False-Positive Syphilis Testing: Confirmation and Causes
A suspected false-positive syphilis screening test should be confirmed using a treponemal-specific test (FTA-ABS, TP-PA, or TPHA), and if the initial screen was treponemal-based, confirm with a nontreponemal test (RPR/VDRL) followed by a different treponemal assay if discordant.
Confirmation Algorithm
Traditional Screening (Nontreponemal First)
- When a nontreponemal test (RPR or VDRL) is reactive, confirm with a treponemal test (FTA-ABS, TP-PA, or TPHA) 1
- If the treponemal test is nonreactive, this represents a biological false-positive (BFP) 1
- Most BFPs occur at low titers (≤1:4), representing over 90% of false-positives 2
- However, high-titer false-positives (≥1:16) can occur, particularly in HIV-positive injection drug users 1
Reverse Sequence Screening (Treponemal First)
- When a treponemal EIA/CIA is reactive initially, follow with a nontreponemal test (RPR/VDRL) 3
- Among sera reactive on treponemal screening, 56.7% had nonreactive RPR tests 3
- Of these discordant results, 31.6% were also nonreactive by confirmatory treponemal testing (TP-PA or FTA-ABS), representing true false-positives 3
- The false-positive rate is 2.9 times higher in low-prevalence populations 3
Common Causes of False-Positive Results
Pregnancy
- False-positive rate: 0.6% in pregnant women 1
- Lower than non-pregnant females (1.1%) 1
- Among pregnant women with VDRL titers <1:8, 31% were confirmed as false-positives 1
Autoimmune Conditions
- Systemic lupus erythematosus and connective tissue diseases are well-established causes 1
- In patients with autoimmune connective tissue diseases, 7/74 had false-positive RPR and 6/74 had false-positive VDRL 1
- No false-positives occurred in healthy blood donors in the same study 1
HIV Infection
- HIV infection increases false-positive risk substantially 1
- HIV-positive individuals have a 10-fold higher rate of false-positives (2.1% vs 0.24%) 1
- Among HIV-positive patients, 6.9% had false-positives compared to 0.2% in HIV-negative patients (OR 39.45) 1
- The false-positive rate was 4% in HIV-positive patients versus 0.8% in HIV-negative patients (OR 5.0) 1
Hepatitis C Virus
- HCV infection is independently associated with false-positives 4
- 4% of HCV-infected women had false-positives compared to 1% of uninfected women (OR 3.3) 4
- After controlling for HIV and injection drug use, HCV-infected women still had higher rates (6% vs 1%, OR 7.62) 4
Other Infectious Diseases
- Leprosy: 14/50 leprosy patients without syphilis history had reactive RPR but negative FTA 1
- Yaws and bejel: Cross-reactivity occurs with other treponemal species 1
Age-Related Factors
- Elderly patients (≥60 years) have higher false-positive rates (0.34% vs 0.25%) 1
- Very high-titer false-positives (≥1:128) are more common in patients over 60 years (OR 2.68) 2
- Individuals under 18 years and over 45 years are at increased risk 5
Injection Drug Use
- Injection drug users have elevated false-positive rates 1
- Among 229 injection drug users with initial false-positives, only 20.5% had persistent false-positives at 18-month follow-up 1
Critical Pitfalls to Avoid
Do Not Dismiss High-Titer Positives as False
- 1% of false-positives can have titers ≥1:32 2
- High-titer false-positives (≥1:16) are documented, especially in HIV-positive injection drug users 1
- 654 cases of high-titer false-positives (≥1:32) were identified in a large surveillance study 2
Monitor for Rising Titers
- 14% of individuals with false-positives demonstrated 4-fold titer increases 2
- Serial testing over at least 6 months is necessary to distinguish acute from chronic false-positives 6
- Most acute false-positives resolve within 10 weeks (25/30 cases) 1
Consider Coagulation Disorders
- Coagulation function abnormalities are associated with false-positive results 5
- Treponemal antibody titer levels can help assess false-positive likelihood 5