Erythema multiformeassociated with recurrent herpes simplex labialis

Herpes simplex labialis (HSL) is a common disease caused most often by herpes simplex virus type 1 (HSV-1). Primary infection is usually acquired during childhood or adolescence through direct mucosal membrane exposure to the virus in the saliva or lesional fluid of a person with active infection. Younger children (aged 1 to 5 years) are more likely to develop a symptomatic primary HSV-1 infection. This may present as primary herpetic gingivostomatitis, involving intra- and perioral vesicles and ulcers that can interfere with eating and drinking1 and may require antiviral therapy with oral acyclovir. In older, otherwise-healthy patients, primary HSV-1 orofacial infection is likely less debilitating, and management may involve palliative treatment with oral analgesics and/or topical anesthetics.


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Antiviral treatment does not eradicate the virus, which remains latent in sensory ganglia with lifelong potential for reactivation. Even though most recurrent HSL episodes are mild and limited to perioral mucocutaneous sites, lesions can cause discomfort, interfere with speaking or eating, and have a psychosocial impact related to cosmetic disfigurement and stigma. Between 57% and 80% of U.S. adults show serologic evidence of HSV-1 infection;2 15% to 40% of these have symptomatic recurrence.1

Factors that may trigger recurrent HSL include upper-respiratory infections or febrile illnesses, psychological stress, intense UV light exposure, immunosuppression, menstruation, and local tissue trauma. Recurrence is usually signaled by a prodrome, with symptoms of tingling, itching, and/or burning. Evolution of recurrent HSL lesions begins with erythema and progresses to papules, vesicles, ulcers, hard crust, dry flaking/residual swelling and healed, normal skin. In about 25% of recurrences, the lesion is aborted after the papule stage,3 minimizing the morbidity generally associated with “ulcerative” lesions (i.e., vesicles, ulcers, and crusts).

Management of recurrent HSL varies, depending on episode frequency and severity as well as comorbidities (e.g., immune status, association with recurrent erythema multiforme [EM]). It can range from no or palliative treatment for mild, occasional reactivations to chronic, suppressive oral antiviral therapy for frequent and/or debilitating recurrences. Episodic antiviral therapy involves either topical agents or oral medications. In clinical studies, episodic antiviral treatment initiated during the prodrome shortened symptom duration, limited lesion development, hastened time to healing, and/or reduced viral shedding.

Options for episodic topical treatment include docosanol 10% cream (available OTC), penciclovir 1% cream, acyclovir 5% ointment and cream, and a fixed-combination cream containing acyclovir 5% and hydrocortisone 1%. Pivotal trial results showed the combination cream was significantly more effective than acyclovir cream for preventing ulcerative episodes and significantly reduced mean episode duration and healing time compared with placebo among study patients who developed ulcerative lesions.4 Oral acyclovir, famciclovir, and valacyclovir are all approved for episodic treatment of recurrent HSL.

In addition to chronic suppressive antiviral therapy to prevent recurrent HSL, patients may initiate antiviral therapy before trigger exposure (e.g., prior to a beach vacation). Strategies include sunscreens to mitigate the effects of UV light or behavioral therapy to reduce stress.

EM is an acute, self-limiting disease considered a delayed-type hypersensitivity reaction caused by various inciting factors, including certain drugs and infections, particularly reactivation of HSV-1 and -2.

EM typically occurs in teenagers and young to middle-aged adults (up to age 40 years); a slight male and female preponderance both have been reported in different series.5 EM manifests with an acute onset, usually with no or minimal prodromal symptoms. Herpes-associated EM (HAEM) lesions usually develop within a few days to a few weeks after asymptomatic or symptomatic HSV reactivation, although the HSV recurrence can develop simultaneously or even after the EM eruption.

EM lesions are usually distributed symmetrically and appear first on distal extremities, from which they spread centripetally. Characteristic lesions begin as erythematous macules and/or papules that evolve into classic “targetoid” lesions with a central blistering or purpura, an intermediate pink or edematous zone, and a darker erythematous outer rim. Mucosal lesions most often involve the oral cavity but may also appear on genital and/or ocular surfaces and occasionally are a solitary finding.5,6

The diagnosis of EM is generally based on clinical findings; it may be made in this patient based on the morphology of her lesions and appearance after onset of recurrent HSL. Biopsy and serologic testing usually are not performed but can be ordered if the diagnosis is uncertain because of an atypical presentation.

Left untreated, EM lesions heal within two to six weeks without significant sequelae aside from possible skin-pigment changes. However, approximately 20% to 25% of affected patients have recurrent disease, with frequency varying between two and 24 outbreaks per year and persistence between two and 36 years.6,7 HSV is implicated as the cause in the majority (61% to 100%) of recurrent EM cases.5

Treatment of EM depends on disease severity and whether the episode is primary or recurring. In mild HAEM, management is largely symptomatic and may include wound care for cutaneous lesions, oral antihistamines, analgesics, topical anesthetics, and liquid diet as necessary if there are painful oral lesions. There is limited evidence that an oral antiviral agent started early after EM onset associated with HSV shortens symptom duration and hastens lesion resolution.6 A topical corticosteroid may also be used for symptomatic relief and to control the immune reaction. Systemic corticosteroid use is controversial because it has been reported to prolong duration of EM.5,8

As recurrent HAEM can cause significant morbidity,6 continuous suppressive oral antiviral treatment can be given as prophylactic therapy. Acyclovir 400 mg b.i.d. was effective in a double-blind, placebo-controlled trial of patients with recurrent EM.8 Valacyclovir 500 mg b.i.d. has been reported effective for recurrent EM unresponsive to acyclovir prophylaxis.9 The dosage of antiviral may be reduced once patients are recurrence-free for four months and discontinued if there are no further recurrences.10

This patient was advised about symptomatic measures for managing her EM. She was also given a prescription for topical acyclovir 5%/hydrocortisone 1% to treat future HSL recurrences, with instructions to begin application with the onset of prodromal symptoms.

Stephen K. Tyring, MD, PhD, MBA is a Clinical Professor in the Departments of Dermatology, Microbiology/Molecular Genetics and Internal Medicine, University of Texas Health Science Center, and Medical Director of the Center for Clinical Studies in Houston, Texas. He has received grant/research support from GlaxoSmithKline and Novartis.

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


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References

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

2. Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med. 2008;168:1137-1144.

3. Opstelten W, Neven AK, Eekhof J. Treatment and prevention of herpes labialis. Can Fam Physician. 2008;54:1683-1687.

4. Hull CM, Harmenberg J, Arlander E, et al. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol. 2010 Sep 17. [Published online ahead of print].

5. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62:45-53.

6. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol. 1993;128:542-545.

7. Osterne RL, Matos Brito RG, Pacheco IA, et al. Management of erythema multiforme associated with recurrent herpes infection: a case report. J Can Dent Assoc. 2009;75:597-601.

8. Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. 1995;132:267-270.

9. Kerob D, Assier-Bonnet H, Esnault-Gelly P, et al. Recurrent erythema multiforme unresponsive to acyclovir prophylaxis and responsive to valacyclovir continuous therapy. Arch Dermatol. 1998;134:876-877.

10. Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am Fam Physician. 2006;74:1883-1888.

All electronic documents accessed November 15, 2010.