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Herpes Simplex Virus (HSV) Infections

(Herpes Labialis; Herpetic Gingivostomatitis)

By Kenneth M. Kaye, MD

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Herpes simplex viruses (human herpesviruses types 1 and 2) commonly cause recurrent infection affecting the skin, mouth, lips, eyes, and genitals. Common severe infections include encephalitis, meningitis, neonatal herpes, and, in immunocompromised patients, disseminated infection. Mucocutaneous infections cause clusters of small painful vesicles on an erythematous base. Diagnosis is clinical; laboratory confirmation by culture, PCR, direct immunofluorescence, or serologic testing can be done. Treatment is symptomatic; antiviral therapy with acyclovir, valacyclovir, or famciclovir is helpful for severe infections and, if begun early, for recurrent or primary infections.

Both types of herpes simplex virus (HSV), HSV-1 and HSV-2, can cause oral or genital infection. Most often, HSV-1 causes gingivostomatitis, herpes labialis, and herpes keratitis. HSV-2 usually causes genital lesions.

Transmission of HSV results from close contact with a person who is actively shedding virus. Viral shedding occurs from lesions but can occur even when lesions are not apparent.

After the initial infection, HSV remains dormant in nerve ganglia, from which it can periodically emerge, causing symptoms. Recurrent herpetic eruptions are precipitated by

  • Overexposure to sunlight

  • Febrile illnesses

  • Physical or emotional stress

  • Immunosuppression

  • Unknown stimuli

Generally, recurrent eruptions are less severe and occur less frequently over time.

Diseases Caused by Herpes Simplex Virus

Diseases include

  • Mucocutaneous infection (most common), including genital herpes

  • Ocular infection (herpes keratitis)

  • CNS infection

  • Neonatal herpes

HSV rarely causes fulminant hepatitis in the absence of cutaneous lesions.

In patients with HIV infection, herpetic infections can be particularly severe. Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur.

HSV outbreaks may be followed by erythema multiforme, possibly caused by an immune reaction to the virus. Eczema herpeticum is a complication of HSV infection in which severe herpetic disease develops in skin regions with eczema.

Mucocutaneous HSV infection

Lesions may appear anywhere on the skin or mucosa but are most frequent in the following locations:

  • Mouth or lips (perioral infection)

  • Genitals

  • Conjunctiva and cornea

Generally, after a prodromal period (typically < 6 h in recurrent HSV-1) of tingling discomfort or itching, clusters of small, tense vesicles appear on an erythematous base. Clusters vary in size from 0.5 to 1.5 cm but may coalesce. Lesions on the nose, ears, eyes, fingers, or genitals may be particularly painful.

Vesicles typically persist for a few days, then rupture and dry, forming a thin, yellowish crust.

Healing generally occurs within 10 to 19 days after onset in primary infection or within 5 to 10 days in recurrent infection. Lesions usually heal completely, but recurrent lesions at the same site may cause atrophy and scarring. Skin lesions can develop secondary bacterial infection. In patients with depressed cell-mediated immunity due to HIV infection or other conditions, prolonged or progressive lesions may persist for weeks or longer. Localized infections can disseminate, particularly—and often dramatically—in immunocompromised patients.

Acute herpetic gingivostomatitis usually results from primary infection with HSV-1, typically in children. Herpetic pharyngitis can occur in adults as well as children. Occasionally, through oral-genital contact, the cause is HSV-2. Intraoral and gingival vesicles rupture, usually within several hours to 1 or 2 days, to form ulcers. Fever and pain often occur. Difficulty eating and drinking may lead to dehydration. After resolution, the virus resides dormant in the semilunar ganglion.

Herpes labialis is usually a recurrence of HSV. It develops as ulcers (cold sores) on the vermilion border of the lip or, much less commonly, as ulcerations of the mucosa of the hard palate.

Genital herpes is the most common ulcerative sexually transmitted disease in developed countries. Genital HSV can be caused by HSV-1 or HSV-2.

Herpes simplex keratitis

Herpes simplex keratitis (HSV infection of the corneal epithelium) causes pain, tearing, photophobia, and corneal ulcers that often have a branching pattern.

Herpetic whitlow

Herpetic whitlow, a swollen, painful, erythematous lesion of the distal phalanx, results from inoculation of HSV through the skin and is most common among health care practitioners.

Neonatal herpes simplex

Neonatal HSV infection develops in neonates, including those whose mothers have no suggestion of current or past herpes infection. It is most commonly transmitted during birth through contact with vaginal secretions containing HSV and usually involves HSV-2.

Neonatal HSV infection usually develops between the 1st and 4th wk of life, often causing mucocutaneous vesicles or CNS involvement. It causes major morbidity and mortality.

CNS infection

Herpes encephalitis occurs sporadically and may be severe. Multiple early seizures are characteristic.

Viral meningitis may result from HSV-2. It is usually self-limited and may involve lumbosacral myeloradiculitis, which may cause urinary retention or obstipation.


  • Clinical evaluation

  • Sometimes laboratory confirmation

  • PCR of CSF and MRI for HSV encephalitis

Diagnosis is often clinical based on characteristic lesions.

Laboratory confirmation can be helpful, especially if infection is severe, the patient is immunocompromised or pregnant, or lesions are atypical. A Tzanck test (a superficial scraping from the base of a freshly ruptured vesicle stained with Wright-Giemsa stain) often reveals multinucleate giant cells in HSV or varicella-zoster virus infection.

Definitive diagnosis is with culture, seroconversion involving the appropriate serotype (in primary infections), PCR, and antigen detection. Fluid and material for culture should be obtained from the base of a vesicle or of a freshly ulcerated lesion. HSV can sometimes be identified using direct immunofluorescence assay of scrapings of lesions. PCR of CSF and MRI are used to diagnose HSV encephalitis.

HSV should be distinguished from herpes zoster, which rarely recurs and usually causes more severe pain and larger groups of lesions that are distributed along a dermatome.

Clusters of vesicles or ulcers on an erythematous base are unusual in genital ulcers other than those due to HSV infection.

If herpes infections recur frequently, do not resolve, or do not respond to antiviral drugs as expected, immunocompromise, possibly due to HIV infection, should be suspected.


  • Usually acyclovir, valacyclovir, or famciclovir

  • For keratitis, topical trifluridine

Mucocutaneous infection

Isolated infections often go untreated without consequence.

Acyclovir, valacyclovir, or famciclovir can be used to treat infection, especially when it is primary. Infection with acyclovir-resistant HSV is rare and occurs almost exclusively in immunocompromised patients. Foscarnet may be effective for acyclovir-resistant infections.

Secondary bacterial infections are treated with topical antibiotics (eg, mupirocin or neomycin-bacitracin) or, if severe, with systemic antibiotics (eg, penicillinase-resistant β-lactams). Systemic analgesics may help.

Gingivostomatitis and pharyngitis may require symptom relief with topical anesthetics (eg, dyclonine, benzocaine, viscous lidocaine). (Note: Lidocaine must not be swallowed because it anesthetizes the oropharynx, the hypopharynx, and possibly the epiglottis. Children must be watched for signs of aspiration.) Severe cases can be treated with acyclovir, valacyclovir, or famciclovir.

Herpes labialis responds to oral and topical acyclovir. The duration of a recurrent eruption may be decreased by about a day by applying penciclovir 1% cream q 2 h while awake for 4 days, beginning during the prodrome or when the first lesion appears. Toxicity appears to be minimal. Famciclovir 1500 mg as one dose or valacyclovir 2 g po q 12 h for 1 day can be used to treat recurrent herpes labialis. Acyclovir-resistant strains are resistant to penciclovir, famciclovir, and valacyclovir. Docosanol 10% cream may be effective when used 5 times/day.

Herpetic whitlow heals in 2 to 3 wk without treatment. Topical acyclovir has not been shown to be effective. Oral or IV acyclovir can be used in immunosuppressed patients and those with severe infection.

Pearls & Pitfalls

  • Treating primary herpes infection with drugs, even if done early, does not prevent recurrence.

Herpes simplex keratitis

Treatment of herpes simplex keratitis involves topical antivirals, such as trifluridine, and should be supervised by an ophthalmologist.

Neonatal herpes simplex

Acyclovir 20 mg/kg IV q 8 h for 14 to 21 days should be used if renal function is normal. A dose of 20 mg/kg IV q 8 h for at least 21 days is indicated for CNS and disseminated HSV disease.

CNS infection

Encephalitis is treated with acyclovir 10 mg/kg IV q 8 h for 14 to 21 days if renal function is normal. Treatment for 14 to 21 days is preferred to prevent potential relapse. Higher doses up to 20 mg/kg IV q 8 h are used in children.

Viral meningitis is usually treated with IV acyclovir. Acyclovir is generally very well-tolerated. However, adverse effects can include phlebitis, renal dysfunction, and, rarely, neurotoxicity (lethargy, confusion, seizures, coma).

Key Points

  • HSV usually causes mucocutaneous infection but sometimes causes keratitis, and serious CNS infection can occur in neonates and in adults.

  • After initial infection, HSV remains dormant in nerve ganglia, from which it can periodically emerge, causing symptoms.

  • Diagnose mucocutaneous infections clinically, but do viral culture, PCR, or antigen detection if patients are neonates, immunocompromised, or pregnant or have a CNS infection or severe disease.

  • Give IV acyclovir to patients with serious infections.

  • For mucocutaneous infections, consider oral acyclovir, valacyclovir, or famciclovir; for herpes labialis, an alternative is topical penciclovir or docosanol.

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* This is the Professional Version. *