What is the appropriate next step in management for a patient with an equivocal treponemal antibody test and a negative rapid plasma reagin (RPR) result?

Management of Equivocal Treponemal Antibody with Negative RPR

Repeat the treponemal test using a different treponemal assay (TP-PA or line immunoassay) to resolve the equivocal result; if the second treponemal test is negative, no treatment is indicated, but if positive, proceed with clinical evaluation and staging. 1

Understanding the Serologic Pattern

• An equivocal treponemal test with a negative RPR represents an indeterminate result that requires further clarification before making any treatment decisions. 1
• Both a reactive nontreponemal test (RPR/VDRL) AND a reactive treponemal test are required to diagnose syphilis—a single test type alone is insufficient. 1
• Equivocal treponemal results occur at the threshold of detection and may represent very early infection, resolving past infection, or technical variability rather than true infection. 2

Immediate Next Steps

1. Repeat Treponemal Testing with Alternative Method

• Order a confirmatory treponemal test using a different platform (e.g., if the initial equivocal result was from an EIA/CLIA, order TP-PA or INNO-LIA). 1, 2
• TP-PA demonstrates 100% specificity and superior sensitivity (94.5-100% across all stages except late latent where it ranges 86.8-98.5%), making it the preferred adjudication test for discordant or equivocal results. 2
• The FTA-ABS should not be used to resolve equivocal results because it has poor sensitivity in primary syphilis (only 78.2%) compared to TP-PA or immunoassays (94.5-96.4%). 2

2. Clinical Evaluation

• Perform a focused physical examination looking specifically for: 1

  • Genital, oral, or anal ulcers/chancres (primary syphilis)
  • Diffuse maculopapular rash involving palms and soles (secondary syphilis)
  • Mucocutaneous lesions (condyloma lata, mucous patches)
  • Generalized lymphadenopathy
  • Neurologic symptoms (cranial nerve palsies, meningismus, confusion)
  • Ocular symptoms (vision changes, eye pain, photophobia)

• Obtain a detailed sexual history including: 1

  • Number and HIV status of partners in past 90 days
  • History of prior syphilis diagnosis or treatment
  • Symptoms suggestive of primary or secondary syphilis in past 12 months

3. HIV Testing

• Test for HIV infection immediately if status is unknown, as HIV co-infection significantly affects monitoring frequency, increases neurosyphilis risk, and can cause atypical serologic responses. 1

Interpretation Algorithm

If Repeat Treponemal Test is NEGATIVE:

• No treatment is indicated. 1
• The initial equivocal result was likely a false-positive or technical artifact. 1
• No further syphilis testing is needed unless new high-risk exposure occurs or clinical signs develop. 1

If Repeat Treponemal Test is POSITIVE:

• The patient has either current syphilis infection or past treated syphilis. 1
• The negative RPR does NOT exclude syphilis, particularly in late latent or tertiary disease where RPR sensitivity drops to 61-75% and 47-64%, respectively. 1
• Proceed with staging evaluation: 1
  • If clinical signs of primary or secondary syphilis are present → treat as early syphilis with benzathine penicillin G 2.4 million units IM × 1 dose
  • If no clinical signs but infection likely acquired within past 12 months → treat as early latent syphilis with benzathine penicillin G 2.4 million units IM × 1 dose
  • If infection duration >12 months or unknown → treat as late latent syphilis with benzathine penicillin G 2.4 million units IM weekly × 3 weeks

If Neurologic or Ocular Symptoms Present:

• Perform lumbar puncture with CSF examination immediately (cell count, protein, CSF-VDRL). 1
• Treat as neurosyphilis with aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days if CSF is abnormal. 1

Special Considerations for Negative RPR with Positive Treponemal Test

• In late-stage syphilis, 25-39% of late latent cases have non-reactive RPR, making the negative RPR unreliable for excluding infection in this population. 1
• If clinical suspicion remains high despite negative RPR: 1
  • Screen for symptoms of neurosyphilis (headache, vision changes, hearing loss, confusion)
  • Screen for tertiary manifestations (cardiovascular symptoms, gummatous lesions)
  • Consider direct detection methods (darkfield microscopy, PCR) if lesions are present

Common Pitfalls to Avoid

• Never treat based on an equivocal treponemal test alone—always confirm with a second treponemal assay using a different method. 1
• Do not assume a negative RPR excludes syphilis in patients with positive treponemal tests, especially if infection may be late-stage. 1
• Do not use FTA-ABS to resolve equivocal results—TP-PA is superior for this purpose. 2
• Do not delay HIV testing—it must be performed in all patients with confirmed or suspected syphilis. 1
• Recognize that HIV-infected patients may have atypical serologic responses with unusually low, high, or fluctuating titers. 1

If Patient Has High Clinical Suspicion but Confirmatory Testing is Delayed

• In patients with characteristic clinical findings (chancre, rash, mucocutaneous lesions) and high-risk exposure, empirical treatment with benzathine penicillin G 2.4 million units IM may be initiated while awaiting confirmatory treponemal testing, especially if the patient is at high risk for loss to follow-up. 1