Non-Treponemal Test

Aka: Non-Treponemal Test, Indirect Syphilis Serology, Non-Treponemal Antibody Syphilis Test, Rapid Plasma Reagin, RPR, Serum Toluidine Red Unheated Serum Test, TRUST, Venereal Disease Research Laboratory, VDRL

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II. Indications: Syphilis Diagnosis

  1. Non-Treponemal Tests are used in Syphilis Screening and diagnosis protocols
    1. Standard sequence (step 1) Syphilis Screening and confirmed by Treponemal Tests (e.g. TP-PA)
    2. Reverse sequence (step 2) Syphilis Screening as a confirmation of a positive rapid immunoassay
  2. Both RPR and VDRL use cardiolipin/lecithin Antigen extracts to detect Syphilis
    1. VDRL is preferred in CSF testing for Syphilis
    2. RPR Is preferred for serum testing (simple, rapid)
      1. RPR uses carbon particles, allowing it to be performed on a paper card
      2. RPR may therefore be read with the naked eye (as opposed to VDRL which requires a microscope)

III. Mechanism

  1. RPR and VDRL are Non-Treponemal Test based on development of cardiolipin and lecithin antibodies in Syphilis
    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. RPR and VDRL use an Antigen 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 both RPR and VDRL
  3. Antigen mix precipitates Antibody
    1. Non-specific Syphilis antibodies bind Antigens, and result in observed Agglutination in either RPR or VDRL

IV. Labs

  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)

V. Efficacy: Non-Treponemal Tests

  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]

VI. Causes: Negative (Non-Reactive)

  1. Normal (Syphilis not detected)
  2. 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

VII. Causes: Positive (Reactive)

  1. See Syphilis False Positive Test
  2. Syphilis RPR positive test will be returned with titer (e.g. 1:16)
    1. After treatment, by 6 months, RPR should fall by a factor of 4 (e.g. 1:4)
    2. On subsequent infection, expect the RPR titer to once again rise
    3. Confirm all positive RPR tests with the more specific Fluorescent Treponemal Antibody Test
  3. False Positives
    1. Autoimmune disorders or Malignancy
      1. Systemic Lupus Erythematosus
      2. Rheumatoid Arthritis
      3. Lymphoma
    2. Cohorts
      1. Pregnancy
      2. Advanced age
      3. Intravenous Drug Abuse (IVDA)
      4. Recent Immunizations (e.g. COVID19 Vaccine)
    3. Recent infections
      1. Malaria
      2. Measles
      3. Endocarditis
      4. Infectious Mononucleosis
      5. Infectious Hepatitis
      6. Leprosy
      7. Miliary Tuberculosis
      8. Leptospirosis
      9. Lyme Disease
      10. Brucellosis
      11. Atypical Pneumonia
      12. Rat Bite Fever
      13. Typhus
      14. Other Treponemal infections (Yaws, Pinta, Bejel)
        1. False Positive in both Treponemal and nontreponemal tests

VIII. References

  1. Clement (2014) JAMA 312(18):1922-3 +PMID: 25387191 [PubMed]
  2. Lum (2023) Rapid Plasma Reagin, StatPearls, Treasure Island< FL [PubMed]
    1. https://www.ncbi.nlm.nih.gov/books/NBK557732/

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Related Studies

Ontology: Rapid Plasma Reagin Measurement (C0201405)

Definition (NCI) The determination of the antibodies produced by cellular damage caused by Treponema pallidum present in a sample.
Definition (NCI_CDISC) A measurement of the antibodies produced by cellular damage caused by Treponema pallidum (syphilis) in a biological specimen.
Concepts Laboratory Procedure (T059)
SnomedCT 19869000
LNC LP70657-9
English Rapid Plasma Reagin Measurement, RPR, rapid plasma reagin (rpr) test, rapid plasma reagin test, Rapid Plasma Reagin, Rapid plasma reagin test, RPR test, Rapid plasma reagin test (procedure)
Spanish RPR, Prueba de reagina plasmática rápida, prueba RPR, prueba de la reagina plasmática rápida (procedimiento), prueba de la reagina plasmática rápida
Portuguese RPR, Prova de reagina plasmática rápida
French Test RPR (test rapide de la réagine plasmatique), Test rapide de la réagine plasmatique
German RPR Test, schnelles Plasma Reagin-Test
Czech Rychlá reaginová reakce, RRR
Italian Test rapido per reagine plasmatiche
Dutch rapid plasma reagine test, RPR
Japanese 血漿レアギン迅速試験, RPR, ＲＰＲ, ｹｯｼｮｳﾚｱｷﾞﾝｼﾞﾝｿｸｼｹﾝ
Hungarian Plazma reagin gyorsteszt, RPR
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: VDRL test (C0201406)

Concepts Laboratory Procedure (T059)
SnomedCT 7786006, 143189002
LNC LP70656-1
English VDRL test (procedure), Venereal Disease Research Laboratory (VDRL) test, VDRL - VD research lab test, Venereal dis research lab test, Venereal diseases research laboratory test, VDRL, vdrl test, venereal disease research laboratory (VDRL) test, VDRL test, Venereal Disease Research Laboratory test, Venereal Disease Research Laboratory test (procedure), Venereal Disease Research Laboratory (VDRL) test (procedure), Venereal diseases research laboratory test (procedure), VDRL - Venereal diseases research laboratory test, VDRL test, NOS
Spanish prueba VDRL, prueba VDRL (procedimiento), VDRL (enfermedades venéreas), prueba del Laboratorio de Investigación de Enfermedades Venéreas, prueba del Venereal Disease Research Laboratory, prueba del Venereal Disease Research Laboratory (procedimiento), prueba del Venereal Disease Research Laboratory (VDRL) (procedimiento), prueba de laboratorio de investigación de enfermedades venéreas, prueba del Venereal Disease Research Laboratory (VDRL)
Portuguese VDRL
Dutch VDRL
French Test VRDL
German VDRL
Italian VDRL
Czech VDRL
Japanese ＶＤＲＬ, VDRL
Hungarian VDRL
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Toluidine red unheated serum test (C0201409)

Concepts Laboratory Procedure (T059)
SnomedCT 19815002
English Toluidine red unheated serum test, Toluidine red unheated serum test (procedure)
Spanish prueba con rojo de toluidina en suero no pre - calentado (procedimiento), prueba con rojo de toluidina en suero no pre - calentado
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Indirect Serologic Test for Syphilis (Reagin / VDRL Test) (C1254815)

Concepts Laboratory Procedure (T059)
English Indirect Serologic Test for Syphilis (Reagin / VDRL Test)
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Syphilis test, non-treponemal antibody (C3702085)

Concepts Laboratory Procedure (T059)
CPT 1011977
English Syphilis test, non-treponemal antibody
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pathology and Laboratory Medicine

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