Treponema pallidum - Syphilis

Primary Author: Couturier, Marc Roger, PhD, D(ABMM).

  • Key Points
  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Treponema pallidum, the spirochete bacteria that cause syphilis, cannot be cultured. Ideally, early syphilis could be diagnosed by direct detection methods, such as dark-field examination, but these methods are often unavailable and may miss up to 30% of primary cases. Therefore, syphilis is usually diagnosed with serologic tests.

Traditional serologic screening for syphilis initially uses nontreponemal testing, with confirmation of reactive results using a treponemal test. New “reverse algorithms” are gaining popularity due to the development of point-of-care enzyme and chemiluminescence immunoassays (EIA/CIA). Reverse algorithms initially use treponemal testing (usually EIA or CIA), with confirmation of reactive results using a nontreponemal test.

Traditional versus Reverse Algorithm Syphilis Testing (Pros and Cons)
 

Traditional testing

Begins with nontreponemal testing (quantitative)

Reverse testing

Begins with treponemal testing (qualitative)

Pros
  • Detects active infection
  • Use of nontreponemal testing followed by treponemal test for confirmation results in a high positive predictive value
  • Inexpensive and rapid
  • Detects early primary and treated infection that might be missed with traditional algorithm
  • Automated – low cost if used in high-volume settings
  • No  false negatives as a result of prozone reaction
Cons
  • Reactivity declines over time
  • Often misses early primary or treated infection
  • Moderately high rate of false positives for initial nontreponemal tests
    • Reactive test requires confirmation with treponemal tests
  • Reactivity lasts over a lifetime
    • Cannot detect active versus previously treated infection
    • Follow-up nontreponemal test with titer required for all reactive tests to detect active infection
  • Highly sensitive; not highly specific
    • In low-risk populations, frequent false-positive test results (initial reactive treponemal with negative confirmatory nontreponemal test) requires confirmation with second treponemal test
Source: http://www.cdc.gov/std/syphilis/Syphilis-Webinar-Slides.pdf
Nontreponemal and Treponemal Tests
Nontreponemal Tests (Quantitative) ARUP Tests
  • Rapid plasma reagin (RPR)
  • Venereal Disease Research Laboratory (VDRL)
  • Toluidine red unheated serum test (TRUST)

Rapid Plasma Reagin (RPR) with Reflex to Titer and TP-PA Confirmation 0050478

Rapid Plasma Reagin (RPR) with Reflex to RPR Titer or T. pallidum Antibody by Particle Agglutination 2007443

Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471

Treponema pallidum (VDRL), Serum with Reflex to Titer 0093093

Treponemal Tests (Qualitative/Semi-Quantitative) ARUP Tests
  • Chemiluminescence immunoassays (CIAs)
  • Enzyme immunoassays (EIAs)
  • Treponema pallidum particle agglutination (TP-PA)
  • Fluorescent treponemal antibody absorbed (FTA-ABS)
  • Microbead immunoassays (MBIAs)

Treponema pallidum Antibody by TP-PA 0050777

Treponema pallidum Antibody, IgG by ELISA 0050920

Indications for Testing

  • Suspicion of syphilis (classic lesions, known exposure, high-risk behaviors)
  • Use as one of the tests for concurrent sexually transmitted infections (STI) testing

Laboratory Testing

  • Traditional and reverse sequence syphilis screening overview (CDC)
    • Refer to Key Points section for treponemal and nontreponemal testing comparisons
  • Dark-field exam only if chancre (primary) or condylomata lata (secondary) is present
  • Neurosyphilis
    • In suspected cases, order Venereal Disease Research Laboratory (VDRL) test on cerebrospinal fluid (CSF) with concurrent rapid plasma reagin (RPR) serum test
    • If RPR is negative and a high index of suspicion for neurosyphilis remains, perform fluorescent treponemal antibody absorbed (FTA-ABS)on serum
      • Some patients have nonreactive nontreponemal test results in late neurosyphilis
    • CNS is often an affected site in a patient with HIV
  • For further testing recommendations, see the Syphilis Testing Algorithm

Differential Diagnosis

  • All pregnant females should be screened at initial prenatal visit using Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin (RPR) test (traditional testing algorithm)
    • Follow positive results with fluorescent treponemal antibody absorbed (FTA-ABS) or Treponema pallidum antibody by particle agglutination (TP-PA) testing (USPSTF, ACOG, CDC, AAFP recommendations [see table below])
  • STI screening recommendations for pregnant women (STI/Syphilis) node 1192

  • Screen all females at increased risk
  • STI screening recommendations for sexually active nonpregnant women (STI/Syphilis) node 1218

  • HIV/syphilis co-testing
    • Patient with newly diagnosed HIV should have syphilis testing, and patient with newly diagnosed syphilis should have HIV testing
    • If patient has a negative test result but continues to engage in high-risk behavior, retest in 3-12 months
  • Syphilis screening recommendations for men
    • USPSTF (2004; reaffirmed 2016)
      • No screening if not engaging in high-risk behaviors
      • If engaging in high-risk behaviors, screen for syphilis and HIV
    • CDC
      • Screen for HIV in all men who seek medical care
      • Men who have sex with men – test annually for rectal and urethral gonorrhea and pharyngeal chlamydia; annual syphilis testing is recommended
  • Treatment follow-up
    • Nontreponemal tests  measure IgM and IgG antibodies; best for monitoring treatment or for testing for reinfection
      • Positive titers are used to follow response to therapy for infected patients
        • Titers should decrease with effective treatment
        • Serofast state – nontreponemal antibodies decline in titers but fail to completely revert to nonreactive (patient likely “a cure”)
      • Rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) titers (serum testing)
        • Use same test serially (cannot interchange titer results)
    • Neurosyphilis – CSF titers with VDRL test
      • Titers should decrease with effective treatment

Treponema pallidum subspecies pallidum is the causative agent of venereal syphilis, a sexually transmitted infection (STI).

Epidemiology

  • Incidence (CDC, 2014)
    • ~55,000 new cases per year in U.S.
    • Varies by region and ethnicity
      • Black men have 5-fold incidence compared to white men
    • Incidence has increased in last 5-10 years
      • Highest increase is in men having sex with men
        • Often associated with high-risk behavior, as well as co-infection with HIV
  • Age – highest rates in third decade (20-29 years)
  • Sex – M>F
  • Transmission  
    • Sexual contact
    • Maternal vertical transmission

Organism

  • T. pallidum subspecies pallidum is a member of the Spirochaetales order, Spirochaetaceae family, which causes venereal syphilis and is distinct from the subspecies that cause  the following
    • Yaws (T. pallidum subspecies pertenue)
    • Pinta (T. pallidum subspecies carateum)
    • Endemic syphilis (T. pallidum subspecies endemicum)
  • The Spirochaetales order also includes the following
  • Leptospira spp. (Leptospiraceae family)
  • Borrelia spp., including B. burgdorferi (Spirochaetaceae family)

Risk Factors for Syphilis

  • Early age at onset of sexual activity
  • HIV infection
  • Gonorrhea infection
  • Multiple sex partners
  • Non-Caucasian race
  • Nonuse of barrier methods of birth control
  • Previous history of STI

Clinical Presentation (adapted from Clement, 2014)

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Rapid Plasma Reagin (RPR) with Reflex to Titer and TP-PA Confirmation 0050478
Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination

Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471
Method: Semi-Quantitative Charcoal Agglutination

Limitations 

False positives may be caused by HIV, herpes simplex virus (HSV), malaria, intravenous drug use (IVDU), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), pregnancy, leprosy, endemic treponematoses

Treponema pallidum (VDRL), Serum with Reflex to Titer 0093093
Method: Semi-Quantitative Flocculation

Limitations 

Use rapid plasma reagin (RPR) preferentially to decrease false-positive rate

False positives may be caused by HIV, HSV, malaria, IVDU, SLE, RA, pregnancy, leprosy, endemic treponematoses

Rapid Plasma Reagin (RPR) with Reflex to RPR Titer or T. pallidum Antibody by Particle Agglutination 2007443
Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination

Treponema pallidum Antibody, IgG by ELISA 0050920
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Treponema pallidum Antibody by TP-PA 0050777
Method: Semi-Quantitative Particle Agglutination

Limitations 

Cannot differentiate between IgG and IgM antibodies

Compares favorably to FTA test but slightly less sensitive in untreated early primary syphilis

Cannot be tested with CSF

Treponema pallidum Antibody, IgG by IFA (FTA-ABS), Serum 0050477
Method: Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

May be falsely positive in some cases of systemic lupus erythematosus, pregnancy, and leprosy

Cannot be tested with CSF

Guidelines

Cantor AG, Pappas M, Daeges M, Nelson HD. Screening for Syphilis: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2016;315(21):2328-2337.

U.S. Preventive Services Task Force. Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009; 150(10): 705-9. PubMed

Wolff T, Shelton E, Sessions C, Miller T. Screening for syphilis infection in pregnant women: evidence for the U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009; 150(10): 710-6. PubMed

Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015 MMWR Recomm Rep. 2015; 64(RR-03): 1-137. PubMed

General References

Clement ME, Okeke L, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014; 312(18): 1905-17. PubMed

French P. Syphilis. BMJ. 2007; 334(7585): 143-7. PubMed

Ho EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011; 121(12): 4584-92. PubMed

Mattei PL, Beachkofsky TM, Gilson RT, Wisco OJ. Syphilis: a reemerging infection. Am Fam Physician. 2012; 86(5): 433-40. PubMed

Morshed MG, Lee M, Jorgensen D, Isaac-Renton JL. Molecular methods used in clinical laboratory: prospects and pitfalls. FEMS Immunol Med Microbiol. 2007; 49(2): 184-91. PubMed

Roett MA, Mayor MT, Uduhiri KA. Diagnosis and management of genital ulcers. Am Fam Physician. 2012; 85(3): 254-62. PubMed

Seña AC, White BL, Sparling F. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010; 51(6): 700-8. PubMed

Tucker JD, Bu J, Brown LB, Yin Y, Chen X, Cohen MS. Accelerating worldwide syphilis screening through rapid testing: a systematic review. Lancet Infect Dis. 2010; 10(6): 381-6. PubMed

Walker GJ, Walker DG. Congenital syphilis: a continuing but neglected problem. Semin Fetal Neonatal Med. 2007; 12(3): 198-206. PubMed

Zetola NM, Engelman J, Jensen TP, Klausner JD. Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection. Mayo Clin Proc. 2007; 82(9): 1091-102. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Owen WE, Martins TB, Litwin CM, Roberts WL. Performance characteristics of six IMMULITE 2000 TORCH assays. Am J Clin Pathol. 2006; 126(6): 900-5. PubMed

Welch RJ, Litwin CM. Evaluation of two immunoblot assays and a Western blot assay for the detection of antisyphilis immunoglobulin g antibodies. Clin Vaccine Immunol. 2010; 17(1): 183-4. PubMed

Medical Reviewers

Last Update: August 2016