Herpes simplex virus infections

Herpes simplex virus (HSV) infections are caused by herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Worldwide seroprevalence is high, with antibodies detectable in over 90% of the population. After primary infection, HSV remains dormant in ganglion neurons. Reactivation can be triggered by various factors (e.g., stress, trauma, immune deficiency). Mucocutaneous HSV infections affect the mucosa (e.g., lips, mouth, esophagus, genital area) and/or the skin and manifest as painful, grouped vesicles on an erythematous base that progress to ulcers with or without prodromal symptoms (e.g., pain, tingling, burning sensation). Nonmucocutaneous HSV infections are less common and may affect the CNS (e.g., HSV encephalitis, HSV meningitis) and/or the eyes (e.g., HSV keratitis, HSV conjunctivitis). Diagnosis is based on clinical presentation and/or confirmatory laboratory studies. Treatment comprises antivirals (e.g., acyclovir or valacyclovir) and supportive care.

• More than 90% of the world's population over the age of 40 years carries HSV. ^[1]
• Recurrent infections are more common in immunocompromised individuals. ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Types
  • Herpes simplex virus type 1 (HSV-1), human herpes virus type 1 (HHV-1)
  • Herpes simplex virus type 2 (HSV-2), human herpes virus type 2 (HHV-2)
• Transmission
  • Direct contact with mucosal tissue or secretions of another infected person
  • Infection with HSV-1 is usually acquired in childhood via saliva.
  • HSV-2 is mostly spread through genital contact and should, therefore, raise suspicion for sexual abuse if found in children.
  • Perinatal transmission (e.g., during childbirth if the birthing parent is symptomatic) is more common for HSV-2.
• Type of infection
  • Primary infection
    • Mostly asymptomatic (up to 80% of cases, but virus is still shed)
    • If symptomatic, the infection is often sudden and severe with systemic symptoms (e.g., fever, malaise, myalgias, and headaches)
  • Reactivation of infection
    • Frequency and severity vary individually; symptoms are usually less severe than in primary infection.
    • Often at the same site as primary infection

• Inoculation: The virus enters the body through mucosal surfaces or small dermal lesions.
• Neurovirulence: The virus invades, spreads, and replicates in nerve cells.
• Latency: After primary infection, the virus remains dormant in the ganglion neurons.
  • Trigeminal ganglion: HSV-1
  • Sacral ganglion: HSV-2
• Reactivation: triggered by various factors (e.g., immunodeficiency, stress, trauma) → clinical manifestations
• Dissemination
  • Disseminated HSV infection spreads to unusual sites (e.g., lungs, gastrointestinal tract, eyes)
  • May occur in pregnant patients or patients with severe immunodeficiency (e.g., malnutrition, recipients of organ transplants, patients with AIDS)

Approach ^[3][4][5]

• Make a clinical diagnosis of HSV infection or reactivation.
• Confirmatory testing with PCR and/or viral culture is indicated for:
  • First episode of genital HSV (or a recurrent episode if diagnosis was never confirmed) ^[3]
  • Severe infections (e.g., eczema herpeticum, CNS involvement, ocular involvement, disseminated infection) ^[2]
  • High-risk patients (e.g., neonates and young infants, pregnant individuals, and immunocompromised individuals) ^[2][6]
  • Diagnostic uncertainty (e.g., atypical lesions, frequent recurrence) ^[3]
• Serology may be indicated in certain cases.

Mucocutaneous HSV infections are primarily a clinical diagnosis based on the classic appearance of vesicular and ulcerative lesions. ^[4]

Confirmatory testing ^[3][7]

Take samples from a genital ulcer or mucocutaneous lesion. See “Infant HSV testing” for recommended studies in neonates and infants.

• PCR
  • Most sensitive laboratory technique for detecting HSV DNA
  • First-line test for confirmation of the following HSV infections:
    • Mucocutaneous
    • Visceral (e.g., esophagitis, pneumonitis)
    • CNS (e.g., meningitis, encephalitis)
  • Performed on a CSF sample in patients with suspected herpes encephalitis or meningitis
• Viral culture
  • Indicated if antiviral sensitivity testing is needed
  • Lower sensitivity than PCR
  • Mucocutaneous samples should be taken from a fresh vesicle.

Serologic testing ^[3]

• Request type-specific HSV testing to differentiate between HSV-1 and HSV-2.
• HSV-2 type-specific HSV testing may be indicated in the following cases: ^[3]
  • Suspected genital infection despite negative confirmatory testing, e.g., patients with recurrent and/or atypical anogenital symptoms
  • Sexual partner with known HSV infection
• HSV serology cannot determine the location of infection.
• Screening of asymptomatic individuals, including pregnant patients, is not recommended. ^[8]

Microscopy ^[7]

Microscopy preparations of ulcer base scrapings are no longer recommended because of poor sensitivity and specificity. ^[3][4]

• Tzanck test
  • Findings
    • Multinucleated giant cells
    • Eosinophilic intranuclear Cowdry A inclusions
  • Cannot be used to differentiate between HSV-1 and HSV-2; also commonly positive in VZV infection
• Direct fluorescent antibody test
  • Detects HSV antigens
  • Can distinguish between HSV-1 and HSV-2

“Tzancks for the herpes!”: Herpes is detected on Tzanck smear.

Microscopic detection of HSV infection is not recommended due to poor sensitivity and specificity. ^[3][4]

Approach

• Initiate symptomatic treatment as needed.
  • IV fluids
  • Barrier creams to avoid lip adhesion
  • Oral analgesics or parenteral analgesics
• Start antiviral therapy (if indicated) to reduce severity, duration, and viral shedding.
• Prevent onward transmission.
  • Contact precautions for hospitalized patients with
    • Severe primary mucocutaneous infection
    • Disseminated infection
  • Educate patients on prevention of HSV infections. ^[9]

General principles of antiviral treatment ^[5][10][11]

For dosages, see specific subtypes.

• Goals
  • Decrease in duration and severity of infection (most effective if initiated within 72 hours of onset)
  • Reduction of viral shedding
• Mechanism of action: inhibition of viral replication
• Agents
  • Acyclovir
    • Oral administration: first-line
    • IV administration: for severe infections (e.g., severe odynophagia or dysphagia, disseminated infection)
    • Topical administration: can be helpful if used early
    • Inexpensive but typically requires frequent dosing
  • Valacyclovir
    • Prodrug of acyclovir
    • Oral administration
    • More expensive, but typically requires less frequent dosing
  • Penciclovir
    • Topical administration
    • Effective against HSV-1, HSV-2, VZV, and EBV
  • Famciclovir
    • Prodrug of penciclovir
    • Oral administration
  • Foscarnet: for acyclovir-resistant HSV-1
• Prophylaxis: indicated in the case of frequent or severe relapses; particularly in patients without prodromal symptoms
  • Long-term suppressive therapy with (val)acyclovir
  • Variable results in studies
  • Costly

Early treatment is essential as antiviral drugs only inhibit the virus during its replication phase.

Mucocutaneous HSV infections

Mucocutaneous HSV infections affect the mucosa (e.g., lips, mouth, esophagus, genital area) and/or the skin and manifest with painful vesicles on an erythematous base that progress to ulcers.

Nonmucocutaneous HSV infections

• Congenital HSV (see “TORCH infections”)
• Neonatal HSV
• Herpes simplex keratitis
• Herpes simplex conjunctivitis
• Necrotizing herpetic retinopathy
• Herpes simplex encephalitis
• Viral meningitis (e.g., HSV)
• Benign recurrent lymphocytic meningitis: a rare recurrent aseptic meningitis ^[20]
  • Clinical features
    • Headache, meningismus
    • Transient neurological symptoms in ∼ 50% of cases
    • Usually self-limited: Most affected individuals have spontaneous remission and no long-term neurological sequelae.
  • Management: Antiviral treatment (e.g., IV acyclovir or oral valacyclovir) may be beneficial.

Primary oral HSV infection manifests as herpetic gingivostomatitis and reactivations manifest as labial herpes. ^[21]

Herpetic gingivostomatitis ^[5][21]

• Epidemiology: : peak incidence in children < 5 years of age and young adults ^[21]
• Etiology: mostly HSV-1
• Clinical features
  • Gingivostomatitis
    • Erythema and painful ulcerations on perioral skin and oral mucosa
    • Especially on the inner cheek, soft palate, and tongue
  • Submandibular and/or cervical lymphadenopathy
  • Herpetic pharyngotonsillitis: clusters of vesicles on the tonsils and posterior pharynx ^[22]
  • Prodromal symptoms (up to 15 days after infection): fever, malaise, myalgias, nausea, loss of appetite
• Diagnostics ^[5]
  • Typically a clinical diagnosis.
  • Diagnostic uncertainty: See “Diagnostics of HSV infections.”
• Differential diagnoses: See “Differential diagnosis” in “Labial herpes.”
• Treatment: The following regimens are for immunocompetent patients; for immunocompromised patients, consult a specialist.
  • All patients
    • Provide symptomatic treatment (e.g., oral analgesics, cold foods, topical anesthesia).
    • Assess hydration status
      • Encourage oral hydration.
      • Consider hospital admission for IV fluids for patients who cannot tolerate oral intake.
  • Primary infection within 72 hours of symptom onset: Consider oral acyclovir; (off-label) . ^{[2][4][5][21]}

Herpetic gingivostomatitis may be mistaken for teething in infants. ^[23]

Labial herpes ^[5][24][25]

• Epidemiology: most common recurrent HSV infection
• Etiology: mostly HSV-1
• Clinical features
  • Erythematous vesicles on the lip or vermillion border that progress to ulcerations
  • Prodromal symptoms (lasting ∼ 6 hours): pain, tingling, burning sensation
• Diagnostics
  • Typically a clinical diagnosis.
  • Diagnostic uncertainty: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Shingles (herpes zoster)
  • Aphthous ulcers
  • Herpangina
  • Hand, foot, and mouth disease
  • Candidiasis
  • Syphilitic chancre
• Treatment: The following regimens are for immunocompetent patients; for immunocompromised patients, consult a specialist.
  • Primary infection in adults: oral valacyclovir; (off-label) OR acyclovir (off-label) ^[26]
  • Reactivation
    • In adults and adolescents
      • Oral: valacyclovir OR acyclovir (off-label) ^[2][5]
      • Topical (less-effective than oral): acyclovir cream OR penciclovir cream ^[5]
    • In children < 12 years: Consider oral acyclovir (off-label) . ^[2][5]
  • Suppression in adults : valacyclovir (off-label) OR acyclovir (off-label) ^[26]

There is limited evidence for the efficacy of antivirals in children with labial herpes infection. ^[2]

There is no evidence to support topical therapy to prevent labial herpes reactivation. ^[2][27]

For pregnant individuals, see “Genital herpes in pregnancy.”

• Etiology: : most commonly HSV-2 ^[12]
• Incubation period: 4–7 days ^[12]
• Clinical features ^[7][12][28]
  • Affected individuals are often asymptomatic or have mild symptoms but may still be at risk of transmission.
  • Skin lesions: may be present in both initial and recurrent infection
    • Prodromal symptoms: redness, swelling, tingling, pain, pruritus
    • Grouped erythematous vesicles that progress to painful ulcers in the anogenital area
  • Primary infection
    • Genital tract: skin lesions in the anogenital area, cervicitis, white, thick, and/or foul-smelling vaginal discharge
    • Urinary tract: dysuria, urethritis
    • Associated symptoms: fever, headaches, myalgias, malaise, tender bilateral inguinal lymphadenopathy
  • Recurrent infection
    • Prodromal symptoms (lasting hours to days): pain or tingling in the genitals, legs, buttocks, and/or hips
    • Skin lesions are usually unilateral, less painful, and of shorter duration than in the initial infection.
• Diagnostics ^[29]
  • If lesions are present:
    • Make an initial clinical diagnosis to facilitate timely empiric treatment.
    • Obtain laboratory confirmation (See “Diagnostics of HSV infections”).
  • If lesions are absent: Obtain type-specific HSV testing in selected cases.
  • Obtain other STI testing.
• Differential diagnoses
  • Syphilitic chancre
  • Chancroid
• Treatment for genital herpes: The following regimens are for immunocompetent patients; for immunocompromised patients, consult a specialist. ^[3][12]
  • Initial infection in adults and adolescents
    • Acyclovir ^[2][3]
    • OR valacyclovir (off-label in children) ^[2][3]
    • OR famciclovir (off-label) ^[3]
  • Recurrent episode in adults and adolescents
    • Acyclovir ^[2][3]
    • OR valacyclovir (off-label in children) ^[2][3]
    • OR famciclovir (off-label in children) ^[2][3]
  • Patients with HIV: See “Mucosal and mucocutaneous complications in HIV infection.”
• Suppressive therapy in adults and adolescents
  • Indications
    • Recurrent infections
    • Sexually active patients (to reduce transmission risk)
  • Treatment options: Used for up to 12 months; reassess ongoing need.
    • Acyclovir ^[2][3]
    • OR valacyclovir (off-label in children) (prescribe high-dose valacyclovir for individuals with ≥ 10 recurrences per year) ^[2][3]
    • OR famciclovir (off-label in children) ^[3]
• Management of sexual partners ^[3]
  • Symptomatic: Provide diagnostics and treatment for genital herpes.
  • Asymptomatic: Offer type-specific HSV testing.

Counsel on safer sex practices and STI prevention. ^[3]

Suspect child sexual abuse in children with genital herpes or HSV-2 infection occurring at ≥ 1 month of age and before adolescence. ^[3]

Eczema herpeticum ^[17]

• Etiology
  • HSV-1 or HSV-2
  • Associated with preexisting skin conditions, commonly atopic dermatitis
• Clinical features
  • Appearance
    • Grouped painful umbilicated vesicles on an erythematous base
    • Progression to punched-out erosions
  • Location
    • Areas of existing active or healing eczema (e.g., head, upper body, flexural surfaces) ^[14][15][16]
    • See “Clinical features of eczema” for age-specific features.
  • Associated symptoms: fever, malaise, lymphadenopathy
• Differential diagnoses
  • Chickenpox
  • Impetigo
  • Contact dermatitis
  • Smallpox
• Management ^[14][17][30]
  • Start empiric acyclovir (first-line treatment) while awaiting confirmatory diagnostics for HSV. ^[30]
    • Mild or moderate involvement: oral acyclovir (off-label) in consultation with specialists ^[14][30]
    • Severe involvement, systemic symptoms, immune deficiency, and/or age < 1 year: IV acyclovir (off-label) ^[2][30]
  • Urgently consult dermatology and infectious diseases.
  • Symptomatic management: antihistamines for pruritus, cool compresses, skin care

Eczema herpeticum is a disseminated HSV infection and a dermatologic emergency; treat promptly with acyclovir. ^[17]

Herpetic whitlow ^[13][31][32]

• Etiology
  • HSV-1 or HSV-2
  • Direct contact with infected secretions through a break in the skin (e.g., torn cuticle)
  • Commonly affected individuals
    • Children
    • Health care workers exposed to oral secretions (e.g., dentists)
• Incubation period: 2–20 days ^[13]
• Clinical features
  • Appearance: cluster of vesicles on an erythematous base that progress to ulcerations
  • Location: commonly the distal phalanx of a single finger
  • Associated symptoms
    • Pain, edema, tingling, and a burning sensation in the infected finger
    • Regional lymphadenopathy (e.g., axillary, epitrochlear), dermatomal pain, and, rarely, fever
• Diagnostics
  • Typically diagnosed clinically
  • Diagnostic uncertainty: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Paronychia
  • Cellulitis
  • Felon
• Treatment ^[13]
  • Provide symptomatic management (e.g., analgesia, immobilization, elevation).
  • Keep a dry dressing over the lesions to reduce viral spread.
  • Advise patients that herpetic whitlow is self-limited, with resolution in ∼ 3 weeks.
  • Consider antiviral treatment in consultation with infectious disease for patients with:
    • Lesions < 48 hours old
    • Immune deficiency

Surgical treatment is not indicated for herpetic whitlow and can lead to complications (e.g., inoculation of uninfected skin, bacterial superinfection). ^[31]

Herpes gladiatorum ^[18][33]

• Epidemiology: typically occurs in athletes that participate in close contact sports (e.g., wrestling, rugby)
• Incubation period: 4–11 days
• Etiology
  • HSV-1
  • Direct contact with infected oral secretions through a break in the skin
• Clinical features
  • Appearance: Multiple vesicles on an erythematous base that progress to ulcerations
  • Location: most commonly located on areas with skin-to-skin contact (e.g., head, neck, and arms) ^[16]
  • Associated symptoms: fever, malaise, tender regional lymphadenopathy
• Diagnostics: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Folliculitis
  • Impetigo
• Treatment ^[34]
  • The following regimens are for immunocompetent patients; for immunocompromised patients, consult a specialist.
    • Initial infection: acyclovir (off-label) OR valacyclovir (off-label) ^[18][33][34]
    • Recurrent infection: acyclovir (off-label) OR valacyclovir (off-label) ^[18]
    • Suppression (adults only; off-label) during sports season: acyclovir OR valacyclovir OR famciclovir ^[34]
  • Exclude individuals from skin-skin contact sports until all of the following are met: ^[2][16][34]
    • Has received 5 days of systemic antivirals ^[34]
    • No new lesions for 72 hours ^[34]
    • All lesions are crusted over and covered.
    • Primary episode: no ongoing systemic symptoms
• Complications: ocular manifestations (e.g., follicular conjunctivitis, viral keratitis)

• Epidemiology: typically occurs in patients who are immunocompromised ^[35]
• Clinical features
  • Odynophagia
  • Dysphagia
  • Retrosternal chest pain
• Diagnostics ^[36][37]
  • Endoscopy: superficial punched-out ulcers in the mid and distal esophagus in the absence of plaques ^[38]
  • Histopathology
    • Multinucleated giant cells
    • Intranuclear eosinophilic Cowdry A inclusions
• Differential diagnoses: See “Infectious esophagitis.”
• Treatment ^[36][37]
  • Consider inpatient treatment for patients with severe odynophagia.
  • Optimize nutrition and hydration.
  • Provide pain management.
  • Administer acyclovir.
    • Immunocompetent patients:
    • Immunocompromised patients:
    • Severe odynophagia or dysphagia: IV treatment
  • Consult gastroenterology and infectious disease specialists as needed.
  • In treatment-naive patients with AIDS, evaluate the need to initiate antiretroviral therapy in consultation with infectious disease specialists.

Advise affected individuals of the following: ^[27][39][40]

• All patients
  • Be aware of prodromal symptoms and atypical signs of active herpes lesions.
  • During prodromal symptoms or active lesions, avoid direct contact with uninfected individuals. ^[3][40]
    • Cover skin lesions.
    • Avoid oral and/or genital contact. ^[2]
  • Consider suppressive antiviral therapy to prevent recurrence and transmission.
• Individuals with genital HSV
  • Inform sexual partners; in partners with no history of HSV, offer type-specific serologic testing. ^[40]
  • Use male condoms to reduce the risk of contracting or spreading genital herpes (see “Prevention of STIs”).
• Individuals with oral HSV: Avoid sharing cutlery, drinks, or lip balm. ^[41]
• Pregnant individuals
  • See “Management of genital herpes in pregnant individuals.”
  • See “Prevention of neonatal HSV infection.”

There is a risk of contracting the herpes virus from infected individuals even if they are asymptomatic. ^[40]

Genital herpes in pregnancy ^[2][3][6]

HSV infection during pregnancy can cause disseminated HSV infection (e.g., HSV hepatitis, fulminant liver failure) and vertical transmission. ^[3][42]

Suppressive antiviral therapy and cesarean delivery for certain pregnant individuals reduce the risk of vertical transmission. ^[43]

Prenatal management ^[3][6][8]

• Ask about any history of oral and genital HSV infections.
• Type-specific serologic testing is not routinely recommended.
• No history of oral, labial and/or genital HSV: Recommend avoiding sexual activities during the third trimester if their partner has known or suspected HSV infection.
• Indications for antiviral therapy: The following regimens are for immunocompetent patients; for immunocompromised patients, consult a specialist.
  • Active infection
    • Primary infection: oral acyclovir OR valacyclovir ^[6]
    • Recurrent episodes: oral acyclovir OR valacyclovir ^[6]
    • Severe or disseminated disease: IV acyclovir ^[6]
  • History of genital HSV: suppressive oral antivirals from 36 weeks' gestation until delivery
    • Acyclovir ^[3][6]
    • OR valacyclovir ^[3][6]

Famciclovir is not used during pregnancy as the safety has not been established. ^[6]

Peripartum management ^[6]

• Individuals presenting for labor and delivery
  • Ask about any history of genital herpes; if prior history, examine thoroughly for active HSV lesions.
  • Active genital lesions and preterm prelabor rupture of membranes: Urgently consult obstetrics.
• Considerations for cesarean delivery
  • Active genital lesions or prodromal symptoms at delivery: Recommend cesarean delivery.
  • Primary infection of genital herpes in the third trimester: Offer an elective cesarean delivery at term or near-term.

Postpartum management ^[6]

• Birthing parent: Breastfeeding is safe if there are no lesions on the breast and all active lesions are covered.
• Newborn: Provide prevention of HSV infection in neonates.

• One-Minute Telegram 70-2023-2/3: USPSTF reaffirms: Do not screen asymptomatic patients for HSV!

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