Supportive Care in Cancer

, Volume 18, Issue 8, pp 993–1006 | Cite as

A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea

  • Sharon EladEmail author
  • Yehuda Zadik
  • Ian Hewson
  • Allan Hovan
  • M. Elvira P. Correa
  • Richard Logan
  • Linda S. Elting
  • Fred K. L. Spijkervet
  • Michael T. Brennan
  • Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)
Review Article



Our aim was to evaluate the literature for the prevalence of and interventions for oral viral infections and, based on scientific evidence, point to effective treatment protocols. Quality of life (QOL) and economic impact were assessed if available in the articles reviewed.


Our search of the English literature focused on oral viral infections in cancer patients within the timeframe of 1989–2007. Review methods were standardized. Cohort studies were used to determine the weighted prevalence of oral viral infection in cancer patients. The quality of selected articles were assessed and scored with respect to sources of bias, representativeness, scale validity, and sample size. Interventional studies were utilized to determine management guidelines. Literature search included measures of QOL and economic variables.


Prevalence of oral herpes simplex virus (HSV) infection in neutropenic patients was higher than in patients treated with radiotherapy for head and neck cancer (49.8% vs. 0%, respectively). In patients treated with radiochemotherapy for head and neck cancer, the prevalence of oral HSV infection increases up to 43.2% (CI, 0–100%). Prevalence of HSV infection was higher when oral ulcers existed. Information about other oral viral infections is sparse. There was a significant benefit of using acyclovir to prevent HSV oral infection (at 800 mg/day). Various dosing protocols of valacyclovir achieved prevention of HSV reactivation (500 or 1,000 mg/day). The prevalence of HSV reactivation was similar for acyclovir and valacyclovir. No information about impact on QOL and economic burden was available.


Acyclovir and valacyclovir are equally effective in preventing oral HSV infection. Neutropenic patients, who were primarily treated for hematological malignancies in the studies reviewed, are at a greater risk for viral infection.


Viral Infection Herpes Oral Complication Cancer HSV Acyclovir Valacyclovir 


Conflict of interest

None to declare.


  1. 1.
    Greenberg MS (1996) Herpesvirus infections. Dent Clin N Am 40:359–368PubMedGoogle Scholar
  2. 2.
    Heimdahl A (1999) Prevention and management of oral infections in cancer patients. Support Care Cancer 7:224–228CrossRefPubMedGoogle Scholar
  3. 3.
    Khan SA, Wingard JR (2001) Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr (29):31–36Google Scholar
  4. 4.
    Wingard JR (1990) Oral complications of cancer therapies. Infectious and noninfectious systemic consequences. NCI Monogr (9):21–26Google Scholar
  5. 5.
    Dreizen S, Bodey GP, Valdivieso M (1983) Chemotherapy-associated oral infections in adults with solid tumors. Oral Surg Oral Med Oral Pathol 55:113–120CrossRefPubMedGoogle Scholar
  6. 6.
    Montgomery MT, Redding SW, LeMaistre CF (1986) The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy. Oral Surg Oral Med Oral Pathol 61:238–242CrossRefPubMedGoogle Scholar
  7. 7.
    Barrett AP (1986) A long-term prospective clinical study of orofacial herpes simplex virus infection in acute leukemia. Oral Surg Oral Med Oral Pathol 61:149–152CrossRefPubMedGoogle Scholar
  8. 8.
    Saral R, Burns WH, Laskin OL et al (1981) Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 305:63–67CrossRefPubMedGoogle Scholar
  9. 9.
    Saral R, Ambinder RF, Burns WH et al (1983) Acyclovir prophylaxis against herpes simplex virus infection in patients with leukemia. A randomized, double-blind, placebo-controlled study. Ann Intern Med 99:773–776PubMedGoogle Scholar
  10. 10.
    Wade JC, Newton B, Flournoy N et al (1984) Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med 100:823–828PubMedGoogle Scholar
  11. 11.
    Shepp DH, Dandliker PS, Flournoy N et al (1987) Sequential intravenous and twice-daily oral acyclovir for extended prophylaxis of herpes simplex virus infection in marrow transplant patients. Transplantation 43:654–658CrossRefPubMedGoogle Scholar
  12. 12.
    Mitchell CD, Bean B, Gentry SR et al (1981) Acyclovir therapy for mucocutaneous herpes simplex infections in immunocompromised patients. Lancet 1:1389–1392CrossRefPubMedGoogle Scholar
  13. 13.
    Straus SE, Smith HA, Brickman C et al (1982) Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med 96:270–277PubMedGoogle Scholar
  14. 14.
    Wade JC, Newton B, McLaren C et al (1982) Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial. Ann Intern Med 96:265–269PubMedGoogle Scholar
  15. 15.
    Shepp DH, Newton BA, Dandliker PS et al (1985) Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients. Ann Intern Med 102:783–785PubMedGoogle Scholar
  16. 16.
    Tricot G, De Clercq E, Boogaerts MA et al (1986) Oral bromovinyldeoxyuridine therapy for herpes simplex and varicella-zoster virus infections in severely immunosuppressed patients: a preliminary clinical trial. J Med Virol 18:11–20CrossRefPubMedGoogle Scholar
  17. 17.
    Brennan MS, Elting LS, Spijkervet FK (2010) Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer. doi: 10.1007/s00520-010-0856-3
  18. 18.
    Somerfield M, Padberg J, Pfister D et al (2000) ASCO clinical practice guidelines: process, progress, pitfalls and prospects. Class Pap Curr Comments 4:881–886Google Scholar
  19. 19.
    Hadorn DC, Baker D, Hodges JS et al (1996) Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 49:749–754CrossRefPubMedGoogle Scholar
  20. 20.
    Bergmann OJ, Ellermann-Eriksen S, Mogensen SC et al (1995) Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial. Bmj 310:1169–1172PubMedGoogle Scholar
  21. 21.
    Bergmann OJ, Mogensen SC, Ellermann-Eriksen S et al (1997) Acyclovir prophylaxis and fever during remission-induction therapy of patients with acute myeloid leukemia: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 15:2269–2274PubMedGoogle Scholar
  22. 22.
    Sepulveda E, Brethauer U, Rojas J et al (2005) Oral ulcers in children under chemotherapy: clinical characteristics and their relation with herpes simplex virus type 1 and Candida albicans. Med Oral Patol Oral Cir Bucal 10(Suppl 1):E1–E8Google Scholar
  23. 23.
    Sepulveda Tebache E, Brethauer Meier U, Jimenez Moraga M et al (2003) Herpes simplex virus detection in oral mucosa lesions in patients undergoing oncologic therapy. Med Oral 8:329–333PubMedGoogle Scholar
  24. 24.
    Warkentin DI, Epstein JB, Campbell LM et al (2002) Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients. Ann Pharmacother 36:1525–1531CrossRefPubMedGoogle Scholar
  25. 25.
    Rojas de Morales T, Zambrano O, Rivera L et al (2001) Oral-disease prevention in children with cancer: testing preventive protocol effectiveness. Med Oral 6:326–334PubMedGoogle Scholar
  26. 26.
    Orlowski RZ, Mills SR, Hartley EE et al (2004) Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia. Leuk Lymphoma 45:2215–2219CrossRefPubMedGoogle Scholar
  27. 27.
    Liesveld JL, Abboud CN, Ifthikharuddin JJ et al (2002) Oral valacyclovir versus intravenous acyclovir in preventing herpes simplex virus infections in autologous stem cell transplant recipients. Biol Blood Marrow Transplant 8:662–665CrossRefPubMedGoogle Scholar
  28. 28.
    Eisen D, Essell J, Broun ER et al (2003) Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy. Bone Marrow Transplant 31:51–55CrossRefPubMedGoogle Scholar
  29. 29.
    Redding SW, Luce EB, Boren MW (1990) Oral herpes simplex virus infection in patients receiving head and neck radiation. Oral Surg Oral Med Oral Pathol 69:578–580CrossRefPubMedGoogle Scholar
  30. 30.
    Epstein JB, Gorsky M, Hancock P et al (2002) The prevalence of herpes simplex virus shedding and infection in the oral cavity of seropositive patients undergoing head and neck radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94:712–716CrossRefPubMedGoogle Scholar
  31. 31.
    Nicolatou-Galitis O, Athanassiadou P, Kouloulias V et al (2006) Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis. Support Care Cancer 14:753–762CrossRefPubMedGoogle Scholar
  32. 32.
    Beattie G, Whelan J, Cassidy J et al (1989) Herpes simplex virus, Candida albicans and mouth ulcers in neutropenic patients with non-haematological malignancy. Cancer Chemother Pharmacol 25:75–76CrossRefPubMedGoogle Scholar
  33. 33.
    Ramirez-Amador V, Esquivel-Pedraza L, Mohar A et al (1996) Chemotherapy-associated oral mucosal lesions in patients with leukaemia or lymphoma. Eur J Cancer B Oral Oncol 32B:322–327CrossRefPubMedGoogle Scholar
  34. 34.
    Bergmann OJ, Mogensen SC, Ellegaard J (1990) Herpes simplex virus and intraoral ulcers in immunocompromised patients with haematologic malignancies. Eur J Clin Microbiol Infect Dis 9:184–190CrossRefPubMedGoogle Scholar
  35. 35.
    Carrega G, Castagnola E, Canessa A et al (1994) Herpes simplex virus and oral mucositis in children with cancer. Support Care Cancer 2:266–269CrossRefPubMedGoogle Scholar
  36. 36.
    Gomez RS, Carneiro MA, Souza LN et al (2001) Oral recurrent human herpes virus infection and bone marrow transplantation survival. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 91:552–556CrossRefPubMedGoogle Scholar
  37. 37.
    Epstein JB, Sherlock C, Page JL et al (1990) Clinical study of herpes simplex virus infection in leukemia. Oral Surg Oral Med Oral Pathol 70:38–43CrossRefPubMedGoogle Scholar
  38. 38.
    Stanberry LR, Floyd-Reising SA, Connelly BL et al (1994) Herpes simplex viremia: report of eight pediatric cases and review of the literature. Clin Infect Dis 18:401–407PubMedGoogle Scholar
  39. 39.
    Schubert MM, Peterson DE, Flournoy N et al (1990) Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection. Oral Surg Oral Med Oral Pathol 70:286–293CrossRefPubMedGoogle Scholar
  40. 40.
    Chandrasekar PH, Abraham OC, Klein J et al (2001) Low infectious morbidity after intensive chemotherapy and autologous peripheral blood progenitor cell transplantation in the outpatient setting for women with breast cancer. Clin Infect Dis 32:546–551CrossRefPubMedGoogle Scholar
  41. 41.
    Lloid ME, Schubert MM, Myerson D et al (1994) Cytomegalovirus infection of the tongue following marrow transplantation. Bone Marrow Transplant 14:99–104PubMedGoogle Scholar
  42. 42.
    Nicolatou-Galitis O, Dardoufas K, Markoulatos P et al (2001) Oral pseudomembranous candidiasis, herpes simplex virus-1 infection, and oral mucositis in head and neck cancer patients receiving radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash. J Oral Pathol Med 30:471–480CrossRefPubMedGoogle Scholar
  43. 43.
    Rayani SA, Nimmo CJ, Frighetto L et al (1994) Implementation and evaluation of a standardized herpes simplex virus prophylaxis protocol on a leukemia/bone marrow transplant unit. Ann Pharmacother 28:852–856PubMedGoogle Scholar
  44. 44.
    Pereira CM, de Almeida OP, Correa ME et al (2007) Detection of human herpesvirus 6 in patients with oral chronic graft-vs-host disease following allogeneic progenitor cell transplantation. Oral Dis 13:329–334CrossRefPubMedGoogle Scholar
  45. 45.
    Morfin F, Thouvenot D (2003) Herpes simplex virus resistance to antiviral drugs. J Clin Virol 26:29–37CrossRefPubMedGoogle Scholar
  46. 46.
    Sullivan KM, Dykewicz CA, Longworth DL et al (2001) Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program 392–421Google Scholar
  47. 47.
    Kruger WH, Bohlius J, Cornely OA et al (2005) Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases working party (AGIHO) of the german society of haematology and oncology. Ann Oncol 16:1381–1390CrossRefPubMedGoogle Scholar
  48. 48.
    Apperley J, Carreras E, Gluckman E et al (2004) The EBMT handbook: haematopoietic stem cell transplantation. European School of Haemtology and European Group for Blood and Marrow Transplantation, ParisGoogle Scholar
  49. 49.
    Celkan T, Ozkan A, Apak H et al (2006) Antiviral prophylaxis with continuous low dose acyclovir in childhood cancer. Leuk Lymphoma 47:1418–1420CrossRefPubMedGoogle Scholar
  50. 50.
    Iino T, Gondo H, Ohno Y et al (1996) Successful foscarnet therapy for mucocutaneous infection with herpes simplex virus in a recipient after unrelated bone marrow transplantation. Bone Marrow Transplant 18:1185–1188PubMedGoogle Scholar
  51. 51.
    Christensen MS, Nielsen LP, Hasle H (2005) Few but severe viral infections in children with cancer: a prospective RT-PCR and PCR-based 12-month study. Pediatr Blood Cancer 45:945–951CrossRefPubMedGoogle Scholar
  52. 52.
    Pou AM, Vrabec JT, Jordan J et al (2000) Prevalence of herpes simplex virus in malignant laryngeal lesions. Laryngoscope 110:194–197CrossRefPubMedGoogle Scholar
  53. 53.
    Djuric M, Jankovic L, Jovanovic T et al (2009) Prevalence of oral herpes simplex virus reactivation in cancer patients: a comparison of different techniques of viral detection. J Oral Pathol Med 38:167–173CrossRefPubMedGoogle Scholar
  54. 54.
    Ayala E, Greene J, Sandin R et al (2006) Valganciclovir is safe and effective as pre-emptive therapy for CMV infection in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 37:851–856CrossRefPubMedGoogle Scholar
  55. 55.
    Laurenti L, Piccioni P, Cattani P et al (2004) Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 89:1248–1252PubMedGoogle Scholar
  56. 56.
    Schubert MM, Epstein JB, Lloid ME et al (1993) Oral infections due to cytomegalovirus in immunocompromised patients. J Oral Pathol Med 22:268–273CrossRefPubMedGoogle Scholar
  57. 57.
    LeVeque FG, Ratanatharathorn V, Dan ME et al (1994) Oral cytomegalovirus infection in an unrelated bone marrow transplantation with possible mediation by graft-versus-host disease and the use of cyclosporin-A. Oral Surg Oral Med Oral Pathol 77:248–253CrossRefPubMedGoogle Scholar
  58. 58.
    Thomson KJ, Hart DP, Banerjee L et al (2005) The effect of low-dose aciclovir on reactivation of varicella zoster virus after allogeneic haemopoietic stem cell transplantation. Bone Marrow Transplant 35:1065–1069CrossRefPubMedGoogle Scholar
  59. 59.
    Kim DH, Messner H, Minden M et al (2008) Factors influencing varicella zoster virus infection after allogeneic peripheral blood stem cell transplantation: low-dose acyclovir prophylaxis and pre-transplant diagnosis of lymphoproliferative disorders. Transpl Infect Dis 10:90–98CrossRefPubMedGoogle Scholar
  60. 60.
    Bahnassy AA, Zekri AR, Asaad N et al (2006) Epstein-Barr viral infection in extranodal lymphoma of the head and neck: correlation with prognosis and response to treatment. Histopathology 48:516–528CrossRefPubMedGoogle Scholar
  61. 61.
    Ferrazzo KL, Mesquita RA, Aburad AT et al (2007) EBV detection in HIV-related oral plasmablastic lymphoma. Oral Dis 13:564–569CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sharon Elad
    • 1
    Email author
  • Yehuda Zadik
    • 1
  • Ian Hewson
    • 2
  • Allan Hovan
    • 3
  • M. Elvira P. Correa
    • 4
  • Richard Logan
    • 5
  • Linda S. Elting
    • 6
  • Fred K. L. Spijkervet
    • 7
  • Michael T. Brennan
    • 8
  • Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)
  1. 1.Department of Oral MedicineHebrew University, Hadassah School of Dental MedicineJerusalemIsrael
  2. 2.Dental UnitRoyal Melbourne HospitalParkvilleAustralia
  3. 3.Program in Oral OncologyBC Cancer AgencyVancouverCanada
  4. 4.Ambulatory of Oral Medicine, Hematology and Blood Transfusion CenterUniversity of CampinasCampinasBrazil
  5. 5.Oral Pathology, School of Dentistry, Faculty of Health SciencesThe University of AdelaideAdelaideAustralia
  6. 6.Department of BiostatisticsThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  7. 7.Department of Oral & Maxillofacial SurgeryUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  8. 8.Department of Oral MedicineCarolinas Medical CenterCharlotteUSA

Personalised recommendations