Australian Herpes Management Forum

The Use of Type-Specific Serology for the Diagnosis of Genital Herpes

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Compiled by the Board of the Australian Herpes Management Forum (AHMF)

Introduction

Genital herpes is usually diagnosed at the time of presentation, when a specimen from a blister or ulcer is sent to the laboratory for viral culture, or detection of herpes simplex virus (HSV) DNA (by PCR) or antigen.

These tests are very accurate and reliable for diagnosing the infection, but have a number of problems, including:

• Patients often present when lesions are healing or when lesions are absent.
• HSV may fail to grow in the laboratory or there may be technical difficulties with nucleic acid and amplification tests.

For these reasons, the possibility of diagnosing herpes by means of a blood test is attractive. Until recently, most blood tests (for HSV antibodies) were unable to reliably differentiate between infection by HSV-1 and HSV-2.

HSV-1 is the usual cause of cold sores (recurrent oro-facial herpes). Most infections are acquired during early childhood and over 70% of adults in Australia have evidence of previous infection with this virus¹.

Most genital infections are caused by HSV-2. However, the popularity of oro-genital sex has meant that both HSV-1 genital infections, and HSV-2 oral infections are occurring with increasing frequency. All of these factors may complicate the interpretation of blood tests.

What tests are available?

The first blood tests able to diagnose HSV infection were group-specific antibody tests. These tests did not differentiate between infection due to HSV types 1 and 2.

The first reliable type-specific diagnostic test to become available was the western blot. This is a very sophisticated laboratory test which is able to differentiate accurately and reliably between HSV-1 and HSV-2 infections². This test is technically difficult, and is only available through a small number of laboratories.

There are now a number of simple commercially available ELISA tests for type-specific HSV infection. These tests are relatively simple to perform in the laboratory, and are now being produced by a number of companies. The reliability and reproducibility of these tests varies, and may be dependent upon the experience of the particular laboratory^3,4. The most appropriate test for use in particular situations has yet to be determined. Some of the tests only detect HSV-2 infections, others have unacceptably low sensitivity⁴.

When should these tests be used?

At present there are no agreed guidelines for the use of serological blood tests for HSV-1 and HSV-2 infection. However, there are certain circumstances where these tests may provide useful information.

1. When a couple are considering sexual intercourse, one is thought to have genital herpes, and the other has no history of the infection

Testing both partners will provide useful information about the risk of the apparently uninfected partner already having the infection or of acquiring it. For example, if the partner is infected with HSV-1 and HSV-2, and the apparently uninfected partner is HSV-1 positive but HSV-2 negative, then the apparently uninfected partner is at risk of acquiring HSV-2 infection from the one who already has it. However, if the apparently uninfected partner is HSV-2 positive, then he or she already has the infection and usually cannot acquire it again from their sexual partner^4,5,6,7.

2. An established relationship where one partner has genital herpes and the other apparently does not^6,7

The interpretation of the results would be similar to those mentioned in the first section of the following table.

3. As part of a routine sexual health screen

It has been suggested that type-specific serology could be useful in a situation where a patient requests a sexual health screen, or presents to their doctor with a genital complaint. The goal would be to provide useful information about previous exposure and/or risk of acquiring the infection. However, the use of these tests in this situation is not generally recommended by the AHMF^4,5,6.

4. To assist in the diagnosis of genital blisters or ulcers where cultures are repeatedly negative or the patient cannot attend within the first two days of lesions

A positive test will indicate that the individual has been exposed to herpes in the past, but does not provide direct information that the genital complaints are due to herpes. For example, the individual may have another genital condition (eg: thrush) concurrently with herpes infections^4,5,6,7.

5. To help prevent neonatal herpes

It has been suggested that serology may be helpful for the prevention of neonatal herpes. However, as this approach has not been rigorously evaluated, the AHMF does not recommend the routine use of type-specific HSV serology in this situation^4,8,9,10.

6. In patients who are HIV positive

Patients who are HSV-2 seropositive have an increased risk of acquiring HIV by approximately twofold and individuals who are infected with both viruses (HIV and HSV-2) have enhanced shedding of HIV from mucosal surfaces^11,12. This has led some experts to recommend HSV-2 serological testing in all individuals at risk of acquiring HIV and also in those already HIV infected in attempt to reduce the risk of HIV acquisition by identifying and treating HSV- 2 infected individuals^11,12,13,14. However, the value of this approach is yet to be tested¹⁴.

What do tests mean?

In all circumstances the tests should be performed by trained personnel according to the manufacturer's guidelines³ and interpretation should always be in the context of the history of previous symptoms which may be suggestive of cold sores and/or genital herpes. All individuals should be provided with information about the tests before they are taken and a detailed explanation provided when the results are available⁵.

Test Interpretation

HSV-1	HSV-2	Interpretation
-	-	This result implies that the individual has not been infected with either of these two viruses. However, as these tests may take up to six weeks to become positive, the test results will be unreliable if there has been recent sexual exposure. Furthermore, some tests will miss definite cases of infection 5-20% of the time. Finally, HSV-2 antibodies are lost at a rate of 0 5-1 0% per year, at least in asymptomatic patients.
+	-	This result implies that the individual has been infected with HSV-1 at some time in the past. Usually the infection is acquired in childhood and involves the orofacial region. As noted above, genital infection with HSV-1 is increasingly common.
+	+	This result indicates that the individual has been infected both with HSV-1 and HSV-2. The most likely explanation is that the individual acquired orofacial HSV-1 as a child and then acquired genital HSV-2 as an adult.
-	+	This result implies that the individual has been infected with HSV-2 at some time in the past, almost always sexually3,5,7.

Limitations of Type-Specific Serology

• Tests vary in their reliability and reproducibility.
• A positive test merely implies that the person has been infected with one or both of these viruses at some time in the past.
• Positive tests provide information about previous exposure to one or both of these viruses, but do not provide specific information about whether particular genital symptoms are due to herpes.
• A positive test does not imply that the person is infectious, although evidence suggests that the majority of individuals who have antibodies to one or the other of these viruses may shed the virus asymptomatically or from unrecognised lesions from time to time.
• Some patients appear to lose HSV-2 antibodies with time using the current ELISAs^3,5,7.

References

1. Tideman RL, Taylor J, Marks C, Seifert C, Berry G, Trudinger B, et al. Sexual and demographic risk factors for herpes simplex type 1 and 2 in women attending an antenatal clinic. Sexually Transmitted Infections 2001;77(6):413-5.
2. Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. Journal of Clinical Microbiology 1988;26(4):662-7.
3. Ashley RL. Performance and use of HSV type-specific serology test kits. Herpes 2002;9(2):38-45.
4. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clinical Infectious Diseases 2002;35(Suppl 2):S173-82.
5. Mindel A, Taylor J. Debate: the argument against. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes 2002;9(2):35-7.
6. Song B, Dwyer DE, Mindel A. HSV type specific serology in sexual health clinics: use, benefits, and who gets tested. Sexually Transmitted Infections 2004;80(2):113-7.
7. Patrick DM, Money D. Debate: the argument for. Should every STD clinic patient be considered for type-specific serological screening for HSV? Herpes 2002;9(2):32-4.
8. Mindel A, Taylor J, Tideman RL, Seifert C, Berry G, Wagner K, et al. Neonatal herpes prevention: a minor public health problem in some communities. Sexually Transmitted Infections 2000;76(4):287-91.
9. Kinghorn GR. Debate: the argument for. Should all pregnant women be offered type specific serological screening for HSV infection? Herpes 2002;9(2):46-7.
10. Arvin AM. Debate: the argument against. Should all pregnant women be offered type-specific serological screening for HSV infection? Herpes 2002;9(2):48-50.
11. Celum CL. The Interaction between Herpes Simplex Virus and Human Immunodeficiency Virus. Herpes 2004;11 (Suppl 1):36A-45A.
12. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. Journal of Infectious Diseases 2002;185(1):45-52.
13. Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. Journal of acquired immune deficiency syndrome 2004;35(5):435-445.
14. Freedman E, Mindel A. Epidemiology of herpes and HIV co-infection. Journal of HIV Therapy 2004;9 (1):4-8.

Disclaimer

The AHMF have made considerable efforts to ensure the information upon which the guidelines are based reproduces the evidence as accurately as possible. Users of these guidelines are strongly recommended to confirm that the information contained within them, especially drug indications, is correct by way of independent sources, as this guideline does not indicate an exclusive course of action or serve as a standard of medical care. The AHMF accept no responsibility for any inaccuracies, information perceived as misleading, or the success of any treatment regimen detailed in the guidelines.