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 Events

Preemptive therapy of human herpesvirus-6 encephalitis with foscarnet sodium for high-risk patients after hematopoietic SCT

Bone Marrow Transplantation volume 46, pages 863–869 (2011)Cite this article

Subjects

Abstract

Human herpesvirus-6 (HHV-6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic SCT (HSCT). A prospective, multicenter study was conducted to assess the safety and efficacy of preemptive therapy with foscarnet sodium (PFA) for the prevention of HHV-6 encephalitis. Plasma HHV-6 DNA was measured thrice weekly from day 7 until day 36 after umbilical cord blood transplantation (UCBT) or HSCT from HLA-haploidentical relatives. PFA, 90 mg/kg/day, was started when HHV-6 DNA exceeded 5 × 102 copies/mL. Mild and transient adverse events were associated with PFA in 7 of 8 patients. Twelve of 15 UCBT recipients became positive for HHV-6 DNAemia, defined by greater than 1 × 102 copies/mL of HHV-6 DNA in plasma. The virus exceeded 5 × 102 copies/mL in seven patients, whereas none of the five HLA-haploidentical HSCT recipients became positive. One patient developed mild limbic encephalitis just after initial PFA administration. Preemptive PFA therapy is safe, but as HHV-6 DNAemia can abruptly develop before neutrophil engraftment in UCBT recipients, prophylactic PFA administration from day 7 or earlier after UCBT may be needed.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Rocha V, Wagner Jr JE, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342: 1846–1854.

    Article  CAS  PubMed  Google Scholar 

  2. Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001; 97: 2962–2971.

    Article  CAS  PubMed  Google Scholar 

  3. Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ . Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant 2002; 8: 257–260.

    Article  PubMed  Google Scholar 

  4. Grewal SS, Barker JN, Davies SM, Wagner JE . Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood 2003; 101: 4233–4244.

    Article  CAS  PubMed  Google Scholar 

  5. Moretta A, Maccario R, Fagioli F, Giraldi E, Busca A, Montagna D et al. Analysis of immune reconstitution in children undergoing cord blood transplantation. Exp Hematol 2001; 29: 371–379.

    Article  CAS  PubMed  Google Scholar 

  6. Niehues T, Rocha V, Filipovich AH, Chan KW, Porcher R, Michel G et al. Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children—a Eurocord analysis. Br J Haematol 2001; 114: 42–48.

    Article  CAS  PubMed  Google Scholar 

  7. Locatelli F, Maccario R, Comoli P, Bertolini F, Giorgiani G, Montagna D et al. Hematopoietic and immune recovery after transplantation of cord blood progenitor cells in children. Bone Marrow Transplant 1996; 18: 1095–1101.

    CAS  PubMed  Google Scholar 

  8. Thomson BG, Robertson KA, Gowan D, Heilman D, Broxmeyer HE, Emanuel D et al. Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation. Blood 2000; 96: 2703–2711.

    CAS  PubMed  Google Scholar 

  9. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351: 2265–2275.

    Article  CAS  PubMed  Google Scholar 

  10. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004; 351: 2276–2285.

    Article  CAS  PubMed  Google Scholar 

  11. Yoshikawa T, Ihira M, Ohashi M, Suga S, Asano Y, Miyazaki H et al. Correlation between HHV-6 infection and skin rash after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 77–81.

    Article  CAS  PubMed  Google Scholar 

  12. Yoshikawa T, Suga S, Asano Y, Nakashima T, Yazaki T, Sobue R et al. Human herpesvirus-6 infection in bone marrow transplantation. Blood 1991; 78: 1381–1384.

    CAS  PubMed  Google Scholar 

  13. Drobyski WR, Knox KK, Majewski D, Carrigan DR . Brief report: fatal encephalitis due to variant B human herpesvirus-6 infection in a bone marrow-transplant recipient. N Engl J Med 1994; 330: 1356–1360.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  15. Noguchi T, Mihara F, Yoshiura T, Togao O, Atsumi K, Matsuura T et al. MR imaging of human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation in adults. AJNR Am J Neuroradiol 2006; 27: 2191–2195.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zerr DM, Gupta D, Huang ML, Carter R, Corey L . Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 309–317.

    Article  CAS  PubMed  Google Scholar 

  17. Fujimaki K, Mori T, Kida A, Tanaka M, Kawai N, Matsushima T et al. Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients. Int J Hematol 2006; 84: 432–437.

    Article  CAS  PubMed  Google Scholar 

  18. Huang LM, Kuo PF, Lee CY, Chen JY, Liu MY, Yang CS . Detection of human herpesvirus-6 DNA by polymerase chain reaction in serum or plasma. J Med Virol 1992; 38: 7–10.

    Article  CAS  PubMed  Google Scholar 

  19. Secchiero P, Carrigan DR, Asano Y, Benedetti L, Crowley RW, Komaroff AL et al. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. J Infect Dis 1995; 171: 273–280.

    Article  CAS  PubMed  Google Scholar 

  20. Chan PK, Peiris JS, Yuen KY, Liang RH, Lau YL, Chen FE et al. Human herpesvirus-6 and human herpesvirus-7 infections in bone marrow transplant recipients. J Med Virol 1997; 53: 295–305.

    Article  CAS  PubMed  Google Scholar 

  21. Imbert-Marcille BM, Tang XW, Lepelletier D, Besse B, Moreau P, Billaudel S et al. Human herpesvirus 6 infection after autologous or allogeneic stem cell transplantation: a single-center prospective longitudinal study of 92 patients. Clin Infect Dis 2000; 31: 881–886.

    Article  CAS  PubMed  Google Scholar 

  22. Wang FZ, Dahl H, Linde A, Brytting M, Ehrnst A, Ljungman P . Lymphotropic herpesviruses in allogeneic bone marrow transplantation. Blood 1996; 88: 3615–3620.

    CAS  PubMed  Google Scholar 

  23. Wang H, Zhu L, Xue M, Liu J, Guo Z . Low-dose foscarnet preemptive therapy for cytomegalovirus viremia after haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15: 519–520.

    Article  CAS  PubMed  Google Scholar 

  24. Ogata M, Kikuchi H, Satou T, Kawano R, Ikewaki J, Kohno K et al. Human herpesvirus 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 

  25. Kimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima S 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 

  26. Tanaka N, Kimura H, Hoshino Y, Kato K, Yoshikawa T, Asano Y et al. Monitoring four herpesviruses in unrelated cord blood transplantation. Bone Marrow Transplant 2000; 26: 1193–1197.

    Article  CAS  PubMed  Google Scholar 

  27. Yoshihara S, Kato R, Inoue T, Miyagawa H, Sashihara J, Kawakami M et al. Successful treatment of life-threatening human herpesvirus-6 encephalitis with donor lymphocyte infusion in a patient who had undergone human leukocyte antigen-haploidentical nonmyeloablative stem cell transplantation. Transplantation 2004; 77: 835–838.

    Article  PubMed  Google Scholar 

  28. Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A, Ljungman P . Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: does it have clinical significance? Clin Infect Dis 1999; 28: 562–568.

    Article  CAS  PubMed  Google Scholar 

  29. Singh N, Carrigan DR . Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996; 124: 1065–1071.

    Article  CAS  PubMed  Google Scholar 

  30. Narimatsu H, Kami M, Kato D, Matsumura T, Murashige N, Kusumi E et al. Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation. Transpl Infect Dis 2007; 9: 11–15.

    Article  CAS  PubMed  Google Scholar 

  31. Le Cleach L, Joberty C, Fillet AM, Sutton L, Cordonnier C, Frances C et al. Human herpesvirus 6 infection in patients with exanthema after allogeneic bone marrow transplantation. Arch Dermatol 1998; 134: 759–760.

    Article  CAS  PubMed  Google Scholar 

  32. Cone RW, Huang ML, Corey L, Zeh J, Ashley R, Bowden R . Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations. J Infect Dis 1999; 179: 311–318.

    Article  CAS  PubMed  Google Scholar 

  33. Volin L, Lautenschlager I, Juvonen E, Nihtinen A, Anttila VJ, Ruutu T . Human herpesvirus 6 antigenaemia in allogeneic stem cell transplant recipients: impact on clinical course and association with other beta-herpesviruses. Br J Haematol 2004; 126: 690–696.

    Article  PubMed  Google Scholar 

  34. Yamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y et al. Risk factors for developing human herpesvirus 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 

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

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Rapaport D, Engelhard D, Tagger G, Or R, Frenkel N . Antiviral prophylaxis may prevent human herpesvirus-6 reactivation in bone marrow transplant recipients. Transpl Infect Dis 2002; 4: 10–16.

    Article  CAS  PubMed  Google Scholar 

  38. Tokimasa S, Hara J, Osugi Y, Ohta H, Matsuda Y, Fujisaki H et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 29: 595–598.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms Rie Ohumi (Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, and Kiyotaka Miyamoto, SRL Inc.) for excellent technical assistance. We also thank the following doctors who contributed to this study: Shigeru Shimadoi of Kanazawa University Hospital; Shuichi Miyawaki, Toru Sakura and Satoru Takada of Saiseikai Maebashi Hospital; Toshiro Kurokawa and Jun Ozaki of Toyama Prefectural Central Hospital; and Go Aoki of Ishikawa Prefectural Central Hospital.

Funding: This work was supported by a Grant-in-Aid for Cancer Research (19–1) from the Ministry of Health, Labour and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan

    K Ishiyama & S Nakao

  2. Department of Clinical Laboratory Science, Division of Health Sciences, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan

    T Katagiri

  3. Department of Hematology, Saiseikai Maebashi Hospital, Gunma, Japan

    T Hoshino

  4. Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan

    T Yoshida

  5. Department of Hematology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan

    M Yamaguchi

Authors
  1. K Ishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Nakao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishiyama, K., Katagiri, T., Hoshino, T. et al. Preemptive therapy of human herpesvirus-6 encephalitis with foscarnet sodium for high-risk patients after hematopoietic SCT. Bone Marrow Transplant 46, 863–869 (2011). https://doi.org/10.1038/bmt.2010.201

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2010.201

Keywords

This article is cited by

Search

Advanced search

Quick links