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Herpes Simplex Virus (HSV) Infections

by Kenneth M. Kaye, MD

Herpes simplex viruses (human herpesviruses 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, or unknown stimuli. Generally, recurrent eruptions are less severe and occur less frequently over time.

Diseases Caused by Herpes Simplex

Diseases include

  • Mucocutaneous infection (most common)

  • 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 infection

Lesions may appear anywhere on the skin or mucosa but are most frequent around or in the mouth or on the lips, conjunctiva and cornea, and genitals. 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 8 to 12 days after onset. 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. 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 secondary outbreak 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.

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

Genital herpes is the most common ulcerative sexually transmitted disease in developed countries. It is usually caused by HSV-2, although 10 to 30% of cases involve HSV-1. Primary lesions develop 4 to 7 days after contact. The vesicles usually erode to form ulcers that may coalesce. Lesions may occur on the prepuce, glans penis, and penile shaft in men and on the labia, clitoris, perineum, vagina, and cervix in women. They may occur around the anus and in the rectum in men or women who engage in receptive rectal intercourse. Genital HSV infection may cause urinary hesitancy, dysuria, urinary retention, or constipation. Severe sacral neuralgia may occur. Scarring may follow healing, and the lesions recur in 80% of patients with HSV-2 and in 50% with HSV-1. Primary genital lesions are usually more painful, prolonged, and widespread and are more likely to be bilateral and involve regional adenopathy and constitutional symptoms than recurrent genital lesions. Recurrent lesions may have severe prodromal symptoms and may involve the buttock, groin, or thigh.

Herpes simplex keratitis

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

Neonatal herpes simplex

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. It usually develops between the 1st and 4th wk of life, often causing mucocutaneous vesicles or CNS involvement. It causes major morbidity and mortality (see Neonatal Herpes Simplex Virus (HSV) Infection).

CNS infection

Herpes encephalitis (see also Encephalitis) occurs sporadically and may be severe. Multiple early seizures are characteristic.

Aseptic meningitis (see Overview of Meningitis) may result from HSV-2. It is usually self-limited and may involve lumbosacral myeloradiculitis, which may cause urinary retention or obstipation.

Diagnosis

  • Clinical evaluation

  • Viral culture for serious disease

  • 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 herpes.

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.

Treatment

  • 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). All mucocutaneous herpes infections are treated symptomatically. Systemic analgesics may help.

Gingivostomatitis 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. Docosanol 10% cream may be effective when used 5 times/day.

Genital herpes is treated with antiviral drugs. Acyclovir 800 mg po 2 times/day for 5 days, valacyclovir 1 g po q 12 h for 10 days, or famciclovir 250 mg po tid for 7 to 10 days can be used for primary eruptions. These drugs reduce viral shedding and symptoms in severe primary infections. However, even early treatment of primary infections does not prevent recurrences.

In recurrent eruptions, symptom duration and severity can be reduced marginally by antiviral treatment, particularly during the prodromal phase. Acyclovir 200 mg po q 4 h for 5 days, valacyclovir 500 mg po q 12 h for 3 days, or famciclovir 1000 mg po q 12 h for 1 day can be used. Patients with frequent eruptions (eg, >6 eruptions/yr) may receive suppressive antiviral therapy with acyclovir 400 mg po q 12 h, valacyclovir 500 to 1000 mg po once/day, or famciclovir 250 mg po q 12 h. Doses should be adjusted for renal insufficiency. Adverse effects are infrequent with oral administration but may include nausea, vomiting, diarrhea, headache, and rash.

Pearls & Pitfalls

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

Herpes simplex keratitis

Treatment involves topical antivirals, such as trifluridine, and should be supervised by an ophthalmologist (see Herpes Simplex Keratitis : Treatment).

Neonatal herpes simplex

Acyclovir 20 mg/kg IV q 8 h for 14 to 21 days should be used. 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. Treatment for 14 to 21 days is preferred to prevent potential relapse. Up to 20 mg/kg IV q 8 h can be used in children. Aseptic 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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • ZOVIRAX
  • FAMVIR
  • VALTREX
  • VIROPTIC
  • BACTROBAN
  • ABREVA
  • DENAVIR
  • ANBESOL
  • NEO-FRADIN
  • XYLOCAINE
  • BACIIM
  • FOSCAVIR
  • No US brand name

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