II. Indication

  1. Syphilis (Treponema pallidum) detection
  2. Syphilis Screening at least annually for all Men who have Sex with Men and others at high risk of Syphilis
  3. Skin lesions or other clinical findings suggestive of Syphilis
  4. Confirmation of positive Screening Test
  5. Genital Ulcer

III. Background

  1. Antigen Extracts from beef heart (cardiolipin)
    1. Non-specific Syphilis antibodies bind cardiolipin

IV. Labs: Tests for detection of Treponemal Pallidum Antibody

  1. Non-Treponemal Derived Substance precipitates Antibody (False Negatives in first 4 weeks)
    1. Venereal Disease Research Laboratory (VDRL)
    2. Rapid Plasma Reagin (RPR)
    3. Automated Reagin Test (ART)
    4. Standard Test for Syphilis (STS)
  2. Treponemal Antigen precipitates Antibody (False Negatives in the first 2 weeks)
    1. Fluorescent Treponemal Antibody (FTA-ABS)
      1. Test Sensitivity: 80%
    2. Microhemagglutination - Treponema pallidum (MHA-TP)
      1. Test Sensitivity: 65% to 70%

V. Labs: Non-Antibody Tests

  1. Dark-field Microscopy
    1. Most specific if Chancre or condyloma is present
    2. Can result in immediate diagnosis in the first week without the 3 week delay witing for IgM to develop
    3. Accuracy varies with experience of technician
    4. May detect Syphilis at any stage

VI. Labs: Reverse Sequence Syphilis Screening

  1. Protocol employed by many U.S. labs as of 2022
  2. Step 1: Automated Treponemal Antibody Test
    1. Testing by enzyme immunoassay or similar allows for rapid, high volume sample screening
    2. Risk of False Positives in low risk populations
    3. Treponemal Antibody tests are positive for life after initial infection (regardless of treatment)
  3. Step 2: Nontreponemal Tests (e.g. RPR or VDRL)
    1. Confirmation testing
    2. Levels fall with treatment and over time since infection
    3. Four fold increase in titers suggests reinfection

VII. Protocol: Testing

  1. Screening
    1. Nontreponemal tests (RPR or VDRL)
      1. Syphilis Screening (positive within 3 weeks of developing primary Chancre)
      2. Syphilis RPR positive test will be returned with titer (e.g. 1:16)
      3. After treatment, by 6 months, RPR should fall by a factor of 4 (e.g. 1:4)
      4. On subsequent infection, expect the RPR titer to once again rise
    2. HIV Screening (test all patients who are positive for Syphilis)
      1. HIV coinfection with Syphilis is common
      2. HIV patients are at higher risk of Neurosyphilis
  2. Negative test with lesions present or other strong clinical indicators
    1. Repeat screening in 2-3 weeks
  3. Confirmation of positive Screening Test
    1. Fluorescent Treponemal Antibody (FTA-ABS)
    2. Microhemagglutination - Treponema pallidum (MHA-TP)
  4. Neurosyphilis CSF Evaluation
    1. See Neurosyphilis
    2. Indications for Lumbar Puncture with CSF Exam
      1. All patients with Syphilis and neurologic symptoms
      2. All patients with serologic or exam findings consistent with treatment failure
      3. HIV patient specific criteria
        1. CD4 Count <350 cells/mm3 or
        2. Rapid plasmin reagin (RPR) >1:32
  5. Monitoring response to treatment
    1. Non-Treponemal Antibody test (e.g. RPR) will normalize after treament
      1. Levels decline overtime, and then increase >4 fold with reinfection
    2. Treponemal tests (Antibody) will remain positive for life despite treatment

VIII. Interpretation: False Positives with the Non-Treponemal Tests

  1. Systemic Lupus Erythematosus
  2. Malaria
  3. Measles
  4. Endocarditis
  5. Infectious Mononucleosis
  6. Infectious Hepatitis
  7. Leprosy
  8. Lymphoma
  9. Brucellosis
  10. Atypical Pneumonia
  11. Miliary Tuberculosis
  12. Typhus
  13. Cohorts
    1. Pregnancy
    2. Advanced age
    3. Intravenous Drug Abuse
    4. Post-Vaccination state
  14. Related Treponemal infection
    1. Yaws
    2. Pinta
    3. Bejel

IX. Interpretation: False Positives with Treponemal tests

  1. Other Spirochete infections (Leptospirosis, Lyme Disease, rat bite fever)

X. Efficacy

  1. Diagnostic Test Sensitivity in Primary Syphilis
    1. Dark-field Exam of Chancre: 80%
    2. Non-Treponemal Tests (e.g. RPR): 78-86%
    3. Treponemal tests (e.g. FTA-ABS): 76-84%
  2. Diagnostic Test Sensitivity in Secondary Syphilis
    1. Dark-field Exam of Chancre: 80%
    2. Non-Treponemal Tests (e.g. RPR): 100%
    3. Treponemal tests (e.g. FTA-ABS): 100%
  3. Diagnostic Test Sensitivity in Latent Syphilis
    1. Non-Treponemal Tests (e.g. RPR): 95-100%
    2. Treponemal tests (e.g. FTA-ABS): 97-100%
  4. Diagnostic Test Sensitivity in Tertiary Syphilis
    1. CSF evaluation required (see below)
    2. Non-Treponemal Tests (e.g. RPR): 71-73%
    3. Treponemal tests (e.g. FTA-ABS): 94-96%

XII. Reference

  1. Mason and von Reinhart (2018) EM:Rap 18(6): 19-20
  2. Bakerman (1984) ABCs of Interpretive Lab Data, p. 392
  3. Larsen (1995) Clin Microbiol Rev 8:1-21 [PubMed]

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