Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Post-Transplant Complications

Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT

Abstract

Hematopoietic SCT (HSCT) is often complicated by viral reactivations. In this retrospective cohort study (January 2004–August 2008), predictors for human herpes virus 6 (HHV6)-reactivation and associations between HHV6-reactivation and clinical outcomes after allogeneic HSCT were studied. HHV6 DNA load in plasma was monitored weekly by quantitative real-time PCR. Associations between the main end point HHV6-reactivation and other end points, that is, acute GVHD (aGVHD) and NRM were analyzed using Cox proportional hazard models. In total, 108 patients receiving either a myeloablative (MA; n=60) or non-myeloablative (NMA; n=48) conditioning regimen were included. Median age was 40 years (range 17–65); median follow-up was 20 months (range 3–36). In 16/60 (27%) patients with MA conditioning regimen, a HHV6 reactivation was observed (mean viral load 50 323 cp/mL) compared with 2/48 (4%) patients with a NMA conditioning regimen with low viral load (mean 1100 cp/mL). In multivariate analysis, MA conditioning was the only predictor for HHV6 reactivation (P=0.02). In addition, HHV6 reactivation was associated with grades 2–4 aGVHD (P<0.001) and NRM (P=0.03). Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD, all of which may improve clinical outcome.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Wasserman R, August CS, Plotkin SA . Viral infections in pediatric bone marrow transplant patients. Pediatr Infect Dis J 1988; 7: 109–115.

    Article  CAS  PubMed  Google Scholar 

  2. Gratama JW, Zwaan FE, Stijnen T, Weijers TF, Weiland HT, D'Amaro J et al. Herpes-virus immunity and acute graft-versus-host disease. Lancet 1987; 1: 471–474.

    Article  CAS  PubMed  Google Scholar 

  3. Broers AE, van Der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood 2000; 95: 2240–2245.

    CAS  PubMed  Google Scholar 

  4. de Pagter APJ, Schuurman R, Visscher H, de Vos NM, Bierings M, van Loon AM et al. Human herpes virus 6 plasma DNA positivity after hematopoietic stem cell transplantation in children: an important risk factor for clinical outcome. Biol Blood Marrow Transplant 2008; 14: 831–839.

    Article  PubMed  Google Scholar 

  5. Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M . Clinical outcomes of human herpes virus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40: 932–940.

    Article  PubMed  Google Scholar 

  6. Dulery R, Salleron J, Dewilde A, Rossignol J, Boyle EM, Gay J et al. Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study. Biol Blood Marrow Transplant 2011; 12: 579 (online).

    Google Scholar 

  7. Zerr DM, Boeckh M, Delaney C, Martin PJ, Xie H, Adler AL et al. HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 12: 1016.

    Google Scholar 

  8. de Pagter PJ, Schuurman R, Meijer E, Baarle D, Sanders EA, Boelens J . Human Herpes virus type 6 reactivation after haematopoietic stem cell transplantation. J Clin Virol 2008; 43: 361–368.

    Article  CAS  PubMed  Google Scholar 

  9. De Bolle L, Naesens L, De Clercq E . Update on human herpes virus 6 biology, clinical features, and therapy. Clin Microbiol Rev 2005; 18: 217–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  11. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  12. Hekker AC, Brand-Saathof B, Vis J, Meijers RC . Indirect immunofluorescence test for detection of IgM antibodies to cytomegalovirus. J Infect Dis 1979; 140: 596–600.

    Article  CAS  PubMed  Google Scholar 

  13. Okuno T, Takahashi K, Balachandra K, Shiraki K, Yamanishi K, Takahashi M et al. Seroepidemiology of human herpes virus 6 infection in normal children and adults. J Clin Microbiol 1989; 27: 651–653.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A et al. A population-based study of primary human herpes virus 6 infection. N Engl J Med 2005; 352: 768–776.

    Article  CAS  PubMed  Google Scholar 

  15. Niesters HG, van Esser J, Fries E, Wolthers KC, Cornelissen J, Osterhaus AD . 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 

  16. van Doornum GJ, Guldemeester J, Osterhaus AD, Niesters HG . Diagnosing herpes virus infections by real-time amplification and rapid culture. J Clin Microbiol 2003; 41: 576–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ryncarz AJ, Goddard J, Wald A, Huang ML, Roizman B, Corey L . Development of a high-throughput quantitative assay for detecting herpes simplex virus DNA in clinical samples. J Clin Microbiol 1999; 37: 1941–1947.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Knoll A, Stoehr R, Jilg W, Hartmann A . Low frequency of human polyomavirus BKV and JCV DNA in urothelial carcinomas of the renal pelvis and renal cell carcinomas. Oncol Rep 2003; 10: 487–491.

    PubMed  Google Scholar 

  19. Hawrami K, Breuer J . Development of a fluorogenic polymerase chain reaction assay (TaqMan) for the detection and quantitation of varicella zoster virus. J Virol Methods 1999; 79: 33–40.

    Article  CAS  PubMed  Google Scholar 

  20. Pagter, de PJ, Schuurman R, de Vos NM, Mackay W, van Loon AM . Multicenter external quality assessment of molecular methods for detection of human herpesvirus 6. J Clin Microbiol 2010; 48: 2536–2540.

    Article  Google Scholar 

  21. van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW et al. Prevention of Epstein–Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99: 4364–4369.

    Article  CAS  PubMed  Google Scholar 

  22. Boeckh M, Ljungman P . How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood 2009; 113: 5711–5719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lindemans CA, Leen AM, Boelens JJ . How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood 2010; 116: 5476–5485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tiercy JM . Molecular basis of HLA polymorphism: implications in clinical transplantation. Transpl Immunol. 2002; 9: 173–180.

    Article  CAS  PubMed  Google Scholar 

  25. Hentrich M, Oruzio D, Jäger G, Schlemmer M, Schleuning M, Schiel X et al. Impact of human herpes virus-6 after haematopoietic stem cell transplantation. Br J Haematol 2005; 128: 66–72.

    Article  PubMed  Google Scholar 

  26. Luppi M, Marasca R, Barozzi P, Ferrari S, Ceccherini-Nelli L, Batoni G et al. Three cases of human herpesvirus-6 latent infection: integration of viral genome in peripheral blood mononuclear cell DNA. J Med Virol 1993; 40: 44–52.

    Article  CAS  PubMed  Google Scholar 

  27. De Pagter PJ, Virgili A, Nacheva E, van Baarle D, Schuurman R, Boelens JJ . Chromosomally integrated human herpesvirus 6: transmission via cord blood-derived unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16: 130–132.

    Article  CAS  PubMed  Google Scholar 

  28. Yamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y et al. Risk factors for developing human herpes virus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders. Biol Blood Marrow Transplant 2007; 13: 100–106.

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka M, Taguchi J, Hyo R, Kawano T, Hashimoto C, Motomura S et al. Human herpes virus-6 encephalitis after unrelated cord blood transplantation. Leuk Lymphoma 2005; 46: 561–566.

    Article  CAS  PubMed  Google Scholar 

  30. Sashihara J, Tanaka-Taya K, Tanaka S, Amo K, Miyagawa H, Hosoi G et al. High incidence of human herpes virus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood 2002; 100: 2005–2011.

    CAS  PubMed  Google Scholar 

  31. Tomonari A, Takahashi S, Ooi J, Iseki T, Takasugi K, Uchiyama M et al. Human herpes virus 6 variant B infection in adult patients after unrelated cord blood transplantation. Int J Hematol 2005; 81: 352–355.

    Article  PubMed  Google Scholar 

  32. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 1999; 94: 3234–3241.

    CAS  PubMed  Google Scholar 

  33. Radonic A, Oswald O, Thulke S, Brockhaus N, Nitsche A, Siegert W et al. Infections with human herpes virus 6 variant B delay platelet engraftment after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 131: 480–482.

    Article  PubMed  Google Scholar 

  34. Ogata M, Kikuchi H, Satou T, Kawano R, Ikewaki J, Kohno K et al. Human herpes virus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance. J Infect Dis 2006; 193: 68–79.

    Article  CAS  PubMed  Google Scholar 

  35. Morris ES, Hill GR . Advances in the understanding of acute graft-versus-host disease. Br J Haematol 2007; 137: 3–19.

    Article  CAS  PubMed  Google Scholar 

  36. Shlomchik WD . Graft-versus-host disease. Nat Rev Immunol 2007; 7: 340–352.

    Article  CAS  PubMed  Google Scholar 

  37. Feuchtinger T, Lang P, Handgretinger R . Adenovirus infection after allogeneic stem cell transplantation. Leuk Lymphoma 2007; 48: 244–255.

    Article  CAS  PubMed  Google Scholar 

  38. Via CS, Shanley JD, Shearer GM . Synergistic effect of murine cytomegalovirus on the induction of acute graft-vs-host disease involving MHC class I differences only. Analysis of in vitro T cell function. J Immunol 1990; 145: 3283–3289.

    CAS  PubMed  Google Scholar 

  39. Wang LR, Dong LJ, Zhang MJ, Lu DP . The impact of human herpes virus 6B reactivation on early complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 1031–1037.

    Article  PubMed  Google Scholar 

  40. Yoshikawa T, Goshima F, Akimoto S . Human herpesvirus 6 infection of human epidermal cell line; pathogenesis of skin manifestations. J Med Virol 2003; 71: 62–68.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the HSCT coordinators of UMC Utrecht and Erasmus MC Rotterdam, The Netherlands for their help in collecting clinical data. We thank M Beersma and the Department of Virology, Erasmus MC, Rotterdam, the Netherlands for their help in determining HHV6 viral load.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P J A de Pagter.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Pagter, P., Schuurman, R., Keukens, L. et al. Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT. Bone Marrow Transplant 48, 1460–1464 (2013). https://doi.org/10.1038/bmt.2013.78

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2013.78

Keywords

This article is cited by

Search

Quick links