Cell-Free DNA Maps Tissue Injury and Correlates with Disease Severity in Lung Transplant Candidates

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pre-transplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objective: Evaluate if pre-transplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pre-transplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes including Lung Allocation Score, chronic lung allograft dysfunction and death. Measurements and Main Results: Transplant candidates had 2-fold greater cell-free DNA levels than healthy controls (median [IQR]: 23.7 ng/mL [15.1-35.6] vs 12.9 ng/mL [9.9-18.4], p < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score (p<0.001). High pre-transplant cell-free DNA increased the risk of primary graft dysfunction (OR 1.60, 95% CI [1.09 - 2.46], p = 0.0220), and death (HR 1.43, 95% CI [1.07 - 1.92], p = 0.0171) but not chronic lung allograft dysfunction (HR 1.37, 95% CI [0.97 - 1.94], p = 0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pre-transplant plasma cell-free DNA levels predict post-transplant complications.