Are non-treponemal tests, such as Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test, enough to rule out syphilis infection?

Non-Treponemal Tests Alone Are Not Sufficient to Rule Out Syphilis Infection

Non-treponemal tests such as RPR or VDRL are not sufficient alone to rule out syphilis infection and must be confirmed with treponemal-specific tests for accurate diagnosis. 1

Limitations of Non-Treponemal Tests

• Sensitivity limitations: Non-treponemal tests have variable sensitivity depending on the stage of infection:

  • Primary syphilis: 62-78% sensitivity
  • Secondary syphilis: 97-100% sensitivity
  • Early latent syphilis: 82.1-100% sensitivity 1

• False-negative results: Non-treponemal tests can be negative in:

  • Very early primary syphilis
  • Late-stage syphilis
  • Previously treated syphilis 2, 1

• Recent evidence concerns: A 2024 study found that among patients with clinically active secondary syphilis (confirmed by treponemal tests), 52.63% had VDRL titers less than 1:8, with 5 patients having completely non-reactive results 3

Recommended Diagnostic Approach

The CDC and other guidelines recommend two possible testing algorithms:

1. Traditional Algorithm

• Initial screening with non-treponemal test (RPR or VDRL)
• Confirmation of reactive results with treponemal test (TP-PA, FTA-ABS, EIA, or CIA) 1, 2

2. Reverse Sequence Algorithm

• Initial screening with treponemal test (EIA or CIA)
• Follow-up testing of reactive samples with non-treponemal test
• Additional treponemal testing (TP-PA or FTA-ABS) for discordant results 1, 4

Interpretation of Test Results

Non-Treponemal Result	Treponemal Result	Interpretation
Positive	Positive	Confirmed syphilis (current or past)
Positive	Negative	Likely false-positive non-treponemal test
Negative	Positive	Possible very early infection, previously treated syphilis, or late-stage syphilis
Negative	Negative	No evidence of syphilis [1]

Special Considerations

• HIV co-infection: While clinical experience suggests that HIV infection does not significantly change the performance of standard tests for syphilis diagnosis, atypical responses to non-treponemal tests (higher, lower, or delayed) may occur 2

• False-positive non-treponemal tests: These can occur in various conditions including pregnancy, autoimmune diseases, and other infections 2

• Prozone phenomenon: In some cases of secondary syphilis with very high antibody titers, non-treponemal tests may yield false-negative results due to the prozone effect 2

Clinical Implications

• Relying solely on non-treponemal tests could miss cases of syphilis, particularly in early primary or late stages of infection
• The 2024 study showing 52.63% of secondary syphilis cases with low or negative non-treponemal titers raises significant concerns about missed diagnoses 3
• When clinical suspicion is high but serologic tests are negative, additional diagnostic procedures should be pursued (repeat serology in 1-2 weeks, exclusion of prozone phenomenon, biopsy, darkfield examination, or direct fluorescent antibody staining) 2

In conclusion, while non-treponemal tests are valuable screening tools, they must always be used in conjunction with treponemal-specific tests to accurately diagnose or rule out syphilis infection.