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 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.
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.
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]
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]
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.
Men are 20% more likely to develop recurrences of HSV-2 than are women, although women have higher rates of HSV-2 infection.[3]
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 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
Submandibular lymphadenopathy
Fever
Genital herpes
Inguinal lymphadenopathy
Genital lesions, especially urethral lesions, may cause transient urinary retention in women
Vaginal discharge
Keratoconjunctivitis
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
Pediatrics, Meningitis and Encephalitis
Pediatrics, Pharyngitis
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.
Intranuclear inclusions
Viral culture from skin vesicles (more sensitive that Tzanck smear but dependent on duration of viral shedding); consider the following:
Monoclonal antibody testing; consider the following:
Serology
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:
*Treatment can be extended if healing is incomplete after 10 days of therapy.
Suppressive therapy for recurrent genital herpes is as follows:
*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:
Episodic therapy for recurrent genital herpes in immunocompromised patients is as follows:[16]
Severe disease (HSV meningoencephalitis, disseminated infection, pneumonitis) is treated as follows:
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.
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.
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.
Prodrug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA synthesis/replication. Useful for recurrent episodes of genital HSV.
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.
Replaces thymidine in viral DNA, resulting in production of defective proteins and thus inhibiting viral replication. Useful in treatment of keratoconjunctivitis.
Prevents viral entry and replication at cellular level. Use at first sign of cold sore or fever blister.
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.