Donor derived cell free DNA in lung transplant recipients rises in setting of allograft instability

Purpose: The purpose of this study was to evaluate the correlation between longitudinal monitoring of donor-derived cell free DNA (dd-cfDNA) in lung transplant recipients and a "gold standard" of existing tools (pulmonary function testing, radiographic imaging, laboratory and bronchoscopy data, clinical judgment) to assess allograft function.

Methods: 24 consecutive transplant recipients were prospectively enrolled in this study measuring dd-cfDNA levels monthly in the first year after bilateral lung transplant. Blinded clinical adjudications were performed at the same timepoints to categorize allograft function as stable (FEV1 within 10% of prior value or when compared to best two averaged post-transplant values) or unstable. When deemed unstable, etiology of unstable graft function was elicited based on available clinical data. We then evaluated the association between dd-cfDNA and the clinical impression of allograft function using linear mixed models which adjusted for patient-level covariates and time since transplant.

Results: Unstable allografts were associated with 54.4% higher measures of dd-cfDNA, controlling for time since transplant and demographic covariates [adjusted mean ratio (aMR) = 1.54, 95% CI: 1.25-1.91]. Females tended to have higher measures of dd-cfDNA (aMR = 1.90 95%CI: 1.14-3.16). A two-fold increase in dd-cfDNA was associated with declines in FEV1 and FVC of 0.047 and 0.066 L, respectively, controlling for time since transplant and demographic covariates (slope: -0.047 95%CI: -0.076 to -0.019, and slope: -0.066 95%CI: -0.097 to -0.035, respectively). Discussion: Donor derived cell free DNA presents a potential additional minimally invasive clinical tool in lung transplant allograft monitoring within the first year of transplant, with unstable allografts correlating with higher dd-cfDNA values.