Version May 2024
INTRODUCTION — Genital herpes simplex virus (HSV) infections are a major global public health problem:
●A dramatic upsurge in genital HSV infections has been documented from seroprevalence studies.
●There is a wide diversity of the clinical spectrum of genital HSV disease.
●Like all herpes virus strains, HSV establishes a latent state followed by viral reactivation and recurrent local disease.
●Perinatal transmission of HSV can lead to significant fetal morbidity and mortality.
●A link has been established between HSV-related genital ulcer disease and sexual transmission of HIV.
The epidemiology, varied clinical manifestations, and diagnosis of genital HSV infection will be reviewed here. The treatment of this disorder and issues related to genital herpes in pregnancy are discussed separately. (See "Treatment of genital herpes simplex virus infection" and "Prevention of genital herpes virus infections" and "Genital herpes simplex virus infection and pregnancy".)
EPIDEMIOLOGY — Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are common infections worldwide. Both HSV-1 and HSV-2 can cause genital herpes, and infection of the same anatomic site by both HSV-1 and HSV-2 has been documented [1]. However, genital HSV is frequently under-recognized because infection is often subclinical [2-4].
Most cases of recurrent genital herpes are caused by HSV-2 [5,6]. From 2005 to 2010, the seroprevalence of HSV-2 in the United States was approximately 16 percent among patients aged 14 to 49 [7]. In one study that evaluated 7293 patients in this age group, the seroprevalence increased with age and number of sexual partners, and was greater among women compared with men (21 versus 12 percent) [8]. HSV-2 seroprevalence was also three times greater among non-Hispanic Black patients (39 percent) than among non-Hispanic White patients (12 percent). Similar risk factors for HSV-2 positivity have been noted in other surveys [3,9-13]. Prior HSV-1 infection does not appear to affect the rate of HSV-2 acquisition [14].
However, HSV-1 has been associated with an increasing proportion of cases of genital herpes infection, especially among young women and men who have sex with men [3,5,15-17]. As examples:
●Over a two-year follow-up of 1427 HIV-seronegative MSM in Australia, incidence rates for HSV-1 and HSV-2 infection were 5.9 and 1.5 cases per 100 person-years, respectively [17]. In a multivariate analysis, incident infection with HSV-1 was significantly associated with younger age and reports of insertive oral sex with casual partners.
●In a retrospective analysis of genital herpes isolates from a university student health service in the United States, HSV-1 was more commonly isolated in women than men, and the proportion of newly diagnosed HSV-1 genital infection had increased from 31 percent in 1993 to 78 percent in 2001 [16].
●Among 3438 HSV-seronegative women between the ages of 18 and 30 in the United States and Canada who were enrolled in the control arm of a herpes vaccine study and who were followed prospectively between 2003 and 2007, 183 became infected with HSV: 127 (3.7 percent) with HSV-1 and 56 (1.6 percent) with HSV-2 [3]. The rate of infection for HSV-1 was more than twice the rate for HSV-2 (2.5 versus 1.1 per 100 person-years, respectively). HSV-1 was more common than HSV-2 as a cause of genital mucosal infections.
It is estimated that the majority of genital herpes infections are transmitted by persons unaware that they have the infection, or are asymptomatic when transmission occurs [6]. As an example, in a population-based cross-sectional survey of adults living in New York City, nearly 28 percent were infected with HSV-2 and 88 percent had no prior knowledge of their diagnosis [4]. In addition, prior HSV-1 infection increases the likelihood of asymptomatic HSV-2 infection by threefold [14].
TYPES OF INFECTION — The clinical designations of genital herpes simplex virus (HSV) infection are: primary, nonprimary first episode, and recurrent (table 1):
Primary — Primary infection refers to infection in a patient without preexisting antibodies to either herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2).
Nonprimary — Nonprimary first episode infection refers to the acquisition of genital HSV-1 in a patient with preexisting antibodies to HSV-2 or the acquisition of genital HSV-2 in a patient with preexisting antibodies to HSV-1 (eg, an individual with prior orolabial herpes and subsequent development of an HSV-1 antibody response develops genital herpes due to HSV-2 exposure).
Recurrent — Recurrent infection refers to reactivation of genital HSV in which the HSV type recovered in the lesion is the same type as antibodies in the serum.
Each of these types can be either symptomatic or asymptomatic (also called subclinical). Asymptomatic infection will be detected only if the patient is tested by culture or polymerase chain reaction (PCR).
TRANSMISSION — Transmission of herpes simplex virus (HSV) may occur quickly in new sexual relationships. In a prospective study of 199 patients with newly acquired HSV genital infection, the median duration of the sexual relationship was 3.5 months (range 1.5 to 10 months) and the median number of sex acts before transmission was 40 [18]. Condom use was infrequent (50 percent during first intercourse; 20 percent during last intercourse before diagnosis). The median time to infection was greater in participants whose partners informed them that they had genital herpes than in those whose partners did not (270 versus 60 days).
Transmission may also occur during periods of subclinical viral shedding (eg, when symptoms are absent). (See 'Viral shedding' below.)
CLINICAL FEATURES — The clinical manifestations of genital herpes simplex virus (HSV) vary widely depending upon whether the infection is primary, nonprimary or recurrent.
Primary infection — The average incubation period for developing genital herpes after an exposure is four days (range 2 to 12 days) [19]. The clinical manifestations of primary genital HSV infection are highly variable [19,20]. The initial presentation can be severe with painful genital ulcers, dysuria, fever, tender local inguinal lymphadenopathy (picture 1A-B), and headache. In other patients, however, the infection is mild, subclinical, or entirely asymptomatic [12,20]. There are no clear differences in clinical presentation based on infecting virus (ie, HSV-1 versus HSV-2) [3].
The characteristic skin lesions of HSV infection begin as grouped 2 to 4 mm vesicles with associated underlying erythema that progress to vesicopustules, erosions, and ulcerations. Vesicles and pustules may exhibit a central depression, referred to as an "umbilicated" appearance. Erosions and ulcerations often have scalloped borders.
In one review, patients with primary infections usually had multiple, bilateral, ulcerating, pustular lesions which resolved after a mean of 19 days [20]. Symptoms tended to be more severe in women than in men. Other symptoms and signs in these first episode infections included:
●Systemic symptoms, including fever, headache, malaise, and myalgias (67 percent)
●Local pain and itching (98 percent)
●Dysuria (63 percent)
●Tender lymphadenopathy (80 percent)
The clinician should differentiate dysuria from acute urinary retention, which can occur during severe primary HSV infection. Dysuria can lead to reluctance to void because of the passage of acidic urine on open and inflamed vesicles; this is best managed with Sitz baths. However, acute urinary retention with loss of sacral sensation can occur due to lumbosacral radiculomyelitis secondary to severe primary HSV infection. (See 'Sacral radiculitis' below.)
Primary genital herpes is commonly associated with viremia; of 164 adults with confirmed primary genital HSV infection, 40 (24 percent) had HSV DNA detected in plasma [21]. In one study, virus was isolated most commonly from the urethra and cervix of women with first episode infection (82 and 88 percent, respectively) [20]. Viral isolation was less frequent from the urethra in men (28 percent) and the pharynx in either women or men (13 and 7 percent, respectively).
Nonprimary infection — Nonprimary first episode infection is associated with fewer lesions and less systemic symptoms than primary infection, presumably because antibodies against one HSV type offer some protection against the other [19,20]. In one study, prior HSV-1 infection increased the likelihood of asymptomatic infection three-fold [14].
Recurrent infection — Clinical recurrences of genital HSV are common, but are typically less severe than primary or nonprimary infections (picture 2A-D). The mean duration of lesions is generally shorter with recurrences than in primary infection (10 versus 19 days) and the duration of viral shedding is usually two to five days [12,20,22].
In one study that included a subset of 362 patients with recurrent infection, lesions were described as unilateral small vesicular or ulcerative lesions [20]. Atypical vaginal lesions include fissures or vulvar irritation. Systemic symptoms are infrequent and approximately 25 percent of recurrent episodes are completely asymptomatic [20]. As many as 50 percent of patients with symptomatic recurrences have prodromal symptoms before eruption such as local mild tingling or shooting pains in the buttocks, legs, and hips [19].
Factors that contribute to decreased recurrences include infection with HSV-1 compared to HSV-2 and the duration and severity of the primary infection [12]. Treatment with acyclovir does not influence recurrence rates [2].
EXTRAGENITAL COMPLICATIONS — Extragenital manifestations (eg, radiculitis, aseptic meningitis, urinary retention) typically occur during the primary episode of herpes simplex virus (HSV) infection, but they can recur with subsequent episodes.
Neurologic — Extragenital complications occur in a minority of patients who present with primary herpes simplex virus (HSV) infection. In one study, extragenital complications included aseptic meningitis (8 percent) and urinary bladder retention due to sacral autonomic nervous system dysfunction (2 percent), [20]. Other series have noted higher rates of aseptic meningitis (25 percent) and urinary retention syndromes (10 to 15 percent) in women with primary infection [12].
Meningitis — In patients with HSV meningitis, the cerebrospinal fluid (CSF) profile includes a pleocytosis (median white cell count 300 to 400/mm3) with a predominance of lymphocytes, and a normal CSF glucose concentration, although hypoglycorrhachia has been reported [20]. HSV has been isolated from 0.5 to 3 percent of CSF samples from patients with aseptic meningitis. (See "Aseptic meningitis in adults".)
HSV-2 can also cause recurrent episodes of meningitis, called Mollaret's meningitis. Most patients do not have evidence of genital lesions at the time of presentation. (See "Aseptic meningitis in adults".)
Sacral radiculitis — Acute urinary retention with loss of sacral sensation can occur due to lumbosacral radiculitis secondary to severe primary HSV infection [23]. This complication is transient but usually requires catheterization until clinical improvement ensues. In a series of 30 patients who developed acute lumbosacral radiculitis featuring cauda equina syndrome with myelitis (referred to as Elsberg syndrome), urinary retention was present in 77 percent, and half had lower extremity weakness [24]. Neurologic manifestations in immunocompromised patients are discussed below. (See 'Immunosuppressed patients' below.)
Proctitis — HSV can also cause proctitis, particularly in men who have sex with men (MSM). The differential diagnosis of proctitis in MSM includes N. gonorrhoeae, herpes simplex virus, and Treponema pallidum infections. The frequency of these causes was evaluated in a review of 101 episodes of proctitis among MSM in San Francisco; anoscopy was performed and specimens obtained that were tested for the above organisms [25]. The following etiologies were noted in 55 percent of cases with a confirmed diagnosis:
●Gonorrhea (20 percent)
●Herpes simplex (13 percent)
●Chlamydia (11 percent)
●Mixed infections (10 percent, including 3 percent with herpes)
●Syphilis (1 percent)
FREQUENCY OF RECURRENCES — Patients with primary genital herpes simplex virus (HSV) need to be counseled that recurrence is expected. The frequency of recurrence depends on the severity and duration of the initial episode, the infecting serotype, and the host.
In one series of 457 patients with HSV-2 primary infection, 89 percent had one recurrence during a follow-up of 391 days [2]. Furthermore, 38 percent of patients had as many as six recurrences and 20 percent had more than ten. Patients with primary infection lasting for five or more weeks experienced recurrences earlier and almost twice as often compared to those with a shorter duration of the initial infection.
Recurrent infection is more common with HSV-2 than HSV-1 [22,26]. The magnitude of this effect was evaluated in a prospective study of 137 patients with a first symptomatic episode of genital herpes [26]. The likelihood of recurrence was much higher with HSV-2 infections (60 versus 14 percent with HSV-1). As a result, the proportion of episodes due to HSV-1 fell from 15 percent in primary first episodes to 2 percent in recurrent episodes.
Recurrences are also more common in immunosuppressed patients. (See 'Immunosuppressed patients' below.)
VIRAL SHEDDING — After resolution of the primary genital herpes simplex virus (HSV) infection, asymptomatic intermittent viral shedding occurs in both men and women, even in the absence of genital lesions [13,27-30]. A prospective study of 498 immunocompetent HSV-2-seropositive persons demonstrated that HSV was shed more frequently in the 410 symptomatic persons compared with the 88 asymptomatic persons (20 percent versus 10 percent of days), although the quantities of virus were similar between the two groups [30]. HSV genital shedding can also occur during a clinical outbreak primarily affecting the buttock region, which may reflect reactivation from sacral neural ganglia [31]. Subclinical HSV shedding is important since infection can be transmitted unknowingly to susceptible sexual partners and neonates. (See 'Sex partners' below and "Genital herpes simplex virus infection and pregnancy".)
The frequency of shedding is influenced by the infecting serotype, whether the infection is primary or nonprimary and the duration of time since the first clinical episode.
●Primary genital HSV-2 infections have been linked to more frequent and prolonged asymptomatic viral shedding from the genitourinary tract compared to HSV-1 infections [15,22,26].
●In one study of 110 women with a median follow-up period of 105 days, viral shedding occurred on a mean of two percent of days, most often within seven days of a symptomatic recurrence, and was more likely to occur in patients with HSV-2 or mixed HSV-1 and HSV-2 infections compared to HSV-1 alone (55 and 52 versus 29 percent of patients) [22].
●A lower frequency of subclinical infection was noted in a cohort study of 306 women with a first episode of genital HSV infection [32]. Asymptomatic viral shedding was detected among 18, 23, and 12 percent of women with primary HSV-2, nonprimary HSV-2, and primary HSV-1 genital infections, respectively. Asymptomatic cervical viral shedding was three times more frequent during the first three months following resolution of primary HSV-2 disease than at later time points and was consistently more common in patients with HSV-2 compared to HSV-1 genital infections.
●Time since the first genital HSV episode was significantly associated with reduced genital shedding in a study of 377 adults who self-collected anogenital swabs for HSV-2 DNA for a minimum of 30 consecutive days [33]. The frequency of subclinical HSV shedding occurred in 26 percent of days among patients infected less than one year to 9 percent of days among those infected for more than 10 years. Although the frequency of subclinical shedding decreased, the quantity of virus remained stable over time, which may be associated with continued risk for transmission.
SEX PARTNERS — Several studies have evaluated the risk of sexual transmission of genital herpes from index patients with recurrent herpes simplex virus (HSV) genital disease to susceptible partners [34,35]. In one report, 144 heterosexual couples, in which the source partner had symptomatic recurrent genital HSV, were evaluated over a median of 334 days for development of culture-confirmed HSV infection or type-specific antibodies in the susceptible partner [34]. The following findings were noted:
●Transmission of genital HSV was documented in 14 couples (10 percent); the risk was greater with male than with female source partners (17 versus 4 percent).
●In susceptible women who lacked HSV-1 and HSV-2 antibodies at entry, the rate of acquiring genital herpes infections was higher than in women with preexisting HSV-1 antibodies (32 versus 9 percent)
●In 70 percent of patients, transmission of genital herpes was linked to sexual contact during periods of asymptomatic viral shedding. (See 'Viral shedding' above.)
A second smaller study supported these findings of a greater risk of HSV acquisition with male source partners [35]. However, studies have demonstrated discordant findings regarding the risk of acquiring HSV-2 in patients with prior HSV-1 infection [35,36].
A more detailed discussion of how to prevent transmission of HSV to sex partners is found elsewhere. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)
IMMUNOSUPPRESSED PATIENTS — Most genital herpes simplex virus (HSV) infections occurring in immunosuppressed adults reflect reactivation syndromes. The clinical presentation of symptomatic episodes may include extensive mucocutaneous involvement, variable appearance of genital lesions, and the development of chronic and recurrent ulcers (picture 3A-B). Recurrences are often more frequent, more extensive, and of longer duration than in immunocompetent patients [37,38]. In addition, immunosuppressed patients may have prolonged viral shedding.
A prospective trial evaluated 217 HIV-infected women who underwent twice yearly pelvic examination, including cultures of cervicovaginal specimens and swab specimens from genital lesions, if lesions were present [39]. The following findings were noted:
●One-third had genital HSV-2 infection based upon history alone or positive culture results.
●Among these women, an HSV-2 culture was positive in one-third of visits; a positive culture was not associated with an apparent genital lesion approximately one-third of the time.
●Positive cultures occurred more frequently in patients with lower CD4 cell counts and higher plasma HIV-1 RNA levels. However, in one study, even optimum CD4 gains and viral suppression with ART did not eliminate the risk of significantly more genital lesions in HIV-infected women compared to controls [40].
In addition to genital symptoms, neurologic complications occasionally develop and rapidly evolve in the setting of genital and mucocutaneous HSV infection occurring in transplant recipients and in HIV-infected patients with advanced disease. These complications include aseptic meningitis, sacral radiculopathy, and transverse myelitis [41-43].
PREGNANCY — Genital herpes simplex virus (HSV) infection is of particular concern in pregnant women because of the risk of transmission to the infant during delivery. This issue is discussed elsewhere. (See "Genital herpes simplex virus infection and pregnancy".)
HSV-2 AND RISK OF HIV TRANSMISSION — Herpes simplex virus type 2 (HSV-2) genital ulcer disease has been definitively linked to an increased risk for acquisition of HIV-1 infection in regions with high seroprevalence rates of HSV-2 infection [44-54].
Epidemiology — A 2002 meta-analysis of 31 studies was undertaken to assess the risk of acquiring HIV infection in HSV-2 seropositive individuals [47]. Depending upon the type of study, the risk estimate in HSV-2 seropositive individuals varied from 2.1 (95% CI 1.4-3.2) to 3.9 (95% CI 3.1-5.1). However, the temporal sequence of the two infections could not be determined.
In a subsequent meta-analysis, 18 longitudinal studies were selected in which the relative timing of HSV-2 and HIV infections could be determined [55]. This study demonstrated that prevalent HSV-2 infection was associated with a three-fold increased risk of HIV acquisition among both men and women in the general population. Modeling studies also demonstrate that HSV-2 epidemics could theoretically double the peak HIV incidence and create a "core group" of HIV transmitters in areas where HSV is highly prevalent [51].
Subsequent studies have underscored the relative importance of recent HSV infection, as compared to remote HSV infection, as a risk factor for HIV acquisition [46,52,56]. In a pivotal seroepidemiologic study conducted in India, a cohort of 2732 HIV-seronegative patients (17 percent female) followed at sexually transmitted disease (STD) and reproductive tract clinics underwent HSV-2 antibody screening at baseline and were prospectively followed to assess for seroconversion to HIV-1 and HSV-2 [46]. The prevalence of HSV-2 at the time of enrollment was 43 percent, almost one-half of whom reported no history of genital ulcer disease. The following findings were noted during follow-up:
●The incidence of HSV-2 and HIV infection was 11.4 cases and 5.8 cases/100 person-years, respectively.
●The risk of acquiring HIV infection in this cohort was 3.6 percent for HSV-2 seronegative individuals at baseline, 7.5 percent for individuals with positive HSV-2 serology at baseline, and 22.6 percent for individuals with confirmed recent HSV-2 seroconversion within the past 6 months. The adjusted hazard ratios for HIV infection were 1.67 for HSV-2 infection at study entry, 1.92 for remote incident HSV-2 infection, and 3.81 for recent incident HSV-2 infection.
This association between HIV acquisition and HSV infection, particularly recent HSV infection, was confirmed in a nested case-control study in Tanzanian patients attending STD clinics [52].
These findings underscore the need for effective HSV-2 interventions when implementing infection control strategies designed to limit HIV transmission. Clinical trials evaluating the impact of antiviral treatment of HSV-2 infected individuals with acyclovir or valacyclovir on the incidence of HIV sexual transmission may provide pivotal information about how to implement interventional therapies on a global scale [51,53,57]. There is also promising data on the use of an intravaginal gel that has antiviral activity against both HIV and HSV [58].
Mechanisms — At least three mechanisms may be important for the increase in HIV-1 transmission associated with sexual activity in patients with HSV-2 infection:
●Symptomatic HSV-2 genital ulcers frequently cause local inflammation and mucosal disruption in the genital tract, which can facilitate HIV-1 entry during exposure to HIV-infected genital fluids [27].
●Genital HSV-2 ulcers selectively increase local recruitment of CD4 positive cells, which may serve as targets for HIV-1 attachment in mucosal tissue [59,60].
●Replication competent virus has been isolated in HSV-2 lesions [44].
DIFFERENTIAL DIAGNOSIS — Among patients with genital herpes who present with a genital ulcer, the primary differential diagnosis includes syphilis and chancroid among infectious causes, and drug eruptions and Behçet’s syndrome among noninfectious causes. (See "Approach to the patient with genital ulcers".)
A diagnosis based upon history and physical examination alone is often inaccurate. Therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing. Nonetheless, some findings are more common in certain infections [61].
●The classic presentation of genital herpes is with multiple, shallow, tender ulcers that may be vesicular; in addition, only herpes simplex virus (HSV) is associated with recurrent disease.
●The classic genital presentation of primary syphilis is with a painless, indurated, clean-based ulcer, called a chancre.
●The classic genital presentation of chancroid is with a deep, undermined, purulent ulcer that may be associated with painful inguinal lymphadenitis. (See "Chancroid".)
DIAGNOSIS — A clinical diagnosis of genital herpes should be confirmed with laboratory testing [62]. The classical presentation with multiple vesicles on an erythematous base is often absent in many patients. Thus, it is important to confirm the diagnosis of herpes simplex virus (HSV) infection with either of the following techniques: viral culture, polymerase chain reaction (PCR), direct fluorescence antibody, and type-specific serologic tests. The choice of test varies with the clinical presentation [62]. PCR-based testing and cell culture are the preferred tests for a patient presenting with active lesions, although PCR-based testing has the greatest overall sensitivity and specificity.
Virologic tests
Polymerase chain reaction — While viral culture has remained the standard diagnostic method for isolating HSV, real-time HSV PCR assays have emerged as a more sensitive method to confirm HSV infection in clinical specimens obtained from genital ulcers and mucocutaneous sites; PCR is the test of choice for cerebrospinal fluid [6,63-66]. (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis".)
The enhanced sensitivity of HSV PCR compared to viral culture can be illustrated by the following observations from different studies:
●HSV DNA levels with PCR testing were 250 times higher from culture-positive compared to culture-negative samples [67].
●Among women with recurrent genital herpes who underwent daily sampling of genital lesions, HSV DNA was detected in ulcerative lesions on 15 of 17 days compared to only 3 of 17 days by viral isolation [68].
●A randomized trial compared valacyclovir, acyclovir, and placebo for suppression of HSV shedding in the genital tract [69]. During the placebo period, both the lesional HSV shedding rate (87 versus 47 percent of days) and the asymptomatic shedding rate (27 versus 7 percent of days) were significantly higher with PCR than with culture. The higher sensitivity of PCR compared to culture was also confirmed in the treatment phase of the study.
Earlier diagnosis by real-time HSV PCR assays may also reduce the transmission of infection during reactivation syndromes that are manifested only by asymptomatic viral shedding [67,70,71]. In clinical studies, PCR testing has been used to evaluate the risk of transmission in discordant couples and the effectiveness of suppression with antiviral therapy [68,69]. (See "Treatment of genital herpes simplex virus infection".)
Further development of this assay now allows differentiation of HSV-1 and HSV-2 using real-time TaqMan PCR techniques [72]. A limiting factor in adopting real-time HSV PCR as the primary diagnostic tool in many clinical reference laboratories is the cost of the assay, which substantially exceeds that of viral culture.
Viral culture — If active genital lesions are present, the vesicle should be unroofed for sampling of vesicular fluid for culture. However, the overall sensitivity of viral culture of genital lesions is only approximately 50 percent [70,73]. The diagnostic yield of culture is highest in the early stages of disease, when lesions are typically vesicular, and declines rapidly as the lesions begin to heal [71]. Viral isolation rates are also higher with primary compared to recurrent genital herpes, particularly in the setting of asymptomatic recurrences with subclinical shedding.
Specimens for culture should be directly placed in viral culture media and rapidly transported to the laboratory. Viral isolates usually grow in tissue culture by five days and are typed by antibody staining.
Direct fluorescent antibody — Many diagnostic laboratories provide a rapid type-specific direct fluorescent antibody (DFA) test to detect HSV in clinical specimens. This test is specific and reproducible.
Serologic testing — Several FDA-approved type-specific HSV serologic tests are commercially available to clinicians evaluating genital ulcer disease in adults [74-76]. Type-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely [6]. Most serologic tests are laboratory-based glycoprotein G type-specific tests, although rapid tests are also available and can be completed in 15 minutes at the point of care [77]. The availability of type-specific serology using surface glycoproteins (gG2 and gG1 for HSV-2 and HSV-1, respectively) to distinguish HSV-1 and HSV-2 enables the clinician to determine if the patient is at risk of acquisition or has evidence of prior infection with either subtype [28,78].
●When to consider serologic testing – In patients with genital ulcer disease, serologic testing can be used to support the diagnosis of HSV infection in certain settings [6,74,75]. These include:
•A patient with a history of genital lesions who did not have a diagnostic workup or had a negative HSV culture or PCR.
•A patient with an atypical presentation. In some patients (eg, those with atypical vaginal/genital burning pain, dysesthesias), the use of PCR testing in addition to serology may be helpful. (See 'Polymerase chain reaction' above.)
HSV IgM testing is not type specific and is generally not recommended since is not useful for differentiating oral versus genital infection or discriminating primary versus recurrent episodes of HSV infection.
The use of serologic testing for screening asymptomatic patients (eg, during pregnancy, determining susceptibility of a sexual partner of a patient with documented genital HSV infection) is discussed below. (See 'Screening' below.)
●Interpretation – Positive serologic testing for HSV-2 typically indicates anogenital infection, whereas positive serologic testing for HSV-1 can be consistent with either anogenital or orolabial infection. However, since genital ulcers have many possible etiologies, a positive HSV IgG antibody alone cannot be used to confirm a diagnosis of HSV. Confirmation of HSV in a patient with an active genital ulcer requires further diagnostic evaluation, such as PCR or culture. (See 'Virologic tests' above.)
In addition, there are several limitations to serologic testing. As an example, the sensitivities of glycoprotein G type-specific tests for detecting HSV-2 antibody vary from 80 to 98 percent, and false negative results may occur at early stages of infection [6]. In cases of recent suspected HSV-2 acquisition, repeat type-specific antibody testing can be performed 12 weeks after the presumed time of acquisition. In addition, a positive culture or PCR test for HSV in an HSV-seronegative patient is strong evidence of primary infection [62].
False-positive HSV-2 test results can also occur; this is frequently seen at low index values (1.1 to 3) with the most commonly used test, HerpeSelect HSV-2 enzyme immunoassay (EIA) [6,79]. In the setting of low index values, a confirmatory test (Biokit or Western blot) with a second method should be performed, particularly if testing was ordered in someone at low-risk for genital HSV. If confirmatory tests are unavailable, patients should be counseled about the limitations of available testing before obtaining serologic tests.
Tzanck smear — The Tzanck smear, which may demonstrate the cytopathic effect of the virus (multinucleate giant cells), can be performed on lesion scrapings from patients with active genital lesions (picture 4). However, it has limited utility since it has low sensitivity and specificity and is only helpful if positive [80]. Furthermore, only a viral culture or PCR-based testing can determine whether the infection is due to HSV-1 or HSV-2. A description of how to do the Tzanck smear is found in a separate topic review. (See "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear'.)
SCREENING
●Approach for most patients – Routine serologic screening for herpes simplex virus-1 or 2 (HSV-1 or HSV-2) is not recommended in most asymptomatic adolescents and adults. This approach is supported by the US Preventive Services Task Force [81]. Although there is a theoretical benefit of serologic screening given the relatively high seroprevalence rate of HSV-2, and the increase in genital herpes due to HSV-1, there are significant limitations of serologic testing. As examples:
•Available HSV-2 serologic tests have a low specificity and a high false-positive rate when used for screening asymptomatic individuals, and confirmatory testing is not widely available. In a systematic review that included 10 studies, the sensitivity and specificity of the most commonly used tests were estimated to be 99 and 81 percent, respectively; assuming the prevalence of HSV-2 is 16 percent, the positive predictive value would be 50 percent [79].
●Serologic tests for HSV-1 cannot differentiate oral from genital infection.
Given these limitations, and the lack of specific treatment interventions for asymptomatic individuals, the anxiety and disruption of personal relationships that can be associated with a positive test result outweigh the potential benefits of screening. More detailed information on the limitations of serologic testing is discussed above. (See 'Serologic testing' above.)
●Considerations in select populations – Screening should be performed to identify asymptomatic HSV infection in pregnant persons, since those with HSV infection are at risk for shedding at the time of delivery with potential transmission to the infant. (See "Genital herpes simplex virus infection and pregnancy".)
In addition, serologic screening is useful for determining susceptibility to HSV in individuals who have a partner with genital herpes. The role of antiviral therapy to reduce the risk of transmission to uninfected partners is presented separately. (See "Prevention of genital herpes virus infections", section on 'Determining partner susceptibility to infection'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Genital herpes (The Basics)")
●Beyond the Basics topics (see "Patient education: Genital herpes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Herpes simplex virus (HSV) is a common sexually transmitted disease worldwide. Although HSV-2 has historically been the main causative agent for virologically confirmed genital infections, HSV-1 is associated with an increasing proportion of cases of genital herpes. (See 'Epidemiology' above.)
●Transmission – Transmission of HSV may occur quickly in new sexual relationships. Among susceptible sexual partners, there is a greater risk of HSV acquisition when the source is male. (See 'Sex partners' above and 'Transmission' above.)
After resolution of the primary genital HSV infection, asymptomatic intermittent viral shedding has been documented in both men and women in the absence of genital lesions. Subclinical HSV shedding is important since infection can be transmitted unknowingly to susceptible sexual partners and neonates. (See 'Viral shedding' above.)
●Types of infection – The clinical designations of genital HSV infection are: primary, nonprimary first episode, and recurrent infection. Primary infection refers to infection in a patient without preexisting antibodies to either HSV-1 or HSV-2. Nonprimary first episode infection refers to the acquisition of genital HSV in a patient with preexisting antibodies to the alternate serotype. Recurrent infection refers to reactivation of genital HSV in which the HSV type recovered in the lesion is the same type as those seen on serologic testing. (See 'Types of infection' above.)
●Clinical manifestations – The clinical manifestations of primary genital HSV infection are highly variable. (See 'Clinical features' above.)
•Initial infection – In some patients, the initial presentation can be severe with painful genital ulcers and constitutional symptoms (picture 1A-B), in others, the infection may be mild or entirely asymptomatic. Nonprimary first episode infection is associated with fewer lesions and less systemic symptoms than primary infection, presumably because antibodies against one HSV type offer some protection against the other. (See 'Nonprimary infection' above.)
•Recurrent infection – Clinical recurrences of genital HSV are common, but are typically less severe than the initial infection (picture 2A-D). The frequency of recurrences depends on the severity and duration of the initial episode, the infecting serotype, and the host. As an example, in immunosuppressed patients, symptomatic episodes may more severe, frequent, and longer in duration (picture 3A-B). (See 'Recurrent infection' above and 'Immunosuppressed patients' above.)
•Extragenital complications – Extragenital complications (eg, aseptic meningitis and urinary retention) occur in a minority of patients, and typically present in those with primary HSV infection. (See 'Extragenital complications' above.)
●Diagnosis – For those with evidence of infection, the diagnosis of HSV is best confirmed through polymerase chain reaction (PCR) testing of a sample obtained from an active genital lesion. Viral culture can also be used to confirm the diagnosis, but it is less sensitive than PCR. For patients without an active lesion at the time of presentation, serologic testing can be performed to support the diagnosis. (See 'Diagnosis' above.)
●Screening – For most asymptomatic adolescents and adults, routine serologic screening for HSV-1 or HSV-2 is not indicated. Exceptions include persons who are pregnant and those with an unknown HSV status if they have a partner with genital herpes. (See 'Screening' above.)
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