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Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care
Michael Keller1, Junfeng Sun2, Cedric Mutebi3
1Laborarory of Applied Precision Omics (APO) and Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland; Department of Critical Care Medicine, National Institute of Health, Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland.
Background:
As a marker of underlying lung allograft injury, donor-derived cell-free DNA (dd-cfDNA) may be used to identify episodes of acute allograft injury in lung transplant recipients. We investigated the utility of dd-cfDNA to monitor subjects at risk of acute rejection or infection in routine clinical practice.
Methods:
This multicenter, retrospective cohort study collected data from lung transplant recipients within 3 years of transplant at 4 centers between March 24, 2020 and September 1, 2020. During this period, as part of routine care during the COVID-19 pandemic, these centers implemented a home-based surveillance program using plasma dd-cfDNA in preference to surveillance bronchoscopy. Dd-cfDNA was used to detect acute lung allograft dysfunction (ALAD) - a composite endpoint of acute rejection and infection. dd-cfDNA levels in patients with ALAD were compared to stable patients. The performance characteristics of dd-cfDNA ≥ 1.0% to detect ALAD were estimated.
Results:
A total of 175 patients underwent 380 dd-cfDNA measurements, of which 290 were for routine surveillance purposes. dd-cfDNA was higher in patients with ALAD than stable patients (Median (IQR) 1.7% (0.63, 3.1) vs 0.35% (0.22, 0.79), p < 0.001). As an indication of underlying ALAD during surveillance testing, the estimated sensitivity of dd-cfDNA ≥1% was 73.9%, specificity of 87.7%, positive predictive value of 43.4% and negative predictive value of 96.5%.
Conclusions:
dd-cfDNA identified acute lung allograft dysfunction in asymptomatic lung transplant patients that may not have been identified by using a clinically indicated biopsy strategy alone. dd-cfDNA <1.0% may be useful in ruling out acute rejection and infection, supporting its use as a potential noninvasive marker for surveillance monitoring.
Insights
Donor-derived cell-free DNA (dd-cfDNA) can detect acute lung allograft dysfunction in transplant recipients. A dd-cfDNA level below 1.0% may rule out rejection or infection, supporting its use in noninvasive monitoring.
Area of Science:
- Transplant immunology
- Molecular diagnostics
- Pulmonology
Background:
- Donor-derived cell-free DNA (dd-cfDNA) is a marker of lung allograft injury.
- It may identify acute allograft injury in lung transplant recipients.
- This study investigated dd-cfDNA's utility for monitoring rejection or infection risk.
Purpose of the Study:
- To evaluate the effectiveness of plasma dd-cfDNA for monitoring lung transplant recipients.
- To assess dd-cfDNA's role in detecting acute lung allograft dysfunction (ALAD) during routine care.
- To compare dd-cfDNA levels in patients with and without ALAD.
Main Methods:
- A multicenter, retrospective cohort study of lung transplant recipients within 3 years post-transplant.
- Plasma dd-cfDNA was used for home-based surveillance, prioritizing it over bronchoscopy.
- dd-cfDNA levels were analyzed to detect ALAD (acute rejection and infection).
Main Results:
- 175 patients had 380 dd-cfDNA measurements; 290 were for surveillance.
- dd-cfDNA was significantly higher in patients with ALAD (1.7%) versus stable patients (0.35%).
- dd-cfDNA ≥1% showed 73.9% sensitivity and 87.7% specificity for ALAD.
Conclusions:
- dd-cfDNA identified asymptomatic ALAD not detected by biopsy alone.
- dd-cfDNA <1.0% can help rule out acute rejection and infection.
- dd-cfDNA shows potential as a noninvasive marker for lung transplant surveillance.
