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Viral Infections

A prospective study of Epstein–Barr virus load in 85 hematopoietic stem cell transplants

Abstract

EBV viral load (EBV-VL) in PBMC was prospectively determined by semi-quantitative PCR in 85 stem cell transplants (40 genoidentical, 45 non-genoidentical) in order to characterize the kinetics of EBV-VL and to assess the ability of this measure to predict the development of EBV-induced lymphoproliferative disease (EBV-LPD). PCR was performed prior to and after transplantation. An EBV-VL >300 copies/μg DNA was chosen as the threshold for risk of developing an EBV-LPD. Two hundred and fifty-eight EBV-VL measures were evaluable. Five patients (5.9%) developed an EBV-LPD. All had an elevated EBV DNA peak level before EBV-LPD. Fifteen out of 80 recipients (18.7%) without EBV-LPD had EBV levels over 300 copies/μg DNA at least once during the follow-up. Overall, the manifestation of at least one EBV-VL over 300 copies/μg DNA during the entire follow-up demonstrated a sensitivity, specificity, positive and negative predictive value for the diagnosis of EBV-LPD of 100%, 81%, 25% and 100%, respectively. In patients without EBV-LPD, HLA incompatibility, grade II acute GVHD and use of an unmanipulated graft were significantly associated with an EBV-VL >300 copies/μg DNA. This strategy appears sensitive for the diagnosis of EBV-LPD but its positive predictive value has to be improved in order to guide pre-emptive therapy.

Bone Marrow Transplantation (2002) 29, 21–28. doi:10.1038/sj.bmt.1703331

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References

  1. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL . Epstein–Barr virus, immunodeficiency, and B cell lymphoproliferation Transplantation 1985 39: 461 472

    Article  CAS  PubMed  Google Scholar 

  2. Shapiro RS, McClain K, Frizzera G et al. Epstein–Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation Blood 1988 71: 1234 1243

    CAS  PubMed  Google Scholar 

  3. Zutter MM, Martin PJ, Sale GE et al. Epstein–Barr virus lymphoproliferation after bone marrow transplantation Blood 1988 72: 520 529

    CAS  PubMed  Google Scholar 

  4. Micallef INM, Chhanabhai M, Gascoyne RD et al. Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience Bone Marrow Transplant 1998 22: 981 987

    Article  CAS  PubMed  Google Scholar 

  5. Swerdlow SH . Post-transplant lymphoproliferative disorders: a morphologic, phenotypic and genotypic spectrum of disease Histopathology 1992 20: 373 385

    Article  CAS  PubMed  Google Scholar 

  6. Gross TG, Steinbuch M, DeFor T et al. B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome Bone Marrow Transplant 1999 23: 251 258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Antin JH, Bierer BE, Smith BR et al. Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies Blood 1991 78: 2139 2149

    CAS  PubMed  Google Scholar 

  8. Gerritsen EJA, Stam ED, Hermans J et al. Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children Bone Marrow Transplant 1996 18: 377 382

    CAS  PubMed  Google Scholar 

  9. Hale G, Waldmann H . Risks of developing EBV-LPD after T cell-depleted marrow transplantation Blood 1998 91: 3079 3083

    CAS  PubMed  Google Scholar 

  10. Martin PJ, Shulman HM, Scubach WH et al. Fatal Epstein–Barr virus-associated proliferation of donor B cells after treatment of acute graft-versus-host disease with a murine anti-T-cell antibody Ann Intern Med 1984 101: 310 315

    Article  CAS  PubMed  Google Scholar 

  11. Curtis RE, Travis LB, Rowlings PA et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study Blood 1999 94: 2208 2216

    CAS  PubMed  Google Scholar 

  12. Papadopoulos EB, Ladanyi M, Emanuel D et al. Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation New Engl J Med 1994 324: 1451 1456

    Google Scholar 

  13. Rooney CM, Smith CA, Ng CYC et al. Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr virus-related lymphoproliferation Lancet 1995 345: 9 13

    Article  CAS  PubMed  Google Scholar 

  14. Heslop HE, Ng CYC, Li C et al. Long-term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes Nat Med 1996 2: 551 555

    Article  CAS  PubMed  Google Scholar 

  15. O‘Reilly RJ, Lacerda JF, Lucas KG et al. Adoptive cell therapy with donor lymphocytes for EBV-associated lymphomas developing after allogeneic marrow transplants. In : DeVita V, Hellman S, Rosenberg SA (eds) Important Advances in Oncology Lippincott: Philadelphia 1996 pp 149 166

    Google Scholar 

  16. Heslop HE, Rooney CM . Adoptive cellular immunotherapy for EBV lymphoproliferative diseases Immunol Rev 1997 157: 217 222

    Article  CAS  PubMed  Google Scholar 

  17. O'Reilly RJ, Small TN, Papadopoulos E et al. Biology and adoptive cell therapy of Epstein–Barr virus-associated lymphoproliferative disorders in recipients of marrow allografts Immunol Rev 1997 157: 195 216

    Article  CAS  PubMed  Google Scholar 

  18. Rooney CM, Smith CA, Ng CYC et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein–Barr virus-induced lymphoma in allogeneic transplant recipients Blood 1998 92: 1549 1555

    CAS  PubMed  Google Scholar 

  19. Gustafsson A, Levitsky V, Zou JZ et al. Epstein–Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells Blood 2000 95: 807 814

    CAS  PubMed  Google Scholar 

  20. Faye A, Van Den Abeele T, Peuchmaur M et al. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders Lancet 1998 352: 1285

    Article  CAS  PubMed  Google Scholar 

  21. Milpied N, Vasseur B, Parquet N et al. Humanized anti-CD20 monoclonal antibody (Rituximab) in post-transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients Ann Oncol 2000 11 (Suppl. 1): S113 S116

    Article  Google Scholar 

  22. Kuehnle I, Huls MH, Liu Z et al. CD20 monoclonal antibody (rituximab) for therapy of Epstein–Barr virus lymphoma after hematopoietic stem-cell transplantation Blood 2000 95: 1502 1505

    CAS  PubMed  Google Scholar 

  23. Riddler SA, Breinig MC, McKnight JK . Increased levels of circulating Epstein–Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of post-transplant lymphoproliferative disease in solid-organ transplant recipients Blood 1994 84: 972 984

    CAS  PubMed  Google Scholar 

  24. Savoie A, Perpete C, Carpentier L et al. 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: 2715 2722

    CAS  PubMed  Google Scholar 

  25. Kenagy DN, Schlesinger Y, Weck K et al. Epstein–Barr virus DNA in peripheral blood leukocytes of patients with post-transplant lymphoproliferative disease Transplantation 1995 60: 547 554

    Article  CAS  PubMed  Google Scholar 

  26. Rooney CM, Loftin SK, Holladay MS et al. Early identification of Epstein–Barr virus-associated post-transplantation lymphoproliferative disease Br J Haematol 1995 89: 98 103

    Article  CAS  PubMed  Google Scholar 

  27. Lucas KG, Burton RL, Zimmerman SE et al. Semiquantitative Epstein–Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation Blood 1998 91: 3654 3661

    CAS  PubMed  Google Scholar 

  28. Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors Transplantation 1974 18: 295 304

    Article  CAS  PubMed  Google Scholar 

  29. Herve P, Bordigoni P, Cahn JY et al. Use of monoclonal antibodies in vivo as therapeutic strategy for acute GVHD in matched and mismatched bone marrow transplantation Transplant Proc 1991 23: 1692 1694

    CAS  PubMed  Google Scholar 

  30. Buisson M, Morand P, Peoc'h M et al. Development of an Epstein–Barr virus type 2 (EBV-2)-associated hepatic B cell non-Hodgkin's lymphoma in an HIV-1-infected patient following a change in the EBV dominant type Leukemia 1999 13: 298 301

    Article  CAS  PubMed  Google Scholar 

  31. Haddad E, Paczesny S, Leblond V et al. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: multicenter phase 1–2 clinical trial Blood 2001 97: 1590 1597

    Article  CAS  PubMed  Google Scholar 

  32. Fina F, Romain S, Ouafik L et al. Frequency and genome load of Epstein–Barr virus in 509 breast cancers from different geographical areas Br J Cancer 2001 84: 783 790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Miyashita EM, Yang B, Lam KM et al. A novel form of Epstein–Barr virus latency in normal B cells in vivo Cell 1995 80: 593 601

    Article  CAS  PubMed  Google Scholar 

  34. Sirvent N, Reviron D, de Lamballerie X, Michel G . First report of Epstein–Barr virus lymphoproliferative disease after cord blood transplantation Bone Marrow Transplant 2000 25: 120 121

    Article  CAS  PubMed  Google Scholar 

  35. Faye A, Quartier P, Reguerre Y et al. Chimeric anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorders (B-PTLD) following stem cell transplantation in children Br J Haematol 2001 115: 112 118

    Article  CAS  PubMed  Google Scholar 

  36. Allen U, Hebert D, Petric M et al. Utility of semiquantitative polymerase chain reaction for Epstein–Barr virus to measure virus load in pediatric organ transplant recipients with and without posttransplant lymphoproliferative disease Clin Infect Dis 2001 33: 145 150

    Article  CAS  PubMed  Google Scholar 

  37. Beck R, Westdörp I, Jahn G et al. Detection of Epstein–Barr virus DNA in plasma from patients with lymphoproliferative disease after allogeneic bone marrow or peripheral stem cell transplantation J Clin Microbiol 1999 37: 3430 3431

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kimura H, Morita M, Yabuta Y et al. Quantitative analysis of Epstein–Barr virus load by using a real-time PCR assay J Clin Microbiol 1999 37: 132 136

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Baldanti F, Grossi P, Furione M et al. High levels of Epstein–Barr virus DNA in blood of solid-organ transplant recipients and their value in predicting posttransplant lymphoproliferative disorders J Clin Microbiol 2000 38: 613 619

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Niesters HGM, van Esser J, Fries E et al. Development of a real-time quantitative assay for detection of Epstein–Barr virus J Clin Microbiol 2000 38: 712 715

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Brengel Pesce K, Morand P, Schmuck A et al. Routine use of real-time quantitative PCR for laboratory diagnosis of Epstein–Barr virus infections J Med Virol (in press)

  42. Stevens SJ, Verschuuren EA, Pronke I et al. Frequent monotoring of Epstein–Barr virus DNA in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients Blood 2001 97: 1165 1171

    Article  CAS  PubMed  Google Scholar 

  43. Fontan J, Bassignot A, Mougin C et al. Detection of Epstein–Barr virus DNA in serum of transplanted patients: a new diagnostic guide for lymphoproliferative diseases Leukemia 1998 12: 772 775

    Article  CAS  PubMed  Google Scholar 

  44. Limaye AP, Huang ML, Atienza EE et al. Detection of Epstein–Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders J Clin Microbiol 1999 37: 1113 1116

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rose C, Green M, Webber S et al. Pediatric solid-organ transplant recipients carry chronic loads of Epstein–Barr virus exclusively in the immunoglobulin D-negative B-cell compartment J Clin Microbiol 2001 39: 1407 1415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rickinson AB, Moss DJ . Human cytotoxic T lymphocyte responses to Epstein–Barr virus infection Annu Rev Immunol 1997 15: 405 431

    Article  CAS  PubMed  Google Scholar 

  47. Flinn I, Orentas R, Noga SJ et al. Low risk of Epstein–Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) in patients receiving elutriated allogeneic marrow transplants may reflect depletion of EBV infected lymphocytes from the graft Blood 1995 86 (Suppl. 1): 626a (Abstr. 2490)

  48. Hale G, Waldmann H for CAMPATH users. Risk of developing Epstein–Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants Blood 1998 91: 3079 3083

    CAS  PubMed  Google Scholar 

  49. Cavazzana-Calvo M, Bensoussan D, Jabado N et al. Prevention of EBV-induced B-lymphoproliferative disorder by ex vivo marrow B-cell depletion in HLA-phenoidentical or non-identical T-depleted bone marrow transplantation Br J Haematol 1998 103: 543 551

    Article  CAS  PubMed  Google Scholar 

  50. Bonnefy-Berard N, Flacher M, Revillard JP . Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines Blood 1992 79: 2164 2170

    Google Scholar 

  51. Lucas KG, Smail TN, Heller G et al. The development of cellular immunity to Epstein–Barr virus following allogeneic bone marrow transplantation Blood 1996 87: 2594 2603

    CAS  PubMed  Google Scholar 

  52. Frank D, Cesarman E, Liu YF et al. Post-transplantation lymphoproliferative disorders frequently contain type A and not type B Epstein–Barr virus Blood 1995 85: 1396 1403

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grant from the Association pour la Recherche contre le Cancer (ARC), Villejuif, France

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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 29, 21–28 (2002). https://doi.org/10.1038/sj.bmt.1703331

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