Noninvasive Monitoring of Infection and Rejection After Lung Transplantation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Oct 14

PMID 26460048

Citations 166

Authors

Iwijn De Vlaminck

Lance Martin

Michael Kertesz

Kapil Patel

Mark Kowarsky

Calvin Strehl

Garrett Cohen

Helen Luikart

Norma F Neff

Jennifer Okamoto

Mark R Nicolls

David Cornfield

David Weill

Hannah Valantine

Kiran K Khush

Stephen R Quake

Affiliations

Soon will be listed here.

Abstract

The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

Citing Articles

Donor-derived cell-free DNA for detection of acute rejection in lung transplant recipients.

Yavuz G, Walter J, Hirv K, Wachter O, Dick A, Kovacs J Front Immunol. 2025; 16:1531774.

PMID: 39944692 PMC: 11814210. DOI: 10.3389/fimmu.2025.1531774.

Integrating Donor Derived Cell-Free DNA Fraction and Absolute Quantification for Enhanced Rejection Diagnosis in Kidney Transplant Recipients.

Nie W, Wang Y, Fu Q, Wu C, Deng R, Yu X Diagnostics (Basel). 2025; 15(3).

PMID: 39941167 PMC: 11817499. DOI: 10.3390/diagnostics15030237.

Donor-derived cell-free DNA in chronic lung allograft dysfunction phenotypes: a pilot study.

Beeckmans H, Pagliazzi A, Kerckhof P, Hofkens R, Debackere F, Zajacova A Front Transplant. 2025; 3:1513101.

PMID: 39764156 PMC: 11701071. DOI: 10.3389/frtra.2024.1513101.

Gene expression profiling in PBMCs for acute rejection in lung transplant recipients reveals myeloid responses.

Liu S, Westra J, Hu S, Verschuuren E, van Kempen L, van Baarle D Front Transplant. 2025; 3:1508419.

PMID: 39744543 PMC: 11688322. DOI: 10.3389/frtra.2024.1508419.

Donor derived cell free DNA in lung transplant recipients rises in setting of allograft instability.

Smith J, Peterson R, Pomponio R, Steele M, Gray A Front Transplant. 2024; 3:1497374.

PMID: 39737412 PMC: 11683734. DOI: 10.3389/frtra.2024.1497374.

References

Dascomb K, Frazer T, Clark R, Kissinger P, Didier E . Microsporidiosis and HIV. J Acquir Immune Defic Syndr. 2000; 24(3):290-2. DOI: 10.1097/00126334-200007010-00018. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Touinssi M, Gallian P, Biagini P, Attoui H, Vialettes B, Berland Y . TT virus infection: prevalence of elevated viraemia and arguments for the immune control of viral load. J Clin Virol. 2001; 21(2):135-41. DOI: 10.1016/s1386-6532(01)00157-3. View

Larroche C, Agbalika F, Poirel H, Martin A, Gautheret-Dejean A, Raphael M . Epstein-Barr virus and human herpesvirus 8 coinfection and concomitant extranodal nasal-type NK/T cell lymphoma and Castleman disease: case report. Clin Infect Dis. 2003; 36(9):e107-10. DOI: 10.1086/374663. View

Zamora M . Cytomegalovirus and lung transplantation. Am J Transplant. 2004; 4(8):1219-26. DOI: 10.1111/j.1600-6143.2004.00505.x. View

Lo Y, Tein M, Pang C, Yeung C, Tong K, Hjelm N . Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients. Lancet. 1998; 351(9112):1329-30. DOI: 10.1016/s0140-6736(05)79055-3. View

Charlson E, Diamond J, Bittinger K, Fitzgerald A, Yadav A, Haas A . Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med. 2012; 186(6):536-45. PMC: 3480531. DOI: 10.1164/rccm.201204-0693OC. View

Wylie K, Weinstock G, Storch G . Emerging view of the human virome. Transl Res. 2012; 160(4):283-90. PMC: 3701101. DOI: 10.1016/j.trsl.2012.03.006. View

Razonable R . Human herpesviruses 6, 7 and 8 in solid organ transplant recipients. Am J Transplant. 2013; 13 Suppl 3:67-77. DOI: 10.1111/ajt.12008. View

10.

Dawson S, Tsui D, Murtaza M, Biggs H, Rueda O, Chin S . Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013; 368(13):1199-209. DOI: 10.1056/NEJMoa1213261. View

11.

Li L, Deng X, Linsuwanon P, Bangsberg D, Bwana M, Hunt P . AIDS alters the commensal plasma virome. J Virol. 2013; 87(19):10912-5. PMC: 3807392. DOI: 10.1128/JVI.01839-13. View

12.

Yusen R, Christie J, Edwards L, Kucheryavaya A, Benden C, Dipchand A . The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Adult Lung and Heart-Lung Transplant Report--2013; focus theme: age. J Heart Lung Transplant. 2013; 32(10):965-78. DOI: 10.1016/j.healun.2013.08.007. View

13.

Barzon L, Lavezzo E, Costanzi G, Franchin E, Toppo S, Palu G . Next-generation sequencing technologies in diagnostic virology. J Clin Virol. 2013; 58(2):346-50. DOI: 10.1016/j.jcv.2013.03.003. View

14.

De Vlaminck I, Khush K, Strehl C, Kohli B, Luikart H, Neff N . Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013; 155(5):1178-87. PMC: 4098717. DOI: 10.1016/j.cell.2013.10.034. View

15.

Bettegowda C, Sausen M, Leary R, Kinde I, Wang Y, Agrawal N . Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014; 6(224):224ra24. PMC: 4017867. DOI: 10.1126/scitranslmed.3007094. View

16.

Wilson M, Naccache S, Samayoa E, Biagtan M, Bashir H, Yu G . Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med. 2014; 370(25):2408-17. PMC: 4134948. DOI: 10.1056/NEJMoa1401268. View

17.

De Vlaminck I, Valantine H, Snyder T, Strehl C, Cohen G, Luikart H . Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014; 6(241):241ra77. PMC: 4326260. DOI: 10.1126/scitranslmed.3007803. View

18.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View

19.

Focosi D, Macera L, Pistello M, Maggi F . Torque Teno virus viremia correlates with intensity of maintenance immunosuppression in adult orthotopic liver transplant. J Infect Dis. 2014; 210(4):667-8. DOI: 10.1093/infdis/jiu209. View

20.

Quinones-Mateu M, Avila S, Reyes-Teran G, Martinez M . Deep sequencing: becoming a critical tool in clinical virology. J Clin Virol. 2014; 61(1):9-19. PMC: 4119849. DOI: 10.1016/j.jcv.2014.06.013. View