What does a positive RPR (Rapid Plasma Reagin) test with reflex to a confirmatory test indicate and how is it treated?

What Does a Positive RPR with Reflex to Confirmatory Testing Mean?

A positive RPR test with reflex to a confirmatory treponemal test indicates possible syphilis infection that requires immediate confirmation and, if confirmed, stage-appropriate penicillin treatment. 1, 2

Understanding the Test Result

The RPR (Rapid Plasma Reagin) is a nontreponemal screening test that detects antibodies against lipid material released from damaged cells during Treponema pallidum infection. 3 When your RPR is positive, the laboratory automatically performs a confirmatory treponemal test (such as TPPA, FTA-ABS, or treponemal EIA/chemiluminescence assay) to distinguish true syphilis infection from false-positive results. 1

Interpreting the Confirmatory Test Results

If both RPR and treponemal test are positive:

• This indicates either current or past syphilis infection 1
• The RPR titer (reported quantitatively, e.g., 1:8,1:16) helps determine disease activity 2, 3
• Titers ≥1:8 strongly suggest active infection requiring treatment 2, 4
• Titers <1:8 may represent treated infection, late-stage disease, or biological false-positive 1

If RPR is positive but treponemal test is negative:

• This is a biological false-positive (BFP) reaction 1, 5
• Common causes include pregnancy (0.6% rate), HIV infection (4-10.7% rate), autoimmune diseases (especially SLE and rheumatoid arthritis), infectious mononucleosis/EBV (10% rate), hepatitis B (8.3% rate), hepatitis C (4.5% rate), malaria, leprosy, and intravenous drug use 5
• No syphilis treatment is needed, but investigate underlying causes 5

Determining Disease Stage and Treatment

Clinical Evaluation Required

Before treatment, evaluate for: 3

• Primary syphilis signs: painless ulcer/chancre at infection site (genitals, mouth, rectum)
• Secondary syphilis signs: diffuse rash (especially palms/soles), mucocutaneous lesions, generalized lymphadenopathy
• Neurologic symptoms: headache, vision changes, hearing loss, confusion, cranial nerve palsies
• Tertiary manifestations: cardiovascular symptoms, gummatous lesions
• Sexual history: timing of potential exposure, partner symptoms

Treatment Based on Stage

Primary, Secondary, or Early Latent Syphilis (<1 year duration):

• Benzathine penicillin G 2.4 million units IM as a single dose 2, 3
• Follow-up at 6 and 12 months with repeat RPR titers 2, 3
• Expect fourfold decrease in titer (e.g., 1:32 to 1:8) within 6-12 months 2

Late Latent Syphilis (>1 year or unknown duration):

• Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 2, 3
• Follow-up at 6,12,18, and 24 months 2, 3
• Expect fourfold decrease in titer within 12-24 months 2

Neurosyphilis, Ocular, or Otic Syphilis:

• Aqueous crystalline penicillin G 18-24 million units per day IV (3-4 million units every 4 hours) for 10-14 days 2, 3
• Consider adding benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing IV therapy 3
• Repeat CSF examination every 6 months until cell count normalizes 3

Critical Pitfalls to Avoid

False-Negative RPR in Active Syphilis

• RPR sensitivity drops significantly in late-stage disease: only 61-75% in late latent syphilis and 47-64% in tertiary syphilis 1
• If clinical suspicion is high (symptoms present, known exposure) but RPR is negative, request treponemal testing directly 1, 6
• The "prozone effect" can cause false-negative RPR in secondary syphilis with very high antibody titers—request serial dilutions if suspected 1

Distinguishing Treatment Failure from Reinfection

• A fourfold increase in RPR titer (e.g., 1:4 to 1:16) indicates either treatment failure or reinfection 2, 3
• Persistent low-level titers (typically <1:8) after treatment is called "serofast" and does NOT necessarily indicate treatment failure 2
• Approximately 15-25% of patients treated during primary syphilis revert to completely negative RPR after 2-3 years, but many remain serofast indefinitely 2

Monitoring Errors

• Never use treponemal test titers to monitor treatment response—they remain positive for life regardless of cure 2
• Always use the same nontreponemal test type (RPR vs VDRL) from the same laboratory for serial monitoring 2
• Do not compare titers between different test types—they are not directly comparable 2

Special Populations

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients 3
• Monitor more frequently: at 3,6,9,12, and 24 months (instead of 6-month intervals) 2, 3
• Consider CSF examination for late latent syphilis to exclude neurosyphilis 2, 3
• May have atypical serologic responses with unusually high, low, or fluctuating titers 2, 3
• Higher risk of false-negative serologic tests despite documented infection 2

Pregnant Women

• Must receive parenteral penicillin G appropriate for disease stage 3
• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after initial dose for primary, secondary, or early latent syphilis 3
• Treatment must occur >4 weeks before delivery for optimal fetal outcomes 3
• Penicillin-allergic pregnant women must undergo desensitization—no alternatives are acceptable 3

Penicillin-Allergic Non-Pregnant Patients

• Doxycycline 100 mg orally twice daily for 14 days is an alternative for primary, secondary, or early latent syphilis 2, 3
• For late latent syphilis or neurosyphilis, penicillin desensitization is strongly preferred over alternatives 2, 3

Essential Additional Testing

• All patients diagnosed with syphilis must be tested for HIV 2, 3
• Sexual partners exposed within 90 days preceding diagnosis should receive presumptive treatment even if seronegative 3
• Warn patients about Jarisch-Herxheimer reaction (fever, headache, myalgias) within 24 hours after treatment 3