Early post-lung transplant cell-free DNA levels are associated with baseline lung allograft dysfunction

Abstract

Background: Baseline lung allograft dysfunction (BLAD) is defined as the failure to achieve normal pulmonary function-specifically, forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) values of ≥80 %-within the first year after lung transplantation. It is hypothesised that early subclinical injury, reflected by elevated donor-derived cell-free DNA (dd-cfDNA), both in absolute concentration and percentage (dd-cfDNA%), as well as total cell-free DNA (cfDNA), may be predictive of subsequent BLAD development.

Methods: We included patients who underwent bilateral lung transplantation between May 2021 and September 2023. Blood samples collected between 3 and 9 months post-transplantation were analysed for dd-cfDNA%, dd-cfDNA concentration (copies/mL), and estimated total cfDNA (copies/mL). BLAD was defined by failure to achieve both FEV₁ and FVC ≥80 % of predicted values within the first year.

Results: A total of 158 samples from 37 patients were analysed. Ten patients (27 %) met the BLAD criteria. Those with BLAD had significantly higher dd-cfDNA levels (median: 39 cp/mL) compared to non-BLAD patients (26 cp/mL; p = 0.01). Similarly, total cfDNA levels were significantly elevated in the BLAD group (22,809 cp/mL vs. 13,840 cp/mL; p = 0.002). However, dd-cfDNA% did not differ significantly (0.23 % vs. 0.15 %; p = 0.2).

Conclusion: Elevated absolute dd-cfDNA and total cfDNA levels in the early post-transplant period were associated with BLAD, suggesting that cfDNA may serve as a potential predictive biomarker. These findings support the potential of cfDNA-based biomarkers to enhance early detection of graft dysfunction, warranting validation in larger cohorts.

Keywords: Baseline lung allograft dysfunction; Donor-derived cell-free DNA; Lung transplantation.