Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease

Michael B Keller; David Newman; Muhtadi Alnababteh; Lucia Ponor; Pali Shah; Joby Matthews; Hyesik Kong; Temesgen Andargie; Woojin Park; Ananth Charya; Helen Luikart; Shambhu Aryal; Steven D Nathan; Jonathan B Orens; Kiran K Khush; Moon Jang; Sean Agbor-Enoh

doi:10.1016/j.healun.2024.04.064

Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease

J Heart Lung Transplant. 2024 May 3:S1053-2498(24)01644-9. doi: 10.1016/j.healun.2024.04.064. Online ahead of print.

Authors

Michael B Keller¹, David Newman², Muhtadi Alnababteh³, Lucia Ponor⁴, Pali Shah⁵, Joby Matthews⁵, Hyesik Kong⁶, Temesgen Andargie⁶, Woojin Park⁶, Ananth Charya⁷, Helen Luikart⁸, Shambhu Aryal⁹, Steven D Nathan⁹, Jonathan B Orens⁵, Kiran K Khush¹⁰, Moon Jang⁶, Sean Agbor-Enoh¹¹

Affiliations

¹ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT); Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD.
² College of Nursing, Florida Atlantic University, FL.
³ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT); Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD.
⁴ Genomic Research Alliance for Transplantation (GRAfT); Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD.
⁵ Genomic Research Alliance for Transplantation (GRAfT); Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD.
⁶ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT).
⁷ Division of Pulmonary and Critical Care Medicine, University of Maryland Medical Center, Baltimore MD.
⁸ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA; Department of Pathology, Stanford University School of Medicine, Palo Alto, CA.
⁹ Genomic Research Alliance for Transplantation (GRAfT); Inova Fairfax Hospital, Falls Church, VA.
¹⁰ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA.
¹¹ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT); Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD. Electronic address: sean.agbor-enoh@nih.gov.

PMID: 38705500
DOI: 10.1016/j.healun.2024.04.064

Abstract

Background: Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of CLAD or death.

Methods: This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥ 5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated to these conditions.

Results: EMI developed in 16% of patients at a median 343.5 (IQR: 177.3-535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.52, 95% CI: 1.10 - 3.82, p= 0.024). The risk remained consistent for Primary EMI (HR: 2.34, 95% CI 1.18-4.85, p=0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC=0.856, 95% CI =.805-908, p<.001).

Conclusions: Episodes of EMI in lung transplant recipients are often isolated and not detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications.

Keywords: Acute rejection; Lung transplant; cell-free DNA; chronic lung allograft dysfunction; extreme molecular allograft dysfunction.