Literature review > Issue_4 > Review on Cherpes et al. 

HSV infections are often difficult to diagnose. Most infections are either asymptomatic or present with atypical manifestations, making diagnosis through viral isolation difficult. In many situations serological determination of HSV infection status can be helpful clinically and is also a valuable epidemiological research tool.

Serological differentiation between HSV-1 and HSV-2 infection is technically demanding. Many antigens are shared between these viruses and cross reactivity of serum can occur.

The gold standard for serologically identifying HSV infection is western blot assays. These require expert interpretation particularly when co-infection is present. Western blots are unavailable commercially and are currently conducted in only some centers.

Recent years have seen the development of a number of type specific serological tests based on immunoblot, ELISA, and radioimmunoassay. Most of these methods rely on the detection of antibodies to glycoprotein gG-1 (of HSV-1) or gG-2 (of HSV-2). Sufficient differences exist between gG-1 and gG-2 to make serological responses type specific with the ability to establish the presence of co-infections. A number of tests have been developed commercially but currently very few are available to the laboratory. In experienced hands they appear to have excellent specificity and sensitivities although this may not be adequate for their routine clinical use in low prevalence populations [1] where positive tests may require validation with western blot assay.

Glycoprotein gG-based ELISAs are frequently used to determine cross-sectional HSV-2 seroprevalence [2-4]. However they are generally felt not to be reliable enough to establish incidence in longitudinal studies. Previous work [5] has suggested that there is a significant positive to negative shift (seroreversion) with time for many of these assays of between 6-21%, making them extremely unreliable in some settings.

This study attempts to determine the extent to which seroreversions occur (HSV-1 or HSV-2 positive to negative) over a one year period when using the Focus glycoprotein gG ELISA test in a population of non-pregnant women (18-30 years) attending health services in North America. Baseline levels of HSV-1 and HSV-2 infections were 46.6% and 24.9%, respectively, which are relatively high compared to many populations. Over a one-year follow up period during which sera were drawn at four monthly intervals seroreversions occurred in 3.4% of HSV-1 and 0.9% of HSV-2 positive women. Subsequent validation of some of these samples using western blot suggested that the majority of these results were due to initial false positive tests. The authors noted that these occurred predominantly in samples where the initial ELISA optical density values were relatively close to the manufacturer's advised cutoff values. Previous work has shown the relative unreliability of positive tests with low optical density readings [5].

The authors concluded that because of the higher risk for false-positive results with lower positive index values, Focus immunoassays should be repeated or confirmed by Western blot analysis when a positive index value from 1.1 to 3.0 is obtained. However, no information is given on what percentage of tests this might apply to in a high or low prevalence population.

Such a strategy could be clinically useful since western blot is rarely available to most clinicians and repeated Focus testing a cheaper and practical alternative. However, the assumption that higher index value readings represent true positives has not been demonstrated in this study and needs to be established before this type of limited retesting protocol can be used in clinical settings. In addition, this study was performed in a high prevalence setting and its conclusions may not be applicable outside this. Finally, some concerns have recently been raised as to the variable performance of HSV assays amongst ethnically diverse populations. This issue was not addressed in this publication. Patients offered the test will need to be provided with detailed information about the test's interpretation and limitations. Careful correlation of laboratory results with history and clinical observation is important and needs to be interpreted in the light of local epidemiology if this test is to be useful clinically.

References:

1. Fisman DN, Hook EW, III, Goldie SJ. Estimating the costs and benefits of screening monogamous, heterosexual couples for unrecognised infection with herpes simplex virus type 2. Sexually Transmitted Infections 2003;79(1):45-52.

2. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK et al. Herpes simplex virus type 2 in the United States, 1976 to 1994.[see comment]. New England Journal of Medicine 1997;337(16):1105-11.

3. Gibson JJ, Hornung CA, Alexander GR, Lee FK, Potts WA, Nahmias AJ. A cross-sectional study of herpes simplex virus types 1 and 2 in college students: occurrence and determinants of infection. Journal of Infectious Diseases 1990;162(2):306-12.

4. Johnson RE, Nahmias AJ, Magder LS, Lee FK, Brooks CA, Snowden CB. A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. New England Journal of Medicine 1989;321(1):7-12.

5. Schmid DS, Brown DR, Nisenbaum R, Burke RL, Alexander D, Ashley R et al. Limits in reliability of glycoprotein G-based type-specific serologic assays for herpes simplex virus types 1 and 2. Journal of Clinical Microbiology 1999;37(2):376-9.

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