Sustained Molecular Allograft Injury After Episodes of Acute Rejection and Organizing Pneumonia Increases the Risk of Lung Allograft Failure

Michael B Keller; Allison Y Lin; Moon Kyoo Jang; Hyesik Kong; Ananth Charya; Gerald J Berry; Charles C Marboe; Ileana L Ponor; Shambhu Aryal; Jonathan B Orens; Pali D Shah; Steven D Nathan; Xin Tian; Sean Agbor-Enoh

doi:10.1097/TXD.0000000000001828

Sustained Molecular Allograft Injury After Episodes of Acute Rejection and Organizing Pneumonia Increases the Risk of Lung Allograft Failure

Transplant Direct. 2025 Jun 27;11(7):e1828. doi: 10.1097/TXD.0000000000001828. eCollection 2025 Jul.

Authors

Michael B Keller^{1

2

3}, Allison Y Lin⁴, Moon Kyoo Jang^{3

4}, Hyesik Kong^{3

4}, Ananth Charya^{1

3}, Gerald J Berry^{3

5}, Charles C Marboe^{3

6}, Ileana L Ponor^{3

7}, Shambhu Aryal^{3

8}, Jonathan B Orens^{3

9}, Pali D Shah^{3

9}, Steven D Nathan^{3

8}, Xin Tian^{4

10}, Sean Agbor-Enoh^{3

4

9}

Affiliations

¹ Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland Medical Center, Baltimore, MD.
² Division of Pulmonary & Critical Care Medicine, Baltimore VA Medical Center, Baltimore, MD.
³ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, MD.
⁴ Laboratory of Applied Precision Omics (APO), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
⁵ Stanford University School of Medicine, Stanford, CA.
⁶ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY.
⁷ Department of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD.
⁸ Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Fairfax, VA.
⁹ Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, MD.
¹⁰ Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Abstract

Background: Despite treatment of major risk factors such as acute rejection (AR) and organizing pneumonia (OP) in lung transplant recipients, chronic lung allograft dysfunction (CLAD) still develops at high rates, suggesting that traditional methods of assessing response to treatment and resolution remain inadequate. It is unknown whether the degree of molecular allograft injury after treatment of AR/OP modulates the risk of CLAD and death.

Methods: To evaluate the association of molecular allograft injury after AR/OP with the incidence of CLAD/death, we conducted a multicenter prospective cohort study that included 93 patients who underwent lung transplantation between 2015 and 2022. The degree of molecular allograft injury after AR/OP was quantified by the mean area under the curve of longitudinal measures of plasma donor-derived cell-free DNA (dd-cfDNA).

Results: Over a median follow-up of 5 y, patients who developed CLAD/death had persistently higher levels of dd-cfDNA in the months after AR/OP. In multivariable Cox regression analysis adjusting for patient and transplant risk factors, mean dd-cfDNA levels after AR/OP were independently associated with an increased risk of CLAD/death (adjusted hazard ratio, 2.84; 95% confidence interval, 1.67-4.83; P < 0.001) and remained consistent when accounting for changes in pulmonary function after AR/OP events (hazard ratio, 2.62; 95% confidence interval, 1.53-4.47; P < 0.001).

Conclusions: The degree of allograft injury on the molecular level after AR/OP events in lung transplant recipients is associated with the risk of developing CLAD or death. This study demonstrates the potential of dd-cfDNA for improving risk stratification and monitoring the resolution and treatment responses of lung allograft injury.