Donor–derived cell-free DNA associated with increased risk of chronic lung allograft dysfunction and mortality: Are absolute levels better than percentage?

BACKGROUND: There is a need for reliable methods to risk-stratify patients for chronic lung allograft dysfunction (CLAD) and death. A proof-of-concept study reported the predictive utility of early post-transplant levels of percent donor-derived cell-free DNA (dd-cfDNA), a measure affected by host cell-free DNA changes. This study assesses the predictive utility of dd-cfDNA in and beyond the early post-transplant period using absolute dd-cfDNA, a measure not affected by host cell-free DNA changes. METHODS: This multicenter study (Genome Research Alliance for Transplantation, NCT02423070) of lung transplant patients measured serial absolute dd-cfDNA in copies/ml and percent dd-cfDNA. We performed multivariable Cox regression analyses to determine the association between dd-cfDNA and the composite outcome of moderate-to-severe CLAD and/or death; the early post-transplant model used mean dd-cfDNA levels within days 30 to 91. A time-dependent model used dd-cfDNA values beyond the early post-transplant period. RESULTS: The cohort included 242 patients and 2,838 serial dd-cfDNA assessments. Absolute dd-cfDNA had similar or better performance than percent dd-cfDNA to risk-stratify patients for moderate-to-severe CLAD/death. High absolute dd-cfDNA levels in the early post-transplant period (hazard ratio 1.29, 95% confidence interval 1.04-1.60, p = 0.018) or at any time post-transplant (hazard ratio 1.51, 95% confidence interval 1.32-1.73, p < 0.001) were associated with an increased risk of moderate-to-severe CLAD/death, and absolute dd-cfDNA levels >250 copies/ml were associated with an elevated risk of moderate-to-severe CLAD/death. CONCLUSIONS: The study reports dd-cfDNA risk assessment models for moderate-to-severe CLAD/death; absolute values showed similar or better predictive performance than percent.