eMedicine Specialties > Dermatology > Viral Infections

Herpes Simplex

Author: Gisela Torres, MD, Staff Physician, Department of Dermatology, University Hospitals of Cleveland; Senior Instructor in Dermatology, Case Western Reserve University
Coauthor(s): Malcolm Schinstine, MD, PhD, Staff Physician, Department of Pathology and Laboratory Medicine, Dartmouth College Hitchcock Medical Center; Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont; Stephen K Tyring, MD, PhD, MBA, Founder and Medical Director, Center for Clinical Studies, Clinical Professor, Departments of Dermatology, Microbiology, and Molecular Genetics, and Internal Medicine (Infectious Diseases), University of Texas Health Science Center at Houston
Contributor Information and Disclosures

Updated: Jun 27, 2007

Introduction

Background

Herpes simplex viruses (HSVs) are DNA viruses that cause acute skin infections and present as grouped vesicles on an erythematous base. Rarely, these viruses can cause serious illness and can affect pregnancy, leading to significant harm to the fetus. Most infections are recurrent and tend to reappear at or near the same location. Herpes labialis is the most common infection caused by HSV type 1 (HSV-1), whereas genital herpes is usually caused by HSV type 2 (HSV-2). Other clinical manifestations of HSV infection are less common.

Pathophysiology

Intimate contact between a susceptible person (without antibodies against the virus) and an individual who is actively shedding the virus or with body fluids containing the virus is required for HSV infection to occur. Contact must involve mucous membranes or open or abraded skin.

HSV invades and replicates in neurons as well as in epidermal and dermal cells. Virions travel from the initial site of infection on the skin or mucosa to the sensory dorsal root ganglion, where latency is established. Viral replication in the sensory ganglia leads to recurrent clinical outbreaks. These outbreaks can be induced by various stimuli, such as trauma, ultraviolet radiation, extremes in temperature, stress, immunosuppression, or hormonal fluctuations. Viral shedding, leading to possible transmission, occurs during primary infection, during subsequent recurrences, and during periods of asymptomatic viral shedding.

HSV-1 reactivates most efficiently from trigeminal ganglia (affecting the face and the oropharyngeal and ocular mucosae), while HSV-2 has a more efficient reactivation in the lumbosacral ganglia (affecting the hips, buttocks, genitalia, and lower extremities). The clinical difference in site-specific reactivation between HSV-1 and HSV-2 appears to be due, in part, to each virus establishing latent infection in different populations of ganglionic neurons.

Frequency

United States

HSV-1 infection is acquired by early childhood, and evidence of serologic infection with HSV-1 approaches 80% in the general adult population. Only about 30% of these individuals have clinically apparent outbreaks. In the United States, approximately 1 in 4-5 adults (21-25%) is serologically positive for HSV-2. For adolescents in the United States, studies have found rates up to 49-53% for HSV-1 and 12-15% for HSV-2. More than half the seropositive individuals do not experience clinically apparent outbreaks, but these individuals still have episodes of viral shedding and can transmit the virus. The incidence of HSV-2 infection is one of the most rapidly increasing rates among sexually transmitted diseases in this country. Independent predictors of HSV-2 seropositivity include female sex, black race, older age, lower education, more lifetime sex partners, prior diagnosis of sexually transmitted disease, and lack of HSV-1 antibody.

International

Serologic evidence of HSV-1 infection by early adulthood ranges from 56-85%, varying by country. HSV-2 seroprevalence has been reported to vary from 13-40% worldwide. More than one third of the world's population has recurrent clinical HSV infections.

In the developing world, HSV-2 is becoming a common cause for genital ulcer disease, especially in countries with a high prevalence of HIV infection. International studies show seroprevalence in people co-infected with HIV being close to 90% for HSV-1 and up to 77% for HSV-2.

Mortality/Morbidity

Severe complications may be associated with herpes simplex. This is especially true in females who are pregnant and in individuals with immunosuppression who may develop disseminated infection and encephalitis.

The most common complication of primary HSV-2 genital infection is bacterial superinfection. In women, systemic complications, such as urinary retention and aseptic meningitis (seen in up to 25% of women), can occur. The associated pain, paresthesia, and discomfort, as well as the psychosocial impact, of herpes simplex outbreaks cause significant morbidity to the individuals who are affected.

Individuals co-infected with HSV and HIV and who have herpetic mucosal lesions are more likely to transmit HIV during sexual contact. In studies, despite being compliant with highly active antiretroviral therapy (HAART) for treatment of HIV-1 infection, 30-50% of women co-infected with HSV-2 and HIV-1 were shown to have genital HIV-1 shedding at least once in a 3-month period. Studies also suggest that co-infection with HSV-2 may accelerate HIV disease progression by elevating the HIV viral load. Organ transplant recipients and patients with HIV/AIDS may develop herpetic lesions that exhibit an unusual morphology. Moreover, patients with Darier disease, severe atopic dermatitis, or mycosis fungoides may develop life-threatening disseminated Kaposi varicelliform eruption.

Another serious consequence of HSV infection is the transmission of the virus to a neonate by a mother who is infected. Asymptomatic maternal shedding occurs approximately 7% of the time and is responsible for most neonatal HSV infections. The risk of HSV transmission to the newborn is as high as 30-50% from a mother who acquired a new HSV infection near the time of delivery. Among women who have acquired HSV infection before their third trimester of pregnancy, the risk of transmission is less than 1%. HSV infections in neonates are most commonly due to HSV-2 and most are acquired peripartum from exposure to lesions (or shedding virus) in the birth canal, although in utero and postpartum transmission rarely can occur. Transmission is estimated to occur at a rate of 1 case in 3500-5000 deliveries in the United States. Neonatal infection can cause long-term sequelae and even death.

Race

African Americans have a higher prevalence of antibodies against HSV-1 than whites. Nonwhite race has been reported as a risk factor for HSV-2 seropositivity.

Sex

The frequency of HSV-1 and HSV-2 antibodies is slightly higher in females than in males. However, women are more likely than men to be protected from genital HSV infection by the use of barrier methods.

In a study of more than 600 pregnant women, 63% were seropositive for HSV-1, 22% for HSV-2, and 13% for both, and 28% were seronegative. Nonwhite race and having had 4 or more sex partners independently correlated with increased HSV-2 infection. Non-Hispanic white pregnant women had the highest percentage of seronegativity for both HSV-1 and HSV-2. However, this group had the highest risk of having a child with neonatal herpes, indicating their susceptibility for new HSV infection during their third trimester of pregnancy (when a mother is most likely to transmit infection to her neonate).

Age

The frequency of HSV-1 infection in children varies with the socioeconomic status. Approximately, one third of children from lower socioeconomic families exhibit some evidence of HSV-1 infection by age 5 years. The frequency increases to 70-80% by early adolescence/adulthood. In contrast, only 20% of children from middle-class families seroconvert. The frequency of infection remains fairly stable until the second to third decade of life when it increases to 40-60%. The rate of HSV-2 seroconversion is highest in sexually active young adults.

Clinical

History

Primary infection with HSVs is clinically more severe than recurrent outbreaks. However, most primary HSV-1 and HSV-2 infections are subclinical and may never be clinically diagnosed.

• Orolabial herpes: Herpes labialis (eg, cold sores, fever blisters) is most commonly associated with HSV-1 infection. Oral lesions caused by HSV-2 have been identified, usually secondary to orogenital contact. Primary HSV-1 infection often occurs in childhood and is usually asymptomatic.
  • Primary infection: Symptoms of primary herpes labialis may include a prodrome of fever, followed by a sore throat and mouth and submandibular or cervical lymphadenopathy. In children, gingivostomatitis and odynophagia are also observed. Painful vesicles develop on the lips, the gingiva, the palate, or the tongue and are often associated with erythema and edema. The lesions ulcerate and heal within 2-3 weeks.
  • Recurrences: The disease remains dormant for a variable amount of time. HSV-1 reactivation in the trigeminal sensory ganglia leads to recurrences in the face and the oral, labial, and ocular mucosae. Pain, burning, itching, or paresthesia usually precedes recurrent vesicular lesions that eventually ulcerate or form a crust. The lesions most commonly occur in the vermillion border, and symptoms of untreated recurrences last approximately 1 week. Recurrent erythema multiforme lesions have been associated with orolabial HSV-1 recurrences. A recent study reported that HSV-1 viral shedding had a median duration of 48-60 hours from the onset of herpes labialis symptoms. They did not detect any virus beyond 96 hours of symptom onset.
• Genital herpes: HSV-2 is identified as the most common cause of herpes genitalis. However, HSV-1 has been increasingly identified as the causative agent in as many as 30% of cases of primary genital herpes infections likely secondary to orogenital contact. Recurrent genital herpes infections are almost exclusively caused by HSV-2.
  • Primary infection: Primary herpes genitalis occurs within 2 days to 2 weeks after exposure to the virus and has the most severe clinical manifestations. Symptoms of the primary episode typically last 2-3 weeks.
    • In men, painful, erythematous, vesicular lesions that ulcerate most commonly occur on the penis, but they can also occur on the anus and the perineum. In women, primary herpes genitalis presents as vesicular/ulcerated lesions on the cervix and as painful vesicles on the external genitalia bilaterally. They can also occur on the vagina, the perineum, the buttocks, and, at times, the legs in a sacral nerve distribution. Associated symptoms include fever, malaise, edema, inguinal lymphadenopathy, dysuria, and vaginal or penile discharge.
    • Females may also have lumbosacral radiculopathy, and as many as 25% of women with primary HSV-2 infections may have associated aseptic meningitis.
  • Recurrences: After primary infection, the virus may be latent for months to years until a recurrence is triggered. Reactivation of HSV-2 in the lumbosacral ganglia leads to recurrences below the waist. Recurrent clinical outbreaks are milder and often preceded by a prodrome of pain, itching, tingling, burning, or paresthesia.
  • Individuals who are exposed to HSV and have asymptomatic primary infections may experience an initial clinical episode of genital herpes months to years after becoming infected. Such an episode is not as severe as a true primary outbreak.
  • More than one half of individuals who are HSV-2 seropositive do not experience clinically apparent outbreaks. However, these individuals still have episodes of viral shedding and can transmit the virus to their sexual partners.
• Other HSV infections
  • Localized or disseminated eczema herpeticum is also known as Kaposi varicelliform eruption. Caused by HSV-1, eczema herpeticum is a variant of HSV infection that commonly develops in patients with atopic dermatitis, burns, or other inflammatory skin conditions. Children are most commonly affected.
  • Herpes whitlow, vesicular outbreaks on the hands and the digits, was most commonly due to infection with HSV-1. It usually occurred in children who sucked their thumbs and, prior to the widespread use of gloves, in dental and medical health care workers. The occurrence of herpes whitlow due to HSV-2 is increasingly recognized, probably due to digital-genital contact.
  • Herpes gladiatorum is caused by HSV-1 and is seen as papular or vesicular eruptions on the torsos of athletes in sports involving close physical contact (classically wrestling).
  • Disseminated HSV infection can occur in females who are pregnant and in individuals who are immunocompromised. These patients may present with atypical signs and symptoms of HSV, and the condition may be difficult to diagnose.
  • Neonatal HSV
    • HSV-2 infection in pregnancy can have devastating effects on the fetus. Neonatal HSV usually manifests within the first 2 weeks of life and clinically ranges from localized skin, mucosal, or eye infections to encephalitis, pneumonitis, disseminated infection, and demise.
    • Most women who deliver infants with neonatal HSV had no prior history, signs, or symptoms of HSV infection. Risk of transmission is highest in pregnant women who are seronegative for both HSV-1 and HSV-2 and acquire a new HSV infection in the third trimester of pregnancy.
    • Factors that increase the risk of transmission from mother to baby include the type of genital infection at the time of delivery (higher risk with active primary infection), active lesions, prolonged rupture of membranes, vaginal delivery, and an absence of transplacental antibodies. The mortality rate for neonates is extremely high (>80%) if untreated.
  • Herpetic sycosis, a follicular infection with HSV, may present as a vesiculopustular eruption on the beard area. This infection often results from autoinoculation after shaving through a recurrent herpetic outbreak. Classically caused by HSV-1, there have been rare reports of relapsing beard folliculitis caused by type 2 HSV.

Physical

• Clinical HSV infections appear as clustered vesicles on an erythematous base. They often progress to pustular or ulcerated lesions, and they eventually form a crust. HSV lesions tend to recur at or near the same location within the distribution of a sensory nerve. Systemic symptoms, such as fever, malaise, and acute toxicity, may accompany the lesions, especially in primary infections. Each condition has associated symptoms and clinical findings (see History above).
  • Although HSV infections may occur anywhere on the body, 70-90% of HSV-1 infections occur above the waist. In contrast, 70-90% of HSV-2 infections occur below the waist.
  • Physical manifestations of HSV infections in patients who are immunocompromised are usually similar to those in healthy patients. However, larger lesions or necrotizing ulcers may occur, and widespread areas may be involved.
  • Neonatal HSV may be difficult to diagnose because, often, no mucocutaneous lesions are present on physical examination. Respiratory distress, jaundice, and seizures may occur.

Causes

• HSV-1 and HSV-2 are the causative agents of herpes genitalis, herpes labialis, herpes gladiatorum, herpes whitlow, herpetic keratoconjunctivitis, eczema herpeticum, herpes folliculitis, lumbosacral herpes, disseminated herpes, neonatal herpes, and herpes encephalitis. They have also been linked to some cases of erythema multiforme. A febrile illness, exposure to ultraviolet light, trauma, upper respiratory infection, or emotional stress may trigger recurrent herpes labialis due to HSV-1.
• The patient's geographical location, socioeconomic status, and age influence the frequency of HSV-1 infections. The highest prevalence of antibodies to HSV-2 occurs in female prostitutes, male homosexuals, and HIV-positive individuals.

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