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

Abstract

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 %FEV 1 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 posttransplant (HR = 1.11, p = .04). No difference in %FEV 1 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.

Advances in lung transplantation: 60 years on

“…They then subsequently decrease over time, reaching a steady state 2–4 months following transplant 106–109 . Unfortunately whilst the sensitivity of using dd‐cfDNA to detect lung allograft injury is promising, it lacks specificity and cannot reliable distinguish between ACR, AMR and infection limiting its clinical utility at present 110,111 …”

“…[106][107][108][109] Unfortunately whilst the sensitivity of using dd-cfDNA to detect lung allograft injury is promising, it lacks specificity and cannot reliable distinguish between ACR, AMR and infection limiting its clinical utility at present. 110,111…”

Acute rejection post lung transplant

“…In addition, change in dd-cfDNA levels versus the absolute value (which is different for single versus bilateral transplant) has been shown to have better diagnostic accuracy for ALAD [39 & ]. One drawback is dd-cfDNA level alone does not delineate the type of allograft, in acute symptomatic infection from respiratory viruses, dd-cfDNA levels have been shown to be elevated similarly to ACR episodes [40], but such elevations are not seen in asymptomatic infections, suggesting a possible role in delineating colonization versus true clinical infection [37].…”

Extracellular Vesicles in Transplantation: Friend or Foe

“…Other studies have also found an association between RVIs and graft dysfunction in LTxRs 1-2 y after infection. 116 Many respiratory viral pathogens are capable of invading human epithelial cells within the respiratory tract and elevating the levels of proinflammatory cytokines, some chemokines, and related signaling pathways. [117][118][119] Respiratory viruses like influenza, respiratory syncytial virus, and coronavirus variants can lead to hemorrhage and diffuse alveolar damage followed by fibrin deposition within the airways, preventing air exchange.…”

“…Other studies have also found an association between RVIs and graft dysfunction in LTxRs 1–2 y after infection. 116…”