Serological Testing for Herpes Simplex Virus (HSV)–1 and HSV-2 Infection
- Reprints or correspondence: Dr. Anna Wald, University of Washington Virology Research Clinic, 1001 Broadway, Ste. 320, Seattle, WA (annawald{at}u.washington.edu).
Abstract
Serological tests for herpes simplex virus (HSV) that can accurately distinguish between HSV-1 and HSV-2 are now commercially available. These tests detect antibodies to HSV glycoproteins G-1 and G-2, which evoke a type-specific antibody response. Focus Technologies produces the HerpeSelect-1 and HerpeSelect-2 enzyme-linked immunosorbent assay tests and the HSV-1 and HSV-2 HerpeSelect1/2 Immunoblot. Diagnology has marketed POCkit-HSV-2, a point-of-care test for HSV-2 that allows blood from a finger stick to be tested in a clinic. These tests can be used to confirm a genital herpes diagnosis, establish diagnosis of HSV infection in patients with atypical complaints, identify asymptomatic carriers, and identify persons at risk for acquiring HSV. Potential settings for use of these tests include sexually transmitted disease clinics, prenatal clinics, and clinics that care for patients with human immunodeficiency virus. Patient interest in HSV serological tests appears high.
Most people with herpes simplex virus (HSV)–2 infection have unrecognized disease [1]. Despite the relatively mild course of their infection, these persons still pose a risk of transmission to their sexual partners [2]. Pregnant women with unrecognized genital HSV infections pose a risk of transmission to their neonates [3]. Even persons with clinical complaints relating to HSV-2 infection often remain undiagnosed, because their presentations are “atypical” and the confirmatory laboratory tests that are in wide use have high rates of false-negative results. The development of diagnostic tools for genital herpes has lagged behind the development of diagnostic tools for other infections that are characterized by a large proportion of asymptomatic individuals, such as syphilis, chlamydia, and HIV. Molecular tests for Chlamydia trachomatis and sensitive and specific antibody tests for HIV rapidly proceeded from research laboratory use in clinical trials to commercial availability and application in clinical or public health practice. In contrast, despite the development in research laboratories of HSV type—specific serological tests over a decade ago [4, 5], the adaptation of these tests to a marketable format has been slow and their clinical use limited. However, during the past 3 years the Food and Drug Administration (FDA) has approved HSV type—specific serologies, and these are now available commercially. Other tests are in development. The next challenge will be to apply these tests to appropriate populations for clinical and public health benefit. The present article reviews the basis for development of type-specific serologies for HSV-1 and HSV-2, discusses the clinical interpretation of test results, and summarizes settings in which the use of such tests may be of benefit.
Serological Diagnosis Of HSV-1 and HSV-2
Antibody tests based on glycoprotein G. HSV-1 and HSV-2 share the majority of their immunogenic sequences. This cross-reactivity results in antibodies that react with almost equal efficiency to both HSV subtypes regardless of whether an HSV-1 or HSV-2 infection has triggered the response [6, 7]. One structural protein, glycoprotein G (gG-1 in HSV-1 and gG-2 in HSV-2), appears to elicit a predominantly type-specific response. The immunodominant human epitopes on HSV-1 are widely distributed through the protein [8]. The most reactive epitopes on HSV-2 glycoprotein G appear to reside within the homologous portions of the protein [9–11] but, in tests with human sera, bind antibodies only from patients with HSV-2 infections.
Several research or reference laboratories have developed tests based on recognition of antibodies to gG-1 or gG-2. Western blot is one alternative that, when performed correctly, is accurate for both HSV-1 and HSV-2 antibody detection [4, 12, 13]. Other formats depend on gG-1 and gG-2 that have been affinity-purified from infected cell protein mixtures by use of monoclonal antibodies [14, 15] or lectins such as Helix pomatia [16]. Recombinant gG-1 and gG-2 constructs have been developed for these tests as well [17].
Commercial type-specific HSV tests. Tests based on glycoprotein G are now on the market in kit form from Focus Technologies (formerly MRL Diagnostics) and from Diagnology (table 1). These kits have been approved by the FDA for herpes serological diagnosis in adults and, in the case of the Focus tests, for detection of HSV antibodies in pregnant women as well. Focus tests include a pair of enzyme-linked immunosorbent assay (ELISA) kits called HerpeSelect-1 ELISA and HerpeSelect-2 ELISA that detect antibodies to gG-1 and gG-2, respectively. The tests are in standard 96-well plate format and contain bacculovirus recombinant gG-1 (HSV-1) or gG-2 (HSV-2). Although 8-well strips can be snapped off for low-volume testing, these tests are basically intended for high-throughput testing and can be run on an automated platform. The second test is called the HerpeSelect1/2 Immunoblot and consists of a single paper strip to which gG-1, gG-2, a type-common antigen, and a control protein (for confirming that serum has been added) have been applied. A single strip is used for simultaneous testing for HSV-1 and HSV-2 antibodies (figure 1). This test is more expensive than ELISA but is well suited to low-volume laboratory settings. Testing by HerpeSelect ELISA or immunoblot can be ordered from Focus Technologies' reference laboratory, or the kits can be purchased by other laboratories. Additional information about these tests can be found at http://www.focusanswers.com or 800-445-0185.
Table 1
Herpes simplex virus (HSV)–2 antibody tests based on glycoprotein G, which is recommended for type-specific HSV antibody testing.
Figure 1
Immunoblots are scored as reactive if a glycoprotein G-1 (gG-1) and/or gG-2 band and the herpes simplex virus (HSV) common antigen band are observed. The anti—human serum band must be observed for the test to be valid.
The Diagnology test (POCkit-HSV-2) uses lectin-purified gG-2 and a lateral flow membrane format that allows capillary blood from a finger stick to be tested in the clinic setting (figure 2). This point-of-care format is designed for direct patient testing of blood but can also be used on single sera in the laboratory. Diagnology is seeking FDA clearance of a Clinical Laboratory Improvement Amendments—waived format for the test that will allow wider use in clinics and offices that do not have trained personnel. Because POCkit-HSV-2 detects only HSV-2 antibodies, patients with genital HSV-1 infection will not be identified by this method. Additional information about POCkit-HSV-2 can be found at http://www.diagnology.com or 877-776-2548.
Figure 2
Diagnology's point-of-care herpes simplex virus (HSV)–2 serology. This test kit is about the size of a credit card and can be performed in <10 min in the office, using capillary blood from a finger stick. The test membrane contains a dot with lectin-purified glycoprotein G-2 (gG-2) on the right and an anti—human antibody reagent on the left. (Left) A positive test result with definitive red color change of both the gG-2–containing dot and the human serum control dots (arrow). (Right) A negative test result with only the control dot showing a red color change. If neither dot turns color, the test is invalid and must be repeated with an additional capillary blood or serum sample.
The HSV gG-1 and gG-2 ELISAs developed by Gull Laboratories have been the most widely studied commercial tests [13, 18–20]. The tests obtained FDA approval in 1999 and were marketed, briefly, as Premier HSV-1 ELISA IgG and Premier HSV-2 ELISA IgG after the purchase of Gull by Meridian Biosciences. Meridian recently withdrew these tests from the market, and they are no longer available.
Quidel Corporation has developed a point-of-care membrane test for antibodies to HSV-1 and HSV-2 ("QuickVue-HSV"). This test is not yet on the market.
Two other gG-2–based tests have been produced by Trinity Biotech (Captia Select EIA, marketed by Wampole Laboratories) and Roche (Cobas Core HSV-2 IgG EIA) but have not undergone FDA review. These tests do not detect HSV-1 antibodies, a potential disadvantage in light of increasing genital HSV-1 incidence [21, 22].
Performance of commercial glycoprotein G–based tests. The Focus ELISA tests have been tested against Western blot in unselected sera with 100% sensitivity and specificities of 98% (HSV-1) and 96% (HSV-2) [23]. We tested the Focus ELISAs against Western blot in sera from 252 clients from the Seattle King County Sexually Transmitted Disease (STD) Clinic. This group had an HSV-1 seroprevalence of 57% and HSV-2 seroprevalence of 33% by Western blot. Sensitivity and specificity of HerpeSelect-1 ELISA were each 89% in this group. Sensitivity and specificity of HerpeSelect-2 ELISA were 96% and 97%, respectively (R.A., unpublished observations). A group of sera from 241 prenatal patients (HSV-1 prevalence 73%; HSV-2 prevalence 24%) was also tested. Sensitivity and specificity of HerpeSelect-1 ELISA were 96% and 95%. Sensitivity and specificity of HerpeSelect-2 ELISA were 100% and 96%, respectively. Preliminary data suggest that HSV-1 and HSV-2 antibodies can be detected a median of 2–3 weeks after the onset of first episodes of genital herpes (R.A., unpublished observations).
The Focus immunoblot also was tested in STD and prenatal populations and had sensitivity and specificity of 99%–100% and 93%–96%, respectively, for HSV-1 and sensitivity and specificity of 97%–100% and 94%–98%, respectively, for HSV-2. All 3 Focus tests performed well in comparison tests performed at the Central Public Health Laboratory (CPHL) in London using their monoclonal antibody blocking assay as a “gold standard” [24].
The POCkit-HSV-2 test has been tested against the CPHL monoclonal antibody blocking ELISA and against the University of Washington Western blot. Sensitivity ranged from 93% to 96% and specificity from 95% to 98% [13, 25, 26]. We also found that a median of only 2 weeks from onset was required to demonstrate HSV-2 seroconversion by POCkit-HSV-2 [27]. Caution is advised in interpreting the POCkit-HSV-2 test, because the reading of a positive result can be subjective. In 1 study that used banked sera, 5%–10% of tests were read differently by 1 of 3 readers [28]. The test dot should have a definitive color change to deep pink or red to be called positive (figure 2).
The HSV-2 type—specific serology tests that are commercially available but not FDA approved have limited performance data against accepted standard tests. Cobas has a sensitivity of 93% and specificity of 98% when culture is used as a marker of infection and pediatric sera (presumed negative) for specificity calculations [18]. The Captia Select HSV-2 EIA has been somewhat less sensitive (90%–92%) with 91%–98% specificity [29, 30].
Commercial tests that are not based on glycoprotein G. Serological assays based on antigen preparations from whole virus or from crude infected-cell protein mixtures detect predominantly type-common antibodies. Although the most serious problem with these tests is their inability to detect HSV-2 antibodies in HSV-1–seropositive patients, the tests also mistakenly type antibodies in patients with only HSV-1 or only HSV-2 infection [19, 31]. HSV-1 and HSV-2 share most of their antigenic sequences; therefore, most herpes antibodies are “type-common.” A number of companies offer tests that are based on relative reactivity of serum antibodies to crude preparations of HSV-1 versus HSV-2 antigens. These tests are either described as “type-specific” in marketing literature or provide kit instructions for determining HSV-1 versus HSV-2 antibodies. However, the accuracy of crude antigen—based tests for HSV-2 antibody detection is low compared with glycoprotein G–based tests, and their use is not recommended (table 2).
Table 2
Tests based on crude antigen, which is not recommended for type-specific testing.
Clinical Use of Type-Specific HSV Serologies
A major reason for the lack of commercial development of glycoprotein G–based HSV testing has been the perception on the part of health care providers that in an asymptomatic patient the diagnosis of HSV-2 infection is undesirable, because it may have adverse psychosocial sequelae and unclear benefits [32–35]. This view has been formed on the basis of substantial literature that shows persistent psychosocial distress in some people who are diagnosed with clinically evident genital herpes [36–38]. There is a general reluctance to inflict on an otherwise healthy person a diagnosis of a condition that might otherwise be asymptomatic if the diagnosis may result in significant distress. In addition, counseling regarding genital herpes generally cannot be accomplished within the short period typically allotted for patient visits. Finally, numerous studies have documented the discomfort of health care providers with obtaining detailed sexual history and providing safer sex counseling [39–41]. However, there are several settings in which type-specific serologies for the diagnosis of HSV-1 and HSV-2 infection are potentially useful and in which the acceptance of these tests by the patients is high (table 3). These settings and the interpretation of the type-specific HSV antibody tests are reviewed below.
Table 3
Acceptance of herpes simplex virus (HSV)–2 type-specific serology testing.
Interpretation of antibody to HSV-2. What is the clinical interpretation of a positive HSV-2 antibody test in a patient with atypical or no genital symptoms? Prospective studies have shown that virtually all patients with HSV-2 antibody have genital herpes [42, 43]. We provided a standardized counseling session regarding clinical manifestations of genital herpes to 42 women and 11 men without a history of genital herpes who had positive antibody tests for HSV-2 [44]. The patients were randomly selected when they presented for primary care [45]. During the follow-up, 33 recognized typical herpes recurrences and 13 reported localized genital soreness or itching; HSV was isolated or detected by PCR in the genital tracts of 44 of 53 of these patients. Thus, all but one had either clinical evidence of a genital herpes recurrence or had documented viral shedding in the genital tract. Overall, the frequency of recurrences was lower and the duration shorter compared with patients who had a clinical history of genital herpes. Such mildly symptomatic or asymptomatic persons may not need antiviral therapy but require education and counseling to prevent transmission of HSV-2 to their sex partners and, potentially, to neonates.
Although oral HSV-2 infection has been reported in ∼20% of patients with primary genital HSV-2, HSV-2 recurs rarely in the mouth, and oral HSV-2 infection in the absence of genital infection is unusual [46, 47]. Thus, antibody to HSV-2 indicates genital herpes in almost all patients. These persons should be counseled similarly to patients with clinical diagnosis of genital herpes.
Interpretation of antibody to HSV-1. What is an appropriate interpretation of a positive HSV-1 test in a person who lacks a history of oral or genital herpes? Serological surveys have indicated that the prevalence of HSV-1 infection rises steadily throughout childhood and adolescence [48]. Most of these infections probably represent oral HSV-1 acquisition. However, in sexually active adults, the incidence of genital HSV-1 is high [21, 22, 49, 50], and seroconversion to HSV-1 can be consistent with genital as well as with oral herpes. In a study of 19 people who seroconverted to HSV-1 during a prospective study of a candidate herpes vaccine, 6 developed genital disease, 6 had oral disease, and 7 acquired HSV-1 antibodies without localizing signs or symptoms [51]. Thus, in a patient who seroconverts to HSV-1 but does not have symptoms that localize the infection in the mouth or genital area, it is not possible to ascertain the site of the infection.
The inability of type-specific serology alone to indicate the site of HSV-1 infection has been used by some clinicians to suggest that serologies for antibody to HSV-1 are not helpful [52]. An alternative interpretation, however, is that a positive HSV-1 antibody test indicates that this person is no longer at risk for HSV-1 infection. Discussion can then take place to review transmission risk from oral or genital sites and to review symptoms of recurrent genital herpes.
Distinguishing between HSV-1 and HSV-2 infections. Although careful studies have shown that the severity of genital herpes episodes is similar in HSV-1 and HSV-2 infections, the predilection for recurrences is much lower for HSV-1 than for HSV-2. Among patients with documented newly acquired HSV-1 infection, the median time to first recurrence was 310 days, compared with the median time to first recurrence of 49 days among patients with newly acquired HSV-2 infection [53]. This means that ∼50% of patients with genital HSV-1 will not have even 1 recurrence in the initial year after infection, compared with patients with HSV-2 infection, who will have, on average, 4–5 recurrences.
The other reason to identify the infecting type is to alert the patient to the risk of acquiring HSV-2 infection in addition to HSV-1. Acquisition of HSV-2 in a person with genital HSV-1 infection has been documented, and a subsequent pattern of recurrences is consistent with HSV-2 infection—that is, frequent recurrences [54–56]. This is especially important when both partners have a history of genital herpes but the type is unknown, because these couples are often told that safer sex is not a necessary precaution from the standpoint of genital herpes.
Of interest, acquisition of HSV-1 in a HSV-2 seropositive patient is very rarely observed, which suggests that HSV-2 offers more protection against HSV-1 than vice versa [5]. When both partners have HSV-1 or both partners have HSV-2 infection, the risk and the clinical sequelae of infection with another strain of HSV-2 (or HSV-1) appears to be insignificant [57].
Confirmation of clinical diagnosis. Clinical diagnosis of genital herpes is often far from certain, even if the presentation appears typical. Many experts recommend that laboratory confirmation be obtained even if the presentation is consistent with genital herpes. A prospective study of 155 patients monitored in a clinical research setting who acquired HSV-2 infection showed that the sensitivity of clinical diagnosis was 39% and the positive predictive value was 81% [51]. Thus, for every 4 correct clinical diagnoses of genital herpes, 1 patient received the diagnosis of genital herpes in error. This suggests that, even among highly trained personnel, genital herpes lesions are often misdiagnosed and that a significant portion of genital herpes diagnoses that are based on clinical examination alone is incorrect.
Although an argument can be made that viral culture is most appropriate in a patient presenting with genital lesions, it is important to remember that viral cultures are not always positive even in primary genital herpes and are usually negative in recurrent genital herpes [58, 59]. The high rate of false-negative viral culture results further complicates the delivery of a diagnosis of genital herpes to the patient. Undoubtedly, many patients are convinced that the clinical diagnosis of genital herpes is erroneous when the opinion of the clinician is followed by a negative result of the confirmatory laboratory test. This scenario can be avoided with appropriate use of serological tests, although care must be taken to ensure that the antibody status is ascertained in an appropriate time frame to allow for the development of antibodies. This situation is analogous to the diagnosis of HIV infection, where a lag is observed after primary infection before serological tests become reactive.
Atypical presentations of genital herpes. Another setting in which serological tests are appropriate is that of patients who present with atypical genital lesions. Studies have shown that these lesions often represent undiagnosed genital herpes [60], usually HSV-2, and because of the mild and infrequent nature of the recurrences in many infected persons, isolation of HSV may be difficult. One approach is to ask the patient to come to the clinic early at the next appearance of these lesions, to obtain fresh material for viral isolation. An alternative is to obtain blood for serological testing for HSV-1 and HSV-2 antibodies. In our experience, the latter approach is usually more direct and more economical.
Partner with genital herpes. Discordance in HSV infection in a sexual partnership can be established only by type-specific testing of the susceptible person, if the type of infection is known in the potential source partner, or by testing of both partners if it is not. At least a quarter of couples that are discordant for genital herpes by clinical history will be concordant by serological tests [61]. This can occur either because the infection was transmitted subclinically earlier in the relationship or because of unrecognized HSV acquisition in a prior relationship.
Accurate knowledge of infection status can guide patient education and counseling if the partnership is discordant and often brings enormous relief if a stable, long-term partnership is found to be herpes-concordant. Because condoms have been found to be effective in reducing the transmission of HSV-2 from men to women, discordant couples can receive counseling on consistent condom use [62]. Antiviral therapy is currently under investigation for reducing the risk of transmission in such partnerships.
HSV serologies during pregnancy. Type-specific serologies are also useful to identify persons who may be at especially high risk for adverse sequelae from HSV acquisition. Perhaps the most obvious example is that of a pregnant woman who does not have HSV-2 infection herself but who has a partner with HSV-2 infection, a scenario that applies to an estimated 10% of couples [63]. Studies have consistently shown that acquisition of genital HSV-2 or HSV-1 toward the end of pregnancy carries a 30%–50% risk of neonatal herpes [64, 65]. Most of those events occur when a woman unknowingly acquires genital herpes and does not have clinical disease at the time of delivery. Thus, targeted behavioral intervention to the susceptible women must rely on the identification of women who are susceptible to acquiring the infection in pregnancy [66].
There are 2 potential schemes for identifying the susceptible women. One is to serologically test those pregnant women without a history of HSV-2 infection, identify those who are susceptible, and, subsequently, test the partners. If the couple is discordant for HSV-1 or HSV-2, appropriate counseling can be provided for the couple to avoid unprotected sexual intercourse and oral-genital contact toward the end of pregnancy. An alternative strategy, if a woman is susceptible and the partner is not able or willing to come in for serological testing, can rely on provision of counseling to the woman without knowledge of partner status. This may have some advantages in terms of implementation of a testing program, despite the inability to precisely tailor the counseling message to the woman's individual situation. Adherence to the counseling messages may be lower if the risk is less well defined. There is urgent need to test these potential strategies for intervention among HSV-susceptible pregnant women.
A woman who tests positive for HSV-2 antibodies during pregnancy can be reassured that her risk of transmission of infection to the neonate is small, but a careful examination is warranted at term [67]. If no symptoms or lesions consistent with genital herpes are present, the woman can deliver vaginally. If there is evidence of HSV reactivation at term in the genital area, an abdominal delivery is recommended. There have been small trials of suppressive acyclovir toward the end of pregnancy for the prevention of recurrences at term [68–71]. Although these data are promising, some experts caution against widespread use of acyclovir, because there is remaining concern about the potential hematologic and renal toxicity of the drug in the fetus.
Women are routinely tested for a variety of infections during pregnancy; thus, it is likely that the routine use of HSV serological tests would be well accepted as has been the experience with HIV antibody tests [72–75]. One study in a London prenatal care clinic showed that 80% of women would consider HSV antibody tests if they were available [76].
HSV serologies in STD clinics. Another setting in which serological testing is likely to be useful is that of STD clinics. Serological surveys in STD clinics have shown that the rates of HSV-2 infection range from 25% to 80%, depending on the sex and race of the population [77, 78]. As among the general population, most patients with HSV-2 antibody who are seen in STD clinics do not have a history of genital herpes [60]. It is important to note that a significant proportion of patients—25% in the Seattle STD clinic—presenting for care in STD clinics request “STD screen” and do not have a specific clinical complaint (M. Golden, personal communication). These patients are usually evaluated for inflammation of the genital tract, and serological tests for syphilis and HIV are performed. However, the current standard of care is not to perform HSV serology, thus avoiding diagnosing an infection that is certainly more frequent in the United States than either unsuspected syphilis or HIV infection.
Patients express considerable interest in obtaining serological testing for HSV-2. For example, in a British STD clinic, >90% of patients wanted to know their HSV-2 antibody status, and a similar proportion were also interested in having their partners tested [79]. Of interest, 65% thought that type-specific serological testing for HSV was included among the standard tests offered.
The acceptance of HSV-2 testing depends partly on the cost of the test. In the Seattle STD clinic, 52% of patients accepted serological testing when it was offered free as part of a research project, compared with 18% of patients who agreed when there was a $15 charge for the test [20]. Other statistically significant correlates of acceptance of HSV serological tests included older age and white race. The largest difference in acceptance of the free versus paid test was among blacks: 42% consented when the test was free, compared with 4% when the test required payment. Among whites, the rate of acceptance was 55% when the test was free, compared with 24% when the test had a fee. These data suggest that economic situation explains much of the differential acceptance of the test among patients seeking STD care. Programmatic budgetary issues have been raised as barriers to the availability of HSV serological tests in STD clinic settings. Although fiscal constraints may truly interfere with offering this test without charge, as with other traditional tests in STD clinics, there should be no such barriers to making these tests available at a small charge. Along with the availability of type-specific HSV serology, patients in STD clinics should be explicitly told when their evaluation does not include a test for HSV, because many patients are under the impression that a comprehensive evaluation is routinely performed [79].
HSV serologies in HIV infection. Numerous studies indicating the interaction between HIV and HSV-2 have been reviewed elsewhere [80]. In brief, several studies have shown that HSV-2 infection facilitates HIV acquisition, and some studies have suggested that HSV-2 infection may also predispose to HIV transmission [81]. Natural history studies of HSV-2 infection in HIV-infected persons have shown that the HSV shedding rate among such persons is significantly higher than among immunocompetent men and that much of the shedding among men who have sex with men occurs from the perianal area and is unrecognized by the patients [82, 83]. This suggests that this population is at higher risk for further transmission of HSV-2 to the sexual partner. Recent recommendations from the Centers for Disease Control and Prevention regarding screening of HIV-infected persons for STDs does not recommend serological testing for HSV infection [84]. However, it seems that testing for HSV-2, in combination with education and counseling, and judicious use of antiviral agents in persons with both HIV and HSV infection is a reasonable approach to limiting further spread of both infections.
In summary, the commercial availability of type-specific antibody tests for HSV-1 and HSV-2 will increase the diagnosis of this infection. The difficulty of ascertaining that the appropriate test is performed is considerable, because neither physicians nor patients have been taught to request brand-name tests. However, only glycoprotein G–based tests have acceptable accuracy, although other tests remain on the market. Several populations appear to be appropriate for serological testing for HSV, including pregnant women, STD clinic patients, and persons with HIV infection. The barriers to serological testing for HSV include fiscal constraints in some settings and, at least as important, reluctance on the part of clinicians to offer the test that patients are increasingly likely to request.
- © 2002 by the Infectious Diseases Society of America
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