Observed elevated donor‐derived cell free DNA in orthotopic heart transplant recipients without clinical evidence of rejection

Donor‐derived cell free DNA (dd‐cfDNA) has rapidly become part of rejection surveillance following orthotopic heart transplantation. However, some patients show elevated dd‐cfDNA without clinical evidence of rejection. With the aim to provide a clinical description of this subpopulation, we retrospectively analyzed 35 cardiac transplant recipients at our center who experienced elevated (≥.20%) dd‐cfDNA in the absence of clinical rejection, out of a total 106 recipients who had dd‐cfDNA results available during the first year. The median time to first elevated dd‐cfDNA level was 46 days, and the highest dd‐cfDNA recorded within 1 year was .31% [inter‐quartile range, .23–.45]. Twenty‐two (63%) patients experienced infections (cytomegalovirus (CMV) or other), and 16 (46%) presented with de novo donor‐specific antibodies. Cluster analysis revealed four distinct groups characterized by (a) subclinical rejection with 50% CMV (n = 16), (b) non‐CMV infections and the longest time to first elevated dd‐cfDNA (187 days) (n = 8), (c) right ventricular dysfunction (n = 6), and (d) women who showed the youngest median age (45 years) and highest median dd‐cfDNA (.50%) (n = 5). Continued prospective analysis is needed to determine if these observations warrant changes in patient management to optimize the utilization of this vital non‐invasive graft surveillance tool.