Conditions Causing False-Positive RPR Tests
RPR tests can be falsely positive in numerous conditions beyond syphilis, most commonly in pregnancy, autoimmune diseases, HIV infection, infectious mononucleosis/EBV, malaria, leprosy, endemic treponematoses (yaws, bejel), and intravenous drug use. 1
Most Common Causes of Biological False-Positive (BFP) RPR
Infectious Conditions
- Infectious mononucleosis/EBV infection: This produces distinctively high RPR titers (median 28.5 RU) compared to other BFP causes, particularly in young patients 2. Studies show 10% false-positive rates in patients with EBV/CMV infection 1
- HIV infection: Significantly increases BFP risk with 4-10.7% false-positive rates compared to 0.8-4.2% in HIV-negative patients (OR 5.0-39.45) 1. The association is particularly strong when combined with injection drug use 1
- Malaria: Documented cause of BFP reactions 1
- Hepatitis C virus: Associated with 4.5% BFP rate 1
- Hepatitis B virus: 8.3% BFP rate, statistically associated with increased BFP risk 1
Endemic Treponematoses
- Yaws (T. pallidum pertenue): Cross-reacts with RPR; 23/24 patients with yaws tested positive by RPR 1
- Bejel (T. pallidum endemicum): Also causes positive RPR due to cross-reactivity 1
- Leprosy: 14/50 (28%) leprosy patients without syphilis history had reactive RPR 1. Another study found 25/270 (9.3%) lepromatous leprosy patients had BFP 1
Autoimmune and Rheumatologic Conditions
- Systemic lupus erythematosus (SLE) and connective tissue diseases: RPR showed 7/74 (9.5%) BFP in patients with autoimmune connective tissue diseases 1
- Rheumatoid arthritis: Documented as a cause of BFP 1
- Antinuclear antibodies and rheumatoid factor positivity: Associated with BFP reactions 1
Pregnancy
- Pregnancy: BFP rate of 0.6% in pregnant women compared to 1.1% in non-pregnant women 1. Among pregnant women with VDRL titers <1:8,31% were confirmed BFP 1
Other Conditions
- Intravenous drug use (IVDU): Strong association with BFP, particularly in HIV-positive patients 1. Notably, high-titer false positives (≥1:16) can occur in IVDUs 1
- Neoplasms: Most common underlying condition in BFP cases (22.1%) 2
- Advanced age: Elderly patients show 9% persistently positive RPR with negative confirmatory testing 1
- Digestive diseases: 8.4% of BFP cases 2
Key Clinical Characteristics of BFP Reactions
Titer Patterns
- Most BFP reactions have low titers (typically <1:8), with median 1.9 RU 2
- Exception: EBV-IM produces high titers despite being BFP, with median 28.5 RU 2
- High-titer BFP (≥1:16) is rare but possible, particularly in HIV-positive IVDUs 1
Temporal Characteristics
- BFP reactions are often transient: Only 20.5% of IVDUs with initial BFP had persistent BFP at 18-month follow-up 1
- Seroreversion typically occurs within 9-14 weeks in most BFP cases 1
Critical Diagnostic Approach
Confirmation Strategy
- Always confirm positive RPR with treponemal tests (FTA-ABS, TPPA, or TPHA) to distinguish true syphilis from BFP 1
- Treponemal tests are NOT affected by conditions causing BFP and will be negative in true BFP reactions 3
Important Caveats
- RPR specificity in primary syphilis is only 87-91% even in true disease, so false positives must be distinguished from true positives 1
- Consider prozone effect (false-negative due to very high antibody titers) when clinical suspicion is high but RPR is negative; request serial dilutions 3
- In Lyme disease testing, 5% of patients with syphilis or positive RPR may have false-positive Lyme serology, demonstrating bidirectional cross-reactivity 1