Herpes simplex virus infections

Herpes simplex virus infections may be caused by two virus genotypes: 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. Of these cases, approx. 60% are caused by HSV-1. The most common infections are labial and genital herpes, which present with painful ulcerations. Two further conditions, seen especially in children, are herpetic gingivostomatitis and herpetic whitlow. While herpetic gingivostomatitis is characterized by painful lesions of the oral and pharyngeal mucosa, herpetic whitlow causes blisters on the fingers with pronounced regional lymphadenopathy. In individuals with underlying dermatological conditions, infection with HSV can cause eczema herpeticum, resulting in painful erosions spread diffusely over the head and upper body. However, the majority of primary infections remain asymptomatic, while recurrent infections present with the typical manifestations. The diagnosis of HSV infections is usually confirmed through viral cultures, but may also be based on detection of HSV DNA in PCR, or multinucleated giant cells in Tzanck smears. Treatment consists mainly of topical or oral acyclovir; IV administration may be needed in critical cases, such as HSV infection in immunocompromised patients.

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

• Pathogen
  • Mostly HSV-1 (HSV-2 in 10–20% of cases)
  • Most common recurrent HSV-1 infection in adults
• Clinical features
  • Prodromal symptoms (∼ 24 hours): pain, tingling, burning
  • Recurring, erythematous vesicles that turn into painful ulcerations, also known as cold sores; (primarily affecting the oral mucosa and lip borders)
• Differential diagnoses ^[2]
  • Shingles (Herpes zoster)
  • Aphthous ulcers
  • Herpangina
  • Hand, foot, and mouth disease
  • Candidiasis
  • Syphilitic chancre or chancroid
• Diagnostics and treatment: See “Diagnostics” and "Treatment" below.

• Pathogen: : HSV-2, HSV-1 (less common)
• Incubation period: 2–12 days
• Clinical findings ^[3]
  • Most patients are asymptomatic.
  • Skin lesions
    • Initially: redness, swelling, tingling, pain, pruritus
    • Lesions with a punched-out appearance that ulcerate after several days in the anogenital area
    • Lesions may appear as single or disseminated, painful red bumps or white vesicles.
  • Initial infection
    • Nonspecific symptoms: fever, headache, malaise myalgia, painful lymphadenopathy in the groin area
    • Lesions in the anogenital area (see above)
    • Urinary tract: dysuria, urethritis, cervicitis, urinary retention (rarely)
    • White, thick, and/or foul-smelling vaginal discharge
  • Recurrent infection
    • Prodromal symptoms (hours to days prior to appearance of lesions): pain or tingling in the genitals, legs, buttocks, or hips
    • Genital and/or perianal lesions (see above): Lesions are usually unilateral, less painful, and of shorter duration than during initial infection.
• Diagnostics and treatment: See “Diagnostics” and "Treatment" below.
• Special patient groups: For genital herpes during pregnancy, see “Herpes simplex virus infection in the newborn.”

• Epidemiology: mainly in children (∼ 1–6 years), but also immunocompromised patients (e.g., agranulocytosis, HIV)
• Etiology: severe manifestation of an (often primary) HSV-1 infection
• Clinical features
  • Prodrome (fever, malaise) often mistaken for teething in children.
  • Pharyngitis, cervical lymphadenopathy
  • Gingivostomatitis: erythema and painful ulcerations on perioral skin and oral mucosa, especially on the inner cheek, soft palate, and tongue
• Differential diagnoses
  • The same as for labial herpes
  • Herpetic pharyngotonsillitis: pharyngitis and tonsillitis caused by HSV-1
    • Predominantly affects adults
    • Severe pharyngitis; other clinical findings similar to herpetic gingivostomatitis
    • Ulcerations on the tonsils and pharynx, fewer on the oral mucosa
• Diagnostics and treatment: See “Diagnostics” and "Treatment" below.

• Synonym: also known as Kaposi varicelliform eruption (KVE)
• Pathogen: most commonly HSV-1 and HSV-2
• Etiology: associated with preexisting skin conditions, most often atopic dermatitis
• Clinical features
  • Fever, malaise, lymphadenopathy
  • Extensive disseminated and painful eruptions on the head and upper body; : erythematous skin with multiple, round, umbilicated vesicles that may progress to punched-out erosions
• Diagnostics and treatment: See “Diagnostics” and "Treatment" below.

Eczema herpeticum is considered a dermatological emergency and treatment with oral or IV acyclovir must be initiated quickly.

• Pathogen: HSV-1 in 60% of cases; HSV-2 in 40% of cases (in the adult population)
• Etiology
  • Direct contact with infected secretions through a break in the skin, e.g., torn cuticle
  • Main groups:
    • Children (via sucking of thumb/fingers (may have a history of labial herpes)
    • Health care workers exposed to oral secretions (e.g., dentists)
• Incubation period: 2–20 days
• Clinical features
  • Possibly history of fever and malaise
  • Infection of the dermal and subcutaneous tissue
  • One or more fingers involved (especially the thumb and index fingers); mostly found on terminal phalanx
  • Pain, tingling, and burning in infected finger
  • Finger edema
  • Grouped, nonpurulent vesicles on an erythematous base for up to 10 days
  • Vesicles may rupture or ulcerate
  • Axillary and epitrochlear lymphadenopathy
• Differential diagnoses: paronychia, cellulitis, felon
• Diagnostics and treatment: See “Diagnostics” and "Treatment" below.

Surgical treatment is not indicated because it may cause severe complications (e.g., bacterial superinfection, systemic spread, herpes encephalitis).

HSV-1

• Herpes simplex encephalitis
  • HSV-1 is the most common pathogen causing sporadic encephalitis in the US.
  • Most commonly involves the temporal lobe
  • Manifests with altered mental status and focal neurologic deficits (e.g., seizures, aphasia)
• Viral keratitis
• Herpes esophagitis
  • Epidemiology: typically occurs in patients who are immunocompromised.
  • Clinical features: odynophagia, dysphagia, and retrosternal chest pain
  • Diagnostics
    • Endoscopy shows superficial ulcers in the mid and distal esophagus in the absence of plaques ^[4]
    • See “Diagnostics” and "Treatment" below.
• Herpes gladiatorum ^[5][6]
  • Epidemiology: typically occurs in athletes that participate in close contact sports (e.g., wrestling, rugby)
  • Incubation period: 4–11 days
  • Etiology: skin lesions exposed to infected oral secretions during close contact or autoinoculation
  • Clinical features: multiple vesicles on an erythematous base located mainly on the head, neck, arms, and/or trunk
  • Complications: ocular manifestations (e.g., follicular conjunctivitis, viral keratitis)

HSV-2

• Congenital herpes simplex, neonatal herpes simplex
• Benign recurrent lymphocytic meningitis: rare benign recurrent aseptic meningitis caused by HSV-2
  • Affected patients have recurrent episodes of meningitis (headache, meningismus) with transient neurological symptoms (in 50% of cases).
  • Most patients have spontaneous remission of symptoms and no permanent neurological sequelae.

Both

• HSV conjunctivitis (including neonatal HSV conjunctivitis)
• Viral meningitis (more commonly caused by HSV-2 than HSV-1)
• Erythema multiforme

Diagnosis is primarily based on clinical features, with confirmation through the following tests:

• Light microscopy findings on a Tzanck smear
  • Detects multinucleated giant cells (nonspecific)
  • Eosinophilic intranuclear Cowdry A inclusion bodies (nonspecific)
  • Results available within 1 hour
  • Unable to differentiate between HSV-1 and HSV-2, also commonly positive in VZV
• Viral culture
  • Can be used to confirm the diagnosis in skin and/or mucosal HSV infections
  • Results are available in 48 hours.
  • The culture should be taken from a fresh vesicle, either from skin or genitals.
• PCR
  • Detects HSV DNA (identification of virus genotype)
  • Method of choice for CNS infections (meningitis, encephalitis), as well as for skin and mucosal lesions
    • CSF sample is used in patients with suspected herpes encephalitis or meningitis.
• Direct fluorescent antibody test : identification of the virus genotype
• Serum antibody testing: shows primary seroconversion; useful in the following:
  • Diagnosis of patients with a history of genital lesions who had no prior diagnostic workup or a negative HSV culture or PCR result
  • Assessment of infection status in individuals who have sexual partners with a documented genital HSV infection
  • Assessment of risk of vertical transmission from mother with HSV infection to child

“I SMEARED my HERPES all over the TANK:” Herpes is detected by TzANcK smear.

Resources: ^[7][8]

Depending on the site, type, and severity of HSV-1 infection, antiviral drugs are administered either topically or systemically. In most cases of recurrent infection, topical and/or symptomatic treatment is sufficient.

Antiviral treatment

• 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
  • First-line: oral acyclovir
    • Immunocompetent patients: oral acyclovir for 7–10 days
    • Immunocompromised patients: oral acyclovir for 14–21 days
    • Severe odynophagia or dysphagia: IV acyclovir
    • Topical may be helpful if used early
  • In case of acyclovir-resistant HSV-1: foscarnet
  • Valacyclovir
    • Prodrug of acyclovir
    • More expensive
    • Oral application
  • Penciclovir
    • Topical application
    • Effective against HSV-1, HSV-2, VZV, and EBV
  • Famciclovir
    • Prodrug of penciclovir
    • Oral application
• Prophylaxis: indicated in the case of frequent or severe relapses; in patients with 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 in cases of lesions on the lips
• Pain relief (oral or IV)
• Antipyretics
• Antibiotics for bacterial superinfection (e.g., amoxicillin, clindamycin)

Prevention

• Use of condoms, gloves
• Consider isolation of hospitalized patients with shedding lesions

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

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