Clinical Sub-Phenotypes of Acute Lung Allograft Dysfunction Associated with Chronic Lung Allograft Dysfunction

Background:Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year following lung transplantation (LTx). Acute lung allograft dysfunction (ALAD), defined by a ≥10% decline in FEV₁ from baseline best for at least 3 weeks, is a precursor to CLAD. However, only 40% of LTx recipients with ALAD progress to CLAD within 1 year. The clinical features present at the time of ALAD, including infection and rejection, that are most strongly associated with the development of CLAD and its phenotypes remain poorly understood. Methods:We conducted a retrospective cohort study of 92 LTx recipients at University of Washington who developed ALAD and underwent bronchoscopy within 30 days of ALAD diagnosis between 2014 and 2018. ALAD was classified as infection-associated, rejection-associated, or non-diagnostic. The primary outcome was a composite of CLAD or death. Secondary outcomes included CLAD phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), mixed, and undefined. Cox proportional hazards and Fine-Gray competing risks regression models were used to evaluate associations between ALAD subphenotypes and CLAD and its phenotypes. Results:Among 92 recipients, 17 had infection-associated ALAD, 23 had rejection-associated ALAD, 6 had both, and 46 had non-diagnostic ALAD. Rejection-associated ALAD was significantly associated with increased risk of CLAD or death (adjusted hazard ratio [aHR] 2.44, 95% CI: 1.24-4.81, p=0.010) when compared with non-diagnostic ALAD, while infection-associated ALAD was not (aHR 1.18, 95% CI: 0.63-2.21, p=0.60). BOS was the most common CLAD phenotype (27.2%). Neither infection- nor rejection-associated ALAD was significantly associated with the development of specific CLAD phenotypes. However, there was a trend towards a higher risk of RAS and lower risk of BOS in both exposure groups. Conclusion:Rejection-associated ALAD is a strong predictor of progression to CLAD or death, whereas infection-associated ALAD may not confer the same increased risk. These findings highlight the importance of early identification and treatment of rejection during acute declines in lung function and underscore the need for better risk stratification tools for CLAD and its phenotypes.