Optimal Serological Testing for Herpes Simplex Virus

Introduction to Serological Testing

The Western blot/immunoblot assay is the gold standard for HSV serological testing, but type-specific glycoprotein G-based enzyme immunoassays (EIA) or chemiluminescent immunoassays (CLIA) are practical first-line serological tests, with critical attention to index values and confirmatory testing for low-positive results 1, 2, 3
The American College of Obstetricians and Gynecologists and CDC recommend type-specific HSV-2 serology for pregnant women at risk of acquiring HSV infection close to delivery, men who have sex with men, people who are HIV positive, and detecting asymptomatic infections in high-risk individuals 6, 7, 8

HSV-1 antibody detection has only 70.2% sensitivity, resulting in frequent false-negative results 1, 2, 3
HSV-2 serologic tests have serious specificity limitations that vary dramatically based on index values, with 39.8% specificity for index values 1.1-2.9 and 78.6% specificity for index values ≥3.0 1, 2, 3, 8
Patients with HSV-1 infection are significantly more likely to have false-positive HSV-2 results, especially at low index values 1, 2, 3, 4

Order a type-specific HSV-2 IgG test using glycoprotein G-based EIA or CLIA as the initial testing strategy 1, 6
Interpret results based on index value, with index values <0.9 considered negative, 0.9-1.1 considered indeterminate, and 1.1-2.9 considered low positive requiring confirmation 1, 6
Confirm low-positive results with a second assay using a different glycoprotein G antigen, which improves specificity from 93.2% to 98.7% and positive predictive value from 80.5% to 95.6% 1, 4, 5

Type-specific HSV-2 serology should be used for pregnant women at risk of acquiring HSV infection close to delivery, men who have sex with men, people who are HIV positive, and detecting asymptomatic infections in high-risk individuals 6, 7, 8
Widespread screening for HSV antibodies in asymptomatic general populations is not recommended 6, 7, 8

Reporting low-positive results without confirmation leads to false-positive diagnoses with significant psychological and relationship consequences 1, 4, 5
Testing too early after exposure will miss infections due to the 12-week window period 1, 2, 6
Using HSV-1 serology to diagnose genital herpes is unreliable due to poor sensitivity and inability to distinguish oral from genital infection 1
Ordering serology when active lesions are present misses the opportunity for definitive NAAT/PCR diagnosis 3, 9, 7