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Review
. 2022;11(3):75-85.
doi: 10.1007/s13665-022-00292-8. Epub 2022 Jul 26.

Why Cell-Free DNA Can Be a "Game Changer" for Lung Allograft Monitoring for Rejection and Infection

J P Rosenheck  1 , B C Keller  2 , G Fehringer  3 , Z P Demko  3 , S M Bohrade  3 , D J Ross  3   4
Affiliations
Review

Why Cell-Free DNA Can Be a "Game Changer" for Lung Allograft Monitoring for Rejection and Infection

J P Rosenheck et al. Curr Pulmonol Rep. 2022.

Abstract

Purpose of review: Although there has been improvement in short-term clinical outcomes for patients following lung transplant (LT), advances have not translated into longer-term allograft survival. Furthermore, invasive biopsies are still standard of practice for monitoring LT recipients for allograft injury. We review the relevant literature supporting the role of using plasma donor-derived cell-free DNA (dd-cfDNA) as a non-invasive biomarker for LT allograft injury surveillance and discuss future research directions.

Recent findings: Accumulating data has demonstrated that dd-cfDNA is associated with molecular and cellular injury due to acute (cellular and antibody-mediated) rejection, chronic lung allograft dysfunction, and relevant infectious pathogens. Strong performance in distinguishing rejection and allograft injury from stable patients has set the stage for clinical trials to assess dd-cfDNA utility for surveillance of LT patients. Research investigating the potential role of dd-cfDNA methylation signatures to map injured tissue and cell-free DNA in detecting allograft injury-related pathogens is ongoing.

Summary: There is an amassed breadth of clinical data to support a role for dd-cfDNA in monitoring rejection and other forms of allograft injury. Rigorously designed, robust clinical trials that encompass the diversity in patient demographics are paramount to furthering our understanding and adoption of plasma dd-cfDNA for surveillance of lung allograft health.

Keywords: Biomarkers; Cell-free DNA; Donor-derived cell-free DNA; Lung transplant; Organ rejection.

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Conflict of interest statement

Competing InterestsGF, SMB, ZPD, and DJR are full-time employees at Natera Inc. with stocks or options to own stocks in the company. BCK serves as a consultant to and on the speaker bureau for CareDx, Inc. and has received research funding from CareDx, Natera, and Zambon. JPR has received research funding from Natera.

Figures

Fig. 1
Fig. 1
Commercial tests to quantify the fraction of donor-derived cell-free DNA. There are approximately 4–5 million SNPs in any individual while more than 100 million SNPs span populations worldwide [67]. Commercially available tests now quantify donor fraction dd-cfDNA from a single recipient plasma sample by leveraging disparities in single nucleotide polymorphisms (SNPs) between donor and recipient with complex bioinformatic algorithms. Quantification utilizes either targeted next-generation sequencing (NGS), massively complexed polymerase chain reaction (mmPCR), or digital droplet PCR (ddPCR). The donor fraction (%) represents donor relative to total background (donor + recipient) cfDNA
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