Herpes Simplex


Key Points

  • Viral infections by herpes simplex (HSV) typically occur in two locations: the orofacial (usually type I) and genital (usually type II).
  • Infections may be primary, recurrent, in the setting of immunosuppression, or superinfection of a pre-existing skin disease (usually atopic dermatitis, e.g., eczema herpeticum).
  • Acyclovir is almost always the first-line treatment given to individuals with healthy immune systems; in immunosuppressed individuals (especially HIV-infected persons), acyclovir resistance is a concern and should always be considered if a patient does not respond to acyclovir therapy.
  • Both orofacial and genital herpes may be recurrent; in frequent cases, chronic viral suppression with systemic acyclovir may be indicated. Some recurrences of orofacial herpes may be triggered by sun exposure, and photoprotection may be an important preventive measure. In recurrent genital HSV, the triggers are less clear, but include menses, sexual intercourse, and stress.

Initial Evaluation

Herpes simplex may result in painful or burning crusted grouped vesicles near the mouth or nares, often recurrent in the same location. Grouped (herpetiform) pustular lesions resulting in erosions with scalloped borders are suggestive of herpes.

Genital and perianal lesions of herpes are usually caused by herpes simplex type II.

Herpetic whitlow may occur when digits are exposed to herpetic lesions.

Eczema herpeticum, superinfection of atopic dermatitis with HSV, is common and can be difficult to distinguish from impetiginized eczema (i.e., atopic dermatitis with bacterial superinfection) clinically. Bacterial and viral cultures may be required to determine which infection is present.

Differential diagnosis

Impetigo contagiosum commonly involves the perioral and perinasal areas of the face and are typified by honey-colored crusting. Lesions may be bullous and together with crusting can mimic herpetic lesions (see below).

Bullous lesions of impetigo

Herpes zoster is caused by dermatomal reactivation of varicella virus and can also result in grouped clear fluid-to-pus-filled vesicles on an erythematous-to-hemorrhagic base. In most cases of localized zoster, a clear dermatomal distribution is noted.

Aphthous ulcers are typically recurrent ulcers that affect the mouth or genitalia, and may occur sporadically or in the context of a systemic disease (such as inflammatory bowel disease). They are marked by a small, often painful pustule with a bright erythematous (but typically not purpuric) border that may resolve after a phase of ulceration.

Treatment
Table 1. Herpes Simplex Therapy for Adults

N.B. Always consider renal dosing in patients with renal impairment
Pattern Orofacial Genital
Primary infection in immunocompetent patient ACV 400 mg 5x per day x 7-10 days or 200 mg 5x per day x 7-10 days VCV 500-1000 mg b.i.d. x 7-10 days ACV 400 mg t.i.d. x 7-10 days or 200 mg 5x per day x 7-10 days VCV 500-1000 mg b.i.d. x 7-10 days Suppression: ACV (400 mg b.i.d. or 200 mg t.i.d.) or VCV (500 mg daily)
Recurrent infection in immunocompetent patient ACV 400 mg 5x per day x 7-10 days or 400 mg t.i.d. x 5 days VCV 2 g b.i.d. x 1 day Topical acyclovir cream (5%) 5x per day x 4 days Topical penciclovir cream (1%) every 2 hours during waking hours x 4 days Suppression: ACV (400 mg b.i.d. or 200 mg t.i.d.) or VCV (500-1000 mg daily) for longer period (months) ACV 400 mg t.i.d. per day x 5-10 days VCV 500 mg b.i.d. x 3 days or 1g daily x 5 days Suppression: ACV (400 mg b.i.d. or 200 mg t.i.d.) or VCV (500-1000 mg daily)

ACV, acyclovir; VCV valacyclovir

Table 2. Herpes Simplex Therapy for Children

N.B. Always consider renal dosing in patients with renal impairment
Pattern Orofacial Genital
Primary infection in immunocompetent patient (age > 2 years) ACV 75 mg/kg divided 5x per day x 7 days Alternative for age>12 years: VCV 2 g b.i.d. x 1 day or 1 g b.i.d. x 7 days ACV 40-80 mg/kg/day divided t.i.d. x 5-10 days
Recurrent infection in immunocompetent patient (age > 2 years) Age > 12 years: ACV 400 mg 5x per day x 7-10 days or VCV 500 mg b.i.d. x 3 days or 1 g daily x 5 days Suppression: ACV 40-80 mg/kg divided t.i.d. Age > 12 years: ACV 200 mg 5 per day x 5 days or 400 mg t.i.d. x 5 days Suppression: ACV 40-80 mg/kg/day divided t.i.d. Alternative for age >12 years: ACV 400 mg b.i.d.-t.i.d

ACV, acyclovir; VCV valacyclovir

Initial therapy

  • Perform viral direct immunofluorescence assay (DFA) and culture to confirm diagnosis of HSV.
  • Culture for coexistent bacterial superinfection (usually S. aureus) and treat appropriately.
  • For eczema herpeticum, treat the underlying atopic dermatitis as well.
  • For genital HSV, evaluate for other sexually transmitted infections.
  • For the immunosuppressed, topical acyclovir 5% ointment (such as Zovirax ointment) 4-5x day may accelerate healing.

Ancillary therapy

General points

  • Recurrent orofacial HSV responds to drying preparations (e.g., benzoyl peroxide gel) b.i.d. Oral and topical acyclovir do not significantly shorten the course in most patients once lesions are present.
  • Aluminum acetate soaks/compresses or sitz baths to dry blisters or remove crusts may be adjunctively beneficial.
  • In recurrent cases, treatment must be begun at the earliest prodrome and be patient initiated. Topical acyclovir ointment is of almost no benefit in this setting.

Pitfalls

  • Failure to adjust the acyclovir dose for decreased renal function can lead to side effects, especially when high-dose intravenous acyclovir is given. Monitor renal function during intravenous acyclovir therapy and ensure adequate hydration to prevent renal impairment.
  • Genital ulcers are difficult to diagnose. HSV II is the most common cause of genital ulcer disease in the United States, and accurate, confirmed diagnosis is essential. Do not tell the patient he/she has herpes unless it is confirmed by culture or fluorescent antibody or Tzanck smear. Serologic testing is in general not useful, except in the primary disease with acute and convalescent titers. The results of serologic testing are usually not available for days, and are only retrospectively of benefit in the rare case.
  • Be alert for the genital ulcer containing multiple pathogens and evaluate patients with genital HSV for other STDs.
  • Rarely acyclovir-resistant mutants of HSV may cause chronic genital or oral ulcers in immunosuppressed (usually HIV-infected) patients.

When to refer to a dermatologist

  • When the diagnosis of herpes simplex infection is not clear.
  • For management of eczema herpeticum.
  • For management of recurrent herpes, not suppressed by standard suppressive therapy, especially in an immunocompromised or immunosuppressed patient.

Clinical Cases

Case 1

  • 7-year-old previously healthy girl with 2 days’ history of erythema on the right oral commissure and right lower cutaneous lip
  • No fevers, chills, malaise
  • No preceding illnesses or trauma

Initial visit

  • Obtain viral DFA and culture for herpes simplex virus from cells or fluid of a fresh sore
  • Empiric treatment with acyclovir 400 mg p.o. t.i.d. x 7 days

1-week follow-up evaluation

  • Viral DFA and culture confirms type I herpes simplex
  • Lesion resolved
  • Acyclovir is discontinued
  • Patient is counseled to use sunscreen-containing lip balm, as sun exposure may trigger recurrences

Case 2

  • 4-year-old boy with prior history of atopic dermatitis with a 5-day history of yellow-colored crusting on face, trunk, arms (in areas of prior skin disease)
  • Low-grade fevers, also chills, malaise
  • Mother with recent history of “cold sore” on lips

Initial visit

  • Obtain skin culture for bacteria
  • Also obtain viral DFA and culture for herpes simplex virus
  • Empiric treatment with acyclovir 400 mg p.o. t.i.d. x 10 days and cephalexin 25 mg/kg/day divided b.i.d. x 10 days
  • Follow-up in 1 week

1-week follow-up evaluation

  • Viral DFA and culture confirm presence of type I herpes simples virus
  • Bacterial culture reveals Staphylococcus aureus, methicillin-sensitive
  • Lesions are much improved
  • Reinforce atopic dermatitis skin care; also counsel for avoiding contact with family members with herpetic lesions when skin is inflamed

Case 3

  • 33-year-old man with a 7-year history of painful, recurrent clustered blisters in the same location on his lower lip, occurring 1-2X year; current outbreak was preceded by a backpacking trip to Yosemite National Park; patient recalls a “burning sensation” in the affected area 6 hours prior to outbreak of blisters
  • Denies blisters elsewhere on the body
  • Previously in excellent health

Initial visit

  • Grouped pustular vesicles on an erythematous base with necrotic skin changes and ulceration on the left lateral, external aspect of his lower lip; no other lesions
  • Tzanck smear of blister fluid reveals presence of multinucleated giant cells
  • Viral DFA and culture for HSV obtained
  • Acyclovir 400 mg p.o. t.i.d. x 5 days
  • Follow-up in 1 week

Follow-up visit

  • Lesions resolving
  • HSV DFA is positive and viral culture reveals Type 1 HSV
  • Prescription for valacyclovir or acyclovir given as abortive therapy for future recurrences (dose valacyclovir 2 g p.o. b.i.d. x 1 day or acyclovir 200 mg 5x a day x 5-10 days)
  • Counseling on photoprotection with sunscreen lip ointment SPF30

References

Spruance SL et al (2003). High dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores, Antimicrob Agents Chemotherapy, 47(3): 1072-1080.

Cernik C, Gallina K, Brodell T (2008). The treatment of herpes simplex infections, an evidence-based review, Arch Int Med, 168:1137-1144.

James SH and Whitley RJ (2010). Treatment of herpes simplex virus infections in pediatric patients: current status and future needs, Clin Pharm Therapeutics, 88:720-724.