Donor-derived, Cell-free DNA levels by Next Generation Targeted Sequencing are Elevated in Allograft Rejection after Lung Transplantation
- 1Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, USA
- 2Meinig School of Biomedical Engineering, Cornell University, Ithaca, USA
- 3Division of Pulmonary and Critical Care Medicine; Department of Medicine, Stanford University, Stanford, USA
- 4CareDx, Brisbane, CA, USA
- Kiran K. Khush, M.D., MAS, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Falk CVRC 263, Stanford, CA 94305. E-mail: Kiran{at}stanford.edu
Abstract
Surveillance after lung transplantation (LT) is critical to the detection of acute cellular rejection (ACR) and prevention of Chronic Lung Allograft Dysfunction (CLAD). Therefore, we measured donor-derived cell-free DNA (dd-cfDNA) implementing a clinical-grade, next generation targeted sequencing assay in 107 plasma samples from 38 unique LT recipients with diagnostic cohorts classified as: (1) Biopsy-confirmed or treated acute cellular rejection (ACR), (2) antibody-mediated rejection (AMR), (3) Obstructive chronic lung allograft dysfunction (CLAD), (4) allograft infection (INFXN), and (5) Stable healthy allografts (STABLE). Our principal findings: (1) dd-cfDNA level was elevated in ACR (median 0.91%; IQR: 0.39–2.07%), CLAD (2.06%; IQR: 0.57–3.67%), and an aggregated cohort of rejection encompassing allograft injury (1.06%; IQR :0.38–2.51%), compared with the STABLE cohort (0.38%; IQR: 0.23–0.87%) (p=0.02). (2) dd-cfDNA level with AMR was elevated (1.34%; IQR: 0.34–2.40%) compared to STABLE although did not reach statistical significance (p=0.07) due to limitations in sample size. (3) No difference in dd-cfDNA for allograft INFXN (0.39%; IQR: 0.18–0.67%) versus STABLE, that may relate to differences in “tissue injury” with spectrum of bronchial colonisation versus invasive infection. (4) No difference for dd-cfDNA in unilateral versus bilateral LT. (5) “Optimal Threshold” for dd-cfDNA for aggregated rejection events representing allograft injury was determined as 0.85%, with Sensitivity=55.6%, Specificity=75.8%, Positive Predictive Value (PPV)=43.3%, and Negative Predictive Value (NPV)=83.6%. Measurement of plasma dd-cfDNA may be a clinically useful tool for the assessment of lung allograft health and surveillance for “tissue injury” with a spectrum of rejection.
Footnotes
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Khush reports grants and personal fees from CareDx, Inc., outside the submitted work;.
Conflict of interest: Dr. de vlaminck has nothing to disclose.
Conflict of interest: Ms. Luikart has nothing to disclose.
Conflict of interest: Dr. ross has nothing to disclose.
Conflict of interest: Dr. NICOLLS has nothing to disclose.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received July 4, 2020.
- Accepted September 18, 2020.
- Copyright ©ERS 2020
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.