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Herpes Simplex
Sonia Rivera-Martinez, DO, FACOFP
Sharon L. Koehler, DO, FACS
image BASICS
  • Characteristic vesicular rash primarily located in oral and genital regions as the result of infection with
    • Herpes simplex virus (HSV)-1 is primarily associated with blisters on lips, in mouth, face, eyes.
    • HSV-2 is the primary source of genital herpes, although cross-reactivity is common (HSV-1 can cause genital sores through oral-genital contact).
  • Associated with a wide range of sequelae. Complexity and variation of presentation depends on the age and immune status of host, whether the infection is primary or recurrent and the degree of dissemination.
  • Viral shedding is typically greatest in the first (primary) infection and lessens with recurrences.
  • Meningitis/encephalitis and pneumonia are serious systemic manifestations associated with HSV infection.
  • Predominant age: Affects all ages; however, most HSV-1 is acquired in childhood, and most HSV-2 is acquired in young-middle adulthood.
  • Predominant sex: male = female
  • Over 1,000,000 new cases of HSV per year
  • HSV can reactivate, causing recurrent disease.
  • Widespread; 0.65-25% of adults may shed HSV-1 or HSV-2 at any given time. Many are unaware of their infection status.
  • Prevalence of antibodies to HSV-1 is 90% by adulthood in the general population. 30% of adults have antibodies to HSV-2.
HSV-1 and 2 are double-stranded DNA viruses from the family Herpesviridae. HSV-1 and 2 are transmitted by contact with infected skin during periods of viral shedding. Transmission also occurs vertically during childbirth. Most often, HSV-1 is associated with oral lesions and HSV-2 with genital lesions.
  • Immunocompromised state
    • Chemotherapy, malignancy/chronic disease states such as diabetes or AIDS, old age
  • Atopic eczema, especially in children
  • Prior HSV infection
  • Sexual intercourse with infected person (condoms help minimize HSV transmission, but lesions outside condom-protected areas can spread virus)
  • Occupational exposure
    • Dental professionals at higher risk for HSV-1 and resulting herpetic whitlow
  • Neonatal herpes simplex: Primary infection is lifethreatening and usually acquired by vaginal birth to an infected mother; fetal and neonatal risk are greatest in mothers with primary genital herpes infection; incubation is usually from 5 to 7 days (rarely 4 weeks); cutaneous, mucous membrane, or ocular signs seen in only 70%.
  • If active lesions are present, avoid direct contact with immunocompromised people, elderly, and newborns.
  • Hand hygiene
  • Kissing, sharing beverages, and sharing utensils/toothbrushes can transmit HSV.
  • Genital herpes: Avoid sexual contact if active lesions (herpes simplex is also transmitted when disease appears to be inactive), discuss condom benefits and limits, consider antiviral therapy to reduce viral shedding, encourage safe sex.
  • Topical microbicides (not yet commercially available) may prevent transmission of HSV-2.
  • Erythema multiforme: 50% of associated cases are caused by HSV-1 or -2.
  • Screen all severe, unusual locations, or treatment-resistant HSV cases for HIV.
  • Vesicles are often clustered and become painful ulcerated lesions, often with erythematous base.
  • Primary genital herpes: See “Herpes, Genital.”
  • Primary herpetic gingivostomatitis and pharyngitis: usually in early childhood; incubation from 2 to 12 days, followed by fever, sore throat, pharyngeal edema, and erythema
    • Small vesicles develop on pharyngeal and oral mucosa, rapidly ulcerate, and increase in number to involve soft palate, buccal mucosa, tongue, floor of mouth, lips, and cheeks; tender, bleeding gums; cervical adenopathy; fever, general toxicity, poor oral intake, and excess salivation contribute to dehydration; autoinoculation of other sites may occur; resolves in 10 to 14 days
  • Primary herpes keratoconjunctivitis: unilateral conjunctivitis with regional adenopathy, blepharitis with vesicles on lid marginal keratitis with dendritic lesions, or with punctate opacities; lasts 2 to 3 weeks; systemic involvement prolongs process
  • Eczema herpeticum: diffuse pox-like eruption complicating atopic dermatitis; sudden appearance of lesions in typical atopic areas (upper trunk, neck, head); high fever, localized edema, adenopathy
  • Herpetic whitlow: localized infection of affected finger with intense itching and pain, followed by vesicles that may coalesce with swelling and erythema. Mimics pyogenic paronychia; neuralgia and axillary adenopathy are possible; heals in 2 to 3 weeks
  • Congenital infection through transplacental transfer may present with jaundice, hepatosplenomegaly, disseminated intravascular coagulation (DIC), encephalitis, seizures, temperature instability, chorioretinitis, and conjunctivitis with or without vesicles.
  • Recurrent diseases from endogenous reactivation
    • Herpes labialis: recurrent lesions with HSV-1; usually <1 recurrence/6 months, but 5-25% may have >1 attack/month; vesicles often at vermilion border, then ulcerate and crust within 48 hours; heal within 8 to 10 days; may have local adenopathy
    • Ocular herpes: May recur as keratitis, blepharitis, or keratoconjunctivitis; dendritic ulcers, decreased corneal sensation, decreased visual acuity; uveitis may cause permanent visual loss.
  • Impetigo: honey-crusted vesicles
  • Aphthous stomatitis: grayish, shallow erosions with ring of hyperemia of anterior in mouth and lips
  • Herpes zoster: unilateral dermatome distribution
  • Syphilitic chancre: painless ulcer
  • Folliculitis: may mimic “shave bumps” in genital area
  • Herpangina: Vesicles predominate on anterior tonsillar pillars, soft palate, uvula, and oropharynx but not more anteriorly on lips/gums (usually caused by group A coxsackievirus).
  • Stevens-Johnson syndrome
  • Screen for other sexually transmitted infections (STIs) in patients with primary genital herpes.
  • Viral: HIV, hepatitis B and C, and human papillomavirus (HPV) have crossover
  • Bacterial: Screen for concurrent gonorrhea, chlamydia in new primary genital outbreaks.
Initial Tests (lab, imaging)
  • Tzanck smear shows multinucleated giant cells often with eosinophilic intranuclear inclusions (scrape material from lesion to slide, fix with ethanol/methanol, stain with Giemsa or Wright stain); varicella (herpes zoster) has identical findings.
  • HSV culture: Swab and plate on viral-specific media. Sample may need to be refrigerated; can take up to 6 days to be positive. Highly specific, hence, reliable if positive but has 20% false-negative rate.
  • HSV type-specific antibody tests distinguish between HSV-1 and HSV-2.
    • Polymerase chain reaction (PCR), direct fluorescent antibody (DFA), ELISA, and Western blot
    • 3 weeks after infection, 50% of those infected test positive; 70%, 6 weeks after infection; by 16 weeks nearly all infected test positive
Diagnostic Procedures/Other
Biopsy is occasionally needed to confirm diagnosis.
Test Interpretation
  • Intraepithelial edema (ballooning degeneration) and intracellular edema
  • Brain biopsy (in encephalitis) shows hemorrhagic necrosis of gray and white matter with acute and chronic inflammation, thrombosis, and fibrinoid necrosis of parenchymal vessels; intranuclear inclusions in astrocytes, oligodendroglia, and neurons

  • Cool dressings moistened with aluminum acetate solution
  • Painful urination and inability to void due to painful genital lesions is helped by pouring a cup of warm water over genitals while urinating or by sitting in a warm bath while urinating (sitz baths).
  • Children with gingivostomatitis who resist oral intake due to pain or extensive skin disease (eczema herpeticum) may require IV hydration.
First Line
  • Begin treatment promptly, preferably in prodromal phase.
  • Acyclovir (generic)
    • Mucocutaneous (or genital) HSV
      • Primary/first infection: 400 mg TID or 200 mg 5 times per day for 7 to 10 days
      • If severe, start with IV q8h dosing for the first few days, then complete 10-day course PO route.
      • Recurrence: 400 mg PO TID for 5 days or 800 mg BID for 5 days or 800 mg TID for 2 days
      • Suppression: 400 mg BID daily (1)[B]
    • Keratitis HSV: 400 mg PO 5 times per day; however, topical treatment is preferred as first line.
    • Pediatric dosing: neonatal herpes simplex or encephalitis: 60 mg/kg/day IV divided q8h for 14 to 21 days (2)[B]
      • Older (>3 months of age) immunocompetent is weight-based dosing (40 to 80 mg/kg/day [max 1,000 mg/day] divided q8h for 5 to 7 days).
    • Safe in pregnancy and lactation—Category B
    • Recurrent herpes labialis: 800 to 1,600 mg/day for prevention (3,4,5)[B]
  • Penciclovir (Denavir): 1% cream. Apply to oral lesions q2h during waking hours for 4 days (6)[B].
  • Valacyclovir (Valtrex)
    • Primary genital herpes: 1 g PO BID for 7 to 10 days. Recurrent genital herpes: 500 mg PO BID for 3 days; suppression: 500 to 1,000 mg PO daily (depending on frequency of outbreaks); labialis HSV (cold sores/oral lesions): 2,000 mg PO q12h for 1 day (3,4,5)[B]
    • 500-mg daily dose if suppression is needed/desired
    • Recurrent herpes labialis: 500 mg/day for 4 months for prevention (3,4)[B]
  • Famciclovir (Famvir)
    • Primary genital herpes: 250 mg PO TID for 7 to 10 days
    • Recurrence: 125 mg PO BID for 5 days or 1,000 mg PO BID for 1 day
    • Suppression: 250 mg PO BID
  • Precautions
    • Renal dosing for all oral antivirals
    • Significant possible interactions: Probenecid with IV acyclovir and possibly probenecid with valacyclovir may reduce renal clearance and elevate antiviral drug levels.
Second Line
  • Foscarnet
    • Drug of choice for acyclovir resistance in immunocompromised persons with systemic HSV
    • 40 mg/kg IV q8h (assume valacyclovir and famciclovir resistance also if acyclovir resistance occurs)
  • Other topicals
    • Ophthalmic preparations for herpes keratoconjunctivitis; acyclovir, vidarabine (Vira-A), ganciclovir, trifluridine
    • Topical acyclovir and penciclovir improve recurrent herpes labialis healing times by ˜10% (3)[B].
    • Topical analgesics: Lidocaine 2% or 5% helps reduce pain associated with vulvar and penile outbreaks.
  • Over-the-counter topical antivirals: docosanol
Refer recurrent cases of herpes keratoconjunctivitis to an ophthalmologist.
Admission Criteria/Initial Stabilization
  • Pregnancy considerations
    • Caesarean section and/or acyclovir are indicated if any active genital lesions (or prodrome) present at time of delivery; consider cesarean delivery if primary genital herpes is suspected within previous 4 weeks (6)[B].
    • Daily oral antivirals from 36 weeks onward in women with history of recurrent genital herpes to prevent outbreak near to/at time of delivery
    • Avoid fetal scalp electrodes, forceps, vacuum extractor, and artificial rupture of membranes if mother has history of genital HSV.
    • Risk of viral shedding at delivery from asymptomatic recurrent genital HSV is low (˜1.6%).
  • Pediatric considerations
    • Neonates with likely exposure (high index of suspicion) to HSV at birth or those who exhibit signs of HSV infection should have all body fluids cultured and immediately start treatment with IV acyclovir.
  • For most cases, follow-up is not necessary. Lesions and symptoms resolve rapidly within 10 days. Extensive cases should be rechecked in 1 week; monitor for secondary bacterial infections.
  • Consider long-term suppression.
If oral lesions are present, avoid salty, acidic, or sharp foods (e.g., snack chips, orange juice).
  • Explain the natural history that timing of exposure is difficult to determine and that the virus will remain in the body indefinitely. Minimize psychological impact of the diagnosis to reduce stigma.
  • Emphasize personal hygiene to avoid self-spreading to other body areas (autoinoculation) or exposing others. Frequent hand washing; avoid scratching; cover active, moist lesions.
  • Reinforce safe sexual practices.
  • Usual duration of primary disease is 5 days to 2 weeks.
  • Antiviral treatment shortens duration, reduces complications, and mitigates recurrences (if used for suppression).
  • Viral shedding during recurrence is briefer than with primary disease; frequency of recurrence is variable and depends on individual host factors.
  • Newborns/immunocompromised individuals are at highest risk for major morbidity/mortality.
  • HSV is never eliminated from the body but stays dormant in dorsal root ganglia and can reactivate, causing recurrent symptoms and lesions.
1. Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007;370(9605):2127-2137.
2. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am. 2013;60(2): 351-365. doi:10.1016/j.pcl.2012.12.005.
3. Rahimi H, Mara T, Costella J, et al. Effectiveness of antiviral agents for the prevention of recurrent herpes labialis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(5):618-627.
4. Harmenberg J, Oberg B, Spruance S. Prevention of ulcerative lesions by episodic treatment of recurrent herpes labialis: a literature review. Acta Derm Venereol. 2010;90(2):122-130.
5. Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med. 2008;168(11):1137-1144.
6. Obiero J, Mwethera PG, Wiysonge CS. Topical microbicides for prevention of sexually transmitted infections. Cochrane Database Syst Rev. 2012;(6):CD007961.
Additional Reading
Wang X, Zhou F, Zhao J, et al. Elevated risk of opportunistic viral infection in patients with Crohn's disease during biological therapies: a meta analysis of randomized controlled trials. Eur J Clin Pharmacol. 2013;69(11):1891-1899.
See Also
  • Herpes, Genital
  • Algorithm: Genital Ulcers
  • B00.9 Herpesviral infection, unspecified
  • A60.00 Herpesviral infection of urogenital system, unspecified
  • B00.1 Herpesviral vesicular dermatitis
Clinical Pearls
  • 25-30% of the U.S. population has evidence of genital herpes (HSV-2), and >80% is seropositive for HSV-1.
  • Most individuals are unaware they are infected. This allows for asymptomatic passage of the virus.
  • Viral suppression therapy for patients with frequent recurrences reduces transmission and decreases outbreak frequency.