 …”