What are the pros and cons of antibody testing for Herpes Simplex Virus (HSV)?

Pros and Cons of HSV Antibody Testing

HSV antibody testing has important clinical utility in specific scenarios—particularly for diagnosing asymptomatic infections in high-risk populations and confirming HSV-2 status when lesions are absent—but significant test limitations including poor HSV-1 sensitivity and HSV-2 false-positives at low index values make widespread screening inappropriate and require careful interpretation with confirmatory testing when indicated. 1, 2

Pros of HSV Antibody Testing

Diagnostic Utility in Specific Clinical Scenarios

• Identifies asymptomatic HSV-2 infections, which is clinically important since many transmissions occur during asymptomatic periods when patients are unaware of their infection status 3

• Useful when active lesions are absent or missed, as HSV molecular assays should not be obtained without genital ulcers due to intermittent viral shedding 1

• Confirms diagnosis in late presenters, particularly when intrathecal HSV-specific IgG antibodies are detected 10-14 days after illness onset in encephalitis cases, especially when earlier CSF was not tested by PCR 1

• Differentiates between HSV-1 and HSV-2 infection for prognostic counseling, as HSV-2 causes more frequent recurrences and subclinical shedding than genital HSV-1 2, 3

Appropriate Screening Populations

• Recommended for pregnant women at risk of acquiring HSV near delivery, where new infection poses significant neonatal risk 4, 3

• Indicated for men who have sex with men and HIV-positive individuals as part of comprehensive STI screening 2, 4

• Helps identify serodiscordant couples where one partner has known HSV-2 and the other's status is unknown, allowing targeted counseling about transmission risk 2

Long-term Infection Marker

• Antibodies persist indefinitely after infection, providing a permanent marker of past exposure and ongoing latent infection with HSV-2 2

• High sensitivity for HSV-2 detection at 92%, making it reliable for ruling in infection when positive with adequate index values 1, 4

Cons of HSV Antibody Testing

Significant Test Performance Limitations

• HSV-1 serologic assays lack sensitivity, with commercial tests detecting antibodies in only 70-88% of confirmed cases, meaning up to 30% false-negative results even in patients with recurrent HSV-1 genital lesions 1, 5, 6

• HSV-2 tests have poor specificity at low index values, with index values of 1.1-2.9 showing only 39.8% specificity compared to Western blot, while values ≥3.0 improve to 78.6% specificity 1, 2

• False-positive HSV-2 results are common in HSV-1 infected individuals, particularly at low index values, creating diagnostic confusion 1, 2

• Commercial assays show variable performance, with some platforms (DiaSorin) yielding false-positive results in nearly one of every three positive HSV-2 tests based on population seroprevalence 6

Clinical Interpretation Challenges

• Cannot distinguish recent from long-standing infection, as type-specific IgG antibodies develop within weeks and persist for life, limiting utility for determining timing of acquisition 2

• Window period of up to 12 weeks means false-negative results occur after recent acquisition, requiring repeat testing 12 weeks post-exposure 1, 4

• Cannot determine anatomic site of infection, as serology cannot distinguish oral from genital HSV infection 1, 3

• Does not establish causation in CNS disease, as antibody detection in serum identifies past or recent infection but not necessarily the cause of encephalitis 1

Need for Confirmatory Testing

• Low positive results require confirmation with second assay using different glycoprotein G antigen to avoid false-positive diagnoses 1, 2

• Biokit HSV-2 rapid assay as confirmatory test improves specificity from 93.2% to 98.7%, and positive predictive value from 80.5% to 95.6%, but access is limited 1, 2

• Western blot is gold standard but has limited availability in clinical settings, restricting ability to confirm equivocal results 1, 4

• Single test results can be unreliable, with 12-30% false-negative rates even in patients with recurrent DNA-positive genital lesions 5

Public Health and Screening Concerns

• Widespread screening is not recommended by CDC and USPSTF due to test limitations, potential for false-positives, and lack of proven interventions to prevent transmission 2, 4, 3

• High costs and potential psychological harms from false-positive results in low-prevalence populations outweigh benefits of routine screening 7

• Stigma associated with HSV diagnosis can cause significant psychological distress, particularly when diagnosis is based on false-positive serology 6

Key Clinical Pitfalls to Avoid

• Never use serology alone to diagnose active genital lesions—NAAT/PCR from lesions is first-line with >90% sensitivity and specificity 4, 3

• Do not accept HSV-2 index values <3.0 as definitive positive without confirmatory testing, as specificity is unacceptably low 1, 2

• Avoid testing during the window period and repeat at 12 weeks if recent exposure is suspected 1, 4

• Do not rely on a single negative antibody test in patients with recurrent genital lesions, as false-negatives occur in 10-30% of confirmed cases 5

• Intrathecal antibody responses may be delayed or absent when antiviral therapy is started early in encephalitis, limiting diagnostic utility 1