It is estimated that 500,000 new cases of genital HSV infection occur annually in the United States and that at least 50 million persons in the U.S. have genital herpes. Overall, 5% to 10% of the population has a history of symptomatic genital HSV-2 infection. A larger percentage of the population has type-specific HSV-2 antibodies (to glycoprotein G) and thus has unequivocal serologic evidence of previous infection with HSV-2. Yet these individuals have never had a recognized symptomatic infection. The overall seroprevalence for HSV-2 infection was 22% and among females was 25%. Seropositivity rates varied by racial and ethnic group. Among white females, the seropositivity rate was 20%. Among Mexican-American females, it was 25%, whereas among black females, it was 55%. HSV-2 seroprevalence also increases with age. For example, among white females, seroprevalence rises from approximately 5% in the teenage years to 20% by age 30 years. In comparison, among black females, seroprevalence rises from about 10% in teenagers to approximately 55% by age 30 years and then to nearly 80% by age 60 years. The overall seroprevalence increased to about 30% (from 16% to 21%) from 1976 to 1980, to 1984 to 1994. Thus, infection is now detectable in about one fifth of adults. On the basis of clinical history, serology, and HSV typing, we now recognize that there are three types of HSV genital infections: primary infection, recurrent infection, and nonprimary first episode, as described in Box 4.1.

Traditionally, it has been taught that primary infection lasts for an average of 20 to 21 days, progressing through vesicular, ulcerative, and crusting stages. These primary infections generally have been thought to be accompanied by fever, malaise, adenopathy, and dysuria. The infections may be complicated by distal site inoculation (whitlow), asymptomatic meningitis, and urinary retention. However, it is now recognized that the vast majority of HSV-2-seropositive adults have no reported episodes clinically diagnosed as genital herpes infection. In addition, based on HSV typing and antibody testing, even most “severe” first episodes are not true primary infections. Further, it has been taught that recurrent infections last 2 to 7 days, with active viral shedding for 1 to 5 days. Recurrent lesions have been thought usually to be preceded by a recognizable prodrome in about 70% of patients and not accompanied by constitutional symptoms. Patients with a history of genital HSV may asymptomatically shed the virus from the genital tract on about 1% of days, and such asymptomatic shedding lasts about 1 to 5 days. Nonprimary first episodes traditionally have been taught to be similar to recurrent episodes clinically. Yet, some “severe” first episodes are actually nonprimary first episodes. Thus, although there are general distinguishing features between true primary and recurrent genital herpes infection, correct classification requires clinical correlation with viral isolation and type-specific serology.

From retrospective databases, less than 10% of individuals seropositive for HSV-2 report a history of clinically evident disease. In a recent prospective study defining the natural history of newly acquired symptomatic and asymptomatic HSV infection in sexually active adults, a larger percentage report symptoms, although these are often not “classic” for genital herpes. Of 155 newly acquired HSV-2 infections, 37% were associated with clinically symptomatic disease. Seventy-five percent of these cases were associated with lesions of the skin and mucosa of the genital tract, but it is noteworthy that presentation was not immediately suggestive of herpes in 13%. In particular, these patients had symptoms suggestive of cystitis, meningitis, urethritis, and cervicitis. In addition, clinical disease subsequently developed in 15% of persons with asymptomatic seroconversion on later follow-up. Overall, this investigation of 2,393 sexually active HSV-2-seronegative persons indicated rates of new HSV-1 and HSV-2 infection of 1.6 and 5.1 cases per 100 person-years, respectively. At the
time of initial presentation of HSV-2 infections, 82% (47/57) of symptomatic cases were correctly diagnosed initially. It also was noted that women were more likely than men to acquire HSV-2 infection (p < 0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of symptomatic seroconversion. Of 19 new HSV-1 cases, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oral HSV-1 infection were the same at 0.5 cases per 100 person-years. Thus, with careful evaluation, nearly 40% of newly acquired HSV-2 infections and nearly two thirds of HSV-1 infections are symptomatic from this prospective study. Among sexually active adults, new genital HSV-1 infections are as common as new orogenital HSV-1 infections.

Some antibody tests available through commercial laboratories still show cross-reactivity between antibodies to HSV-1 and HSV-2 and cannot be used to determine prevalence. However, several commercial glycoprotein G-based enzyme immunoassays have been FDA (Box 4.2) approved and should be the only serologic assays used. The sensitivity and specificity of these tests for HSV-2 are 93% to 99%. Herpes simplex virus may be acquired from an asymptomatic sexual partner. The vast majority (70% to 85%) of individuals with HSV-2 antibodies do not have symptoms.

In surveys of adult females, HSV has been isolated from the genitalia of 0.02% to 4% of women. In high-risk populations, such as women attending a venereal disease clinic, the rate is at the higher end of the range. Among pregnant women, surveys have found positive cultures in 0.01% to 4% of asymptomatic women. Of all patients with positive cultures, those without symptoms have been reported to account for between approximately one and two thirds. Pregnancy probably does not lead to an increase in frequency or severity of genital herpes infections.

Some researchers have reported that maternal infection has adverse effects in early pregnancy, reporting a threefold increase in abortion. Infants with neonatal herpes infections have a high rate of prematurity, but the premature infant may simply be a more susceptible host. Prematurity is not increased in women with recurrent herpes infections. Comparing neonates of 94 mothers who seroconverted to HSV-1 or HSV-2 during pregnancy with those of 6,009 without seroconversion, one group found no observed differences in mean birth weight, gestational age at birth, likelihood of intrauterine growth restriction, stillbirth, or neonatal death. Thus, acquisition of HSV infection during pregnancy usually is devoid of sequelae. The major problem is perinatal neonatal herpes infection. Transplacental infection of the fetus resulting in congenital infection is a rare sequela to maternal infection. Only a few documented cases have been reported. In one report of 13 such cases, the results were devastating, with death in 31% and neurologic sequelae in nearly all survivors.

The important perinatal problem is neonatal herpes infection. Exact estimates of its frequency are subject to error, because up to 50% of infants with culture-proved, fatal disease may not show typical lesions on the skin or mucous membranes. It is estimated that 700 to 1,000 cases of neonatal herpes occur annually in the United States, for an incidence of about 1 in 3,500 to 1 in 5,000.

Neonatal herpes may be acquired perinatally from an infected lower maternal genital tract, most commonly during vaginal delivery. Other cases have occurred in infants delivered by cesarean birth, most often when performed several hours after labor has begun or after the membranes have ruptured. Still other neonates may acquire the virus nosocomially.

As noted earlier, the clinical manifestations of genital HSV occur as three distinct syndromes. The limitations of clinical diagnosis alone have been noted. In general, true primary HSV is associated with more marked local symptoms, for example, multiple painful lesions progress from vesicles to an ulcerative state, inguinal adenopathy, and systemic effects, such as fever, malaise, myalgias, headaches, and nausea. In immunocompetent adults, the disease usually is self-limited. However, a small percentage of those with primary genital herpes will have disseminated disease including pneumonitis, hepatitis, or encephalitis. First-episode nonprimary genital herpes usually is similar to recurrent genital herpes, but it may be variable. Recurrent disease occurs more frequently after primary HSV-2 infection than after HSV-1. The appearance of typical lesions is preceded by local prodromal symptoms of paresthesias, itching, or pain. The prodrome usually lasts about 2 days. Often, mild local symptoms occur and last about half as long as those of primary
first-episode HSV infection. Usually a few lesions occur, and systemic manifestations are absent. In addition, the duration of viral shedding is shorter (usually 3 to 5 days), and the likelihood of concomitant cervical HSV shedding is less than with primary disease. Nevertheless, recurrent episodes (as confirmed by viral isolation of type-specific antibody testing) may present with severe symptomatology. Clinically detectable recurrences occur variably, but about 50% of patients will have recurrent disease within 6 months. Further, the likelihood of recurrence depends on the serotype of HSV. Recurrences are milder, with fewer lesions, fewer constitutional symptoms, and a shorter course (usually 7 to 10 days). Within 12 months of a first episode, 80% of patients with HSV-2 infection had a recurrence (mean 4), whereas 55% with HSV-1 infection had a recurrence (mean, <1).

Until recently, the best diagnostic test to confirm the presence of herpesvirus infection was viral culture. For clinical use, it is fortunate that this virus grows rapidly; most positive cultures are identifiable at 48 to 72 hours. This virus is hearty and can be transported on ice, when necessary. Overall, for a single herpes culture, there is a recognized false-negative rate of perhaps 5% to 30%. Several clinical features influence the likelihood of a positive culture. For example, cultures are more likely to be positive in first episodes than in recurrent episodes. In patients with suspected recurrent genital herpes, the likelihood of a positive viral culture was higher in patients with vesicles or pustules than in patients with ulcerative and crusted lesions. Further, positive cultures were more likely early in the course of a lesion (within 72 hours) than later.

Some women (about 10%) with culture-confirmed HSV infection present with atypical lesions, such as fissures, furuncles, excoriations, or nonspecific vulvar erythema.

Although HSV infection may be suggested by rather typical changes seen in Papanicolaou smear (intranuclear inclusions and multinucleated giant cells), the sensitivity of this test is inadequate, at about 50%.

The monoclonal antibody and enzyme-linked immunosorbent assay tests have modest sensitivity.

The laboratory diagnosis of HSV infections has been revolutionized by advances in molecular biology and serologic techniques. PCR is a 3- to 5-times more sensitive diagnostic technique than viral culture and may replace culture as the primary means of virus detection. However, the PCR tests are currently not FDA approved, and there are no interlaboratory standards.

Neonatal herpes infection may be limited to the skin or may have systemic involvement either with or without cutaneous involvement. Typically, clinical disease begins at the end of the first week of life or later. Because findings depend on the organ system involved, the presentation may include skin lesions, cough, cyanosis, tachypnea, dyspnea, jaundice, seizures, or disseminated intravascular coagulopathy.