Herpes Simplex Virus (HSV) Infections

Etiology, PathogenesisTop

1. Etiologic agents: Herpes simplex virus (HSV), a DNA virus, exists as either type 1 (HSV-1) or type 2 (HSV-2). The virus enters the body through a mucosal surface or through breaks in the skin and replicates, causing viremia; first-episode primary infection typically has the most severe course. Subsequently, the virus enters neuronal cells and is transported via axons to sensory ganglia (in the case of HSV-1, more frequently to the trigeminal ganglion; in the case of HSV-2, more commonly to the sacral nerve root ganglia [S2 to S5]), where it remains latent. Reactivation of the virus with subsequent viral shedding is extremely common; HSV-1 more commonly reactivates at the orolabial mucosa, whereas HSV-2, at the genital mucosa.

2. Reservoir and transmission: Humans are the only reservoir for HSV. Both individuals with active lesions and those with no detectable illness can shed the virus and transmit infection through direct contact. Vertical transmission from the mother is possible either in utero (congenital infection of the fetus) or, much more commonly, via infectious vaginal secretions intrapartum (perinatal infection of the newborn).

3. Epidemiology: HSV infections are prevalent worldwide. HSV-1 infections often occur during childhood, whereas HSV-2 infections are more often sexually transmitted; the incidence of both is higher in populations with lower socioeconomic status. Vertical transmission is rare, with most of these cases representing perinatal transmission. A history of HSV-1 infection does not confer immunity against HSV-2.

4. Incubation and contagious period depends on the form of disease (see Clinical Features, below). The incubation period for primary gingivostomatitis is generally 3 to 6 days.

Clinical FeaturesTop

Symptoms develop as a result of a primary or recurrent infection (reactivation of the latent virus). In both cases, a characteristic vesicular rash typically appears, preceded by initial localized prodromal signs and symptoms (pain, burning, itching, tingling sensations). Subsequently, inflammatory papules appear and continue to evolve into vesicles (which may then turn into pustules), eventually leading to erosions or ulcerations. Primary infections are characterized by a highly dynamic development of coalescing cutaneous eruptions. Recurrent infections typically involve more pronounced prodromal symptoms, while skin lesions are less numerous and clustered on smaller areas. Regional lymphadenopathy is common.

Clinical Spectrum

Note that the differentiation of HSV-1 and HSV-2 infections based on the clinical presentation is extremely difficult, although HSV-1 more commonly recurs at orolabial sites, whereas HSV-2 more commonly recurs at genital sites.

1. Oral-facial infections:

1) Primary infection (may be asymptomatic):

a) Acute gingivostomatitis (orolabial infection): Predominantly affects children and young adults. The infection has a sudden onset and is associated with fever, malaise, anorexia, edema, gingival pain, and erythema, in addition to vesicles and/or erosions of the oral and lingual mucosa as well as of the lips and skin around the mouth. Regional lymphadenopathy is also common. Acute symptoms persist for 5 to 7 days, with the lesions healing after ~2 weeks. Viral shedding in the saliva is observed for 3 weeks, occasionally longer.

b) Acute pharyngitis/tonsillitis: More frequent in adults. Symptoms initially include fever, malaise, headache, sore throat, myalgia, and are later followed by the appearance of vesicles on the tonsils and posterior pharyngeal wall. As the vesicles rupture, grey erosions and ulcerations are formed. Lesions on the lips are present in <10% of patients. In ~30%, a primary HSV-2 infection is accompanied by meningeal signs, and in 5% of patients it causes meningitis with a mild course.

2) Recurrent infection (usually HSV-1): Herpes labialis is the most common presentation of recurrent oral infection. Symptoms of recurrent infection are typically much less severe than those associated with the first episode and persist for a shorter duration. Many individuals shed the virus in the absence of demonstrable orolabial lesions.

2. Genital herpes simplex:

1) Primary infection: Typically has a severe course. General symptoms are present in ~70% of women and ~40% of men and include fever, headache, and myalgia. Cutaneous lesions start as vesicles and evolve rapidly into ulcers, which can coalesce; they are very painful. In men, the cutaneous lesions often appear on the penis, less frequently on the scrotum and inner thighs. In women, the cutaneous lesions often appear on the labia, perineum, vagina, cervix, and thighs. Tender inguinal lymphadenopathy is common, and dysuria frequently occurs. Anal exposure may lead to proctitis. In women, the cutaneous lesions are more extensive and can persist for ~20 days (~16 days in men). Viral shedding continues for 10 to 12 days.

2) Recurrent infection (usually HSV-2): Mild or associated with minor symptoms. Local prodromal symptoms may persist from 2 hours up to 2 days. General symptoms are usually absent. In women, vesicular lesions on the labia (major and minor) and perineum (may be very painful) are observed. In men, the lesions occur predominantly on the penis. Viral shedding can continue for a prolonged period (months) after primary infection.

3. Ocular herpes simplex: Lesions may involve the conjunctiva, cornea, or both (ulcerations develop predominantly as a result of autoinoculation). Inadequate treatment or frequent recurrences may lead to corneal scarring (or even blindness). Patients can develop vesicular lesions in other skin areas in dermatome V1, including the tip of the nose and the eyelids.

4. Central nervous system (CNS) infections:

1) Meningitis commonly develops within 2 weeks of primary genital infection, especially that caused by HSV-2. Presenting symptoms include headache, vomiting, photophobia, and nuchal rigidity. The natural history of this syndrome is self-limiting.

2) Meningoencephalitis, which can be associated with either a primary infection or recurrence, is much rarer than aseptic meningitis and associated with significantly more morbidity and mortality. Dramatic changes in the level of consciousness, seizures, and focal neurologic signs are frequent.

5. Other cutaneous infections: Lesions located outside the face and genital region are less common. Primary infection may be caused by rubbing in of the infected material:

1) Herpetic whitlow often develops in individuals with preexisting HSV infection who expose their fingertips to infected secretions. It has a sudden onset. Signs and symptoms include edema, erythema, pain, and vesicles/pustules involving one or several fingertips.

2) Herpes gladiatorum: Associated with contact sports. Lesions can typically be observed on the chest, ears, face, and hands.

3) Eczema herpeticum: A distinct manifestation developing in patients with atopic dermatitis. It is associated with a generalized vesicular rash that rapidly adopts a crusted “punched-out” appearance. This manifestation has a severe course and may be life-threatening.

6. Perinatal infection is common in women with primary genital infection at the time of labor, although much less so in women with recurrent disease. Caesarean delivery is protective and indicated for any woman with active lesions at the time of labor. There are 3 main neonatal HSV infection syndromes:

1) Skin-eye-mouth disease manifests as grouped vesicular lesions anywhere on the skin surface; conjunctivitis and oral ulcerations can also occur.

2) Disseminated disease often presents as severe sepsis, with hemodynamic compromise, respiratory insufficiency, hepatitis, and coagulopathy. Mortality is high.

3) CNS infection, which can present with protean manifestations, often with fever and irritability; many patients also have cutaneous lesions. Neurodevelopmental sequelae are common.

DiagnosisTop

Diagnosis is usually based on the clinical presentation. The finding of grouped small vesicles (in early stages) or ulcers (later on) is often very suggestive of HSV infection.

Diagnostic Tests

Diagnostic tests are recommended to confirm the involvement of HSV. Identification of the type of HSV in patients with genital herpes is used to predict the risk of recurrence.

1. HSV isolation in cell cultures (specimens: vesicular fluid, cervical swab): Culture of HSV from mucosal samples is relatively rapid; sensitive and specific results are usually obtained within days. Older lesions may not yield the virus.

2. Detection of HSV DNA by polymerase chain reaction (PCR) (specimens: vesicular fluid, cervical swab, vaginal discharge, and cerebrospinal fluid [CSF]) is the most sensitive and therefore primary test for detecting HSV in CSF samples. It is increasingly being used for detection in other samples as well (eg, blood, mucosal swabs).

3. Serology is less useful on a routine basis for the diagnosis of HSV-associated infectious syndromes, as culture or PCR results are usually available sooner. Specific anti-HSV antibodies appear in the blood within a few weeks of infection; note that HSV-1 seropositivity in the general population is relatively high (and increases with age) due to the high prevalence of orolabial HSV infection, which is why detection of HSV antibodies does not necessarily imply active HSV infection/shedding. Detection of anti-HSV-2 antibodies usually indicates genital herpes (sensitivity, 80%-98%; specificity ≥96%).

Differential Diagnosis

1. Oral-facial herpes: Candidiasis, aphthous stomatitis, enteroviral oropharyngeal infections (including herpangina), erythema multiforme major, Mycoplasma-associated mucositis, Stevens-Johnson syndrome, Behçet syndrome.

2. Genital herpes: Syphilis, chancroid, granuloma inguinale, herpes zoster.

TreatmentTop

Antiviral Treatment

Systemic antiviral treatment (acyclovir [INN aciclovir], valacyclovir [INN valaciclovir]) reduces the symptoms associated with primary and recurrent infections; however, the drugs do not eradicate the latent virus, do not make patients less contagious, and do not reduce the frequency or severity of the future recurrences after the treatment is discontinued. Valacyclovir is a prodrug for acyclovir and is generally preferred over oral acyclovir due to more favorable pharmacokinetics.

1. Genital herpes: Topical drugs are not effective.

1) In patients with a primary infection, use oral acyclovir 400 mg every 8 hours or 200 mg every 4 to 5 hours (5 times a day) for 7 to 10 days, or oral valacyclovir 1000 mg every 12 hours for 7 to 10 days. Treatment may be extended in patients in whom the lesions have not resolved completely after 10 days.

2) In patients with recurrent infections (periodic treatment of recurrences), it is preferable to start treatment during the prodromal stage, not later than at the onset of cutaneous eruptions; oral acyclovir 400 mg every 8 hours or 800 mg every 12 hours for 5 days, or oral acyclovir 800 mg every 8 hours for 3 days, oral valacyclovir 500 mg every 12 hours for 3 days, or 1000 mg every 24 hours for 5 days.

2. Meningoencephalitis: IV acyclovir 10 mg/kg every 8 hours for 14 to 21 days; therapy is often continued until CSF HSV PCR is negative.

3. Oral-labial herpes or gingivostomatitis/pharyngitis:

1) In patients with a primary infection, if the infection is highly dynamic, severe, or the patient is immunocompromised (irrespective of the etiology of immunosuppression), use oral acyclovir 200 to 400 mg every 4 to 5 hours (5 times a day) for 3 to 5 days, or oral valacyclovir 2000 mg every 12 hours for 1 day (2 doses) or 1000 mg every 12 hours for 7 to 10 days.

2) In patients with recurrent infections (periodic treatment of severe recurrences), it is preferable to start treatment during the prodromal phase, no later than at the onset of cutaneous eruptions. You may use oral acyclovir 200 mg every 4 to 5 hours (5 times a day) for 3 to 5 days, or oral valacyclovir 2000 mg every 12 hours for 1 day (2 doses). In patients with mild oral-labial herpes, topical acyclovir cream (applied 5 times a day) can also be effective.

4. In pregnant women, acyclovir can be used (it is considered safe for the fetus). Treatment of primary infection or recurrences: see above. In pregnant women with a history of recurrent genital herpes, it is recommended to start prophylactic administration of acyclovir in the third trimester of pregnancy, as antivirals have been shown to reduce HSV shedding and the recurrence of genital lesions at delivery (and therefore caesarian section rates), although no trials have been powered to show a significant decrease in neonatal infection rates (no events among >1000 women).Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to unclear effects on the newborn infection rate (baseline rate is very low). Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD004946. doi: 10.1002/14651858.CD004946.pub2. Review. PMID: 18254066. Cesarean section is preferred in women with active genital lesions or in women with a history of genital herpes and prodromal symptoms (burning, pain).

5. In patients with ocular herpes simplex, immediate referral to an ophthalmologist is indicated for monitoring and treatment with topical antivirals.

Symptomatic Treatment

Analgesics and antipyretics may be used when necessary.

ComplicationsTop

Complications of HSV infections include secondary bacterial or fungal infections of the cutaneous lesions. Disseminated infection can occur (which may involve the esophagus, adrenal glands, lungs, joints, and CNS), especially in immunocompromised individuals. Erythema multiforme has commonly been reported in association with HSV infection.

PrognosisTop

HSV infection is a lifelong recurring disease. Deaths are rare and affect predominantly newborns, severely immunocompromised individuals, and patients with meningoencephalitis.

PreventionTop

Vaccine is not available.

1. Primary prevention: Avoiding high-risk sexual contacts. Using a latex condom during intercourse will decrease but not eliminate the risk of infection, since lesions may often be located outside the covered area. Infected individuals should inform their partners about the infection prior to initiating sexual contacts (risk of infection is also present in the asymptomatic phase of the disease). Patients with active genital lesions or in the prodromal stage of the disease should not have sexual contacts with healthy individuals; however, avoidance of contact at this time will not eliminate transmission, as asymptomatic shedding is not uncommon. Pregnant women with a history of genital herpes should inform their doctors. Healthy women whose partners have a history of genital herpes should refrain from sexual contacts during the third trimester of pregnancy.

2. Secondary prevention (long-term antiviral therapy): In patients with frequent and distressing recurrences, use oral acyclovir 400 mg every 12 hours or oral valacyclovir 500 mg or 1000 mg every 24 hours (acyclovir has been confirmed to be safe and effective when administered daily for 6 years; valacyclovir, for 1 year). The treatment reduces the frequency of recurrences and improves the quality of life. Prophylactic antiviral therapy will also decrease the risk of transmission of genital HSV.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Chi CC, Wang SH, Delamere FM, Wojnarowska F, Peters MC, Kanjirath PP. Interventions for prevention of herpes simplex labialis (cold sores on the lips). Cochrane Database Syst Rev. 2015 Aug 7;2015(8):CD010095. doi: 10.1002/14651858.CD010095.pub2. PMID: 26252373; PMCID: PMC6461191. Le Cleach L, Trinquart L, Do G, et al. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev. 2014 Aug 3;2014(8):CD009036. doi: 10.1002/14651858.CD009036.pub2. PMID: 25086573; PMCID: PMC11022119.