Excerpt from Herpes Simplex Virus Infection

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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 a variety of 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 HSV infection in older adolescents and adults is a major public health problem, having markedly increased in prevalence in the last 3 decades. This increased prevalence of genital HSV infections poses major threats to newborns because most infections in neonates are acquired perinatally. Neonatal HSV infection is a disease with high morbidity and mortality rates.

Laboratory methods used to diagnose HSV 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 HSV infections.

HSV 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

HSVs 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 HSV 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 HSV 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 HSV can be reactivated from the trigeminal, sacral, and vagal ganglia.

Frequency

United States

Although the range of susceptible hosts for HSV infections is wide, humans are the primary hosts for infection. The epidemiology of HSV 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 HSV 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-2.¹  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.²

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

Genital HSV infection in pregnant women is common; 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 HSV during pregnancy. In pregnant women, the prevalence of HSV 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 HSV seroprevalence in a group of pregnant women (n=626).³ 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 HSV types was 13%. HSV seronegativity was noted in 28%. The prevalence of HSV antibodies differed by race and ethnicity, with nonHispanic 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 HSV 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 HSV 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

HSV 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 HSV 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 HSV are discussed in Complications. Mortality associated with HSV is primarily related to perinatal infection, encephalitis, and infection in individuals who are immunocompromised.

• At the time of vaginal delivery, the risk of HSV transmission from a mother with true primary HSV 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 non-primary) have a transmission risk of 25-30%. The neonatal HSV-infection rate is considered to be less than 2% when the mother has active infection caused by the shedding of HSV 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 HSV infection, 60-80% have no evidence of genital HSV 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 HSV disease is estimated to occur in approximately 1 per 3000 deliveries.

Race

Although the risk of HSV 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 the age of 5 years, more than 35% of African American children are infected with HSV-1 versus 18% of white children. Through adolescence, the prevalence of antibodies to HSV-1 in African Americans is approximately twice the rate among whites. By age 40 years, HSV-1 seroprevalence is similar among African Americans and whites.
• The prevalence of HSV-2 antibodies among African Americans 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 African Americans and 20% for whites. By the late 1980s, rates of infection had increased to approximately 60% for African Americans 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 African American women, and 60% in African American men.
• Studies have indicated that the seroprevalence of HSV-2 antibodies among Hispanics ranges from 17-22.3%.
• Infants born to nonHispanic-white women may be at higher risk of HSV infections.  This is a result of a greater likelihood that these women are HSV-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 African American women. This compares with rates of 20% in white men and 60% in African American men.
• See also the Race section above.

Age

Beyond the neonatal period, most childhood HSV 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.

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