Utility of donor-derived cell-free DNA testing after lung transplantation in the precision medicine era

Donor-derived cell-free DNA (dd-cfDNA) is a validated, highly sensitive, plasma molecular biomarker of allograft injury after solid organ transplantation. Robust experiences with dd-cfDNA testing after kidney and heart transplantation have generated interest in this biomarker within the lung transplantation (LTx) community. A growing body of evidence now provides increased insight into dd-cfDNA utility for molecular monitoring of lung allograft health after transplantation. The expanding understanding of lung allograft injury to appropriately frame the advancing role of dd-cfDNA in the evolution of the diagnostic approach after LTx is described. Performance characteristics of both laboratory-based shotgun-sequenced testing from the Genome Transplant Dynamics (GTD) and Genomic Research Alliance for Transplantation (GRAfT) consortia, as well as commercially available central lab-based algorithmic next-generation sequenced dd-cfDNA tests for lung transplant recipients (LTR) (AlloSure, CareDx and Prospera, Natera) are described. Kinetics of dd-cfDNA in LTRs over time, in multiple different clinical scenarios, from several investigator groups are aggregated. Phenotypes of lung allograft injury, such as acute lung allograft dysfunction and associated dd-cfDNA patterns and performance, are identified in alignment with established definitions and evolving molecular injury insights. Certain patterns of molecular injury that may predict long-term outcomes including chronic lung allograft dysfunction and mortality are examined. Lastly, clinical approaches to testing and interpretation of dd-cfDNA results in LTRs, a practical approach to using dd-cfDNA, and a rational framework for interpreting dd-cfDNA results in LTRs are presented.