eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Herpes Simplex Virus Infection

Author: Sherman Alter, MD, Associate Professor, Department of Pediatrics, Wright State University Boonshoft School of Medicine; Director, Division of Infectious Diseases, Director, Continuing Medical Education, Children's Medical Center of Dayton
Contributor Information and Disclosures

Updated: Aug 6, 2009

Introduction

Background

Herpesvirus hominis, or herpes simplex virus (HSV), is one of the most common agents infecting humans of all ages. The virus occurs worldwide and produces various illnesses, including mucocutaneous infections, infections of the CNS, and occasionally infections of the visceral organs. Infections in children can include neonatal disease, mucocutaneous infections during childhood and adolescence, and serious disease in individuals who are immunocompromised. Genital herpes simplex virus infection in older adolescents and adults is a major public health problem, having markedly increased in prevalence in the last 3 decades.¹ This increased prevalence of genital herpes simplex virus infections poses major threats to newborns because most infections in neonates are acquired perinatally. Neonatal herpes simplex virus infection is a disease with high morbidity and mortality rates.

Laboratory methods used to diagnose herpes simplex virus infections have improved over time. The rapidity, sensitivity, and specificity of newer tools have improved the accuracy and timeliness of management and have enhanced our understanding of herpes simplex virus infections.

Herpes simplex virus infections are among the few non-HIV viral infections that can be managed with antiviral therapy. Available antiviral chemotherapy can be used to prevent disease and recurrences, to shorten the clinical course, and to treat the infection.

Pathophysiology

Herpes simplex viruses tend to infect cells of ectodermal origin. After direct exposure to infectious material (ie, saliva, genital secretions), initial viral replication occurs at the entry site in the skin or mucous membrane.

The biologic properties of herpes simplex virus that control the course of infection are neuroinvasiveness (the ability of the virus to invade the brain), its neurotoxicity (its ability to multiply and destroy the brain), and its latency (its ability to remain in a nonreplicating form in the dorsal root ganglia of the CNS).

After retrograde axonal flow from neurons at the viral point of entry and local replication, the viral genome becomes latent. No viral particles are produced during latency. In rare cases, the initial replication may lead to disease and life-threatening infection (eg, encephalitis).

After the initial nonspecific inflammatory response to primary infection, specific antibody response occurs in a few days, followed by a cellular immune response in the second or third week. In persons with cellular immune defects, primary herpes simplex virus infection can result in life-threatening disseminated disease.

A stimulus (eg, physical or emotional stress, fever, ultraviolet light) reactivates the virus in the form of skin vesicles or mucosal ulcers, with symptoms less severe than those of the primary infection. Latent herpes simplex virus can be reactivated from the trigeminal, sacral, and vagal ganglia.

Frequency

United States

Although the range of susceptible hosts for herpes simplex virus infections is wide, humans are the primary hosts for infection. The epidemiology of herpes simplex virus involves symptomatic and asymptomatic infection, with resultant transmission and maintenance of a large pool of individuals with latent infection. Continued spread of the infection is ensured by the vast reservoir of the virus, which can be transmitted through symptomatic recurrences and asymptomatic disease.

Beyond the neonatal period, most childhood herpes simplex virus infections are caused by herpesvirus type 1 (HSV-1), which is transmitted primarily by contact with infected saliva. Herpesvirus type 2 (HSV-2) infections are usually sexually transmitted, and genital herpes infections are among the most common sexually transmitted diseases (STDs). As a reflection of the association of infection with sexual activity, many HSV-2 infections occur around puberty and early adolescence. In the United States, HSV-2 seroprevalence increases from about 20-30% in patients aged 15-29 years to 35-60% in patients aged 60 years. This change represents a 30% increase compared with data from 1976-1980.

The prevalence of HSV-2 infections has dramatically increased in recent years. The third National Health and Nutrition Examination Survey (1988-1994) found that 22% of the general US population older than 12 years had antibodies to HSV-2.²  In another survey of patients in a suburban primary care office, 25.5% of patients were seropositive for HSV-2. Approximately 500,000 primary infections occur each year.³

Factors that increase the frequency of HSV-2 infection in older adolescents and adults include sex (more women than men), race (more blacks than whites), marital status (more divorced individuals than single or married individuals), and place of residence (more city residents than suburban residents).

Genital herpes simplex virus infection in pregnant women is common;⁴  20-30% of pregnant women have antibodies to HSV-2. Approximately 10% of pregnant women who are HSV-2 seronegative have a sexual partner who is HSV-2 seropositive and are, therefore, at risk of contracting a primary HSV-2 infection during pregnancy. Overall, approximately 2% of women acquire herpes simplex virus during pregnancy. In pregnant women, the prevalence of herpes simplex virus excretion from the genital tract at term is estimated to be 0.3-1.9%. Surveys of women of childbearing age in the late 1980s revealed HSV-2 antibodies in 35-60%

One study evaluated herpes simplex virus seroprevalence in a group of pregnant women (n=626).⁵  The mean age of the women was 27 years, and the median number of lifetime sexual partners was 4. Seroprevalence to HSV-1 was 63%, whereas seroprevalence to HSV-2 was 22%. Infection with both herpes simplex virus types was 13%. Herpes simplex virus seronegativity was noted in 28%. The prevalence of herpes simplex virus antibodies differed by race and ethnicity, with non-Hispanic white patients more likely to be seronegative compared with other racial and ethnic groups (40% vs 11%, P <.001). Increased numbers of lifetime sexual partners also correlated with higher rates of herpes simplex virus seropositivity in these women. This study projected the rate of neonatal herpes to be 33 cases per 100,000 live births.

Importantly, as many as 90% of individuals with genital herpes do not know that they are infected. Virtually all of these individuals intermittently shed herpes simplex virus from the genital tract, and some have mild, recurrent symptomatic disease. Most sexual transmission occurs during periods of subclinical reactivation among persons who do not know that they are infected.

International

Herpes simplex virus is well distributed worldwide. The prevalence rate of genital herpes in developing countries is 2-74%, depending on the country. In some African countries that are experiencing HIV epidemics, HSV-2 infection is highly prevalent (>70%). Evidence suggests that genital herpes simplex virus infection increases the risk of HIV infection and that persons infected with both viruses are more likely to transmit HIV infection.

Mortality/Morbidity

Most cases of infection with either HSV-1 or HSV-2 do not result in serious morbidity. Morbidity and mortality associated with herpes simplex virus are discussed in Complications. Mortality associated with herpes simplex virus is primarily related to perinatal infection, encephalitis, and infection in individuals who are immunocompromised.

At the time of vaginal delivery, the risk of herpes simplex virus transmission from a mother with true primary herpes simplex virus infection to her infant is approximately 50%. Women with primary infections at delivery are 10-30 times more likely than women with a recurrent infection to transmit the virus to their babies. Infants born to mothers with newly acquired infections who do not have primary infections in the presence of preexisting immunity caused by another viral infection (ie, first-episode nonprimary) have a transmission risk of 25-30%. The neonatal herpes simplex virus infection rate is considered to be less than 2% when the mother has active infection caused by the shedding of herpes simplex virus acquired before pregnancy or during gestation before the onset of labor (recurrent infection).

Approximately two thirds of women who acquire genital herpes during pregnancy have no symptoms. Of mothers who deliver an infant with herpes simplex virus infection, 60-80% have no evidence of genital herpes simplex virus infection at the time of delivery and have no history of previous genital infection in themselves or in their sexual partners. Of babies born to mothers with a primary infection near the time of delivery, 30-50% acquire the infection. Currently, neonatal herpes simplex virus disease is estimated to occur in approximately 1 per 3000 deliveries.

A recent study determined that herpes simplex virus infection in neonates and infants was associated with substantial morbidity and mortality and, most notably, a significant resource use.⁶ Patients with an associated congenital cardiac anomaly had a significantly longer length of stay.

Race

Although the risk of herpes simplex virus infection is not related to race, infection rates in the United States vary with race because of various factors, such as racial and ethnic differences in the prevalences of poverty and low socioeconomic status, access to health care, sexual and health-related behavior, and illicit drug use.

By age 5 years, more than 35% of black children are infected with HSV-1 versus 18% of white children. Through adolescence, the prevalence of antibodies to HSV-1 in blacks is approximately twice the rate among whites. By age 40 years, HSV-1 seroprevalence is similar among blacks and whites.

The prevalence of HSV-2 antibodies among blacks is 3-4 times higher than that among whites. Seroprevalence among women of childbearing age in the late 1970s was estimated to be 50% for blacks and 20% for whites. By the late 1980s, rates of infection had increased to approximately 60% for blacks and 35% for whites. As shown in 2 nationwide surveys of HSV-2 seroprevalence in the last 2 decades, the cumulative lifetime incidence of HSV-2 reaches 25% in white women, 20% in white men, 80% in black women, and 60% in black men.

Studies have indicated that the seroprevalence of HSV-2 antibodies among Hispanics ranges from 17-22.3%. Infants born to non-Hispanic white women may be at higher risk of herpes simplex virus infections. This is a result of a greater likelihood that these women are herpes simplex virus seronegative and at risk of acquiring a primary HSV-1 or HSV-2 infection in late pregnancy.

Sex

Infection rates with HSV-1 tend to be similar in both sexes during early childhood. However, through adolescence, the prevalence of antibodies to HSV-1 is slightly higher among female individuals than among male individuals. Rates of HSV-2 infection are higher in women than in men.

Nationwide surveys of HSV-2 seroprevalence during the last 2 decades have demonstrated cumulative lifetime incidences of 25% in white women and 80% in black women. This compares with rates of 20% in white men and 60% in black men. See also the Race section above.

Age

Beyond the neonatal period, most childhood herpes simplex virus infections are caused by HSV-1. The seroprevalence of HSV-1 antibodies increases with age, and its rate is 20% by age 5 years. No increase occurs until 20-40 years of age, when 40-60% of individuals are HSV-1 seropositive.

As a reflection of the association between infection and sexual activity, many HSV-2 infections occur around puberty and early adolescence. A progressive increase in HSV-2 infections occurs in all populations beginning in adolescence. In the United States, HSV-2 seroprevalence increases from approximately 20-30% in those aged 15-29 years to 35-60% in those aged 60 years.

Most neonatal infections are caused by HSV-2, but increasing proportions are being caused by HSV-1. See also the Race section above.

Clinical

History

Herpes simplex virus (HSV) may cause a myriad of clinical presentations. The course depends on the age of the patient, the immune status of the host, the site of infection, to person's previous immunity to autologous or heterologous viruses, and the antigenic type of the virus. Although variability in the clinical presentation of herpes simplex virus infection is great, infection is generally asymptomatic.

Herpes simplex virus type 1 (HSV-1) infection is normally associated with orofacial infections and encephalitis, whereas herpes simplex virus type 2 (HSV-2) usually causes genital infections and can be transmitted from an infected mother to her infant. Compared with latent infection, primary infection with either virus is typically associated with systemic signs, prolonged duration and increased severity of symptoms, and increased rates of complications. On reactivation, both viruses establish latent infections in sensory neurons and cause recurrent disease at or near the entry site into the body. HSV-1 and HSV-2 may cause similar infections.

• Neonatal herpes simplex virus infection
  • Infection with herpes simplex virus limited to the skin, eye, or to mucous membranes (SEM) historically accounts for about 20% of all neonatal HSV infections. With the introduction of early antiviral therapy, the frequency has increased to about 45%. Infants with SEM infections generally present at age 10-12 days. Eye infection may cause conjunctival injection and a watery discharge. Although uncommon, vesicular lesions may be noted in the oropharynx. Many newborns with herpes simplex virus–related SEM disease do not present with symptoms of systemic illness. SEM disease without treatment is associated with a high risk of progression to serious disease. Subtle CNS abnormalities have been observed after SEM disease, possibly because of reactivation of the virus during the first 6 months of life.
  • Disseminated disease now accounts for approximately 25% of herpes simplex virus infections in newborns. The recognition and treatment of herpes simplex virus–related SEM disease early has resulted in lower rates of progression to disseminated disease than in years past. Although most infected babies appear well at birth, the illness can appear within 24 hours. Most infants with disseminated herpes simplex virus disease have symptoms of illness within the first week of life; however, symptoms may not arise until the second week (usually around 10-12 d of life).
    • Viremia associated with disseminated herpes simplex virus disease results in spread of the virus to multiple organs. Manifestations of illness represent the organ systems involved (eg, CNS, lungs, GI tract, heart, kidneys).
    • Initial symptoms of infection may include irritability, poor feeding, respiratory distress, jaundice, seizure activity, and evidence of bleeding (GI hemorrhage, purpura).
    • Involvement of the CNS is common in infants with disseminated herpes simplex virus infection. About 60-75% of infants with disseminated disease have infection in the CNS.
    • No more than 20% of children with disseminated disease develop the classic vesicular rash. In most cases, no rash is observed when symptoms begin.
  • Nearly one third of infants with neonatal herpes simplex virus infection have encephalitis as the sole manifestation of disease. Patients usually present with symptoms or signs of illness at 16-19 days of life, but they occasionally present at 4-6 weeks.
    • Initial manifestations of encephalitis include lethargy, irritability, poor feeding, seizure activity (focal or generalized), tremors, fever or hypothermia, and bulging fontanelle.
    • Approximately 10-70% of babies CNS disease have associated skin vesicles at some point in the course of the disease.
    • Patients may have a history of lesions of the skin or eye that was previously unrecognized as being herpetic.
    • Approximately 40% of patients with herpes simplex virus encephalitis never develop the characteristic rash.
• Acute herpetic gingivostomatitis
  • The most common clinical presentation of first-episode, primary herpes simplex virus infection in children, usually aged 6 months to 5 years, is acute herpetic gingivostomatitis (see Media file 1). Adolescent or adult infection may occur, but their overall clinical presentation usually resembles pharyngotonsillitis and is less severe than that of infants and children.
    
    

    

    Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in Media file 2.

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    Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in Media file 2.

  • Herpes simplex virus is transmitted by means of infectious saliva from an adult or child. Both the viral titer in oral secretions and the risk of transmission are highest when active lesions are present. The incubation period is approximately 4 days and ranges from 2-12 days. Primary herpes simplex virus infection of the oropharynx results in viral excretion from day 7 to day 23. Asymptomatic shedding has been documented in 2-9% of adults and in 5-8% of children.
  • Clinical features include the following:
    • Abrupt onset of illness
    • Fever (temperature of 102-104°F)
    • Listlessness or irritability
    • Inability to eat and/or drink
    • Gingivitis (with markedly swollen, erythematous, and occasionally bleeding gums)
    • Occasional episodes of increased drooling in infants due to pain on swallowing
    • Vesicular lesions on the tongue, buccal mucosa, and palate with extension, at times, to the lips and face (These may rupture and coalesce to form large, ulcerated areas.)
    • Tender submandibular or cervical adenopathy
  • The lesions can be quite painful and symptoms may persist for 10-14 days. Primary herpes simplex virus infection of the oropharynx may be associated with viral shedding for as long as 23 days.
• Acute herpetic pharyngotonsillitis
  • Primary HSV-1 infection of the oropharynx in adolescents and adults usually manifests as pharyngotonsillitis rather than gingivostomatitis.
  • Patients usually have fever, malaise, odynophagia, and headache.
  • Vesiculoulcerative lesions develop on the tonsils, with fewer than 10% of patients having associated orolabial vesicles.
  • Primary HSV-2 infection can have a presentation similar to this after orogenital contact, and it may occur concurrently with genital herpes simplex virus infection.
• Recurrent orolabial herpetic infection (herpes labialis)
  • Reactivation of herpes simplex virus, predominantly HSV-1, is rarely associated with systemic signs and symptoms, and patients present with recurrent herpes labialis. A prodrome of localized pain, tingling, burning, or itching frequently herald recurrent orolabial lesions. This prodrome may occur 6-53 hours before the first vesicular lesions appear.
  • A vesicular rash in crops of 3-5 vesicles is noted, frequently arising near the vermillion border. On occasion, vesicles may be noted on other areas of the face or in the nares. Recurrent disease patterns greatly vary from person to person. However, specific triggers may be fairly predictable for individual patients, and the lesions tend to recur at the same site as the original lesions.
  • HSV-1 orolabial infections recur at a rate of approximately 0.1 episode per month or 1.2 per year. Recurrences are often associated with various febrile illnesses, local trauma, sun exposure, and menstruation. Pain is most severe at the onset of infection and diminishes after 4-5 days.
• Primary genital infections
  • The clinical presentations of genital infections with HSV-1 and HSV-2 may be similar. Recurrences are more common with HSV-2 infections than with HSV-1 infections (5 vs 1 per y). Individuals with HSV-2 infection generally have high rates of recurrence in the first and second years followed by a substantial decrease in subsequent years (median, 2 per y). About 25% of individuals have at least 1 recurrence in year 5. HSV-2 infection in an individual with previous HSV-1 infection may result in symptoms that are milder than before (fewer lesions, less pain, diminished risk of complications).
  • Adolescents and adults may have the classic vesicular rash or progressive lesions (pustules or painful ulcerative lesions). Lesions may persist for as long as 3 weeks.
  • Primary, first-episode genital infections are characterized by severe constitutional symptoms, including fever, malaise, myalgias, and occasional headache (most prominent in the first 3-4 d of the infection). New lesions are possible, and symptoms can persist for as long as 4-15 days. The median duration of viral shedding is approximately 12 days.
  • Painful inguinal lymphadenopathy, dysuria, and vaginal discharge are frequent complaints. On occasion, complications in both sexes include paresthesias of the legs and perineum. Urinary retention, more common in women than in men, may be reported. Symptoms associated with an aseptic meningitis syndrome can occur in rare cases.
  • Preexisting antibodies to HSV-1 have an ameliorating effect on the severity of disease caused by HSV-2. Previous orofacial infection with HSV-1 generally protects a person against infection with HSV-1 but not HSV-2.
  • Most primary genital herpes simplex virus infections are asymptomatic, and 70-80% of seropositive individuals have no history of symptomatic genital herpes. Periodic subclinical recurrences with viral shedding make them sources of infection.
• Recurrent genital infections
  • Recurrent genital herpes simplex virus in the female adolescent or adult may cause vulvar irritation and/or ulcerating or vesicular lesions. Symptoms tend to be more severe in female patients than in male patients.
  • Recurrent genital herpes simplex virus in male individuals may result in vesicular lesions on the shaft of the penis. Local symptoms of recurrence include pain, itching, and dysuria.
  • Clinical manifestations may last 8-10 days. Only 5-12% of people with recurrent herpes simplex virus infection have constitutional symptoms. An estimated one third of individuals have more than 6 episodes of recurrent disease per year, one third have 2 per year, and the remainder have only rare recurrences. Of importance, herpes simplex virus may recur (and can be transmitted) in the absence of symptoms.
• Herpes simplex virus CNS infection
  • Herpes simplex virus encephalitis is the most common cause of severe sporadic CNS infection in the United States. One third of all cases of herpes simplex virus encephalitis are believed to occur in the pediatric population.
    • herpes simplex virus encephalitis may be a manifestation of primary or recurrent infection with the virus. However, many cases of encephalitis in children are thought to occur after primary infection with the virus.
    • The infection may have an insidious or an abrupt onset.
    • Most patients are febrile. Headache is an early symptom, and approximately 90% of patients have symptoms and signs that suggest a localized lesion in 1 or both temporal lobes.
    • Early behavioral changes, in the form of personality changes, hallucinations, and bizarre behavior, occur early in the course of the illness and may persist for as long as a week.
    • Seizures, often focal, occur in 40% of patients. Hemiparesis, aphasia, visual-field defects, and paresthesias may be prominent and reflect the area of neurologic involvement by the virus. These focal neurologic findings are usually of an acute presentation, with signs and symptoms lasting less than a week. Some patients rapidly progress from stupor to coma to death without having localizing neurologic symptoms.
  • Aseptic meningitis caused by herpes simplex virus can occur after primary genital HSV-2 infection. Patients with herpes simplex virus meningitis present with headache, fever, stiff neck, and photophobia. Symptoms usually begin 3-12 days after the onset of genital lesions. They reach maximum severity by 2-4 days into the illness, and gradually diminish over 2-3 days. In rare cases, HSV-1 or HSV-2 may cause viral meningitis without genital herpes simplex virus involvement.
  • Dysfunction of the autonomic nervous system and transverse myelitis has been associated with genital herpes simplex virus infection. Symptoms may include hyperesthesia or anesthesia of the lower back, perineum, or sacral region. Urinary retention and constipation are other associated symptoms.
  • CNS sequelae after CNS disease typically occur in untreated individuals.
  • Various behavioral syndromes have been reported in association with HSV-1 encephalitis, including hypomania, various degrees of amnesia, and the Klüver-Bucy syndrome.
• Herpetic infection in immunocompromised hosts
  • Severe herpes simplex virus infection in immunocompromised children is similar to that in adults. Infection usually represents reactivation of endogenous virus.
  • Symptoms of herpes simplex virus infection in recipients of bone marrow transplants, immunosuppressed recipients of solid organ transplants, children with leukemia (especially those receiving chemotherapy and those who are neutropenic), children with HIV-1 infection, and individuals with severe burns depend on the site of involvement.
  • Herpes simplex virus infection typically begins in or around the mouth, with mouth sores progressing to malodorous and extremely painful ulcers. Patients with oral herpes simplex virus may present with fever, odynophagia, drooling (in young children), and poor oral intake. Chronic ulcers sometimes persist for as long as a month. A similar painful syndrome may occur in the perianal or vaginal area of some patients.
  • Herpes simplex virus pneumonitis presents with cough, fever, and dyspnea.
  • Herpes simplex virus esophagitis may be asymptomatic, but it most commonly results in dysphagia, odynophagia, epigastric discomfort, and retrosternal pain.
  • Widespread dissemination of herpes simplex virus may cause signs of specific organ dysfunction progressing to a picture of sepsis and death in approximately 90% of patients. The clinical picture is initially one of fever and skin or mucocutaneous infection, which disseminates instead of improves.
• Other herpes simplex virus infections
  • Patients with herpes simplex virus infection of the finger, or herpetic whitlow (see Media file 2), present with an acute onset of edema, erythema, and localized pain and tenderness in the finger. Associated fever and enlarged regional adenopathy are not uncommon.
    
    

    

    Herpes whitlow in an infant.

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    Herpes whitlow in an infant.

  • Herpes gladiatorum results in painful herpes simplex virus lesions, frequently with numerous cutaneous vesicles. Herpes gladiatorum can occur in wrestlers (see Media file 5).
    
    

    

    Herpes gladiatorum in an adolescent wrestler.

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    Herpes gladiatorum in an adolescent wrestler.

  • Herpes simplex virus infection of the eye, which causes a keratoconjunctivitis, manifests with an acute onset of pain, watery discharge, itching, blurred vision, lid swelling, and conjunctival injection. Fever and malaise may occur. Recurrent eye infection with herpes simplex virus may be associated with findings at least as severe as those of the initial infection. Although rare, acute retinal necrosis caused by herpes simplex virus can cause blindness.
  • Symptoms of meningitis can occur in approximately one fourth of patients with primary genital herpes simplex virus infection, but they rarely need hospitalization. HSV-2 is the chief causative agent. However, in Mollaret meningitis, recurrent aseptic meningitis is typically recognized in some children and adolescents, but it is most frequently observed in adults. Low-grade fever, headache, and myalgias may occur with these episodes. Approximately 50% of patients have transitory neurologic symptoms of meningeal irritation. The disease usually spontaneously remits over days. The patient's medical history frequently reveals concurrent genital herpes simplex virus infection with the episodes.
  • Some cases of erythema multiforme (EM) are believed to represent an allergic response to recurrent HSV infection. Approximately 15% to nearly all patients with EM, especially individuals with recurrent EM, provide a history of recurrent herpes simplex virus infections before the characteristic skin lesions erupt. Most cases of EM occur 8-14 days after the onset of cold sores, and skin manifestations may last as long as 14-21 days.

Physical

• Neonatal infection
  • Vesicles occur in 90% of children with herpes simplex virus–related SEM disease. Skin vesicles typically develop from an erythematous base and are 1-2 mm in diameter. New lesions form adjacent to old vesicles, coalescing into larger, irregular vesicles or, less commonly, bullae. Because of the viremia associated with the infection, the rash can spread to other cutaneous sites (see Media file 4).
    
    

    

    Vesicular scalp lesions caused by herpes simplex virus (HSV) in a 7-day-old infant.

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    Vesicular scalp lesions caused by herpes simplex virus (HSV) in a 7-day-old infant.

  • Tearing, discharge, and the characteristic dendritic lesions on fluorescein staining of the cornea characterize herpes simplex virus keratoconjunctivitis in the newborn. In the absence of treatment, lesions progress to geographic ulcers. Ocular infection may be the only manifestation of herpes simplex virus infection in the neonate. A localized eye infection associated with microphthalmos and retinal dysplasia suggests an intrauterine infection.
  • Localized infection of the oropharynx is unusual in the newborn. Only 10% of patients have herpes simplex virus isolated from oropharyngeal secretions. Most likely, many children do not undergo extensive evaluation of the oropharynx to detect lesions associated with viral shedding.
  • Long-term neurologic abnormalities may be observed in children whose newborn herpes simplex virus disease appeared localized to the SEM. In these children, severe abnormalities can include quadriplegia, microcephaly, and blindness. However, the incidence of these adverse events has decreased dramatically during the antiviral era. At present, less than 2% of babies with herpes simplex virus–related SEM disease who are treated with acyclovir have developmental delays after they recover.
  • Herpes simplex virus vesicular lesions may recur for months or years in some children infected with skin herpes simplex virus infection as neonates. This pattern is particularly true when the infecting virus is HSV-2 and may occur whether antiviral therapy is administered. In only rare cases are neurologic abnormalities effectively treated in children.
• Orolabial herpes simplex virus infections
  • Primary herpetic gingivostomatitis results in vesicles and ulcers involving the hard and soft palate, gingiva, tongue, and lips. These lesions are initially vesicular, but rupture fairly rapidly leaving 1-mm to 3-mm, shallow, gray-white ulcers on erythematous bases. Fever with a body temperature as high as 104°F and cervical and/or submandibular adenopathy frequently occur. Infectious saliva may result in cutaneous lesions around the mouth and face (see Media file 1).
    
    

    

    Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in Media file 2.

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    Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in Media file 2.

  • Oral intake of fluids in young children may be poor because of severe, localized pain. Signs of dehydration may be evident.
  • Patients with herpes simplex virus pharyngotonsillitis typically present with ulcers and exudates on the posterior pharynx, pillars, or both. Lesions may also be noted on the tongue, buccal mucosa, or gingiva. Fever may last 2-7 days. Cervical adenopathy is common.
• Recurrent orolabial herpetic infection (herpes labialis)
  • A prodrome of pain, burning, tingling, or itching frequently herald recurrent oral herpes simplex virus disease. The prodromal period lasts about 6 hours and is followed by the emergence of painful vesicals 24-48 hours later. Vesicles usually appear on the vermillion border of the lip.
  • Evaluation of the patient over time reveals an orderly progression of cutaneous findings. A few papules persist for 12-36 hours. They develop into vesicles for up to 48 hours, become pustular or ulcerative with formation of crusts within 72-96 hours, and heal over 8-10 days.
  • Adenopathy is uncommon with recurrent disease.
• Primary genital infections
  • Primary genital herpes appears as macules and papules, followed by vesicles, pustules, and ulcers. Fever and localized inguinal adenopathy frequently are noted.
  • Systemic complications occur in both sexes, affecting as many as 70% of patients. Neurologic dysfunction may be detected, with paresthesias and dysesthesias in the perineum or lower extremities.
  • In women, vulvar lesions are frequently bilateral, and the cervix is regularly involved. Vesicles are observed in dry areas. However, in wet areas, the vesicles rapidly break down into ulcers. New lesions can occur during the course of recurrences.
  • The painful and tender lesions are associated with dysuria and may involve the buttocks, perineum, and vagina. Urinary retention with bladder distention may be observed in 10-15% of female patients.
  • As many as 25% of women with genital herpes simplex virus have findings indicative of meningitis.
  • The number of lesions in both sexes is decreased after nonprimary initial genital infection or in an HSV-2 genital infection in an individual with previous immunity to a heterologous virus (HSV-1).
• Recurrent genital infections
  • Vesicles (usually 3-5) superimposed on an erythematous base are the most common manifestations of primary genital herpes simplex virus in the male adolescent or adult. These vesicles usually appear on the glans penis or shaft. Vesicular lesions may also be noted on the thigh, buttocks, or perineal area.
  • Recurrent herpes simplex virus infection in women causes ulcerating vesicle lesions or merely irritation of the vulva.
  • The disease in both sexes lasts about 8-10 days.
  • Herpes simplex virus can be transmitted to sexual partners in the presence or absence of symptoms.
• Herpes simplex virus CNS disease
  • Infection may begin with malaise, irritability, and nonspecific symptoms lasting 1-7 days.
  • Most patients present with a fairly acute onset of fever and focal neurologic signs, frequently seizures (especially temporal-lobe findings).
  • Signs of CNS involvement include dysphasia, personality changes and altered consciousness, ataxia, and autonomic dysfunction. Meningeal signs are uncommon. Symptoms of CNS involvement progress over the next 3-7 days to coma and death.
  • At times, the clinical picture of herpes simplex virus encephalitis may be difficult to differentiate from that of other causes of acute encephalitis.
  • CNS involvement resulting from herpes simplex virus–induced aseptic meningitis must be differentiated from cases of encephalitis. Usually, complications of HSV-2 genital infection, fever, and stiff neck occur shortly after genital lesions are noted. Seizures and focal neurologic deficits are uncommon. Infrequently, herpes simplex virus meningitis may occur in the absence of genital disease.
• Herpes simplex virus in the immunocompromised patient
  • Patients with primary immunodeficiencies, AIDS, malignancy, malnutrition, or burns and transplant recipients (eg, bone marrow, organs) receiving immunosuppressive therapy can have unusually severe herpes simplex virus infections.
  • Severe orolabial infections may begin as typical herpes simplex virus lesions in or around the mouth. Over several days, the papules and vesicles can progress to bullae, frequently with hemorrhagic fluid. These bullae then may evolve into large, chronic, bloody lesions that coalesce and erode into the subcutaneous tissue or deeper.
  • Herpes simplex virus infections in severe burns may convert second-degree burns to third-degree burns.
  • In some patients who are immunocompromised, herpes simplex virus may infect an organ, frequently one contiguous to a body orifice. Herpes simplex virus esophagitis may cause fever in a patient who refuses to eat and who reports retrosternal discomfort and odynophagia.
  • Although uncommon in children who are immunocompromised, herpes simplex virus pneumonitis may cause fever and rales in a patient with worsening respiratory distress.
  • When elevated levels of liver enzymes accompany fever and abdominal pain, herpes simplex virus hepatitis must be included in the differential diagnosis.
  • Disseminated disease is the most severe form of herpes simplex virus infection in patients who are immunocompromised. In a patient with fever and mucocutaneous herpes simplex virus infection, the vesicular rash usually disseminates rather than heals. Large hemorrhagic vesicles and bullae may appear, and evidence of multiple organ dysfunction ensues. Even with antiviral therapy, about 90% of patients die.
• Other herpes simplex virus infections
  • Primary herpes simplex virus infection of the eye may appear as blepharitis, follicular conjunctivitis, or keratoconjunctivitis. Signs may include corneal or conjunctival injection, watery discharge, lid swelling, and preauricular adenopathy.
  • Early corneal infection may involve tiny vesicles at the corneal margin. Eye findings may demonstrate stromal involvement, uveitis, and, in rare cases, retinitis. The last finding manifests as multiple, whitish yellow, punctate retinal lesions.
  • Direct viral damage to the eye or injury due to immunologic responses to the infection results in worsening disease in the eye, with recurrent infection. With recurrences, corneal ulcers extended and deepen. Scarring follows, and sight is impaired.
  • Patients with Mollaret meningitis may have fever, nuchal rigidity, and transitory neurologic findings that accompany meningeal irritation.

Causes

Herpes simplex virus is transmitted through close personal contact.

• Genital herpes simplex virus infection (with mainly HSV-2) can be transferred to a fetus (in rare cases) and result in a congenital herpes simplex virus infection.
• Newborns may acquire infection after exposure to infected secretions in the mother's genital tract.
• HSV-1 is transmitted primarily by contact with infected saliva, whereas HSV-2 is mainly transmitted sexually.
• In susceptible individuals, mucocutaneous infection follows inoculation of the virus into mucosal surfaces (oropharynx, cervix, conjunctiva) or through abraded or cracked skin.

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