Restrictive Allograft Syndrome Patients Have Higher Cell-Free DNA Assessed Allograft Injury Prior to Diagnosis

Abstract

Purpose Restrictive Allograft Syndrome (RAS) and Bronchiolitis Obliterans Syndrome (BOS) are two forms of chronic lung allograft dysfunction (CLAD), an irreversible loss of allograft function and a major cause of death in lung transplant recipients (LTR). Clinical features and trends in allograft injury associated with RAS and BOS remain incompletely understood. This study examines the clinical characteristics and trends of allograft injury, as assessed by donor-derived cell free DNA (ddcfDNA), in RAS and BOS. Methods 369 LTR enrolled in two cohorts were examined for the development of BOS or RAS, as judged by adjudication committees using standardized definitions for CLAD. Demographic and clinical variables were collected prospectively for each patient. Serial plasma samples were collected for ddcfDNA quantification via shotgun sequencing. Results During the median 38 months follow-up (IQR 24.3-49.7), 116 patients (31.4%) developed CLAD, including 83 (71.5%) with BOS and 33 (28.4%) with RAS. There were no significant differences in demographic and baseline clinical factors between the two groups, including sex, race, BMI, pre-transplant diagnosis, or lung allocation score. RAS patients had a higher percentage of positive donor-specific antibodies (80.6%) compared to BOS (60.5%) (p=0.03). RAS patients had higher levels of ddcfDNA than BOS before CLAD diagnosis (p=0.02), with a rise in ddcfDNA levels preceding RAS diagnosis by 3 months (Fig 1a). RAS patients had significantly lower baseline forced expiratory volume in 1 second (FEV1) (p=0.007) and forced vital capacity (FVC) (p=0.001) six months prior to CLAD diagnosis (Fig 1b). Conclusion RAS patients showed more prevalent DSA and significantly lower baseline lung function compared to BOS. RAS patients also showed higher allograft injury measured via ddcfDNA than BOS patients, with a ddcfDNA rise preceding RAS diagnosis by 3 months. This study demonstrates differences in clinical variables and molecular injury between RAS and BOS. Restrictive Allograft Syndrome (RAS) and Bronchiolitis Obliterans Syndrome (BOS) are two forms of chronic lung allograft dysfunction (CLAD), an irreversible loss of allograft function and a major cause of death in lung transplant recipients (LTR). Clinical features and trends in allograft injury associated with RAS and BOS remain incompletely understood. This study examines the clinical characteristics and trends of allograft injury, as assessed by donor-derived cell free DNA (ddcfDNA), in RAS and BOS. 369 LTR enrolled in two cohorts were examined for the development of BOS or RAS, as judged by adjudication committees using standardized definitions for CLAD. Demographic and clinical variables were collected prospectively for each patient. Serial plasma samples were collected for ddcfDNA quantification via shotgun sequencing. During the median 38 months follow-up (IQR 24.3-49.7), 116 patients (31.4%) developed CLAD, including 83 (71.5%) with BOS and 33 (28.4%) with RAS. There were no significant differences in demographic and baseline clinical factors between the two groups, including sex, race, BMI, pre-transplant diagnosis, or lung allocation score. RAS patients had a higher percentage of positive donor-specific antibodies (80.6%) compared to BOS (60.5%) (p=0.03). RAS patients had higher levels of ddcfDNA than BOS before CLAD diagnosis (p=0.02), with a rise in ddcfDNA levels preceding RAS diagnosis by 3 months (Fig 1a). RAS patients had significantly lower baseline forced expiratory volume in 1 second (FEV1) (p=0.007) and forced vital capacity (FVC) (p=0.001) six months prior to CLAD diagnosis (Fig 1b). RAS patients showed more prevalent DSA and significantly lower baseline lung function compared to BOS. RAS patients also showed higher allograft injury measured via ddcfDNA than BOS patients, with a ddcfDNA rise preceding RAS diagnosis by 3 months. This study demonstrates differences in clinical variables and molecular injury between RAS and BOS.