Donor-derived cell-free DNA is a valuable monitoring tool after single lung transplantation: Multicenter analysis

Abstract

Background: Donor-derived cell-free DNA (dd-cfDNA) is a nonspecific plasma biomarker for tissue injury that has been validated for monitoring acute rejection (AR) after lung transplantation (LT). However, no studies to date have focused specifically on single lung transplantation (SLT). Herein, we report the performance of dd-cfDNA in detecting AR in SLT from 6 academic centers that implemented this biomarker surveillance in their standard of practice (SOP). Methods: dd-cfDNA test results were corrected for SLT by an algorithm in the Clinical Laboratory Improvement Amendments (CLIA) laboratory to permit comparison against the same 1.0% threshold used in double-lung transplant. Investigators reviewed patient SOP electronic medical record clinical data to assign test results into cohorts based on clinical allograft health status. To avoid ambiguity in interpretation, samples drawn after a prior AR or infection event or without histopathologic confirmation of AR were excluded from further analysis. Diagnostic cohorts included AR (N=25 samples), healthy (STABLE, N=137), allograft infection (INFXN, N=41), chronic lung allograft dysfunction (CLAD, N=7), and “OTHER” types of graft injury (N=12). Results: The study included a total of 257 dd-cfDNA results from 103 SLT patients with one patient excluded due to active cancer. Samples were drawn a median of 233 days (interquartile range: 96-489) after SLT. Laterality for SLT (R vs L) and median dd-cfDNA fraction in AR and STABLE cohort were not statistically different. The median dd-cfDNA fraction was elevated with AR (1.8%) and INFXN (1.1%) vs STABLE (0.46%; p < 0.0001). dd-cfDNA with CLAD was also significantly higher than STABLE cohort (p = 0.0155). The area under receiver operator characteristics curve was 0.850 (95% confidence interval: 0.72-0.95, p < 0.0001) for AR vs STABLE cohort. Applying the dd-cfDNA threshold ≥1.0% for detection of AR yielded a sensitivity = 77.8%, specificity = 84.6%, positive predictive value = 38.31%, and negative predictive value = 96.83%. Conclusions: These multicenter data, incorporating real-world experiences, support the clinical validity and utility of dd-cfDNA monitoring of SLT recipients. Additional studies of the impact of biomarker surveillance on clinically meaningful outcomes should be forthcoming from robust, prospective, and clinical trials already in progress.

Keywords

• cell-free DNA
• lung transplant
• allograft rejection
• single lung transplant
• biomarker