From the New York University Medical Center, New York, NY.
Serologic tests for antibodies to herpes simplex virus (HSV) have traditionally played a limited role in the treatment of patients with genital herpes. The epidemiological gold standard has been the Western blot analysis, which is only available in a few research centers and is expensive. The gold standard of diagnosis for HSV infection has been viral culture. Diagnosis by viral culture has severely underestimated the number of individuals infected. The majority of patients who are seropositive for herpes simplex virus type 2 (HSV-2) by Western blot analysis are unaware of their symptoms (unrecognized infection) or have subclinical infection. These patients are unlikely to present for culture. Enzyme-linked immunosorbent assay (ELISA) for the serologic diagnosis of herpes has been available for many years but suffers from poor sensitivity and specificity. Reliable, convenient serologic tests for antibodies that distinguish between prior infection with HSV-1 and HSV-2 have recently become commercially available.
Viral culture is presently the chief means of diagnosing genital herpes. However, in recurrent episodes, up to 50% to 60% of cultures are negative.1 There are many reasons for a negative culture. The culture must be obtained from active lesions during viral shedding, which, on average, lasts 4 days. Vesicles and wet erosions give a higher yield than dry erosions or crusts. The viral medium must be refrigerated for best results.
Another means of identifying herpes simplex virus (HSV) infection would be useful in suspected cases that are culture negative. Herpes simplex virus type 1 (HSV-1) seropositivity is usually associated with orolabial infection, although the number of genital HSV-1 infections has been increasing. Herpes simplex virus type 2 seropositivity is considered synonymous for genital infection, although HSV-2 infection limited to the oral mucosa occurs rarely.2
The majority of HSV-2 antibody–seropositive individuals do not manifest symptoms or have unrecognized infection. In one study, only 9.2% of those who were HSV-2 seropositive were aware that they carried a diagnosis of genital herpes.3 One study of highly motivated seropositive patients showed that up to 60% of "asymptomatic" patients can be taught to recognize symptoms of outbreaks.4 Clearly, undiagnosed genital herpes is fueling an epidemic, and asymptomatic transmission is the major route of infection.5 Genital herpes is often acquired from individuals who are unaware that they are infected. Diagnosing patients and altering behavior patterns and management may lower seroprevalence rates. Most HSV-2–seropositive patients have been found to intermittently shed the virus.6
A review of serologic commercial immunoassays for HSV antibodies in 1991 found that these tests suffered from poor sensitivity and specificity.7 These tests used relative reactivity against HSV-1 and HSV-2 to determine which subtype was dominant. Unfortunately, the 2 viruses share many of the same antigens. The overall sensitivity and specificity was about 70%. Inaccurate or misleading results were obtained in 26% to 37% of patients. The tests were often unable to detect antibodies to HSV-2 in patients with antibodies to both viral subtypes. Seroconversion to HSV-2 was effectively masked by the anamnestic response to type-common antigens recognized in an earlier HSV-1 infection. Conversely, one assay, used to examine a population of patients with only HSV-1 antibodies by Western blot analysis, falsely labeled 40% of patients as both HSV-1 and HSV-2 seropositive.
A new generation of enzyme immunoassays with a high degree of sensitivity and specificity has been developed. The results are rapidly obtained and inexpensive. This test is based on the type-specific glycoproteins gG-1 from HSV-1 and gG-2 from HSV-2.
Recently, the Food and Drug Administration approved several herpes serology tests, including 2 tests from Meridian Diagnostics (Cincinnati, Ohio), the Premier type-specific HSV-1 IgG enzyme-linked immunosorbent assay (ELISA) and type-specific HSV-2 IgG ELISA. Also approved was the POCkit HSV-2 Rapid Test (Diagnology Inc; Research Triangle Park, NC). MRL Diagnostics (Cypress, Calif) and Roche Diagnostics Corp (Indianapolis, Ind) also have assays in use. Since a detailed description is beyond the scope of this text, readers are referred to a comprehensive review of methodology by Dr Ashley.8 Several tests are reviewed below in detail.
The POCkit HSV-2 Rapid Test can be performed in the physician's office and provides rapid (6 minutes) results. Serum sensitivity was 96% and specificity was 97% compared with the Western blot analysis.9 The POCkit tests can detect HSV-2 antibodies in 2 weeks on average. However, the response time varied from 3 to 102 days. Seroconversion was detected within 4 weeks in 80% of patients with HSV-2 episodes. The POCkit test determines HSV-2 seropositivity only and cannot test for HSV-1 antibodies; as such, it is not useful in diagnosing genital HSV-1 infection.
The Meridian Premier tests can detect both HSV-1 and HSV-2 type-specific HSV antibodies.10 In a study comparing the Meridian Premier tests with the Western blot analysis, the sensitivity for HSV-1 was 95% and the specificity was 96%. The sensitivity for HSV-2 was 98% and the specificity was 97%. With the Premier tests, seroconversion to HSV-2 can take up to 4 months, so negative results should be confirmed by Western blot analysis or a later serum sample should be tested if seroconversion is suspected.
MRL Diagnostics has an assay that is similar to the Premier test. Comparison with an in-house Western blot assay revealed a sensitivity and specificity of 95%.8 Roche Diagnostics Corp has developed the Cobas Core HSV-2 IgG Enzyme Immunoassay. Comparison with in-house ELISA assays revealed a sensitivity and specificity of 98%.11
The cost-effectiveness of testing may prove to be best for pregnant women who are at risk of acquiring herpes in the third trimester. One of the most feared sequelae of genital herpes is vertical transmission to the neonate during birth, resulting in neonatal herpes, with its devastating, often fatal results. Infection is most common when the mother develops primary infection late in pregnancy.12 Theoretically, discordant couples with a pregnant seronegative woman could be identified and then counseled appropriately to avoid transmission during the third trimester. Since the seroconversion rate during pregnancy is less than 2%, large numbers of couples would have to be screened for the test to be cost-effective. Alternatively, an HSV-2–seropositive woman could be counseled that her risk of transmission to her fetus is low and that most patients can have a normal vaginal delivery. If a woman is entirely seronegative and her partner is HSV-1 positive, they should be instructed to avoid oral-genital and genital-genital contact in the last trimester, as HSV-1 accounts for up to 30% of cases of neonatal herpes. A seropositive man in a discordant relationship unwilling to abstain sexually or to use condoms might benefit from suppressive therapy. Any beneficial effect of suppressive therapy on transmission, while plausible, awaits further study.
Many couples present to the physician's office seeking ways to minimize transmission. A reliable blood test may show that, in many apparently HSV-discordant couples, both partners are infected, thereby minimizing concern to those in monogamous relationships. For couples who are serologically confirmed to be discordant for HSV type-specific antibody, the frequency of transmission, asymptomatic shedding, condoms, and suppressive therapy can be discussed. Suppressive antiviral therapy to prevent HSV transmission has not been established. The protective role of HSV-1 in decreasing the transmission of HSV-2 in females can also be discussed. Offering evaluation to partners of patients with a sexually transmitted disease is an important aspect of their treatment. Genital herpes is no exception. The new serologic tools will aid the evaluation of partners of patients.
As dermatologists, we frequently see patients with recurrent genital eruptions of unknown cause. They frequently present after a week of symptoms, at which point the virus can no longer be successfully cultured. While a clinical diagnosis can often be made from the history and examination, the presence of HSV-2 seropositivity may support a diagnosis and give the patient some objective evidence of infection. Many patients express frustration that a negative culture or no findings on examination does not exclude genital herpes. A serologic test positive for HSV-2 antibody may help assuage the patient's doubts about the diagnosis. Genital herpes can mimic many other conditions, such as atopic dermatitis, erosive lichen planus, or urethritis. Other patients may have been falsely diagnosed with a yeast infection, trauma, or folliculitis. Because the symptoms of genital herpes improve as an episode resolves, the patient and clinician may mistakenly believe that corticosteroid creams or antibiotics were helpful. This may lead to further inappropriate treatment. While a positive HSV-2 serologic test result does not exclude other causes of a genital eruption, it provides objective evidence of viral infection and may be useful to justify antiviral treatment in selected patients. Conversely, the complete absence of seropositivity may be useful to exclude genital herpes. Up to 12% of patients with a clinical history of genital herpes have no serological evidence of infection.13 A study by Munday et al14 found that serologic testing contributed to diagnosis in 79% of patients with recurrent genital eruption of unknown cause.
Because of the increased prevalence of HSV-1 genital infection, a seropositive HSV-1 result does not determine whether the infection is orolabial or genital. The patient needs to return for a viral culture of a genital eruption to confirm the diagnosis. As HSV-1 recurs less frequently than HSV-2, typing has prognostic utility.15
HSV-2 seropositivity is markedly elevated in patients at high risk for acquisition of human immunodeficiency virus type 1 (HIV-1),16 and HSV-2 has been linked to the acquisition and transmission of HIV-1.17 Genital ulcers from HSV may facilitate the transmission of HIV through mucosal disruption. The infiltration of CD4+ lymphocytes in herpetic lesions creates targets for HIV attachment and entry.18 In patients at high risk of HIV acquisition, using serologic testing to identify the added risk factor of genital herpes deserves consideration. It is not known whether antiviral suppression in HSV-2–seropositive patients can reduce transmission of HIV, but this area deserves more attention.
Many clinicians feel that a blood test would have unforeseen consequences, such as labeling possibly millions of people with an incurable disease that causes minimal symptoms in a majority of patients. Large numbers of individuals (21% of the US population is HSV-2 seropositive) may be subjected to the knowledge and anxiety that they are infected with a chronic incurable illness. Identifying and counseling large numbers of HSV-2–seropositive patients would place an imposing burden on health care workers.
It is uncertain whether our health care system can afford the cost of suppressive therapy if it is proven to decrease transmission, and it is unclear who should be making this decision. Some public health officials fear we are in a herpes epidemic, with ever-increasing rates of seroprevalence even in the HIV era.19 It is possible that testing may lead to less risky behavior, as suggested by studies of HIV counseling. A study in the United Kingdom found that 92% of respondents at a sexually transmitted disease center wanted the HSV type-specific antibody test even after the implications were thoroughly discussed.20
The new herpes type-specific serologic tests include only 1 protein, whereas the Western blot assay incorporates a battery of proteins to distinguish HSV-1 from HSV-2. In a low-incidence population, false positives may occur in significant numbers, and Western blot assays may still be needed for individual confirmation. False negatives will also occur, particularly in new infections, and clinical correlation will be needed. The clinician will need to be familiar with the sensitivity and specificity of the HSV type-specific serologic test the clinician's laboratory employs to interpret the results appropriately.
Most HSV-2–seropositive patients who are "asymptomatic" shed the virus from the genitals and are presumably capable of transmission. A recent study by Wald et al6 prospectively identified 53 HSV-2–seropositive patients who reported no history of genital herpes. In these patients, HSV was isolated from the genital mucosa in 38 (72%) of the subjects using daily swabs over a 98-day period. The rate of subclinical shedding of HSV in subjects without a history of genital herpes was similar to that in a control group of subjects with a history of genital herpes. It has previously been shown that many HSV-2–seropositive patients without a history of genital herpes can be taught to recognize minor or atypical outbreaks.4 In the recent study by Wald et al,6 a similar group of HSV-2–seropositive patients were taught to recognize minor symptoms and signs of outbreaks. Subsequently, 33 (62%) of 53 subjects reported herpetic lesions. Further study is needed to corroborate these results.
Patients who are identified as seropositive for HSV-2 antibody need counseling. Patients need to be educated on the common as well as atypical manifestations of genital herpes. Subclinical shedding and the possibility of transmission need to be discussed. Suppressive therapy should be considered for discordant couples or those with difficult psychological adjustment problems. However, the impact of suppressive therapy in monogamous couples from a public health perspective is questionable.21 The value of suppressive therapy for patients who are unable to maintain monogamous relationships and are asymptomatic is undetermined. It is unlikely that they will want long-term antiviral therapy with an expensive medication.
We have described a new generation of type-specific HSV antibody serologic tests. The benefits of serological testing for antibodies to HSV as a routine screening test have not been established. The lack of effective management options makes the medical benefit of widespread serologic testing questionable. The cost-effectiveness of diagnosing asymptomatic infected patients and using suppressive therapy or other options to reduce transmission is unclear. A vaccine is needed to make the test instrumental in decreasing the incidence of genital herpes. Testing should not be denied to those who are willing to accept the responsibility of a positive result.
Herpes serologic testing can be helpful in selected patients. We propose these indications:
Counseling pregnant women without a history of genital herpes whose partner is known to be infected or is seropositive.
Counseling couples in monogamous relationships in which one partner has clinical or serologic evidence of herpes.
Diagnosis or exclusion of genital herpes as a cause of recurrent genital eruption when the diagnosis cannot be made by other means.
Identifying HSV-2 infection in patients at high risk for HIV acquisition.
Test results will require complex interpretation and public health issues will need to be addressed before mass screenings are performed.
Accepted for publication April 27, 2000.
The author thanks M. Joyce Rico, MD, for her comments regarding the preparation of the manuscript.
Corresponding author/reprints: Barry D. Goldman, MD, 170 William St, NYU Downtown Hospital, New York, NY 10038 (e-mail: Bgjagold@aol.com).
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