Elevated cell-free DNA in respiratory viral infection and associated lung allograft dysfunction

Respiratory viral infection (RVI) in lung transplant recipients (LTRs) is a risk for chronic lung allograft dysfunction (CLAD). We hypothesize that donor-derived cell-free DNA (%ddcfDNA), at the time of RVI predicts CLAD progression. We followed 39 LTRs with RVI enrolled in the Genomic Research Alliance for Transplantation for 1 year. Plasma %ddcfDNA was measured by shotgun sequencing, with high %ddcfDNA as ≥1% within 7 days of RVI. We examined %ddcfDNA, spirometry, and a composite (progression/failure) of CLAD stage progression, re-transplant, and death from respiratory failure. Fifty-nine RVI episodes, 38 low and 21 high %ddcfDNA were analyzed. High %ddcfDNA subjects had a greater median %FEV₁ decline at RVI (−13.83 vs. −1.83, p =.007), day 90 (−7.97 vs. 0.91, p =.04), and 365 (−20.05 vs. 1.09, p =.047), compared to those with low %ddcfDNA and experienced greater progression/failure within 365 days (52.4% vs. 21.6%, p =.01). Elevated %ddcfDNA at RVI was associated with an increased risk of progression/failure adjusting for symptoms and days post-transplant (HR = 1.11, p =.04). No difference in %FEV₁ decline was seen at any time point when RVIs were grouped by histopathology result at RVI. %ddcfDNA delineates LTRs with RVI who will recover lung function and who will experience sustained decline, a utility not seen with histopathology.