Transfusion-related Epstein-Barr virus (EBV) infection: A multicenter prospective cohort study among pediatric recipients of hematopoietic stem cell transplants (TREASuRE study).
Blood Donors
/ statistics & numerical data
Blood Transfusion
/ methods
Canada
/ epidemiology
Child
Child, Preschool
Cohort Studies
Epstein-Barr Virus Infections
/ diagnosis
Epstein-Barr Virus Nuclear Antigens
/ genetics
Female
Genotype
Hematopoietic Stem Cell Transplantation
/ adverse effects
Herpesvirus 4, Human
/ genetics
Humans
Immunosuppression Therapy
/ adverse effects
Male
Prospective Studies
Transfusion Reaction
/ virology
Transplant Recipients
/ statistics & numerical data
Viral Matrix Proteins
/ genetics
Journal
Transfusion
ISSN: 1537-2995
Titre abrégé: Transfusion
Pays: United States
ID NLM: 0417360
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
26
04
2020
revised:
31
08
2020
accepted:
11
09
2020
pubmed:
23
10
2020
medline:
6
7
2021
entrez:
22
10
2020
Statut:
ppublish
Résumé
Epstein-Barr virus (EBV) is carried in the blood of most adults, and transfusion-related infections have been reported. EBV is particularly deleterious in immunosuppressed transplant patients. The aim was to determine if EBV transmission occurred through leukodepleted blood product transfusion in pediatric recipients of hematopoietic stem cell transplants (HSCT). This prospective Canadian multi-center cohort study includes 156 allogeneic HSCT pediatric recipients. The association between EBV and transfusion was analyzed using Cox regressions. EBV infection, defined by a PCR+ test in the blood of seronegative recipients of an EBV-negative graft, was monitored in order to correlate the recipient EBV strain with that of the blood donors. EBV genotypes were determined by PCR amplification followed by DNA sequencing at two loci (EBNA3b and LMP1). No statistically significant associations were found between transfusions and EBV. One case of post-transplant EBV infection was identified among the 21 EBV-seronegative recipients receiving an EBV-negative graft. A total of 22 blood donors were retraced to determine whether the recipient's EBV strain matched that of a donor. One donor strain showed 100% sequence homology at the EBNA3b locus, but differed by one or two point mutations and by a 132-bp deletion at the LMP1 locus. The blood donor in question was alone among the 22 donors to show amplifiable virus in plasma. Blood from this donor readily produced an immortalized lymphoblastoid cell line in culture. While considered a rare event, EBV transmission through transfusion may occur in the context of severe immunosuppression.
Sections du résumé
BACKGROUND
Epstein-Barr virus (EBV) is carried in the blood of most adults, and transfusion-related infections have been reported. EBV is particularly deleterious in immunosuppressed transplant patients. The aim was to determine if EBV transmission occurred through leukodepleted blood product transfusion in pediatric recipients of hematopoietic stem cell transplants (HSCT).
STUDY DESIGN AND METHODS
This prospective Canadian multi-center cohort study includes 156 allogeneic HSCT pediatric recipients. The association between EBV and transfusion was analyzed using Cox regressions. EBV infection, defined by a PCR+ test in the blood of seronegative recipients of an EBV-negative graft, was monitored in order to correlate the recipient EBV strain with that of the blood donors. EBV genotypes were determined by PCR amplification followed by DNA sequencing at two loci (EBNA3b and LMP1).
RESULTS
No statistically significant associations were found between transfusions and EBV. One case of post-transplant EBV infection was identified among the 21 EBV-seronegative recipients receiving an EBV-negative graft. A total of 22 blood donors were retraced to determine whether the recipient's EBV strain matched that of a donor. One donor strain showed 100% sequence homology at the EBNA3b locus, but differed by one or two point mutations and by a 132-bp deletion at the LMP1 locus. The blood donor in question was alone among the 22 donors to show amplifiable virus in plasma. Blood from this donor readily produced an immortalized lymphoblastoid cell line in culture.
CONCLUSION
While considered a rare event, EBV transmission through transfusion may occur in the context of severe immunosuppression.
Substances chimiques
EBNA-3B antigen
0
EBV-associated membrane antigen, Epstein-Barr virus
0
Epstein-Barr Virus Nuclear Antigens
0
Viral Matrix Proteins
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
144-158Subventions
Organisme : Canadian Blood Services
Informations de copyright
© 2020 AABB.
Références
Aalto SM, Juvonen E, Tarkkanen J, et al. Epstein-Barr viral load and disease prediction in a large cohort of allogeneic stem cell transplant recipients. Clin Infect Dis. 2007;45(10):1305-1309.
Allen U, Alfieri C, Preiksaitis J, et al. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis. 2002;13(2):89-99.
Ocheni S, Kroeger N, Zabelina T, et al. EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transplant. 2008;42(3):181-186.
Smith JM, Corey L, Healey PJ, Davis CL, McDonald RA. Adolescents are more likely to develop posttransplant lymphoproliferative disorder after primary Epstein-Barr virus infection than younger renal transplant recipients. Transplantation. 2007;83(11):1423-1428.
Cohen JI. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore). 1991;70(2):137-160.
Ho M, Miller G, Atchison RW, et al. Epstein-Barr virus infections and DNA hybridization studies in posttransplantation lymphoma and lymphoproliferative lesions: The role of primary infection. J Infect Dis. 1985;152(5):876-886.
Savoie A, Perpete C, Carpentier L, Joncas J, Alfieri C. Direct correlation between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease. Blood. 1994;83(9):2715-2722.
Cen H, Breinig MC, Atchison RW, Ho M, McKnight JL. Epstein-Barr virus transmission via the donor organs in solid organ transplantation: Polymerase chain reaction and restriction fragment length polymorphism analysis of IR2, IR3, and IR4. J Virol. 1991;65(2):976-980.
Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992-5001.
Van Der Velden WJFM, Mori T, Stevens WBC, et al. Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab. Bone Marrow Transplant. 2013;48(11):1465-1471.
Xuan L, Jiang X, Sun J, et al. Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation. Transplantation. 2013;96(6):560-566.
Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99(2):346-352.
Kalra A, Roessner C, Jupp J, et al. Risk factors for post-transplant lymphoproliferative disorder after thymoglobulin-conditioned hematopoietic cell transplantation. Clinl Transplant. 2018;32(1):e13150.
Styczynski J, van der Velden W, Fox CP, et al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica. 2016;101(7):803-811.
Fujimoto A, Hiramoto N, Yamasaki S, et al. Risk factors and predictive scoring system for post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(7):1441-1449.
Sanz J, Arango M, Senent L, et al. EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases. Bone Marrow Transplant. 2014;49(3):397-402.
Xu LP, Zhang CL, Mo XD, et al. Epstein-Barr virus-related post-transplantation lymphoproliferative disorder after unmanipulated human leukocyte antigen haploidentical hematopoietic stem cell transplantation: Incidence, risk factors, treatment, and clinical outcomes. Biol Blood Marrow Transplant. 2015;21(12):2185-2191.
Van Esser JWJ, Van Der Holt B, Meijer E, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT. Blood. 2001;98(4):972-978.
Cesaro S, Murrone A, Mengoli C, et al. The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2004;128(2):224-233.
Kullberg-Lindh C, Mellgren K, Friman V, et al. Opportunistic virus DNA levels after pediatric stem cell transplantation: Serostatus matching, anti-thymocyte globulin, and total body irradiation are additive risk factors. Transpl Infect Dis. 2011;13(2):122-130.
Fan J, Jing M, Yang M, et al. Herpesvirus infections in hematopoietic stem cell transplant recipients seropositive for human cytomegalovirus before transplantation. Int J Infect Dis. 2016;46:89-93.
Juvonen E, Aalto S, Tarkkanen J, Volin L, Hedman K, Ruutu T. Retrospective evaluation of serum Epstein Barr virus DNA levels in 406 allogeneic stem cell transplant patients. Haematologica. 2007;92(6):819-825.
Liu Q, Xuan L, Liu H, et al. Molecular monitoring and stepwise preemptive therapy for Epstein-Barr virus viremia after allogeneic stem cell transplantation. Am J Hematol. 2013;88(7):550-555.
Peric Z, Cahu X, Chevallier P, et al. Features of Epstein-Barr virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia. 2011;25(6):932-938.
Gao X-N, Lin J, Wang L-J, et al. Risk factors and clinical outcomes of Epstein-Barr virus DNAemia and post-transplant lymphoproliferative disorders after haploidentical and matched-sibling PBSCT in patients with hematologic malignancies. Ann Hematol. 2019;98(9):2163-2177.
Cohen J, Gandhi M, Naik P, et al. Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning. Br J Haematol. 2005;129(2):229-239.
Elmahdi S, Muramatsu H, Narita A, et al. Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. Pediatr Transplant. 2016;20(1):105-113.
Hiwarkar P, Gaspar HB, Gilmour K, et al. Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transplant. 2013;48(6):803-808.
Sirvent-Von Bueltzingsloewen A, Morand P, Buisson M, et al. A prospective study of Epstein-Barr virus load in 85 hematopoietic stem cell transplants. Bone Marrow Transplant. 2002;29(1):21-28.
Omar H, Hagglund H, Gustafsson-Jernberg A, et al. Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein-Barr virus polymerase chain reaction. Transpl Infect Dis. 2009;11(5):393-399.
Laberko A, Bogoyavlenskaya A, Shelikhova L, et al. Risk factors for and the clinical impact of cytomegalovirus and Epstein-Barr virus infections in pediatric recipients of TCR-alpha/beta- and CD19-depleted grafts. Biol Blood Marrow Transplant. 2017;23(3):483-490.
Bogunia-Kubik K, Jaskula E, Lange A. The presence of functional CCR5 and EBV reactivation after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;40(2):145-150.
Zallio F, Primon V, Tamiazzo S, et al. Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation. Clin Transplant. 2013;27(4):E491-E497.
Tsoumakas K, Giamaiou K, Goussetis E, et al. Epidemiology of viral infections among children undergoing hematopoietic stem cell transplant: Α prospective single-center study. Transpl Infect Dis. 2019;21(4):e13095.
Alfieri C, Tanner J, Carpentier L, et al. Epstein-Barr virus transmission from a blood donor to an organ transplant recipient with recovery of the same virus strain from the recipientʼs blood and oropharynx. Blood. 1996;87(2):812-817.
Hudnall SD, Chen T, Allison P, Tyring SK, Heath A. Herpesvirus prevalence and viral load in healthy blood donors by quantitative real-time polymerase chain reaction. Transfusion. 2008;48(6):1180-1187.
Tattevin P, Cremieux AC, Descamps D, Carbon C. Transfusion-related infectious mononucleosis. Scand J Infect Dis. 2002;34(10):777-778.
Trottier H, Buteau C, Robitaille N, et al. Transfusion-related Epstein-Barr virus infection among stem cell transplant recipients: A retrospective cohort study in children. Transfusion. 2012;52(12):2653-2663.
Carpentier L, Tapiero B, Alvarez F, Viau C, Alfieri C. Epstein-Barr virus (EBV) early-antigen serologic testing in conjunction with peripheral blood EBV DNA load as a marker for risk of posttransplantation lymphoproliferative disease. J Infect Dis. 2003;188(12):1853-1864.
Chang RS, Blankenship W. Spontaneous in vitro transformation of leukocytes from a neonate. Proc Soc Exp Biol Med. 1973;144(1):337-339.
Weinberg A, Enomoto L, Li S, Shen D, Coll J, Shpall EJ. Risk of transmission of herpesviruses through cord blood transplantation. Biol Blood Marrow Transplant. 2005;11(1):35-38.
Palser AL, Grayson NE, White RE, et al. Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. J Virol. 2015;89(10):5222-5237.
Walling DM, Andritsos LA, Etienne W, et al. Molecular markers of clonality and identity in epstein-barr virus-associated B-cell lymphoproliferative disease. J Med Virol. 2004;74(1):94-101.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154.
Dunkler D, Plischke M, Leffondré K, Heinze G. Augmented backward elimination: A pragmatic and purposeful way to develop statistical models. PLoS One. 2014;9(11):e113677.
Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol. 2008;168(6):656-664.
Fewell Z, Hernán MA, Wolfe F, Tilling K, Choi H, Sterne JA. Controlling for time-dependent confounding using marginal structural models. Stata J. 2004;4(4):402-420.
Hernán MÁ, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11:561-570.
Karim ME, Gustafson P, Petkau J, et al. Marginal structural Cox models for estimating the association between β-interferon exposure and disease progression in a multiple sclerosis cohort. Am J Epidemiol. 2014;180(2):160-171.
Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550-560.
van der Wal WM, Geskus RB. Ipw: An R package for inverse probability weighting. J Stat Softw. 2011;43(13):1-23.
Alonso A, Seguí-Gómez M, De Irala J, Sánchez-Villegas A, Beunza JJ, Martínez-Gonzalez MÁ. Predictors of follow-up and assessment of selection bias from dropouts using inverse probability weighting in a cohort of university graduates. Eur J Epidemiol. 2006;21(5):351-358.
Buchanan AL, Hudgens MG, Cole SR, Lau B, Adimora AA, Womenʼs Interagency HIV Study. Worth the weight: Using inverse probability weighted Cox models in AIDS research. AIDS Res Hum Retroviruses. 2014;30(12):1170-1177.
Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004;15(5):615-625.
Willems S, Schat A, van Noorden M, Fiocco M. Correcting for dependent censoring in routine outcome monitoring data by applying the inverse probability censoring weighted estimator. Stat Methods Med Res. 2018;27(2):323-335.
Austin PC. The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33(7):1242-1258.
Cleves MA, Gould W, Marchenko YV. An introduction to survival analysis using Stata. 3rd ed. College Station, TX: Stata Press, 2016.
Sher GD. Leukoreduction of the blood supply. Canadian Blood Services. May 1999. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.523.5667&rep=rep1&type=pdf
Qu L, Xu S, Rowe D, Triulzi D. Efficacy of Epstein-Barr virus removal by leukoreduction of red blood cells. Transfusion. 2005;45(4):591-595.
Wagner HJ, Kluter H, Kruse A, Kirchner H. Relevance of transmission of Epstein-Barr virus through blood transfusion. Beitr Infusionsther Transfusionsmed. 1994;32:138-141.
Qu L, Rowe DT, Donnenberg AD, Griffin DL, Triulzi DJ. Effects of storage and leukoreduction on lymphocytes and Epstein-Barr virus genomes in platelet concentrates. Transfusion. 2009;49(8):1580-1583.
Trottier H, Delage G, Hu J, et al. Detection of Epstein-Barr virus in leucoreduced blood products. Vox Sang. 2016;110(2):199-201.
Macallan DC, Wallace DL, Zhang Y, et al. B-cell kinetics in humans: Rapid turnover of peripheral blood memory cells. Blood. 2005;105(9):3633-3640. https://doi.org/10.1182/blood-2004-3609-3740
van der Maas NG, Berghuis D, van der Burg M, Lankester AC. B cell reconstitution and influencing factors after hematopoietic stem cell transplantation in children. Front Immunol. 2019;10:782.
Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano JS. Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med. 1984;310(19):1225-1230.
Balfour HH Jr, Holman CJ, Hokanson KM, et al. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis. 2005;192(9):1505-1512.
Izumi KM, McFarland EC, Riley EA, Rizzo D, Chen Y, Kieff E. The residues between the two transformation effector sites of Epstein-Barr virus latent membrane protein 1 are not critical for B-lymphocyte growth transformation. J Virol. 1999;73(12):9908-9916.