Herpes Simplex

Background

Herpes simplex viruses are ubiquitous, host-adapted pathogens that cause a wide variety of disease states. Two types exist: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Both are closely related but differ in epidemiology. HSV-1 is traditionally associated with orofacial disease (see the image below), while HSV-2 is traditionally associated with genital disease. Lesion location, however, is not necessarily indicative of viral type, as HSV-1 is associated with genital infections more often than HSV-2 in some unique subpopulations.

The term herpes is derived from the Greek word “to creep or crawl” and dates back to early Greek civilization, approximately 2000 years ago, in reference to the spreading nature of herpetic skin lesions.

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Herpes simplex virus type 1. Primary herpes can affect the lips, and the ruptured vesicles may appear as bleeding of the lips. Courtesy of A.K. ElGene....

See Herpes Simplex Viruses: Test Your Knowledge, a Critical Images slideshow, for more information on clinical, histologic, and radiographic imaging findings in HSV-1 and HSV-2.

Also, see the 20 Signs of Sexually Transmitted Infections and Clues in the Oral Cavity: Are You Missing the Diagnosis? slideshows to help make an accurate diagnosis.

Up to 80% of herpes simplex infections are asymptomatic. Symptomatic infections can be characterized by significant morbidity and recurrence. In immunocompromised hosts, infections can cause life-threatening complications.

The prevalence of HSV infection worldwide has increased over the last several decades, making it a major public health concern. Prompt recognition of herpes simplex infection and early initiation of therapy are of utmost importance in the management of the disease.

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Microbiology

HSV belongs to the alpha herpesvirus group. It is an enveloped virus that is approximately 160 nm in diameter with a linear, double-stranded DNA genome. The overall sequence homology between HSV-1 and HSV-2 is about 50%. HSV-1 has tropism for oral epithelium, while HSV-2 has tropism for genital epithelium. HSV infection is mediated through attachment via ubiquitous receptors to cells, including sensory neurons, leading to establishment of latency.^[1]

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Pathophysiology

HSV-1 and HSV-2 are characterized by the following unique biological properties:^[1]

• Neurovirulence (the capacity to invade and replicate in the nervous system)
• Latency (the establishment and maintenance of latent infection in nerve cell ganglia proximal to the site of infection): In orofacial HSV infections, the trigeminal ganglia are most commonly involved, while, in genital HSV infection, the sacral nerve root ganglia (S2-S5) are involved.
• Reactivation: The reactivation and replication of latent HSV, always in the area supplied by the ganglia in which latency was established, can be induced by various stimuli (eg, fever, trauma, emotional stress, sunlight, menstruation), resulting in overt or covert recurrent infection and shedding of HSV. In immunocompetent persons who are at an equal risk of acquiring HSV-1 and HSV-2 both orally and genitally, HSV-1 reactivates more frequently in the oral rather than the genital region. On the other hand, HSV-2 reactivates 8-10 times more commonly in the genital region than in the orolabial regions. Reactivation is more common and severe in immunocompromised individuals.^[2]

Cellular immunity is an important defense against herpes simplex. Dissemination of herpes simplex infection can occur in people with impaired T-cell immunity, such as in organ transplant recipients and in individuals with AIDS. Herpes simplex infection can also complicate burn wounds or damaged skin such as in atopic dermatitis or other allergic dermatoses.

HSV is distributed worldwide. Humans are the only natural reservoirs, and no vectors are involved in transmission. Endemicity is easily maintained in most human communities owing to latent infection, periodic reactivation, and asymptomatic virus shedding.^[3]

HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and fomitic spread are rare.

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Epidemiology

Frequency

United States

HSV is the most common cause of genital ulcers in the United States. HSV-1 is usually acquired in childhood by contact with oral secretions that contain the virus. The presence of HSV-2 can be used as an indirect measure of sexual activity. Seroprevalence rates do not reflect how many of these individuals have or will have symptomatic episodes of HSV recurrence, as the presence of antibodies is poorly correlated with disease protection.

Seroprevalence: Antibodies to HSV-1 increase with age starting in childhood and correlate with socioeconomic status, race, and cultural group. By age 30 years, 50% of individuals in a high socioeconomic status and 80% in a lower socioeconomic status are seropositive. Antibodies to HSV-2 begin to emerge at puberty, correlating with the degree of sexual activity. The lifetime seroprevalence can be 20%-80%.^[4] More than 90% of adults have antibodies to HSV-1 by the fifth decade of life.^[1] ​A slight crossover of immunity occurs between HSV-1 and HSV-2, allowing for milder subsequent infection by the partner virus type.

International

HSV is well distributed worldwide, with over 23 million new cases per year. An increase in seroprevalence of antibodies to HSV-2 has been documented throughout the world (including the United States) over the last 20 years.^[1]

Mortality/Morbidity

Morbidity and mortality rates associated with HSV infections are discussed in Complications. Overall, the mortality rate associated with herpes simplex infections is related to 3 situations: perinatal infection, encephalitis, and infection in the immunocompromised host.

Race

A national health survey conducted in the United States revealed a seroprevalence of HSV-2 antibodies in 45% of blacks, 22% of Mexican-Americans, and 17% of whites.^[4]

Sex

Seropositivity to HSV-2 is more common in women (25%) than in men (17%).^[4]

Age

HSV-1 infections transmitted via saliva are common in children, although primary herpes gingivostomatitis can be observed at any age. HSV-2 infections are clustered perinatally (from a maternal episode at delivery) and primarily once sexual activity begins. HSV-2 genital infections in children can be an indication of sexual abuse. Increased age (after onset of sexual activity) and total number of sexual partners are independent factors associated with increased seroprevalence of HSV-2 antibodies.^[4]

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History

HSV can cause either primary or reactivation (recurrent) infections. Both HSV-1 and HSV-2 are implicated in genital and orofacial primary infections after contact with infectious secretions that contain either HSV-1 (usually oral secretions) or HSV-2 (usually genital secretions). The clinical course depends on the age and immune status of the host, the anatomic site of involvement, and the antigenic virus type. Primary HSV-1 and HSV-2 infections are accompanied by systemic signs, longer duration of symptoms, and higher rate of complications. Recurrent infections are typically milder and shorter. HSV infections in immunocompromised host tend to be more severe, prolonged, and widespread and are more likely to recur than HSV infections in immunocompetent individuals.

Acute herpetic gingivostomatitis

This is a manifestation of primary HSV-1 infection that occurs in children aged 6 months to 5 years. Adults may also develop acute gingivostomatitis, but it is less severe and is associated more often with a posterior pharyngitis.^[5]

Infected saliva from an adult or another child is the mode of infection. The incubation period is 3-6 days.

Clinical features include the following:

• Abrupt onset
• High temperature (102-104°F)
• Anorexia and listlessness
• Gingivitis (This is the most striking feature, with markedly swollen, erythematous, friable gums.)
• Vesicular lesions (These develop on the oral mucosa, tongue, and lips and later rupture and coalesce, leaving ulcerated plaques.)
• Tender regional lymphadenopathy
• Perioral skin involvement due to contamination with infected saliva

Course: Acute herpetic gingivostomatitis lasts 5-7 days, and the symptoms subside in 2 weeks. Viral shedding from the saliva may continue for 3 weeks or more.

Acute herpetic pharyngotonsillitis

In adults, oropharyngeal HSV-1 infection causes pharyngitis and tonsillitis more often than gingivostomatitis.

Fever, malaise, headache, and sore throat are presenting features.

The vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils and the posterior pharynx.

Associated oral and labial lesions occur in fewer than 10% of patients.

HSV-2 infection can cause similar symptoms and can be associated with orogenital contact or can occur concurrently with genital herpes.

Herpes labialis

This is the most common manifestation of recurrent HSV-1 infection, referred to by many as ”cold sores.” A prodrome of pain, burning, and tingling often occurs at the affected site, commonly the face, around the lips, followed by the development of erythematous papules that rapidly develop into tiny, thin-walled, intraepidermal vesicles that become pustular and ulcerate. In most patients, fewer than two recurrences manifest each year, but some individuals experience monthly recurrences.^[6]

Maximum viral shedding is in the first 24 hours of the acute illness but may last 5 days.

Herpetic whitlow

HSV infection of the finger, termed herpetic whitlow, can occur following inoculation of the virus from primary orofacial or genital infections. Inoculation may occur from self or from other infected persons. Healthcare workers, including dentists, are at risk for herpetic whitlow owing to oral examinations and other oral care provided with ungloved hands.

Herpes gladiatorum

Herpes gladiatorum is HSV infection of the face, arms, neck and upper trunk, typically seen in wrestlers and participants in some contact sports such as rugby. Infection is promoted by trauma to the skin sustained during matches.

Eczema herpeticum

Eczema herpeticum is secondary HSV infection superimposed on an underlying damaged or diseased skin, as seen in uncontrolled atopic dermatitis. Extensive infection can occur and increases the risk of invasive disease, increased morbidity, and mortality.

Genital herpes

The severity and frequency of the disease and the recurrence rate depend on numerous factors, including viral type, prior immunity to autologous or heterologous virus, gender, and immune status of the host.^{[7, 2]}

Primary genital herpes

Primary genital herpes can be caused by both HSV-1 and HSV-2 and can be asymptomatic. HSV-2 tends to have tropism for genital mucosa and has been traditionally more associated with genital infections. However, HSV-1 is increasingly associated with genital infection and has been reported to cause more genital infections than HSV-2, especially in young people and homosexual males.^{[8, 9]} The clinical features and course of primary genital herpes caused by both HSV-1 and HSV-2 are indistinguishable, but recurrences are more common with HSV-2.

Primary genital herpes is characterized by severe and prolonged systemic and local symptoms. Preexisting antibodies to HSV-1 have an ameliorating effect on disease severity caused by HSV-2. Prior orolabial HSV-1 infection appears to protect against or may lower genital HSV-1 infection risk. Symptoms of primary genital herpes are more severe in women, as are complications.^{[10, 11, 12, 13]}

Clinical features: The incubation period of primary genital herpes is 3-7 days (range, 1 day to 3 weeks). Constitutional symptoms include fever, headache, malaise, and myalgia (prominent in the first 3-4 days). Local symptoms include pain, itching, dysuria, vaginal and urethral discharge, and tender lymphadenopathy.

Clinical features in women: Herpetic vesicles appear on the external genitalia, labia majora, labia minora, vaginal vestibule, and introitus. In moist areas, the vesicles rupture, leaving exquisitely tender ulcers. Ulcers are seen more commonly than vesicles at the time of presentation because of the frailty and thin walls of the vesicles. The vaginal mucosa is inflamed and edematous. The cervix is involved in 70%-90% of cases and is characterized by ulcerative or necrotic cervical mucosa. Cervicitis is the sole manifestation in some patients. Dysuria may be very severe and may cause urinary retention. Dysuria is associated with urethritis, and HSV can be isolated in the urine. HSV-1 infection causes urethritis more often than does HSV-2 infection.

Clinical features in men: Herpetic vesicles appear in the glans penis, the prepuce, the shaft of the penis, and sometimes on the scrotum, thighs, and buttocks. In dry areas, the lesions progress to pustules and then encrust. Herpetic urethritis occurs in 30%-40% of affected men and is characterized by severe dysuria and mucoid discharge. The perianal area and rectum may be involved in persons who engage in anal intercourse, resulting in herpetic proctitis.

In men and women, the ulcerative lesions persist from 4-15 days until encrusting and reepithelialization occur. The median duration of viral shedding is about 12 days.

Recurrent genital herpes

Recurrent infection implies infection by the same HSV type as the antibody in the serum. The major morbidity of genital herpes is due to its frequent reactivation rate. The duration of symptoms is usually shorter in recurrent infection than in primary infection.

Recurrent genital herpes is preceded by a prodrome of tenderness, pain, and burning at the site of eruption that may last from 2 hours to 2 days. In some patients, severe ipsilateral sacral neuralgia occurs.

In women, the vesicles are found on the labia majora, labia minora, or perineum. The lesions are often very painful. Fever and constitutional symptoms are uncommon. The lesions heal in 8-10 days, and viral shedding lasts an average 5 days. The symptoms are more severe in women than men.

In men, recurrent genital herpes presents as 1 or more patches of grouped vesicles on the shaft of the penis, prepuce, or glans. Urethritis is uncommon. Pain is mild, and lesions heal in 7-10 days. The frequency and severity of recurrences decrease with time.^[2]

Subclinical genital herpes

Most primary genital HSV infections are asymptomatic, with 70%-80% of seropositive individuals having no history of known genital herpes. HSV-2 seropositivity has been associated with viral shedding in the genital tract, even among individuals with no reported history or symptoms of genital herpes.^[14] However, upon education regarding the varied clinical manifestations, many patients recognize the symptoms of genital herpes.

Truly asymptomatic viral shedding may occur in 1%-2% of infected immunocompetent persons and may be as high as 6% in the first few months after acquisition of the infection.^{[3, 15]} This feature is important when attempting to prevent transmission sexually or perinatally.

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Physical

This section describes physical examination findings of the herpetic lesion as it relates to primary and recurrent lesions of cutaneous or mucosal HSV infection. This can be related to either oral or genital infection.^{[1, 2, 5]}

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Herpes simplex virus type 1. Recurrent herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the lip....

Primary mucocutaneous HSV infections

Some primary infections are asymptomatic.

Primary (first-episode) infections manifest within several days of exposure to secretions containing viable virus.

Often painful, the lesions quickly progress to vesicles and can continue to erupt over 1-2 weeks.

The lesions are prominent and are often present internally on the mucosal surface of the oral or genital area, as well as on the surrounding skin.

Constitutional symptoms (fever, malaise, myalgias, and anorexia) are often prominent. Weight loss is not uncommon and is due either to illness or dysphagia (in primary gingivostomatitis).

Individual vesicles on mucosal surfaces break down rapidly, forming shallow painful ulcers (usually < 8-10 mm in diameter). They may be covered with a white exudate that can be confused with mucosal candidiasis. Those on cutaneous surfaces remain as vesicles longer, only to evolve into crusted ulcers that heal within 5-7 days.

Recurrent mucocutaneous HSV infections

Following the establishment of latency in the corresponding sensory nerve ganglion cells, HSV can cause recurrent infection that can be subclinical (manifesting as viral excretion without lesions) or overt (manifesting as mucosal or cutaneous lesions with viral excretion).

Oral recurrences are often triggered by recognizable stimuli such as pyrexia (fever blisters and cold sores), stress, or sunburn. Genital recurrences are more likely to be linked to stress rather than to pyrexia. Females may relate a relationship to the menstrual cycle.

Localized burning or paraesthesias may precede recurrent lesions. Unlike primary infection, constitutional symptoms are minimal in most cases.

Recurrences last 3-7 days and can occur numerous times per year or once or twice in a lifetime. Overall, the number of yearly recurrences tends to decrease over time.^[16]

Although recurrent HSV infections may last much longer (>30 d) in immunocompromised hosts, such as individuals with AIDS, frequent recurrences are not necessarily a sign of an altered immune system.

Because recurrences can be clinically unrecognizable, transmission to susceptible individuals can occur in the absence of overt lesions.

Vesicles occurring in a sacral dermatomal distribution (zosteriform) can occur in recurrent genital HSV disease and be confused with herpes zoster. A history of similar recurrences should alert the clinician to this possibility.

Sacral HSV infection recurrences also may present with signs and symptoms of meningeal inflammation; and, in fact, a picture consistent with aseptic meningitis can be found upon examination of the cerebrospinal fluid (CSF).^[17]

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Herpes simplex virus type 1. Recurrent herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only ke....

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Causes

HSV is transmitted via close personal contact.

HSV infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin.

The virus is inactivated readily at room temperature and by drying; hence, aerosol and fomitic spread are rare.

HSV-1 is transmitted chiefly by contact with infected saliva, whereas HSV-2 is transmitted sexually or from a mother's genital tract infection to her newborn. However, lesion location does not always indicate viral type.

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Laboratory Studies

Culture

Herpes simplex virus (HSV) infection is best confirmed by isolation of the virus in tissue culture (the criterion standard for diagnosis). Tissue culture success is operator-dependent, but this modality can yield positive results within 48 hours of inoculation.

Characteristic cytopathic effect with ballooning of cells and cell death are observed, and death of the entire monolayer of cells may be rapid.

Immunofluorescent staining of the tissue culture cells can be used to quickly identify HSV and can distinguish between types 1 and 2.

Tzank smear

The characteristic cytologic changes induced by HSV can be demonstrated in Tzank smears (see Procedures); however, this procedure does not distinguish between HSV-1 and HSV-2.

Rapid diagnosis (usually within an hour) is possible based on the histological appearance of the lesion.

Multinucleated giant cells and epithelial cells containing eosinophilic intranuclear inclusion bodies distinguish the lesions of herpesviruses.

Punch biopsy provides more reliable material for histological examination, particularly when lesions are infected with bacteria and fungi.

Polymerase chain reaction

Detection of HSV DNA in clinical specimens is possible with polymerase chain reaction (PCR) techniques. PCR is more sensitive than culture and is the preferred test for CNS and ocular infections.

In HSV encephalitis, PCR using CSF provides a rapid, noninvasive diagnostic technique that is as sensitive as brain biopsy.^[18]

PCR has been used to detect HSV-2 as the cause of recurrent meningitis (Mollaret) and has shown a strong association between HSV-1 and Bell's palsy.

PCR can be used to detect asymptomatic viral shedding.

Direct fluorescent antigen (Immunofluorescence)

Cells scraped from ulcer bases can be stained with a direct fluorescent antibody, used to distinguish HSV-1 from HSV-2. Additionally, tissue culture cells can also be stained (see above). This procedure can usually be performed within 2-3 hours.^[19]

Antibody testing

Antibody testing can demonstrate a primary seroconversion, particularly with HSV-1 in childhood.^[1] If serology results are negative while viral culture of specimen is positive, one can assume primary infection.

Because of sero–cross-reactivity, HSV-1 and HSV-2 are not generally distinguishable unless a glycoprotein G antibody assay is available. Testing for HSV-specific immunoglobulin M (IgM) antibodies is not available.

Antibody titer increases generally do not occur during recurrences of HSV infection. Therefore, the test is generally not used for the diagnosis of mucocutaneous HSV relapse.

Antibody testing has been the mainstay of large-scale epidemiologic studies.

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Imaging Studies

Brain imaging studies in HSV encephalitis generally demonstrate focal localization in the temporal area that is associated with edema and contrast enhancement.

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Procedures

Tzanck preparation

Tzanck preparation is a time-honored procedure for assisting in the diagnosis of cutaneous herpesvirus infections. However, it does not easily distinguish HSV-1, HSV-2, and varicella-zoster virus.

Typically, an intact vesicle is used from which the vesicular fluid is aspirated by puncture with a sterile tuberculin syringe. This fluid can be used for viral culture or PCR.

Aspiration should facilitate complete collapse of the vesicle because it is not multiloculated as cutaneous poxvirus infections can be.

After aspiration, the vesicle should be unroofed aseptically.

Using a sterile instrument, the floor of the newly produced ulcer can then be scraped. The obtained material can be spread on a glass microscope slide and then dried and fixed for staining.

Staining can be performed with a Papanicolaou smear stain or, alternatively, whatever is available will suffice (eg, Gram, Giemsa, or Wright stain).

A positive result is the finding of multinucleate giant cells.

Direct fluorescent antigen

Using appropriate immunofluorescent antibody reagents, the smear can be used to distinguish different herpesviruses and nonherpesviruses that may be present (eg, vaccinia, smallpox).

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Medical Care

Overall, medical treatment of herpes simplex virus (HSV) infection is centered around specific antiviral treatment. While the same medications are active against HSV-1 and HSV-2, the location of the lesions and the chronicity (primary or reactivation) of the infection dictate the dosage and frequency of medication. It is important to note that life-threatening HSV infections in immunocompromised patients and HSV encephalitis require high-dose intravenous acyclovir, often started empirically.^[20]

When constitutional effects such as fever occur, symptomatic treatment can be used.

Appropriate wound care is needed, and treatment for secondary bacterial skin infections may be required.

Acyclovir-resistant HSV infections

Acyclovir-resistant HSV infections are often seen in immunocompromised patients (eg, patients with HIV infection). The options for treatment include cidofovir and foscarnet, but both are very nephrotoxic.

Recurrent HSV infections

Options for recurrent HSV infections include no treatment (for infrequent episodes) or episodic treatment with topical agents or oral antiviral agents. Long-term suppressive therapy, which can be continued for up to one year, is also an option. A modest benefit with lower recurrences has been reported using this method.^{[21, 22]}

The best approach is to determine the frequency and severity of recurrent infections and the patient's preference concerning prophylaxis. Options for long-term suppressive therapy include acyclovir 400 mg orally twice daily or valacyclovir 500 mg orally twice daily for up to a year, with reassessment at the end of therapy.

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Consultations

Consultation with a dermatologist may be beneficial in cases of atypical lesions.

In immunocompromised patients with invasive HSV infection, consultation of specialty associated with the organ system affected should be sought early (eg, pulmonologist for possible HSV pneumonitis) in order to aid in diagnosis. Infectious diseases consultation is reasonable for immunocompromised patients with CNS herpes infection.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

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Penciclovir (Denavir)

• Dosing, Interactions, etc.

Clinical Context:  Inhibitor of DNA polymerase in HSV-1 and HSV-2 strains, inhibiting viral replication. Only topical preparations available, and they are well suited for herpes labialis (cold sores).

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Acyclovir (Zovirax)

• Dosing, Interactions, etc.

Clinical Context:  Synthetic purine nucleoside analogue with activity against a number of herpes viruses, including herpes simplex and varicella-zoster. Highly selective for virus-infected cells because of its high affinity for viral thymidine kinase enzyme. This effect serves to concentrate acyclovir monophosphate into virus-infected cells. The monophosphate then is metabolized into the triphosphate active form by cellular kinases.

Double dose is suggested for herpes simplex proctitis or ocular infections. Ocular infections also can be treated with topical acyclovir. Oral suspension available (40 mg/mL).

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Valacyclovir (Valtrex)

• Dosing, Interactions, etc.

Clinical Context:  Prodrug rapidly converted to the active drug acyclovir by intestinal and hepatic metabolism. Better absorbed than acyclovir and more expensive but has a more convenient dosing regimen.

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Famciclovir (Famvir)

• Dosing, Interactions, etc.

Clinical Context:  Prodrug that when biotransformed into active metabolite, penciclovir, may inhibit viral DNA synthesis/replication. Similarly to valacyclovir but has better bioavailability than acyclovir. Used against herpes simplex and varicella-zoster viruses.

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Class Summary

Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

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Deterrence/Prevention

Because of the ubiquitous and cosmopolitan nature of herpes simplex virus (HSV), avoiding contact with individuals who (often asymptomatically) are excreting the virus in saliva or genital secretions is difficult. Daily antiviral therapy can be given to reduce episodes of asymptomatic genital shedding and to further reduce the risk of transmission; however, it is unclear how long this should be administered.

Although not easily applicable to oral-oral contact, barrier protection using latex condoms is recommended to minimize exposure to genital HSV infections.

Because HSV genital ulcers may occur outside of areas covered by the condom, transmission can occur in those areas.

Herpetic whitlow can be avoided with latex gloves when health care workers insert their hands into the oral cavity of patients. Transmission of genital virus to the hand can occur during unprotected finger-genital contact during sexual activities.

Suppressive antiviral therapy can be used in individuals with frequent and/or particularly symptomatic relapses, but clinical trials have shown variable results.

Some benefit, especially in terms of shortened duration of episodes, has been attributed to suppressive antiviral treatment compared with no treatment. However, high-dose antiviral therapy, as opposed to standard dosing, has shown mixed results. In three randomized open-label crossover trials, high-dose valacyclovir (1 g tid) significantly improved symptom duration over standard-dose valacyclovir (500 mg bid), but similar benefits were not observed with high-dose acyclovir (800 mg tid) versus standard-dose valacyclovir. The study also noted that short bursts of subclinical genital HSV reactivation were frequent and that transmission can still occur during standard-dose or high-dose suppressive antiviral therapy.^[23]

Prophylactic antiviral agents are typically given to recipients of solid organ transplants and hematopoietic stem cell transplants during the pre-engraftment phase to minimize risk of infection.

An investigational HSV vaccine was not effective in preventing HSV-2 disease or infection in a study population that was representative of the general population of HSV-1– and HSV-2–seronegative women. The investigational vaccine was effective in preventing HSV-1 genital disease and infection.^[24]

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Complications

Bacterial and fungal superinfections

Bacterial and fungal superinfections are not uncommon.

Balanitis can occur in an uncircumcised male as a result of bacterial infection of the herpetic ulcers.

Candidal vaginitis has been described in as many as 10% of women with primary genital herpes, particularly in women with diabetes. Care should be taken to confirm the diagnosis of candidiasis, as ulcerative herpetic disease can have whitish mucosal lesions that can be confused with yeast infection.

Ocular infections

This complication is not uncommon in children as a result of autoinoculation during acute herpetic gingivostomatosis or asymptomatic oropharyngeal HSV infection.

Ocular infection is caused primarily by HSV-1, except in neonates, in whom it may be caused by HSV-2, and manifests as unilateral follicular conjunctivitis or as acute herpetic keratoconjuctivitis with dendritic corneal ulcers.^{[25, 26]}

Other ocular complications attributable to HSV include keratitis, retinal necrosis, and chorioretinitis.

Recurrences occur in as many as 25% of patients and can be associated with progressive scarring of the cornea. HSV has been the leading infectious cause of blindness in the United States.

Skin infections

Various cutaneous complications related to HSV can occur.

Eczema herpeticum: This occurs in individuals with underlying dermatitis and may be localized (which can be confused with herpes zoster) or disseminated. The process can also occur in patients with extensive skin breakdown as with burns, pemphigus, or Sézary syndrome.

Herpetic whitlow: HSV infections of the fingers occur at or near the cuticle or at other sites associated with trauma. When involving the nail area, it has been confused with a bacterial felon and been subjected, inappropriately, to incision and drainage. Herpetic whitlow is associated with HSV-1 in health care workers and children related to saliva exposure and with HSV-2 related to digital-genital exposure.

Herpes gladiatorum: Scattered cutaneous HSV-1 lesions have been observed in wrestlers who have had viral contact through exposure to infectious saliva during a match.

Visceral infections

HSV infection of the visceral organs usually results from viremia, and multiple organ involvement is common. This may occur during otherwise asymptomatic primary infections and sometimes in seemingly immunocompetent hosts but more often in immunocompromised hosts. Visceral infections also tend to be more common in neonates. In fact, neonates have the highest number of visceral infections than any HSV-infected populations.

In most cases of disseminated herpes, the lesions are confined to the skin; however, fatal visceral dissemination can occur with or without vesicular skin lesions. Multiple organs are involved, but fulminant HSV hepatitis is usually clinically prominent. HSV-1 and HSV-2 are both implicated in fulminant hepatitis.

Disseminated disease is often associated with leukopenia, thrombocytopenia, and disseminated intravascular coagulation.

Disseminated HSV-1 and HSV-2 infections can also result in herpetic esophagitis, adrenal necrosis, interstitial HSV pneumonitis, HSV cystitis, HSV arthritis, HSV meningitis, and HSV encephalitis.

Respiratory tract infections

Herpes infection of the upper airway is fairly common in children and can involve the epiglottitis, laryngitis, and tracheobronchitis. Symptoms usually last about 2 weeks and are typically self-limiting. Lower respiratory tract infections, including pneumonias, are rare and could follow disease extension from an upper airway herpetic infection. Cases have been described in immunocompromised hosts, including patients with HIV infection, recipients of solid organ and bone marrow transplants, individuals with malignancies, and patients with burns.^{[27, 28, 29]}

Central nervous system complications

Aseptic meningitis

Aseptic meningitis is an acute, generally benign lymphocytic meningitis. It is recurrent and self-limiting (also known as benign lymphocytic recurrent meningitis [Mollaret meningitis]) and is typically more common with HSV-2 infection. Meningeal symptoms usually start 3-12 days after the onset of genital lesions; they reach a maximum 2-4 days into the illness and recede over 2-4 days. However, a history of clinical genital herpes is not always reported. Typically, there are more than two recurrences of fever and meningeal signs with spontaneous recovery. Signs and symptoms of encephalitis are unusual, and neurological sequelae are rare. HSV-2 has been identified by PCR in the CSF of patients with benign lymphocytic recurrent meningitis, suggesting that HSV may be the cause of this so-called idiopathic syndrome.^{[17, 30]}

Ganglionitis and myelitis

Genital and anorectal HSV infections may be complicated by urinary retention, sacral neuralgia, and sacral anesthesia. This is due to associated ganglionitis and radiculitis. The symptoms usually resolve in 1-2 weeks. Transverse myelitis is rarely reported.

Herpes simplex encephalitis

This is an acute necrotizing viral encephalitis that, beyond the neonatal period, is nearly always caused by HSV-1. It accounts for 10%-20% of all cases of encephalitis and is the most common cause of sporadic acute necrotizing encephalitis in the United States. Herpes simplex encephalitis occurs as a primary infection in about 50% of cases and may be due to recurrent infection or to reinfection with a different strain of HSV-1 in the remainder.

Clinical features include the following:

• Nonspecific findings common to all forms of encephalitis, which include headache, signs of meningeal irritation, altered mental status, and generalized seizures
• Changes referable to focal necrosis of the orbitofrontal and temporal cortex and the limbic system, including anosmia, memory loss, olfactory and gustatory hallucinations, and focal seizures
• Rapid development of hemiparesis and coma may occur. In some patients, the clinical picture is protracted, mimicking acute psychosis or delirium tremens.
• The CSF has moderate pleocytosis with mixed mononuclear cells and polymorphonuclear cells, moderate RBC counts, and mildly elevated protein levels with normal glucose levels.
• Brain imaging options include CT and MRI. MRI is the most sensitive imaging procedure.
• The most sensitive method of diagnosis is the demonstration of HSV DNA by PCR.
• The mortality rate is high (70%) in untreated patients. Even with treatment, a high incidence of neurological sequelae remains

Other neurologic complications attributable to HSV include transverse myelitis and Bell palsy.

Genital herpes and pregnancy

Recurrent genital herpes is similar in pregnant and nonpregnant women, although an increase in the number of recurrences in the course of pregnancy may occur.

Recurrent genital herpes accounts for 1%-2% of all cases of neonatal herpes. Cesarean delivery is recommended in mothers who have active genital lesions during labor. However, presence of active genital lesions is not a good indicator of HSV viral shedding.^[31] Thus, the American College of Obstetricians and Gynecologists (ACOG) recommends that suppressive antiviral therapy be given in the last 4 weeks of pregnancy to all women with a history of recurrent genital HSV.^[32]

A large nationwide cohort study in Denmark did not find any association between first trimester in utero antiviral drug (ie, acyclovir, valacyclovir, famciclovir) exposure and birth congenital anomalies. In 1804 pregnancies exposed to an antiviral drug during the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) unexposed pregnancies.^[33]

Primary genital infection during pregnancy

First-episode infections have more severe consequences to the mother and infant. Thus, identification of women at risk for primary infection (seronegative for HSV-2) is paramount.

The prevalence of genital infection varies by age, socioeconomic status, and sexual activity. HSV-2 still causes most genital infection in pregnancy, but HSV-1 is associated with an increasing number of cases, especially in young women.

Infection in the third trimester of pregnancy is associated with neonatal HSV infections, intrauterine growth retardation, and prematurity.

Neonatal HSV disease

Ninety percent of infections are acquired perinatally, 5%-8% are acquired congenitally, and a few are acquired postnatally.

Neonatal HSV infection is caused by contact with infected genital secretions.

In 70% of mothers, the infection is asymptomatic. The risk of transmission from a mother with primary infection is about 50%.^[34]

Neonates and infants (aged < 6 wk) have a very high frequency of visceral and CNS infections. Without therapy, the mortality rate is 65%, and a high degree of neurological sequelae exists.

The disease may be confined to the skin, eyes, or mouth, or it may manifest as encephalitis or disseminated visceral disease involving the lungs, liver, heart, adrenals, and skin.

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This neonate displayed a maculopapular outbreak on his feet due to congenitally acquired herpes simplex virus infection. Courtesy of the CDC/Judith Fa....

Copathogenesis with HIV

HSV and HIV can probably be best described as co-partners in disease, with the presence of one aiding the establishment of the other. Advanced HIV disease causing loss of cellular immunity generally predisposes to more severe and possibly widespread HSV disease, while genital ulcers and chronic genital inflammation due to herpes infection (especially HSV-2) has been shown to promote the acquisition of HIV.^[35] Multiple studies have also shown that the presence of antibodies to HSV-2 increases the risk of becoming infected with HIV, independent of the presence of genital ulcers.^[36] While early studies in Africa have demonstrated a reduction of HIV viral load in patients with HIV infection receiving therapy directed toward HSV infection, the mechanism is unclear.^{[37, 38]} The association between HIV and HSV may change the epidemiologic approach to sexually transmitted diseases worldwide.

• References

Patient Education

For patient education resources, see the Sexual Health Center and the Oral Health Center. Also, see the patient education articles Genital Herpes, Oral Herpes, Birth Control Overview, and Birth Control Methods.

• References