Herpes simplex virus infections

Herpes simplex virus (HSV) infections can be 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. Following primary infection, HSV remains dormant in ganglion neurons, after which reactivation can be triggered by various factors (e.g., stress, trauma, immunodeficiency). HSV infection typically manifests as oral, genital, or cutaneous lesions composed of painful grouped erythematous vesicles that progress to ulcers. Less common manifestations include herpes simplex keratitis, herpes simplex encephalitis, and herpes esophagitis. Oral herpes is typically caused by HSV-1 and includes herpetic gingivostomatitis and labial herpes. Clinical features of herpetic gingivostomatitis include painful lesions on the oral mucosa and prodromal symptoms. Labial herpes is a manifestation of HSV-1 reactivation. Patients typically present with prodromal symptoms (e.g., pain, tingling, burning sensation) followed by lesions on the lip or vermillion border. Genital herpes is usually caused by HSV-2 and can manifest during primary infection or reactivation. Patients may be asymptomatic or may present with skin lesions. Cutaneous herpes includes eczema herpeticum and herpes gladiatorum (on the head and neck), and herpetic whitlow (on the finger). HSV infection is usually a clinical diagnosis, with laboratory testing used for confirmation. Treatment mainly comprises antivirals (e.g., acyclovir or valacyclovir) and supportive care.

See also “Herpes simplex encephalitis,” “Herpes simplex keratitis,” “Herpes simplex conjunctivitis,” “Necrotizing herpetic retinopathy,” and “Neonatal herpes simplex virus infection.”

Epidemiology

More than 90% of the world's population over the age of 40 years carries HSV. ^[1]

Etiology

• 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 usually is 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 mother 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 ^[2][3][4]

• Make a clinical diagnosis of HSV infection or reactivation.
• Confirm diagnosis with PCR and/or viral culture in patients with suspected infection or reactivation regardless of symptoms. ^[3]
• Serology may be indicated in certain cases.

Microscopic detection of HSV infection is not recommended due to poor sensitivity and specificity. ^[2][3]

Mucocutaneous HSV infections are primarily a clinical diagnosis based on the classic appearance of vesicular and ulcerative lesions. ^[3]

Confirmatory testing ^[2][5]

Take samples from a genital ulcer or mucocutaneous lesion.

• PCR
  • Most sensitive laboratory technique for detecting HSV DNA
  • First-line test for confirmation of mucocutaneous, visceral (e.g., esophagitis, pneumonitis), or CNS (e.g., meningitis, encephalitis) HSV infection
  • 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 ^[2]

• 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: ^[2]
  • 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. ^[6]

Microscopy ^[5]

Microscopy preparations of ulcer base scrapings are no longer recommended because of poor sensitivity and specificity. ^[2][3]

• 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.

Use contact precautions for hospitalized patients with mucocutaneous, disseminated, or severe primary infections.

Antiviral treatment ^[4][7][8]

For dosages, see specific subtypes.

• Effect
  • Decrease in duration and severity of infection (most effective if therapy is initiated within 72 hours of onset of infection)
  • Reduction of viral shedding
  • However, recurrence cannot be prevented.
• Agents
  • Acyclovir
    • Oral administration: first-line
    • IV administration: for severe odynophagia or dysphagia
    • 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
• Dosages: based on subtype
  • See “Herpetic gingivostomatitis.”
  • See “Labial herpes.”
  • See “Genital herpes.”
  • See “Eczema herpeticum.”
  • See “Herpes gladiatorum.”
  • See “Herpes esophagitis.”
• 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 of herpes infections is essential to prevent complications because antiviral drugs only inhibit the virus during its replication phase.

Symptomatic treatment

• IV fluids
• Barrier creams to avoid lip adhesion
• Oral analgesics or parenteral analgesics
• Antipyretics

HSV infections typically manifest with painful vesicles on an erythematous base that progress to ulcerations.

Primary oral HSV infection manifests as herpetic gingivostomatitis and reactivations manifest as labial herpes. ^[14]

Herpetic gingivostomatitis ^[4][14]

• Epidemiology: : peak incidence in children < 5 years of age and young adults ^[14]
• 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 ^[15]
  • Prodromal symptoms (up to 15 days after infection): fever, malaise, myalgias, nausea, loss of appetite
• Diagnostics: See “Diagnostics of HSV infections.”
• Differential diagnoses: See “Differential diagnosis” in “Labial herpes.”
• Treatment
  • Initiate acyclovir (off-label) as soon as possible. ^[3][4][14]
  • Provide symptomatic management (e.g., oral analgesics, cold foods, topical anesthesia).
  • Encourage oral hydration to avoid dehydration.
  • Consider hospital admission for IV fluids for patients who cannot tolerate oral intake.

Herpetic gingivostomatitis may be mistaken for teething in infants. ^[16]

Labial herpes ^[4][17][18]

Reactivation of herpetic gingivostomatitis manifests as labial herpes.

• 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: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Shingles (herpes zoster)
  • Aphthous ulcers
  • Herpangina
  • Hand, foot, and mouth disease
  • Candidiasis
  • Syphilitic chancre
• Treatment
  • Oral: valacyclovir OR acyclovir (off-label) ^[4]
  • Topical: docosanol cream OR acyclovir cream ^[4]
  • Patients with HIV: See “Mucosal and mucocutaneous complications in HIV infection.”

Topical treatments are less effective than oral treatments for labial herpes. ^[4]

For genital herpes during pregnancy, see “Congenital herpes simplex virus infection.”

• Etiology: : most commonly HSV-2 ^[9]
• Incubation period: 4–7 days ^[9]
• Clinical features ^[5][9][19]
  • 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 ^[20]
  • 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.
• Differential diagnoses
  • Syphilitic chancre
  • Chancroid
• Treatment for genital herpes ^[2][9]
  • Initial infection
    • Acyclovir ^[2]
    • OR famciclovir (off-label) ^[2]
    • OR valacyclovir ^[2]
  • Recurrent episode
    • Acyclovir ^[2]
    • OR famciclovir ^[2]
    • OR valacyclovir ^[2]
  • Patients with HIV: See “Mucosal and mucocutaneous complications in HIV infection.”
• Suppressive therapy
  • Indications
    • Recurrent infections
    • Sexually active patients (to reduce transmission risk)
  • Treatment options
    • Acyclovir ^[2]
    • OR valacyclovir ^[2]
    • OR famciclovir ^[2]
• Management of sexual partners ^[2]
  • Symptomatic: Provide diagnostics and treatment for genital herpes.
  • Asymptomatic: Offer type-specific HSV testing.

Counsel on safer sex practices and STI prevention.

Eczema herpeticum ^[10]

• Etiology
  • HSV-1 or HSV-2
  • Associated with preexisting skin conditions, commonly atopic dermatitis
• Clinical features
  • Grouped painful umbilicated vesicles on an erythematous base that progress to punched-out erosions
  • Most commonly located on the head and upper body
  • Associated symptoms: fever, malaise, lymphadenopathy
• Differential diagnoses
  • Chickenpox
  • Impetigo
  • Contact dermatitis
  • Smallpox
• Diagnostics: initially clinical diagnosis, then confirmed with laboratory testing (see “Diagnostics of HSV infections.”)
• Treatment
  • First line: IV acyclovir (off-label) ^[10]
  • Consult dermatology urgently for assistance with management.

Eczema herpeticum is a dermatologic emergency; prompt treatment with acyclovir is required. ^[10]

Herpetic whitlow ^[11][21][22]

• 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 ^[11]
• Clinical features
  • Cluster of vesicles on an erythematous base that progress to ulcerations
  • Pain, edema, tingling, and a burning sensation in the infected finger
  • Commonly, a single digit is involved.
  • Associated symptoms: regional lymphadenopathy (e.g., axillary, epitrochlear), dermatomal pain, and, rarely, fever
• Diagnostics: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Paronychia
  • Cellulitis
  • Felon
• Treatment ^[11]
  • 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 consulting an infectious disease specialist for antiviral treatment for patients with lesions < 48 hours old and immunocompromised patients.

Surgical treatment is not indicated for herpetic whitlow and can lead to complications (e.g., inoculation of uninfected skin, bacterial superinfection). ^[21]

Herpes gladiatorum ^[12][23]

• 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
  • Multiple vesicles on an erythematous base that progress to ulcerations
  • Most commonly located on the head, neck, and arms
  • Associated symptoms: fever, malaise, tender regional lymphadenopathy
• Diagnostics: See “Diagnostics of HSV infections.”
• Differential diagnoses
  • Folliculitis
  • Impetigo
• Treatment
  • Initial infection: acyclovir (off-label) OR valacyclovir (off-label) ^[12]
  • Recurrent infection: acyclovir (off-label) OR valacyclovir (off-label) ^[12]
• Complications: ocular manifestations (e.g., follicular conjunctivitis, viral keratitis)

• Epidemiology: typically occurs in patients who are immunocompromised ^[24]
• Clinical features
  • Odynophagia
  • Dysphagia
  • Retrosternal chest pain
• Diagnostics ^[25][26]
  • Endoscopy: superficial punched-out ulcers in the mid and distal esophagus in the absence of plaques ^[27]
  • Histopathology
    • Multinucleated giant cells
    • Intranuclear eosinophilic Cowdry A inclusions
• Differential diagnoses: See “Infectious esophagitis.”
• Treatment ^[25][26]
  • 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.

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

Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.