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

Donor-derived cell-free DNA is increasingly used in clinical practice to monitor lung transplant patients for acute rejection. However, its association with conventional approaches to monitor immunosuppression remains unclear. This multicenter observational cohort study examines the association of donor-derived cell free DNA with surrogate measures of immunosuppression. Serial plasma samples were collected for quantification of donor-derived cell-free DNA and anellovirus abundance via shotgun and metagenomic sequencing. Adjudication committees reviewed clinical data to define acute cellular and antibody-mediated rejection. The association between ddcfDNA, anellovirus abundance, and serum tacrolimus trough concentrations over the study period and during episodes of acute rejection were examined via linear mixed effects modeling. Donor-derived cell-free DNA demonstrated a significant inverse association with tacrolimus troughs (p=0.027) and anellovirus abundance (p<0.001) over time. Acute rejection episodes were associated with significantly decreased anellovirus abundance (median, 0.042 vs. 0.708, p<0.001) and higher ddcfDNA levels (1.49% vs. 0.26%, p<0.001) compared to stable control timepoints. However, tacrolimus levels were similar between acute rejection and controls (10.1 ng/ml vs 10.3 ng/ml, p = 0.13). Our findings suggest donor-derived cell-free DNA correlates with measures of immunosuppression in lung transplant patients. Additional studies are needed to assess the utility of donor-derived cell-free DNA to assess immunosuppression adequacy.