Syphilis Serology

Aka: Syphilis Serology, Syphilis Antibody, Syphilis Testing, Treponema Pallidum Antibody Measurement, Syphilis Screening, Syphilis Diagnosis, Syphilis False Positive

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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. Labs: Non-Treponemal Tests

  1. Background
    1. Non-Treponemal Test (Syphilis Serology)
      1. Syphilis infection and its associated cellular injury releases multiple Antigens
      2. Released Antigens (e.g. cardiolipin, lecithin) trigger Antibody development in Syphilis infected patients
    2. Antigen is an extract from beef heart (Non-Treponemal Derived Substance)
      1. Combination of Cholesterol, cardiolipin and lecithin (extracts of beef heart)
      2. Antigen mix is a similar for RPR and VDRL
    3. Antigen mix precipitates Antibody
      1. Non-specific Syphilis antibodies bind Antigens, and result in observed Agglutination (RPR, VDRL)
  2. Tests
    1. Venereal Disease Research Laboratory (VDRL)
      1. VDRL mixes serum and Antigen on a glass slide, and uses light microscopy to visualize Agglutination
    2. Rapid Plasma Reagin (RPR)
      1. RPR uses a a disposable card with impregnated carbon particles (allows for reading with the naked eye)
      2. Agglutination (clumping) indicates serum contains IgG or IgM Antibody to RPR Antigen
      3. Similar to VDRL Test, but faster and more simple to perform (RPR does not require a microscope)
    3. Serum Toluidine Red Unheated Serum Test (TRUST)
      1. Similar, to RPR, but impregnates paint particles into disposable cards
      2. TRUST is typically associated with a higher Test Sensitivity than RPR
    4. Other tests
      1. Automated Reagin Test (ART)
      2. Standard Test for Syphilis (STS)
  3. Efficacy
    1. Serum Test Specificity: 85-99%
      1. See False Positive causes below
    2. Serum Test Sensitivity in untreated Syphilis
      1. Primary Stage (Chancre stage)
        1. False Negatives are most common in the first 4 weeks
        2. After one week: 30%
        3. After three weeks: 90%
      2. Secondary Stage: 100%
      3. Tertiary Stage: 90%
      4. Latent Stage: may be unreactive
    3. CSF Test Sensitivity
      1. VDRL has a higher Test Sensitivity in CSF samples (Neurosyphilis) than RPR
      2. Marra (2012) Sex Transm Dis 39(6):453-7 +PMID: 22592831 [PubMed]
  4. False Negative Causes
    1. Testing too early after infection (esp. first 4 weeks)
    2. Prozone Phenomenon
      1. High Antibody levels result in a paradoxically negative sample
  5. False Positives
    1. See Non-Treponemal Test
    2. Recent infections (e.g. Malaria, HIV, Tuberculosis)
    3. Other Treponemal organisms (Yaws, Pinta, Bejel)
    4. Autoimmune disorders (Systemic Lupus, Rheumatoid Arthritis)
    5. Pregnancy
    6. Recent Immunizations (e.g. COVID19 Vaccine)
    7. Intravenous Drug Abuse

IV. Labs: Treponemal Specific Tests

  1. Background
    1. Treponemal Antigen precipitates Antibody (False Negatives in the first 2 weeks)
    2. Treponemal Specific Tests are identifying Treponemal antibodies
      1. Contrast with Non-Treponemal Tests which identify cardiolipin and lecithin antibodies
    3. Treponemal Tests do NOT differentiate Treponemal species
      1. Other Treponemal infections (Yaws, Pinta, Bejel) will cause false positive Treponema pallidum
  2. Rapid Immunoassays (used as first step in reverse sequence Syphilis Screening below)
    1. Methadologies (dozens of available immunoassays)
      1. Enzyme immunoassay (EIA)
      2. Chemiluminescence immunoassays (CIA)
      3. Microbead Immunoassays (MBIA)
    2. Composite Immunoassay efficacy
      1. Test Specificity >94% (except 83% for TrepSure)
      2. Test Sensitivity: 94 to 100%
        1. Primary Syphilis: >94% (most assays)
        2. Secondary Syphilis: 100%
        3. Early Latent Syphilis: 95% to 100%
        4. Late Latent Syphilis: 92% to 100%
  3. Manual Assays (highest Test Specificity, used as definitive confirmatory test)
    1. Treponema Pallidum Particle Agglutination Assay (TP-PA)
      1. Highest efficacy of the Manual Treponemal Assays
      2. Test Specificity: 99%
      3. Test Sensitivity
        1. Primary Syphilis: 86 to 100%
        2. Secondary Syphilis: 100%
        3. Early Latent Syphilis: 94 to 100%
        4. Late Latent Syphilis: 87 to 100%
    2. Fluorescent Treponemal Antibody (FTA-ABS)
      1. Test Specificity: 87-100%
      2. Test Sensitivity
        1. Primary Syphilis: 78 to 100%
        2. Secondary Syphilis: 93 to 100%
        3. Early Latent Syphilis: 94 to 100%
        4. Late Latent Syphilis: 84 to 93%
    3. Microhemagglutination - Treponema pallidum (MHA-TP)
      1. Test Specificity: 99%
      2. Test Sensitivity
        1. Primary Syphilis: 46 to 89%
        2. Secondary Syphilis: 90 to 100%
        3. Early Latent Syphilis: 94 to 100%
        4. Late Latent Syphilis: 97%
  4. References
    1. Park (2020) Clin Infect Dis 71(Suppl 1):S13-20 +PMID: 32578866 [PubMed]

V. Labs: Dark-field Microscopy

  1. Most specific test if primary or Secondary Syphilis with active lesions available to sample
    1. Most specific if Chancre or Condyloma Latum is present
    2. May detect Syphilis at any stage if an active lesion may be sampled
  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 and a negative test does not exclude Syphilis

VI. Protocol: 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 (EIA, CLIA) 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 requires human read cards/slides for Agglutination
    2. Levels fall with treatment and over time since infection
    3. Four fold increase in titers suggests reinfection
  4. Step 3: Manual manual Treponema pallidum–specific assay (e.g. TP-PA Agglutination Assay)
    1. Indicated if there is a discrepancy, with a positive step 1, but a negative step 2
    2. Not needed if Step 1 and Step 2 are both positive

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. 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%

IX. Resources

  1. Diagnostic Tests for Syphilis
    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999316/

X. Reference

  1. Kirk, McHugh and Parnell (2023) Crit Dec Emerg Med 37(8): 23-9
  2. Mason and von Reinhart (2018) EM:Rap 18(6): 19-20
  3. Bakerman (1984) ABCs of Interpretive Lab Data, p. 392
  4. Larsen (1995) Clin Microbiol Rev 8:1-21 [PubMed]

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Related Studies

Ontology: False-positive serological test for syphilis (C0159128)

Concepts Finding (T033)
ICD9 795.6
ICD10 R76.2
SnomedCT 207499000, 207501008, 158689005, 158687007, 274684006
English False pos.serol.syph. NOS, False posit.serol.syph.test, False positive serological syphilis test, False positive serological syphilis test NOS, [D]False positive serological syphilis test (context-dependent category), [D]False positive serological syphilis test NOS (context-dependent category), [D]False pos.serol.syph. NOS, [D]False posit.serol.syph.test, [D]False positive serological syphilis test, [D]False positive serological syphilis test NOS, False-pos serol test-syphilis, False pos sero test-syph, False positive serological test for syphilis, [D]False positive serological syphilis test NOS (situation), [D]False positive serological syphilis test (situation), False-positive serological test for syphilis, False-positive serological test for syphilis (finding), false-positive; serology for syphilis, false; positive serological test for syphilis, positive serological test for syphilis; false, positive; serology for syphilis, false, serology; syphilis, false-positive, serology; syphilis, positive, false, syphilis; serology, false-positive
Spanish [D]resultado falso positivo en prueba serológica para sífilis (categoría dependiente del contexto), [D]resultado falso positivo de prueba serológica para sífilis, SAI (categoría dependiente del contexto), [D]resultado falso positivo de prueba serológica para sífilis, SAI, [D]resultado falso positivo en prueba serológica para sífilis, [D]resultado falso positivo en prueba serológica para sífilis (situación), [D]resultado falso positivo de prueba serológica para sífilis, SAI (situación), Prueba serológica para la sífilis falsamente positiva, prueba serológica para sífilis: falso positivo (hallazgo), prueba serológica para sífilis: falso positivo
German Falsch-positiver serologischer Syphilistest, falsch positive Luesserologie
Korean 매독의 가양성 혈청 시험
Portuguese Teste serológico falso-positivo da sífilis
Czech Sérologická reakce na syfilis falešně pozitivní
Dutch vals positieve serologische test voor syfilis, positief; serologie voor syfilis, vals, positieve serologische test voor syfilis; vals, serologie; syfilis, positief, vals, serologie; syfilis, vals-positief, syfilis; serologie, vals-positief, vals-positief; serologie voor syfilis, vals; positieve serologische test voor syfilis, Vals positieve serologisch test voor syfilis
Italian Reazione sierologica falsamente positiva della sifilide
French Test sérologique faussement positif pour la syphilis
Japanese 梅毒血清反応偽陽性, ﾊﾞｲﾄﾞｸｹｯｾｲﾊﾝﾉｳｷﾞﾖｳｾｲ
Hungarian Álpozitív szifilisz szerológiai vizsgálat
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Treponema pallidum antibody measurement (C0919842)

Definition (MSH) Serologic tests for syphilis.
Concepts Laboratory Procedure (T059)
MSH D013588
SnomedCT 165779003, 269830006, 143185008, 165787002, 143194002, 165788007, 40675008, 269828009
CPT 86780
English Serodiagnoses, Syphilis, Serodiagnosis, Syphilis, Syphilis Serodiagnoses, Syphilis Serodiagnosis, syphilis serodiagnosis, Syphilis titer test NOS, Syphilis titre test NOS, SERODIAG SYPHILIS, SYPHILIS SERODIAG, syphilis test, syphilis test (lab test), Antibody; Treponema pallidum, TREPONEMA PALLIDUM, ANTIBODY TREPONEMA PALLIDUM, Treponema pallidum, Treponema pallidum antibody, Syphilis test, Syphilis test NOS, syphilis serology, test syphilis, syphilis tests, Test;syphilis serology, syphilis testing, serologic syphilis test, serologic test for syphilis, serology syphilis, Treponema pallidum antibody measurement, Assay for Treponema pallidum antibody, Analysis for antibody, Treponema pallidum, Syphilis infect. titer, Syphilis infect. titre, Syphilis serology (procedure), Syphilis titer test NOS (procedure), Serum Syphilis Test, Serologic test for syphilis, Syphilis infectious titer test, Syphilis infectious titre test, Syphilis serology, Serologic test for syphilis (procedure), Syphilis infectious titer test (procedure), Serologic test for syphilis, NOS, Treponema pallidum antibody measurement, NOS, syphilis serology test
Swedish Syfilisserodiagnostik
Czech syfilis - sérodiagnóza, Vyšetření na syfilis NOS, Protilátky proti Treponema pallidum, Reakce na syfilis
Finnish Kupan serodiagnoosi
French Sérodiagnostic de syphilis, Sérodiagnostic de la syphilis, Anticorps anti-treponema pallidum, Test de la syphilis SAI, Test de la syphilis
Russian VASSERMANA REAKTSIIA, KANA REAKTSIIA, SIFILISA SERODIAGNOSTIKA, ВАССЕРМАНА РЕАКЦИЯ, КАНА РЕАКЦИЯ, СИФИЛИСА СЕРОДИАГНОСТИКА
Japanese カーンテスト, 梅毒血清テスト, 梅毒血清学的テスト, Wassermann反応, ワッセルマン反応, ﾊﾞｲﾄﾞｸｹﾝｻNOS, ﾊﾞｲﾄﾞｸﾄﾚﾎﾟﾈｰﾏｺｳﾀｲ, ﾊﾞｲﾄﾞｸｹﾝｻ, 梅毒検査, 梅毒検査ＮＯＳ, 梅毒トレポネーマ抗体, Kahnテスト, 梅毒血清反応
Croatian LUES, SERODIJAGNOSTIKA
Spanish Prueba de sífilis NEOM, Prueba de sífilis, Anticuerpos anti-Treponema Pallidum, ensayo de titulación para diagnostico de sífilis, SAI, ensayo de titulación para diagnostico de sífilis, SAI (procedimiento), Diagnóstico Serológico de la Sífilis, medición de anticuerpos anti - Treponema pallidum, prueba para diagnóstico de títulos infecciosos de T. pallidum (procedimiento), prueba para diagnóstico de títulos infecciosos de T. pallidum, prueba serológica para la detección de sífilis (procedimiento), prueba serológica para la detección de sífilis, Serodiagnóstico de la Sífilis
Portuguese Análise de sífilis, Análise de sífilis NE, Anticorpo de Treponema pallidum, Sorodiagnóstico da Sífilis
Italian Test per la sifilide NAS, Anticorpo anti-treponema pallidum, Test per la sifilide, Sierodiagnosi della sifilide
Dutch syfilistest NAO, syfilistest, Treponema pallidum-antistof, Syfilis, serodiagnose, Syfilis, serologische diagnostiek
German Syphilistest, Syphilistest NNB, Treponema pallidum-Antikoerper, Syphilis-Serodiagnostik
Polish Odczyn Kahna, Serodiagnostyka kiły, Odczyn Wassermanna
Hungarian Syphilis vizsgálat k.m.n., Treponema pallidum antitest, Syphilis vizsgálat
Norwegian Serologisk syfilistest, Serodiagnostikk, syfilis
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Treponema test positive (C2748134)

Concepts Laboratory or Test Result (T034)
English Treponema test positive
Spanish Prueba de Treponema positiva
Portuguese Teste de Treponema positivo
Italian Test per Treponema positivo
French Test Treponema positif
German Treponema-Test positiv
Dutch Treponema-test positief
Czech Test na průkaz treponema pozitivní
Japanese ﾄﾚﾎﾟﾈｰﾏｹﾝｻﾖｳｾｲ, トレポネーマ検査陽性
Hungarian Treponema vizsgálat pozitív
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pathology and Laboratory Medicine

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