Different States of Lung Allograft Injury Assessed by Plasma Donor-Derived and Total Cell-Free DNA

Lung allografts are susceptible to myriad injury types, including acute rejection (AR), infectious disease (ID), baseline lung allograft dysfunction (BLAD), and chronic lung allograft dysfunction (CLAD), that affect outcomes. Donor-derived cell-free DNA (dd-cfDNA) is validated for detecting AR after lung transplantation (LT). However, data are limited regarding the ability of dd-cfDNA or total cell-free DNA (TcfDNA) to detect or differentiate other clinical conditions. This study stratified patients into Stable, AR, CLAD, and ID cohorts. Stable double LT recipients were further stratified into BLAD and non-BLAD over different periods posttransplantation. dd-cfDNA and TcfDNA results were associated with the various cohorts. cfDNA was measured in 354 plasma samples from 66 LT recipients. Median dd-cfDNA was elevated in AR (2.08%; P = 0.014) and ID (1.19%; P = 0.065) versus Stable (0.60%) but not CLAD; TcfDNA was only elevated in the ID cohort (P = 0.0078). dd-cfDNA was analyzed before and after treatment of eight episodes of AR, during which the median dd-cfDNA fraction decreased from 2.41% to 0.80% (P = 0.004). No differences were observed during early time points for BLAD versus non-BLAD, whereas median TcfDNA, but not dd-cfDNA, was elevated for BLAD beyond 12 months (13,843 vs 7768 cp/mL; P = 0.005). Overall, this was the first study that explored dd-cfDNA and TcfDNA levels across AR, ID, BLAD, and CLAD cohorts. These data suggest that cfDNA-based biomarkers have value in assessing allograft dysfunction beyond AR.