Literature review > Issue_1 > Review Eing et al. 

The field of herpes simplex virus serology has expanded in recent years with the growing availability of commercial test kits that can accurately differentiate between antibodies to HSV-1 and those to HSV-2. These tests depend upon the detection of antibodies to glycoprotein G (gG-1 in HSV-1 infection and gG-2 in HSV-2 infection). Several tests, including a point-of-care membrane test ("POCkitä-HSV-2"; Diagnology, Belfast Northern Ireland), a standard ELISA (HerpeSelectâ ELISA; Focus Technologies, Cypress, CA), and a strip immunoblot test (HerpeSelectâ Immunoblot; Focus Technologies) have received FDA licensure in the United States following clinical trials to show both classical sensitivity and specificity (lack of false negative or false positive results, respectively, relative to a comparator test) and herpes specificity (ability to accurately type antibodies) [1].

The CDC 2002 STD Treatment Guidelines stipulate that gG-based tests should be used in diagnosis of genital herpes [2]. Guidelines on how to confirm positive or equivocal results of gG-based tests have been published but not widely tested [1]. In low risk populations, even a test with high specificity can deliver relatively low positive predictive value. For an individual patient, the ability to confirm a positive serology by a separate, unrelated test method may be very important, indeed.

Using HIV as a model, the logical HSV confirmatory test would be HSV Western blot, the current gold standard test for accurate type specific antibody testing. However, the model breaks down with the complexity and high cost of HSV WB; in most parts of the world, HSV WB is not a reasonable option.

Hence, the study of Eing et al. is potentially very important in providing a confirmatory strategy using tests at hand. The high-risk and low-risk cohorts are reasonable and of adequate size to meet the aim of this study. Analyses to derive a kappa statistic might have simplified data presentation but would probably not have changed the outcome.

The authors are to be applauded for recognizing the need for confirmatory testing in designing this study and for handling a very complicated set of results derived from that study. The final result is a data-driven algorithm for testing that may be very useful to laboratories in Germany.

The study's applicability, however, is limited to the region served by purveyors of the Euroimme tests. The Gull test is no longer manufactured and was taken off the market two years ago. It's regrettable that the original journal reviews missed this since 8 of 12 proposed testing algorithms depend on the Gull test. This paper would have been simpler with only 4 alternative algorithms to describe and discuss.

Further, given the huge market in the United States, where at least 22% of the adult population is seropositive for HSV-2 and at least 80% of those individuals have not
been diagnosed [3], it is disappointing that neither of the USA-based HerpeSelect tests was used in this study. Focus Technologies' HerpeSelect ELISA kits have world-wide distribution, including Germany. Had the Focus ELISA been included in the evaluations, the paper could have had very significant practical application in the United States; possibly helping to move official HSV serology confirmation schemes along.

It takes a bit of digging to sort through the data remaining if one removes from consideration one of the screening tests (Radim HSV-2 ELISA) because of its lack of sensitivity and the Gull assay, because its contribution is moot. The reward is to find that the combination of Euroimmun ELISA ("Eu2"; Bad Homburg, Germany) followed by Euroimmun Western blot (EuW) testing of equivocal and positive samples appears to be an effective combination.

A very interesting component of this study involved additional testing by an in-house Western blot ("IhW") following preabsorption of sera. This type of test is the most rigorous of all tests for type specificity but somewhat less sensitive than standard WB due to the loss of antibody titer during the absorption step [4]. This sensitivity loss is quite evident in the figure showing the in-house Western blots. Still, this test picked up a number of sera that were falsely negative by ELISA. The authors appropriately discuss the role of non-gG-2 markers in the higher sensitivity of IhW. Adjusting for this new information, the Eu/EuW combination proved quite acceptable in positive predictive value as well as overall sensitivity and specificity.

This extensive study provides the unstated but inescapable conclusion that Western blot with preadsorption of sera remains the most accurate determinant of HSV type specific serostatus [1]. Commercial enterprises have courageously developed and marketed gG-based ELISA tests. This reviewer hopes that further studies such as that of Eing et al. will encourage rapid commercial development of improved tests that incorporate other antigenic markers.

References:

1. Ashley RL. Performance and use of HSV type-specific test kits. Herpes 2002;9:38-45.

2. CDC Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;51:11-18

3. Fleming DT et al. Herpes simplex virus type 2 in the United Sates, 1976 to 1994. N Engl J Med 1997;337:1105-1111.

4. Ashley RL. Type-specific antibodies sto HSV-1 and HSV-2: review of methodology. Herpes 1998;5:33-38.

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