Variability in plasma donor-derived cell-free DNA levels with CLAD more than 5-years after Lung Transplantation: Pilot data

Background

Chronic lung allograft dysfunction (CLAD) is a highly prevalent and devastating complication in lung transplant (LT), culminating in increased allograft failure, morbidity, and mortality. Determination of the fraction of plasma donor-derived cell-free DNA (dd-cfDNA) has emerged as a valuable noninvasive monitoring tool after LT; however, the increased variance of host cfDNA caused by infection and other inflammation can complicate the approach.

Methods

In a retrospective pilot study, we analyzed both the fraction of dd-cfDNA (%dd-cfDNA) and absolute quantity of dd-cfDNA (cp/mL) in recipients with CLAD ≥ 5-year post-LT with co-morbid conditions (gastro-esophageal reflux, antibody-mediated rejection, or chronic infection) designated as complicated (C-CLAD) and uncomplicated (U-CLAD) cohorts.

Results

Median time post-LT was 2,149 days (1,899-2,920). The median %dd-cfDNA for the C-CLAD (N=5) cohort was 1.79% (IQR: 1.04-2.29) and significantly elevated compared to the U-CLAD cohort (N=7, 0.49%; 0.28-0.88) (p=0.018). Absolute dd-cfDNA was also significantly higher in C-CLAD (43.2 cp/mL; 27.9-89.3) than the in U-CLAD cohort (19.6 cp/mL; 8.1-27.9) (p=0.048).

Conclusions

We report a heretofore undescribed dichotomy of dd-cfDNA levels with CLAD ≥ 5-years, related specifically to elevation in allograft quantity as opposed to alteration in host plasma cfDNA. Further, dd-cfDNA analysis in association with co-morbid conditions in C-CLAD may offer insights for potential treatment and alleviation of molecular injury. Measurement of longitudinal absolute quantity dd-cfDNA may provide additional value for future clinical study design of pathobiology and CLAD treatment algorithms.