Herpes simplex viruses (HSVs) are ubiquitous organisms that produce orolabial and genital infections. Infection with HSV has become the No. 1 topic on the National Sexually Transmitted Disease Hotline and the second greatest concern to sexually active people (next to AIDS). In a survey assessing perceived trauma from various events, respondents considered contracting herpes as worse than breaking up with a significant other, getting fired from one’s job, or failing a course in school. Indeed, a wide disparity exists between the public and medical community regarding the significance of herpes infections. HSV infections continue to be a major public-health problem, with prevalence escalating worldwide. Seropositivity to HSV-2 in America has increased by more than 30% in the past two decades, and up to 1 million patients acquire primary genital HSV annually.

The herpes simplex virus is classified into type 1 (HSV-1, herpes labialis) and type 2 (HSV-2, herpes genitalis). Infections caused by these viruses are further divided into primary and secondary (often referred to as recurrent) infections. HSV infections vary greatly in presentation, with asymptomatic infection being the rule rather than the exception. Primary infections can range from subclinical to severe, with fever, headache, malaise, anorexia, pain, lymphadenopathy, and edema. Secondary infections are usually milder. The term herpetiform denotes numerous small vesicles on an erythematous base.

HSV infections are spread by direct mucocutaneous contact. Orofacial HSV infections affect 15%-30% of the population, with clinical lesions that recur, on average, three to four times a year. Genital HSV is the most common sexually transmitted infection (STI) in both men and women. The incubation period is three days to two weeks after exposure. The average clinical recurrence is three or four times a year, although some patients have monthly outbreaks.

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Herpes is a chronic infection

HSV infection is not a recurrent disease with latent periods between clinical outbreaks. Herpes is a persistent and chronic infection of the sensory ganglia with a varying, unpredictable degree of skin expression. Viral replication occurs in the ganglia, and fluctuating titers of antibodies to HSV have been recorded during the latent period, when no clinical disease is apparent. There is a dynamic interaction between the host and the virus. Viral titers correlate somewhat with severity of infection. Recurrences can vary clinically from severe-to-mild to merely a sensory prodrome or to asymptomatic. It is inaccurate to regard all recurrences as equivalent; this is important when considering treatment and prophylaxis.

Chronic and/or severe HSV infections can also be seen in immunocompromised patients, including transplant recipients, HIV-positive individuals, and those with lymphoma, leukemia, and renal failure. The most common presentation in this category is chronic enlarging ulcerations, lesions at multiple sites, and/or cutaneous dissemination. Individual lesions, which are sometimes atypical, can be verrucous, exophytic, pustular, and/or ulcerative in nature.

Are serologic tests overrated?

Multiple laboratory tests are available to diagnose HSV infections. Molecular techniques are now the gold standard, but viral culture, direct immunofluorescence, transmission electron microscopy, and serology are also performed.1 Although serologic results are often presented as being of major importance, this form of testing has substantial deficiencies and needs to be specifically addressed.

Both the FDA and CDC prefer tests that detect viral glycoprotein-G specific for HSV-1 (gG1) and HSV-2 (gG2). The glycoproteins are located on the viral surfaces and on the surfaces of virus-infected cells. There are at least four type-specific serologic assays based on these glycoproteins, including glycoprotein G-based type-specific herpes tests, type-specific blood tests, HerpeSelect HSV-1 and HSV-2 enzyme-linked immunoabsorbent assays, and HerpeSelect immunoblot. (For more information on HerpeSelect tests, see www.herpeselect.com.)

The POCkit HSV-2 test was designed to rapidly detect HSV-2 antibodies. Finger-prick results can be obtained in-office within six minutes. However, because this test detects only HSV-2, a large percentage of genital herpes caused by HSV-1 (25%) are not diagnosed. In addition, 30% of neonatal herpes is caused by infection with HSV-1, which also limits the value of the POCkit HSV-2.

The seropositivity rate for HSV-2 varies with the population studied. Four percent of fourth-year college students are seropositive for antibodies. In patients presenting to STI clinics, prevalence ranges from 30%-50%. In other studies, 75% of prostitutes and HIV-positive homosexual men have HSV-2 antibodies.2-4 The presence of HSV-2 antibodies directly correlates with female gender, older age, and risk factors that are commonly associated with other STIs, such as prostitution, male homosexuality, multiple sexual partners, and substance abuse. Approximately one in five Americans are serologically proven to be infected with HSV-2.

Serologic testing, however, has numerous problems. First, the tests have limited value in acute clinical diagnosis because of the time delay for seroconversion following initial infection. Of patients who develop seropositivity, 65% do so within six weeks, while approximately 20% do not make antibodies for six months. Additionally, some patients infected with the virus never serologically convert. 

Second, negative serology does not rule out the presence of herpes. Indeed, human exposure to HSV-1 is universal, and HSV-2 exposure appears to be more common than generally accepted. The frequency of positive HSV-2 serology in patients in Costa Rica is 86%,5 while in one American study, polymerase chain reaction (PCR) detected the virus in 50% of semen specimens.2 In short, people display varied immunologic responses to HSV. For example, seropositive patients have been shown to shed the HSV-2 virus on 28% of days tested, yet there are numerous heterosexual couples with discordant HSV serologic pictures. Obviously, the susceptible partner has contracted the virus but does not react serologically. Whether the susceptible partner eventually converts to positive serology after numerous exposures seems minimally significant. This is similar to herpes zoster, in which only 61% of infected individuals ever become serologically positive despite PCR proof of disease. Indeed, serologic tests for infectious diseases rarely approach total diagnostic accuracy.