Diagnosis: Herpes simplex virus-1

Herpes simplex virus-1 (HSV-1) reactivation is common among patients with hematologic malignancies.1,2 Risk factors include mucosal disruption (e.g., after chemotherapy) and neutropenia.1 The report of minimal symptoms prior to chemotherapy suggests that a recurrence of HSV-1 caused her herpes simplex labialis.

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The differential diagnosis for an immunocompromised patient presenting with mucosal ulcers is broad. It should include mucositis due to chemotherapy or other medications; infectious ulcerations, including coxsackie virus, gonorrhea, syphilis, and deep fungal infections; HSV infection or herpes zoster infection; mucocutaneous candidiasis; aphthous ulcers; oral erosive lichen planus; and immune-mediated bullous diseases (i.e., pemphigus vulgaris, bullous pemphigoid).1 The presence of grouped vesicles on the lips and grouped erosions on the gingiva and hard palate are characteristic of primary HSV infection or reactivation in an immunocompromised patient.

Unlike intraoral HSV lesions, aphthous ulcers generally appear as single lesions on the tongue or buccal mucous membranes and tend to be larger and more painful than HSV ulcers. Candida infection is marked by exudate on the tongue and occasionally in the pharynx. Mucositis typically is less painful than HSV-1 lesions.

This patient reported minimal mucositis during chemotherapy previously, which responded to a triple mix of an antihistamine, an antacid, and a local anesthetic (i.e., viscous lidocaine, diphenhydramine, and bismuth salicylate). She mentioned that her current symptoms and pain were much more severe than those associated with her prior mucositis episodes.

Reactivation of HSV-1 in immunocompromised patients is often associated with a more painful and aggressive course marked by slower healing, more prolonged viral shedding, and, rarely, disseminated infection.2,3 HSV-1-associated keratoconjunctivitis is a common cause of corneal blindness in the United States.3 HSV-1 encephalitis is rare but carries a greater than 70% mortality rate.3 HSV pneumonia has been reported in patients with various types of immunosuppression.4,5 Bacterial superinfection with Staphylococcus aureus or streptococci also can occur, sometimes confounding the diagnosis.1 Given the patient’s history of fever, ill appearance, and immunocompromised status, she was hospitalized to rule out systemic disease. The workup included ocular and neurologic examinations, chest x-ray, laboratory testing, polymerase chain reaction (PCR) testing for HSV DNA, and blood cultures.

The lab report revealed leukopenia, anemia, and thrombocytopenia related to the recent chemotherapy treatment. In rare cases, HSV has been associated with hepatitis;6 the patient’s normal-range liver enzymes suggested the absence of hepatic involvement. Swabbing of the skin for viral culture and PCR were both positive for HSV-1. Bacterial blood cultures were negative. All other findings were normal.

Systemic rather than topical therapies are preferred for immunosuppressed patients. All three systemic antivirals approved for treatment of HSV-1 infection inhibit viral DNA polymerase.3 Acyclovir is the prototype antiviral medication. Valacyclovir is the prodrug of acyclovir, with up to five times greater oral bioavailability and less frequent dosing.3 Famciclovir is a prodrug of penciclovir, a topical antiviral agent that also has high oral bioavailability. None of these systemic antivirals is indicated for treatment of recurrent oral HSV-1 infection in immunocompromised patients. Famciclovir is approved for treatment of recurrent orolabial HSV-1 infection in HIV-infected patients,7 while valacyclovir is approved for suppression of recurrent genital herpes in HIV-infected patients.8

A Cochrane review of HSV treatment and prevention in cancer patients reported that compared with placebo, oral or IV acyclovir therapy significantly shortened median duration of viral shedding, time to first decrease in pain and to complete resolution of pain, time to 50% healing, and time to total healing.2

HSV-seropositive individuals or those with a history of recurrent herpes simplex labialis or genital herpes who are receiving chemotherapy for hematologic malignancy should be considered for HSV prophylaxis.1 A recent Cochrane review showed that acyclovir (oral or IV) was significantly superior to placebo in preventing HSV lesions.2 Oral acyclovir was significantly more effective than placebo at preventing viral isolates. In trials comparing acyclovir with valacyclovir or comparing two doses of valacyclovir with each other, there was no significant difference in the prevention of HSV lesions.2

In this patient, the clinician initiated treatment with IV acyclovir (5 mg/kg every eight hours).9 The patient noted improvement in her symptoms and stopped developing new vesicles within 24 hours. Pain-management measures included triple-mix mouthwash and IV fluids. The patient was discharged after two days and prescribed a seven-day course of oral valacyclovir 1 g b.i.d. At a follow-up visit five days after discharge from the hospital, the patient reported her pain had lessened. Lesions were healing and resolved within 14 days after initiation of therapy.

The clinician prescribed prophylaxis with oral acyclovir 400 mg b.i.d. during chemotherapy and instructed the patient to take oral valacyclovir 1 g b.i.d. for seven days if she developed a herpes simplex labialis recurrence. Roughly 60% of individuals experience prodromal symptoms (tingling, burning, or mild discomfort at the site of recent recurrence) 24 hours or so prior to appearance of papules, followed by vesicles and erosions.3 Prodromal symptoms in an immunosuppressed patient also might include lymphadenopathy, fever, and malaise.1

Acyclovir resistance develops in 5% to 14% of immunocompromised patients.1 Lack of immediate response to acyclovir in an immunocompromised patient does not necessarily signal resistance, as immunodeficiency prolongs time to response. The clinician should suspect resistance if lesions do not respond after seven days or if the lesion recurs after initial improvement while the patient is receiving therapy. If viral culture confirms the presence of resistant HSV-1, foscarnet therapy (60 to 90 mg/kg every 12 hours) should be initiated.1,10

Dr. Hull is an assistant professor of dermatology at the University of Utah Health Care in Salt Lake City. He has served as an investigator, consultant, or speaker for Novartis, GlaxoSmithKline, and Medivir.

This activity was supported by an educational grant from Meda Pharmaceuticals.

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1. Fitzmorris KL, Green JN, Sandin RL, Field T. Recognition and management of herpes simplex mucositis in neutropenic patients. Infect Med. 2000;17:413-416.

2. Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T. Interventions for the  prevention and treatment of herpes simplex virus in patients being treated for cancer. Cochrane Database Syst Rev. 2009 ;1:CD006706. 

3. Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections:
Epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57:737-763.

4. Witt MN, Braun GS, Ihrler S, Schmid H. Occurrence of HSV-1-induced pneumonitis in patients under standard immunosuppressive therapy for rheumatic, vasculitic, and connective tissue disease. BMC Pulm Med. 2009;9:22.

5. Ferrari A, Luppi M, Potenza L, et al. Herpes simplex virus pneumonia during standard induction chemotherapy for acute leukemia: case report and review of literature. Leukemia. 2005;19:2019-2021. 

6. Shiley K, Blumberg E. Herpes viruses in transplant recipients: HSV, VZV, human herpes viruses, and EBV. Infect Dis Clin North Am. 2010;24:373-393.

7. Monthly Prescribing Reference. Famvir

8. Monthly Prescribing Reference. Valtrex

9. Monthly Prescribing Reference. Acyclovir inj

10. Safrin S, Assaykeen T, Follansbee S, Mills J. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. J Infect Dis. 1990;161:1078-1084.

All electronic documents accessed October 15, 2010.