What evidence supports a diagnosis of syphilis?

Evidence Supporting a Diagnosis of Syphilis

The diagnosis of syphilis should be based on a combination of serological tests (both nontreponemal and treponemal) along with clinical presentation, as no single test provides sufficient diagnostic accuracy across all stages of infection. 1, 2

Serological Testing Evidence

Nontreponemal Tests (VDRL and RPR)

• Sensitivity varies significantly by stage of syphilis:
  • Primary syphilis: 62-78% sensitivity 1, 2
  • Secondary syphilis: 97-100% sensitivity 1, 2
  • Early latent syphilis: 82-100% sensitivity 1
  • Late latent syphilis: 61-75% sensitivity 1
• RPR generally shows similar or slightly higher sensitivity than VDRL across all stages 1
• Specificity of RPR is approximately 90.6% in people with HIV and 87.3% in people without HIV when evaluating genital ulcer disease 1, 2

Treponemal Tests

• Treponemal tests (FTA-ABS, TPHA) have higher sensitivity than nontreponemal tests, especially in primary syphilis 3, 4
• Recent studies show ELISA-based treponemal tests achieve 100% diagnostic performance across all stages of syphilis 4
• Using TP-PA as first-line diagnostic test yields higher sensitivity (86%) for primary syphilis than the traditional strategy of VDRL/RPR confirmed by treponemal tests (71%) 3

Direct Detection Methods

• Dark-field microscopy of lesion exudate remains the definitive method for diagnosing early syphilis 1, 5
• Spirochetes typical of Treponema pallidum were visible in 78% of primary syphilitic chancres in one large study 5
• PCR testing of lesions can serve as an alternative gold standard in settings where dark-field microscopy is unavailable 1

Special Diagnostic Considerations

Neurosyphilis Diagnosis

• No single test is perfectly sensitive and specific for neurosyphilis diagnosis 6
• VDRL-CSF is the standard serological test for CSF and is considered diagnostic when reactive in the absence of blood contamination 6
• VDRL-CSF sensitivity ranges from 49-87%, while specificity ranges from 74-100% 6
• CSF leukocyte count elevation (>5 cells/mm³) is typically present in active neurosyphilis 6

Seronegative Window Period

• Up to 14.5% of patients with primary syphilis may have negative serology at presentation 5
• Only 0.9% of patients with secondary syphilis have negative serology at presentation, with most converting to positive within one month 5

Diagnostic Pitfalls and Limitations

• Nontreponemal test titers (VDRL and RPR) are not equivalent and should not be used interchangeably for patient monitoring 1, 2
• False positives in nontreponemal tests can occur in pregnancy, autoimmune diseases, malaria, hepatitis C, HIV infection, and illicit drug use 2
• The "prozone phenomenon" (false negative due to antibody excess) can occur in up to 2% of cases, particularly in secondary syphilis, neurosyphilis, and pregnancy 1
• Serum RPR and VDRL titers should decline in a stable pattern following treatment, but a significant proportion of patients may remain serofast 7

Recommended Diagnostic Approach

• For suspected primary syphilis: Direct detection methods (dark-field microscopy or PCR) of lesion exudate combined with both nontreponemal and treponemal serological tests 1, 2
• For suspected secondary or latent syphilis: Combined testing with both nontreponemal (VDRL/RPR) and treponemal tests 1, 2
• For suspected neurosyphilis: CSF examination including VDRL-CSF, cell count, and protein, with consideration of CSF FTA-ABS which has higher sensitivity but lower specificity 6
• In HIV-infected individuals: Standard serological testing remains accurate and reliable for most patients, but direct detection methods should be considered when serological results are abnormal 1, 6