What is the clinical significance and management of a patient with a positive Treponema pallidum hemagglutination assay (TPHA) and a negative Rapid Plasma Reagin (RPR) test?

TPHA Positive and RPR Negative: Clinical Significance and Management

Primary Interpretation

A positive TPHA with negative RPR most commonly represents previously treated syphilis or late latent infection, and does not require treatment unless there is evidence of new infection, inadequate prior treatment, or clinical symptoms suggesting active disease. 1

Understanding the Serologic Pattern

This discordant pattern occurs because:

• Treponemal tests (like TPHA) remain positive for life in most patients regardless of treatment or disease activity, with only 15-25% reverting to negative after 2-3 years when treated during primary syphilis 1
• Nontreponemal tests (like RPR) correlate with disease activity and typically become non-reactive after successful treatment, though some patients remain "serofast" with persistent low titers 1, 2
• In previously treated syphilis, RPR sensitivity drops dramatically to only 30.7-56.9%, while remaining 100% sensitive in active infection 1, 2

Clinical Decision Algorithm

Step 1: Assess for Active Infection

Active syphilis is unlikely if ALL of the following are absent 2:

• No clinical signs or symptoms (chancre, rash, mucocutaneous lesions, neurologic symptoms, ocular symptoms)
• No fourfold or greater increase in RPR titer from previous testing
• No new sexual exposure to a partner with confirmed syphilis
• No documented seroconversion or new reactive treponemal test within the past 12 months

Step 2: Review Treatment History

Obtain documentation of prior treatment 1:

• If adequately treated with appropriate penicillin regimen for the stage of syphilis: no further treatment needed
• If treatment history is uncertain or inadequate: treat as late latent syphilis with benzathine penicillin G 2.4 million units IM once weekly for 3 weeks 1

Step 3: Consider Late Latent Syphilis

Important caveat: RPR can be negative in 25-39% of late latent syphilis cases 1. If the patient has:

• No documented prior treatment
• Unknown infection timing
• Risk factors for syphilis

Then treat as late latent syphilis with benzathine penicillin G 2.4 million units IM once weekly for 3 weeks 1

Critical Red Flags Requiring Immediate Action

Neurologic or Ocular Symptoms

Perform lumbar puncture if any of the following are present 1, 3:

• Neurologic symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies)
• Ocular symptoms (uveitis, vision changes, eye pain)
• Otic symptoms (hearing loss, tinnitus)

Key evidence: Neurosyphilis can occur with negative serum RPR, with studies showing only 22-42% of ocular syphilis cases have positive CSF VDRL 4. Two patients with serodiscordant results (positive treponemal, negative nontreponemal) were successfully treated for ocular syphilis despite negative CSF VDRL 4

HIV-Infected Patients

Consider lumbar puncture in HIV-infected patients with 3:

• CD4 count ≤350 cells/µL
• Any neurologic, ocular, or otic symptoms
• Late latent syphilis or syphilis of unknown duration

HIV-infected patients require more frequent monitoring (every 3 months instead of 6 months) due to atypical serologic responses 1, 2

Confirmatory Testing

Confirm the TPHA result with a second treponemal test (such as TP-PA or FTA-ABS) to rule out false-positive TPHA 5:

• In one study, 28% of TPHA-positive, RPR-negative patients were subsequently TP-PA-negative, suggesting false-positive TPHA results 5
• 23% of patients with positive treponemal immunoassay but negative RPR and negative TP-PA eventually seroreverted to negative, confirming false-positive results 5

Common Pitfalls to Avoid

• Do not assume negative RPR excludes active syphilis in patients with symptoms, as RPR sensitivity is only 30.7% in previously treated syphilis and can be negative in 25-39% of late latent cases 1, 2
• Do not use treponemal test titers to monitor treatment response - they remain positive regardless of cure 1
• Do not compare RPR and VDRL titers directly - they are not interchangeable 2
• Do not overlook ocular or neurosyphilis - these can occur with negative serum RPR and require different treatment regimens 4

Essential Additional Testing

All patients with positive syphilis serology should be 1:

• Tested for HIV infection
• Evaluated for other sexually transmitted infections
• Have sexual contacts identified and evaluated