Donor-derived cell-free DNA is associated with the degree of immunosuppression in lung transplantation

Donor-derived cell-free DNA (ddcfDNA) is increasingly used in clinical practice to monitor lung transplant patients for acute rejection (AR). However, its association with conventional approaches to monitor immunosuppression remains unclear. This multicenter observational cohort study examines the association of ddcfDNA with surrogate measures of immunosuppression. We collected serial plasma samples to quantify ddcfDNA and anellovirus abundance using shotgun and metagenomic sequencing. Adjudication committees reviewed clinical data to define acute cellular and antibody-mediated rejection. The association between ddcfDNA, anellovirus abundance, and tacrolimus trough concentrations in serum over the study period and during episodes of AR was examined using linear mixed-effects modeling. ddcfDNA demonstrated a significant inverse association with tacrolimus troughs (P = .027) and anellovirus abundance (P < .001) over time. AR episodes were associated with significantly decreased anellovirus abundance (median, 0.042 vs 0.708, P < .001) and higher ddcfDNA levels (1.49% vs 0.26%, P < .001) compared with stable control time points. However, tacrolimus levels were similar between AR and controls (10.1 vs 10.3 ng/mL, P = .13). Our findings suggest ddcfDNA correlates with measures of immunosuppression in lung transplant patients. Additional studies are needed to assess the utility of ddcfDNA to assess immunosuppression adequacy.