Herpes Simplex Virus (HSV) in Emergency Medicine

The herpes simplex viruses comprise 2 distinct types of DNA viruses: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). The epidemiology of herpes infection has dramatically changed over the past several decades.[1] HSV-1 causes oral lesions in approximately 80% of cases and genital lesions in 20% of cases. In adolescents, as many as 30-40% of genital herpes is caused by HSV-1, as this proportion is thought to be increasing in the developed world, due to increased oro-genital contact. The reverse is true for HSV-2, which causes genital lesions in 80% and oral lesions in 20%. Cutaneous herpes is shown in the image below.

Approximately 65% of the United States population is seropositive for HSV-1 by the fourth decade of life. Approximately 25% of the United States population is seropositive for HSV-2 by the fourth decade of life, with women being infected more frequently than men.[1] The indirect and direct costs of incident HSV genital infection in the United States are presently approximately $1.8 billion and expected to be greater than $2.7 billion by the year 2015.

Herpes viruses cause a wide range of diseases, including the following:

• Gingivostomatitis

• Keratoconjunctivitis

• Encephalitis

• Genital disease

• Newborn infection

• Chickenpox

• Shingles

Primary infection

Primary infections usually are mild and, in many cases, asymptomatic. Patients who are immunocompromised may develop severe infections involving multiple organ systems. Immunocompetent individuals also may have severe primary infections.

Latency and recurrence

After the patient begins to produce antibodies, the infection becomes latent in the sensory neural ganglia. Most commonly, HSV-1 infection remains latent in the trigeminal ganglia and HSV-2 in the sacral ganglia. The viruses become reactivated secondary to certain stimuli, including fever, physical or emotional stress, ultraviolet light exposure, and axonal injury.

Recurrent infections tend to be less severe because of existing cellular and humoral immunity from prior exposures, unless the person is immunocompromised. Although many persons are seropositive for HSV-1, the recurrence rates range from 10-40% after the primary infection. Infection by HSV requires a break in the skin's barrier; intact skin is resistant to the virus.

HSV-1 infections are spread via respiratory droplets or direct exposure to infected saliva. HSV-2 usually is transmitted via genital contact. The contact must involve mucous membranes or open or damaged skin that comes into contact with genital or oral secretions or an HSV lesion. The incubation period may last from 2-12 days, and vesicles typically erupt 6-48 hours after the onset of a prodrome. An asymptomatic individual without an open lesion can still transmit the HSV-2 virus through genital shedding.[2]

Herpes viruses cause cytolytic infections; therefore, pathologic changes are due to cell necrosis as well as inflammatory changes. Fluid accumulates between the dermis and the epidermal skin layers, causing vesicle formation. The fluid then is absorbed, scabs are formed, and healing is completed without evidence of scarring. Shallow ulcers form after the vesicles rupture on mucous membranes.

Lesions from primary herpes infection typically take longer to form and usually persist for a longer duration of time.

The virus travels from the site of infection in the skin or mucosa to the sensory dorsal root and remains latent until a recurrent outbreak. Outbreaks are usually due to some type of stress including ultraviolet radiation, trauma, emotional or psychological stress, or immunosuppression.

Frequency

United States

Epidemiologic data may be incomplete, as HSV is not currently a nationally reportable condition.

Approximately 80% of adults have antibodies to HSV-1, whereas antibodies to HSV-2 are found in approximately 20% of the population.

The incidence of genital herpes has been estimated to be 500,000-1,000,000 cases per year with a prevalence of 40-60 million affected individuals.

In sexually transmitted disease (STD) clinics, HSV-2 seropositivity approaches 40-50%. Overall, the seroprevalence of HSV-2 is declining, especially within specific cultural groups.[3]

Among uncommon causes of encephalitis in adults, HSV-1 is the most frequent cause, with an estimated frequency of 1 in 200,000-1,000,000 persons. No sexual predilection has been reported, but the age distribution is bimodal.[4]

Neonatal HSV develops in 1 per 2,000-10,000 live births per year. Approximately 70% of cases of neonatal HSV occur when the mother is asymptomatically shedding virus near time of delivery. The risk of neonatal transmission is increased if vaginal delivery occurs during acute maternal infection.

Approximately 90% of HIV-positive individuals are seropositive for HSV-1, and about 77% of HIV-positive individuals are seropositive for HSV-2. The higher rates possibly result from high-risk sexual behavior and immunosuppression with HIV infection. The immunosuppression increases the likelihood of outbreaks, thus increasing the risk of transmission.

International

Just over two thirds of the world's population has recurrent clinical HSV infections. Reportedly, 13-40% of the world's population is seropositive for HSV-2 and 67% is seropositive for HSV-1, varying by country. Africa has higher rates of both HSV-1 and HSV-2. For HSV-2, the second highest rates are found in the Americas, but those countries have the lowest rates of HSV-1.[5]

Mortality/Morbidity

Most patients with herpetic infection experience short-term local pain and irritation, with mild constitutional symptoms.

Infection occasionally may become life threatening.

Immunocompromised patients are at increased risk of developing severe HSV infections.

HSV-1 is a common cause of fatal encephalitis in the US, with a mortality rate 60-80%. Only fewer than 10% of patients are left without significant neurologic sequelae following an infection.

Keratoconjunctivitis may be caused by HSV-1. It is second only to trauma as a cause of corneal blindness in the US. Typically, infection occurs by touching an active lesion and then touching the eye.[6]

Race

African Americans are more likely to be infected with HSV-2 than any other racial or ethnic group.[7] HSV-2 antibodies are present in approximately 20% of Caucasian adults and 65% of African American adults. Some experts consider nonwhite race as a risk factor to contract genital HSV-2.

Sex

Men are 20% more likely to develop recurrences of HSV-2 than are women, although women have higher rates of HSV-2 infection.[3]

Age

Highest incidence of HSV-1 occurs in children aged 6 months to 3 years.[8, 9]

HSV-2 most commonly occurs in those aged 18-25 years.

Genital HSV-2 infection has a high recurrence rate. More than 85% of patients with one symptomatic episode will experience another. Recurrences may be frequent; 38% of the population with genital herpes have more than 6 recurrences per year; 20% have more than 10 recurrences per year.

Antiviral therapy may decrease the clinical manifestations of the disease but does not cure it.

Initiate antiviral therapy as soon as possible after the patient notices symptoms.

Consider prophylaxis for patients who have more than 6 recurrences per year.

Educate patient that HSV-2 is an STD. Follow deterrence measures. Encourage evaluation of sexual partners.

Referral to support groups: The American Social Health Association (ASHA) operates the National Herpes Hotline (919-361-8488), which provides educational materials and counseling for patients.

For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center and Teeth and Mouth Center. Also, see eMedicine's patient education articles Genital Herpes and Oral Herpes.

The typical incubation period from exposure to development of symptoms is 4 days but can range from 1-26 days. Prodromal symptoms of local pain, tingling, itching, and burning often precede development of the rash. Constitutional symptoms of fever, fatigue, myalgias, and headache often accompany the primary herpes simplex virus (HSV) infection.

Herpetic lesions usually begin as clusters of small bumps, then blisters, followed by open sores or ulcers. Lesions coalesce and usually heal over several weeks at various rates.

Many times these classically described lesions in the genital area may not present in all patients and may be difficult to differentiate from other conditions such as syphilis and chancroid.

Local pain is a prominent and common complaint. Patients with genital herpes may also complain of pain in the groin area secondary to local adenopathy. Women often present with complaints of genital swelling, discharge, and dysuria.

Many primary infections are asymptomatic. Up to 63% of women with HSV-2 antibodies have no clinical history of infection.[10] However, when primary infections are symptomatic, they are usually more severe than recurrent infections. Persons with asymptomatic genital HSV-2 infections still shed virus but less frequently than persons with symptomatic infections.[11]

Recurrent lesions are common and typically occur during periods of stress.

• Patients may give a history that includes the following:

  • Occupational exposure

    • Herpetic whitlow, found in health care workers (especially medical or dental)

    • Herpes gladiatorum on bodies of wrestlers

  • Previous history of herpetic diseases

• Immune status

  • HIV

  • Malnourishment

  • Hematological malignancies

  • Bone marrow transplant

  • Renal transplant

  • Cardiac transplant

• Neurologic symptoms

  • Headache

  • Confusion

  • Fever

• Lesions

  • Location varies

  • May be very painful

  • Tenesmus, itching with anal/perianal lesions

  • Dysuria and/or discharge with genital lesions

  • Sore throat with oral lesions

• Prodromal symptoms (present in advance of herpes lesions)

  • Burning

  • Itching

  • Tingling

  • Pain

• Constitutional symptoms (usually present with development of herpes lesions)

  • Anorexia

  • General malaise

  • Fever

  • Headache

  • Myalgias

Physical examination findings of HSV vary depending on location of the lesions.

General findings

• Lesions usually are vesicular or ulcerative on an erythematous base, as shown in the image below.

  Cutaneous vesicles characteristic of herpes simplex virus infection.

   

• Lesions coalesce and then heal over the next several weeks.

• Tender bilateral lymphadenopathy occurs with genital lesions.

Skin infections (HSV-1 or HSV-2)

• Herpetic whitlow or paronychia on the fingers of health care workers (not to be confused with abscess). This is usually is due to infection with HSV-1, but HSV-2 infections may be seen with digital-genital contact.

• Herpes gladiatorum on the bodies of wrestlers and other sports that involve close physical contact. It has been estimated that in Division I National Collegiate Athletic Association (NCAA) wrestling, the incidence of herpes gladiatorum can be as high as 20-40%.

Oropharyngeal disease

• Gingivostomatitis (herpes labialis on the lips, shown in the image below)

  Herpes labialis.

• Submandibular lymphadenopathy

• Fever

Genital herpes

• Painful vesicular or ulcerative lesions may appear similar to chancroid or syphilis (vesicular lesions shown in the image below)

  Penile infection with herpes simplex virus type 2.

• Inguinal lymphadenopathy

• Genital lesions, especially urethral lesions, may cause transient urinary retention in women

• Vaginal discharge

Keratoconjunctivitis

• Dendritic keratitis found with slit lamp (dendritic ulcer shown in the image below)

  Herpes simplex virus dendritic ulcer with fluorescein staining.

• Corneal ulcers

• Vesicles on eyelids

Neurologic

• New psychiatric symptoms (indicative of encephalitis) - Confusion; seizures; meningeal signs (Recurrent lymphocytic meningitis [benign form of meningitis/encephalitis that may occur during primary HSV-2 infection])

• Bell palsy (possible relationship with HSV-1)

Anal/perianal involvement

• Discharge

• Vesicles

• Ulcerations

• Inguinal adenopathy

Transmission occurs via contact with the virus through herpes lesions, mucosal surfaces, and genital or oral secretions.[12]

HSV-1 is transmitted through direct contact with infected saliva or direct contact with contaminated utensils.

HSV-2 is usually acquired as an STD.

The maternal-fetal transmission risk of transmission is greater during primary outbreak (30-50%) than with recurrent outbreaks (< 1%).[7]

Recurrent disease (reactivation) due to certain stimuli: fever, physical or emotional stress, ultraviolet light exposure, or axonal injury

Encephalitis: Rare complication of herpetic infection; commonly HSV-1 (hypothesized to spread to the brain via neural routes after primary or recurrent infection)

Neonatal infections: Range from mild localized infection to a fatal disseminated disease; HSV-2 usually spread via the maternal genital tract; congenital infections possible

Compromised host: Progressive and disseminated disease possible

Genital infection: Acute urinary retention

Scrapings from suspected lesions of herpes simplex (Tzanck smear). This is not a reliable screening test, with a reported sensitivity of 65%. It also does not identify the type of herpes simplex virus (HSV) present.

• Multinucleated giant cells, as shown in the image below

  Tzanck smear showing a multinucleated giant cell.

• Intranuclear inclusions

Viral culture from skin vesicles (more sensitive that Tzanck smear but dependent on duration of viral shedding); consider the following:

• Preferably from vesicular lesions within 3 days of appearance
• The earlier the sample is taken, the more accurate the results

Monoclonal antibody testing; consider the following:

• Primarily used when other methods cannot be used (ie, no active lesions to swab)
• Also used when other methods yielded negative results but there is still significant concern for infection ^[13]

Serology

• HSV IgG detection via ELISA or Western blot

Cerebrospinal fluid (CSF) analysis for lymphocytic pleocytosis

• Bloody CSF

• Polymerase chain reaction (PCR) detects HSV DNA

CT scan and MRI for differentiation of encephalitis from other entities

Slit-lamp examination for dendritic keratitis with ocular involvement

Lumbar puncture, if concerned about encephalitis

Brain biopsy, if encephalitis is considered

ED care consists of diagnosis and appropriate treatment. The concern for possible infection is the basis of initiating treatment. Most patients may be treated in the outpatient setting. Pregnant patients also need to be educated on the importance of follow-up to reduce transmission to the fetus.[14] Identification of patients who need inpatient treatment (ie, encephalitis) and initiation of antiviral and supportive therapy is imperative.[5]

Ophthalmologist for keratoconjunctivitis

Obstetrician for active genital herpes in a near-term pregnancy

Outpatient dermatologist for differentiation of skin infections

Infectious disease specialist for disseminated disease and encephalitis

The psychological effect of HSV diagnosis may require patients to seek further evaluation.[4]

Patients should be counseled on barrier protection methods to prevent HSV transmission to others. A discussion regarding daily prophylaxis can be conducted outside of the emergency department.

HSV-2 is an STD. Patients and all sexual contacts should be tested and treated for accompanying STDs.

Practice abstinence when lesions are present.

Always use condoms because of the potential for asymptomatic viral shedding.

Health care personnel (especially medical, dental) should use universal precautions (eg, gloves) to prevent herpetic whitlow.

Experimental vaccines are currently in clinical trials.

Use sunscreen to decrease herpes labialis recurrences.

Pregnant patients need to be closely monitored by their obstetricians to reduce the risk of an outbreak at the time of delivery.

Patients with herpetic keratitis should be monitored by an ophthalmologist to evaluate for permanent damage (eg, blindness).

Any patient with genital herpes may need referral to a psychologist because of the emotional effect of a permanent and socially stigmatizing disease.

Admission for patients with herpes simplex is necessary in the following instances:

• Encephalitis, hepatitis, or pneumonitis

• Severe gingivostomatitis causing decreased ability to tolerate oral fluids

• Immunocompromised patients with severe or disseminated diseases

The 2015 CDC STD Guidelines on herpes infection are as follows:[15]

The first clinical episode of genital herpes is treated as follows:

• Acyclovir 400 mg orally three times a day for 7-10 days OR
• Acyclovir 200 mg orally five times a day for 7-10 days OR
• Valacyclovir 1 g orally twice a day for 7-10 days OR
• Famciclovir 250 mg orally three times a day for 7-10 days

*Treatment can be extended if healing is incomplete after 10 days of therapy.

Suppressive therapy for recurrent genital herpes is as follows:

• Acyclovir 400 mg orally twice a day OR
• Valacyclovir 500 mg orally once a day* OR
• Valacyclovir 1 g orally once a day OR
• Famciclovir 250 mg orally twice a day

*Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in persons who have very frequent recurrences (ie, ≥10 episodes per year).

Episodic therapy for recurrent genital herpes in immunocompetent persons is as follows:

• Acyclovir 400 mg orally three times a day for 5 days OR
• Acyclovir 800 mg orally twice a day for 5 days OR
• Acyclovir 800 mg orally three times a day for 2 days OR
• Valacyclovir 500 mg orally twice a day for 3 days OR
• Valacyclovir 1 g orally once a day for 5 days OR
• Famciclovir 125 mg orally twice daily for 5 days OR
• Famciclovir 1 gram orally twice daily for 1 day OR
• Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days

Episodic therapy for recurrent genital herpes in immunocompromised patients is as follows:[16]

• Acyclovir 400 mg orally three times daily for 5 days
• Valaciclovir 500 mg orally twice daily for 5 days
• Famciclovir 500 mg orally twice daily for 5 days

Severe disease (HSV meningoencephalitis, disseminated infection, pneumonitis) is treated as follows:

• Acyclovir 5-10 mg/kg IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 total days of therapy
• HSV encephalitis requires 21 days of intravenous therapy; impaired renal function warrants an adjustment in acyclovir dosage

Antiviral drugs with activity against viral DNA synthesis have been effective against HSV infections. These drugs inhibit virus replication and may suppress clinical manifestations but are not a cure for the disease. Since HSV remains latent in sensory ganglia, the rates of relapse are similar in treated and untreated patients.

The 2015 CDC guidelines for STD treatment recommend that all initial genital herpes infections be treated with antivirals to reduce any potential complications.[15, 17]

Acyclovir (Zovirax) provides initial, recurrent, and suppressive therapy for genital HSV. It is effective for mucocutaneous HSV in an immunocompromised host as well as HSV encephalitis. Little evidence supports the routine use of acyclovir for primary oral-labial HSV. Oral acyclovir has been shown to be effective in suppressing herpes labialis in immunocompromised patients with frequent recurrent infections. Begin use during the prodromal period.

Daily suppressive therapy has shown to be 80% effective in preventing recurrences and should be considered in patients who suffer from frequent recurrences.[18]

Administer famciclovir (Famvir) or valacyclovir (Valtrex) for recurrent episodes of genital HSV. Herpes simplex keratoconjunctivitis is treated with topical 1% trifluridine (Viroptic) or ganciclovir (Zirgan).[19]

In pregnancy, the use of antiviral agents such as valacyclovir and acyclovir has been shown to be safe with no increased risk of birth defects.[20]

Use pain medication as needed, such as ibuprofen or acetaminophen. Topical anesthetics may provide some relief from pain and itching.[21] Some patients may require narcotics for the relief of severe pain from the lesions.

Class Summary

The goals in use of antivirals are to (1) shorten the clinical course, (2) prevent complications, (3) prevent the development of latency and/or subsequent recurrences, (4) decrease transmission, and (5) eliminate established latency.

Acyclovir (Zovirax)

DOC; reduces duration of symptomatic lesions. Indicated for patients presenting within 48 h of rash onset. Patients on acyclovir experience less pain and faster resolution of cutaneous lesions.

Famciclovir (Famvir)

Prodrug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA synthesis/replication. Useful for recurrent episodes of genital HSV.

Valacyclovir (Valtrex)

Prodrug that is rapidly converted to acyclovir before exerting its antiviral activity. Valacyclovir is more expensive but has more convenient dosing regimen than acyclovir. Useful for recurrent episodes of genital HSV.

1% Trifluridine (Viroptic)

Replaces thymidine in viral DNA, resulting in production of defective proteins and thus inhibiting viral replication. Useful in treatment of keratoconjunctivitis.

Docosanol cream (Abreva)

Prevents viral entry and replication at cellular level. Use at first sign of cold sore or fever blister.

Ganciclovir ophthalmic (Vitrasert, Zirgan)

A guanosine derivative that, upon phosphorylation, inhibits DNA replication by herpes simplex viruses (HSV). Works by inhibiting the synthesis of viral DNA in 2 ways: competitive inhibition of viral DNA-polymerase and direct incorporation into viral primer strand DNA, resulting in DNA chain termination and prevention of replication. Useful for HSV keratitis.