Serologic Testing for Syphilis in a Patient with No Prior Diagnosis or Treatment
Order both a nontreponemal test (RPR or VDRL) AND a treponemal test (FTA-ABS, TP-PA, or treponemal EIA/CLIA) simultaneously, as both are required to establish a syphilis diagnosis. 1
Why Both Tests Are Mandatory
- A single test type is insufficient for accurate syphilis diagnosis – the CDC explicitly states that both nontreponemal and treponemal antibodies must be detected to confirm infection 1
- Nontreponemal tests alone miss cases: RPR/VDRL sensitivity ranges from only 62-78% in primary syphilis and drops to 47-64% in tertiary disease 1
- Treponemal tests alone cannot distinguish active from past infection: these antibodies remain positive for life in 75-85% of patients regardless of treatment status 1
Recommended Testing Algorithm
Traditional Approach (CDC-Endorsed)
- Start with a nontreponemal test (RPR or VDRL) as the initial screening test 1
- If positive, confirm with a treponemal test (FTA-ABS, TP-PA, or treponemal EIA/CLIA) 1
- Request quantitative titers for the nontreponemal test (e.g., 1:4,1:16,1:64) – never accept just "positive/negative" 1
Alternative Reverse Sequence Algorithm
- Some laboratories now screen first with a treponemal EIA/CLIA, then reflex to quantitative nontreponemal testing if positive 1, 2
- This approach may not be widely recognized among clinicians but is increasingly common 2
Critical Interpretation Principles
Both tests must be reactive to diagnose syphilis:
- RPR positive + Treponemal positive = Confirms syphilis (either active infection or past treated infection; use titer and clinical context to distinguish) 1
- RPR positive + Treponemal negative = Biological false-positive RPR; investigate underlying causes (autoimmune disease, pregnancy, viral hepatitis, HIV) 1
- RPR negative + Treponemal positive = Either very early infection (test too soon), past treated infection, or late-stage disease with declining nontreponemal antibodies 1
- Both negative = Effectively rules out syphilis with >99% certainty if tested at appropriate intervals 1
Essential Concurrent Testing
- HIV testing is mandatory for every patient with confirmed syphilis – HIV co-infection alters monitoring frequency, increases neurosyphilis risk, and modifies treatment response 1, 3
Common Pitfalls to Avoid
- Never rely on nontreponemal tests alone in late-stage disease – 36-53% of tertiary syphilis cases will have negative RPR/VDRL despite active infection 4
- Do not use treponemal test titers to monitor treatment – these correlate poorly with disease activity and remain positive regardless of cure 1, 4
- Ensure sequential tests use the same methodology (RPR vs VDRL) and preferably the same laboratory, as titers are not interchangeable between methods 1
- Recognize that false-positive RPR results occur in 5.2% of the general population and are more common with HIV (10.7%), hepatitis C (4.5%), hepatitis B (8.3%), advanced age, and pregnancy (0.6%) 1
Special Considerations
- HIV-infected patients may have atypical serologic responses with unusually high, low, or fluctuating titers, though standard tests remain accurate for most 1
- In very early infection (<4 weeks post-exposure), both tests may be negative – if clinical suspicion is high, consider direct detection methods (darkfield microscopy, PCR) or repeat testing in 2-4 weeks 1
- Automated RPR methods may show titers one dilution higher than manual methods 1