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:

Microbial Issues

Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients

Bone Marrow Transplantation volume 47, pages 1222–1228 (2012)Cite this article

Subjects

Abstract

Ulcerative oral mucositis and infection are frequent complications in hematopoietic stem cell transplant (HSCT) recipients. The aim of this study was to investigate the relationship between oral ulcerations and HSV-1, EBV and CMV excretion and the presence of aciclovir-resistant HSV-1 strains in HSCT recipients. This prospective observational study included 49 adult patients who underwent allogeneic HSCT. In total, 26 patients received myeloablative and 23 received non-myeloablative conditioning. Ulcerations on non-keratinized and keratinized oral mucosa were scored and oral rinsing samples were taken twice weekly. Viral loads were determined by real-time PCR. Samples from patients remaining HSV-1 positive despite antiviral treatment were studied for resistance to antivirals. Having an HSV-1 or EBV DNA–positive sample was a significant predictor for ulceration of keratinized mucosa. HSV-1 was a significant predictor for ulcerations on non-keratinized mucosa as well. Persistent HSV-1 infection occurred in 12 of 28 patients treated with antiviral medication and aciclovir-resistant HSV-1 was found in 5 persistent infections. In conclusion, HSV-1 is a predictor of ulcerations on non-keratinized as well as keratinized oral mucosa following HSCT. The role of EBV deserves further study. Persistent HSV-1 replication despite antiviral treatment is common and is due to resistance in 18% of treated patients.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. McGuire DB, Altomonte V, Peterson DE, Wingard JR, Jones RJ, Grochow LB . Patterns of mucositis and pain in patients receiving preparative chemotherapy and bone marrow transplantation. Oncol Nurs Forum 1993; 20: 1493–1502.

    CAS  PubMed  Google Scholar 

  2. Takahashi K, Soga Y, Murayama Y, Udagawa M, Nishimoto H, Sugiura Y et al. Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen. Support Care Cancer 2009; 18: 115–119.

    Article  PubMed  Google Scholar 

  3. Vagliano L, Feraut C, Gobetto G, Trunfio A, Errico A, Campani V et al. Incidence and severity of oral mucositis in patients undergoing haematopoietic SCT (HSCT)-results of a multicentre study. Bone Marrow Transplant 2010; 46: 727–732.

    Article  PubMed  Google Scholar 

  4. Woo SB, Sonis ST, Sonis AL . The role of herpes simplex virus in the development of oral mucositis in bone marrow transplant recipients. Cancer 1990; 66: 2375–2379.

    Article  CAS  PubMed  Google Scholar 

  5. Woo SB, Sonis ST, Monopoli MM, Sonis AL . A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer 1993; 72: 1612–1617.

    Article  CAS  PubMed  Google Scholar 

  6. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ . Patient reports of complications of bone marrow transplantation. Support Care Cancer 2000; 8: 33–39.

    CAS  PubMed  Google Scholar 

  7. Fanning SR, Rybicki L, Kalaycio M, Andresen S, Kuczkowski E, Pohlman B et al. Severe mucositis is associated with reduced survival after autologous stem cell transplantation for lymphoid malignancies. Br J Haematol 2006; 135: 374–381.

    Article  CAS  PubMed  Google Scholar 

  8. Djuric M, Jankovic L, Jovanovic T, Pavlica D, Brkic S, Knezevic A et al. Prevalence of oral herpes simplex virus reactivation in cancer patients: a comparison of different techniques of viral detection. J Oral Pathol Med 2009; 38: 167–173.

    Article  CAS  PubMed  Google Scholar 

  9. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R et al. A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea. Support Care Cancer 2010; 18: 993–1006.

    Article  PubMed  Google Scholar 

  10. Schubert MM, Peterson DE, Flournoy N, Meyers JD, Truelove EL . Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection. Oral Surg Oral Med Oral Pathol 1990; 70: 286–293.

    Article  CAS  PubMed  Google Scholar 

  11. Kameyama T, Sujaku C, Yamamoto S, Hwang CB, Shillitoe EJ . Shedding of herpes simplex virus type 1 into saliva. J Oral Pathol 1988; 17: 478–481.

    Article  CAS  PubMed  Google Scholar 

  12. Danve-Szatanek C, Aymard M, Thouvenot D, Morfin F, Agius G, Bertin I et al. Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up. J Clin Microbiol 2004; 42: 242–249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morfin F, Bilger K, Boucher A, Thiebaut A, Najioullah F, Bleyzac N et al. HSV excretion after bone marrow transplantation: a 4-year survey. J Clin Virol 2004; 30: 341–345.

    Article  PubMed  Google Scholar 

  14. Stranska R, Schuurman R, Nienhuis E, Goedegebuure IW, Polman M, Weel JF et al. Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol 2005; 32: 7–18.

    Article  CAS  PubMed  Google Scholar 

  15. Lloid ME, Schubert MM, Myerson D, Bowden R, Meyers JD, Hackman RC . Cytomegalovirus infection of the tongue following marrow transplantation. Bone Marrow Transplant 1994; 14: 99–104.

    CAS  PubMed  Google Scholar 

  16. Birek C, Patterson B, Maximiw WC, Minden MD . EBV and HSV infections in a patient who had undergone bone marrow transplantation: oral manifestations and diagnosis by in situ nucleic acid hybridization. Oral Surg Oral Med Oral Pathol 1989; 68: 612–617.

    Article  CAS  PubMed  Google Scholar 

  17. Ling PD, Lednicky JA, Keitel WA, Poston DG, White ZS, Peng R et al. The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J Infect Dis 2003; 187: 1571–1580.

    Article  PubMed  Google Scholar 

  18. Lucht E, Brytting M, Bjerregaard L, Julander I, Linde A . Shedding of cytomegalovirus and herpesviruses 6, 7, and 8 in saliva of human immunodeficiency virus type 1-infected patients and healthy controls. Clin Infect Dis 1998; 27: 137–141.

    Article  CAS  PubMed  Google Scholar 

  19. Kalpoe JS, van der Heiden PL, Vaessen N, Claas EC, Barge RM, Kroes AC . Comparable incidence and severity of cytomegalovirus infections following T cell-depleted allogeneic stem cell transplantation preceded by reduced intensity or myeloablative conditioning. Bone Marrow Transplant 2007; 40: 137–143.

    Article  CAS  PubMed  Google Scholar 

  20. Barge RM, Brouwer RE, Beersma MF, Starrenburg CW, Zwinderman AH, Hale G et al. Comparison of allogeneic T cell-depleted peripheral blood stem cell and bone marrow transplantation: effect of stem cell source on short- and long-term outcome. Bone Marrow Transplant 2001; 27: 1053–1058.

    Article  CAS  PubMed  Google Scholar 

  21. Barge RM, Osanto S, Marijt WA, Starrenburg CW, Fibbe WE, Nortier JW et al. Minimal GVHD following in-vitro T cell-depleted allogeneic stem cell transplantation with reduced-intensity conditioning allowing subsequent infusions of donor lymphocytes in patients with hematological malignancies and solid tumors. Exp Hematol 2003; 31: 865–872.

    Article  CAS  PubMed  Google Scholar 

  22. World Health Organization. Handbook for reporting results of cancer treatment. World Health Organization: Geneva, pp. 1979, 16–17.

  23. Kalpoe JS, Kroes AC, de Jong MD, Schinkel J, de Brouwer CS, Beersma MF et al. Validation of clinical application of cytomegalovirus plasma DNA load measurement and definition of treatment criteria by analysis of correlation to antigen detection. J Clin Microbiol 2004; 42: 1498–1504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Niesters HG, van EJ, 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 

  25. van der Beek MT, Claas EC, van der Blij-de Brouwer CS, Morfin F, Rusman LG, Kroes ACM et al. Rapid susceptibility testing for Herpes Simplex Virus type 1. Antiviral Res (submitted).

  26. Gaudreau A, Hill E, Balfour Jr HH, Erice A, Boivin G . Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis 1998; 178: 297–303.

    Article  CAS  PubMed  Google Scholar 

  27. Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009; 43: 757–770.

    Article  CAS  PubMed  Google Scholar 

  28. Ruping MJ, Keulertz C, Vehreschild JJ, Lovenich H, Sohngen D, Wieland U et al. Association of HSV reactivation and pro-inflammatory cytokine levels with the severity of stomatitis after BEAM chemotherapy and autologous SCT. Support Care Cancer 2010; 19: 1211–1216.

    Article  PubMed  Google Scholar 

  29. Andrei G, Balzarini J, Fiten P, De CE, Opdenakker G, Snoeck R . Characterization of herpes simplex virus type 1 thymidine kinase mutants selected under a single round of high-dose brivudin. J Virol 2005; 79: 5863–5869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Duan R, de Vries RD, van Dun JM, van Loenen FB, Osterhaus AD, Remeijer L et al. Acyclovir susceptibility and genetic characteristics of sequential herpes simplex virus type 1 corneal isolates from patients with recurrent herpetic keratitis. J Infect Dis 2009; 200: 1402–1414.

    Article  CAS  PubMed  Google Scholar 

  31. Schmit I, Boivin G . Characterization of the DNA polymerase and thymidine kinase genesof herpes simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed. J Infect Dis 1999; 180: 487–490.

    Article  CAS  PubMed  Google Scholar 

  32. Ambinder RF, Wingard JR, Burns WH, Hayward SD, Saral R, Perry HR et al. Detection of Epstein-Barr virus DNA in mouthwashes by hybridization. J Clin Microbiol 1985; 21: 353–356.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mendoza N, Diamantis M, Arora A, Bartlett B, Gewirtzman A, Tremaine AM et al. Mucocutaneous manifestations of Epstein-Barr virus infection. Am J Clin Dermatol 2008; 9: 295–305.

    Article  PubMed  Google Scholar 

  34. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES . EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010; 34: 405–417.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Tom Vreeswijk for technical assistance and Harrie Tran, Els Penders, Nicole Dekkers, Pamela Dekkers, Willemien Molenaar, Tina Klemann, Tricia Garman and Cindy Verdegaal for assisting in the sample collection.

Author information

Author notes

  1. M T van der Beek and A M G A Laheij: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

    M T van der Beek, C S van der Blij-de Brouwer, E C J Claas, A C M Kroes & A C T M Vossen

  2. Department of Preventive Dentistry, Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University, Amsterdam, The Netherlands

    A M G A Laheij, J E Raber-Durlacher, C van Loveren & J J de Soet

  3. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    J E Raber-Durlacher & P A von dem Borne

  4. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands

    R Wolterbeek

Authors
  1. M T van der Beek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M G A Laheij
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J E Raber-Durlacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P A von dem Borne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Wolterbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C S van der Blij-de Brouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C van Loveren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E C J Claas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A C M Kroes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J J de Soet
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A C T M Vossen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M T van der Beek.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van der Beek, M., Laheij, A., Raber-Durlacher, J. et al. Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 47, 1222–1228 (2012). https://doi.org/10.1038/bmt.2012.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.2

Keywords

This article is cited by

Search

Advanced search

Quick links