What does a raised Rapid Plasma Reagin (RPR) test but negative Treponema Pallidum Haemagglutination Assay (TPHA) result indicate?

Raised RPR with Negative TPHA: Biological False-Positive Reaction

A positive RPR with negative TPHA most commonly represents a biological false-positive (BFP) reaction rather than true syphilis infection. 1, 2

Understanding the Serologic Pattern

• The negative TPHA effectively rules out syphilis because treponemal tests (like TPHA) are highly specific for true treponemal infection and are not affected by the conditions that cause false-positive nontreponemal tests. 2

• BFP reactions occur in 0.24-1.36% of the general population, with rates varying by demographic and clinical factors. 1

• The specificity of nontreponemal tests like RPR ranges from 80.8-98.27% depending on the population tested, meaning false positives are well-documented. 1

Most Common Causes of BFP Reactions

Infectious causes:

• HIV infection is the most significant risk factor, with BFP rates of 4-10.7% in HIV-positive patients compared to 0.8-4.2% in HIV-negative patients (odds ratio 5.0-39.45). 1, 2
• Infectious mononucleosis/EBV produces distinctively high RPR titers with 10% false-positive rates. 2
• Hepatitis B is associated with 8.3% BFP rate. 1, 2
• Hepatitis C is associated with 4.5% BFP rate. 1, 2
• Malaria is a documented cause of BFP reactions. 2
• Leprosy shows 9.3-28% BFP rates. 2

Autoimmune and rheumatologic conditions:

• Systemic lupus erythematosus and connective tissue diseases show 9.5% BFP rates. 1, 2
• Rheumatoid arthritis is a documented cause. 2
• Presence of antinuclear antibodies and rheumatoid factor increases BFP risk. 2

Other causes:

• Pregnancy (0.6% BFP rate). 1, 2
• Intravenous drug use, particularly in HIV-positive patients. 1, 2
• Advanced age (9% persistently positive RPR in elderly patients). 1, 2

Clinical Characteristics of BFP Reactions

• Most BFP reactions have low titers (<1:8), though high-titer BFP (≥1:16) is possible, particularly in HIV-positive intravenous drug users. 1, 2

• BFP reactions are often transient, with seroreversion typically occurring within 9-14 weeks in most cases. 1, 2

• Only 20.5% of patients with initial BFP have persistent BFP at 18-month follow-up. 2

Recommended Clinical Approach

Immediate evaluation:

• Test for HIV infection given the strong association between HIV and BFP reactions. 1, 2
• Screen for hepatitis B and C. 1, 2
• Evaluate for autoimmune conditions if clinically indicated (check ANA, rheumatoid factor). 2
• Review for recent viral infections, particularly EBV/mononucleosis. 2

Confirm the diagnosis:

• The negative TPHA already confirms this is not syphilis, but consider repeating the treponemal test if there is high clinical suspicion. 2
• Document the RPR titer quantitatively. 1

Follow-up:

• Repeat RPR testing in 2-3 months to assess for seroreversion, which would further confirm BFP. 1, 2
• If RPR remains positive at low titer without identifiable cause, this represents a "classical BFP" that may persist. 1

Critical Pitfalls to Avoid

• Do not treat for syphilis based on RPR alone when TPHA is negative—this represents BFP, not syphilis. 2

• Be aware that in extremely rare cases of very early primary syphilis (within 1-4 weeks of infection), TPHA may not yet be positive while RPR could be reactive, but this is uncommon. 3

• Consider the prozone phenomenon if clinical suspicion for secondary syphilis is very high despite negative results—request serial dilutions. 1, 2

• Remember that endemic treponematoses (yaws, bejel) would cause both RPR and TPHA to be positive, so negative TPHA excludes these. 2