Syphilis: Screening and diagnostic testing

This guide is about management of primary, secondary, latent and tertiary syphilis. Some information about neurosyphilis and congenital syphilis is included, however their treatment is outside the scope of this document. Individuals with these conditions should be managed by or in consultation with an infectious disease specialist or an experienced colleague.

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Screening

Screening is recommended for anyone presenting with risk factors for syphilis to prevent complications, transmission and reinfection.

Health care providers should follow local public health recommendations and laboratory screening protocols during a syphilis outbreak.

Screening in pregnancy

Universal screening is recommended for pregnant people during the first trimester or at first prenatal visit.

Repeat screening at 28-32 weeks of pregnancy (or as close to this interval as possible) and again at delivery:

Consider more frequent screening for pregnant people at high risk.  

Screen all woman who deliver a stillborn infant after 20 weeks gestation.

Other STBBIs

STBBI screening varies by age, gender/sex, medical and sexual history. Any person with STBBI risk factors should be screened for STBBIs and treated appropriately to prevent transmission and reinfection.

Syphilis increases the risk of acquisition and transmission of HIVFootnote 1.

People being evaluated or treated for a syphilis infection should be screened for:

Diagnostic testing

Consider a diagnosis of syphilis in anyone with signs or symptoms compatible with syphilis. Depending on the stage and clinical presentation, diagnostic testing may be done on blood, lesions and/or samples of cerebral spinal fluid.

Pregnant people diagnosed with infectious syphilis should be managed in consultation with an obstetric/maternal-fetal specialist. Assessment for possible congenital syphilis should be done:

Test infants presenting with signs or symptoms compatible with early congenital syphilis even if their mother was seronegative at delivery because they may have become infected near term.

Refer to the Canadian Paediatric Society's article Congenital syphilis: No longer just of historical interest for information about how to manage infants born to mothers with reactive treponemal tests (TTs) during pregnancy.

Serologic testing

Serologic testing should always be done regardless of suspected stage. Two (2) types of serologic screening algorithms are used in CanadaFootnote 6. Most provinces and territories use the reverse algorithm. Consult your local laboratory regarding testing protocols.

The traditional algorithm uses a non-treponemal test (NTT) —typically a rapid plasma reagin (RPR) test— to screen sera, followed by one (1) or two (2) TTs on the positive samples. An alternative approach is to use a reverse sequence algorithm, which uses a TT to screen and a quantitative NTT to confirm the positives. A second confirmatory TT may be done in some laboratories.

TTs such as the treponemal-specific enzyme immunoassay (EIA) are more sensitive tests for syphilis. Several commercial EIAs have been developed to detect IgG or IgM to specific T. pallidum antigens. Although EIA is highly sensitive, it may lack specificity; therefore if the EIA screen is positive, a second treponemal-specific test [e.g. T. pallidum particle agglutination (TP-PA), microhemagglutination assay for T. pallidum (MHA-TP), fluorescent treponemal antibody absorption(FTA-ABS), or INNO-LIA™ (if available)] can confirm the diagnosis.

Once reactive, TTs usually remain reactive for life regardless of treatment, although 15% to 25% of people will serorevert if treated during the primary stageFootnote 7. False positive serologic tests for syphilis may occur with certain conditions such as collagen-vascular disease, pregnancy, injection drug use, Lyme Disease or a condition inherent to the test or testing technique.

NTT antibody titres usually correlate with disease activity and can help stage infection, monitor response to treatment and detect re-infection. The NTT may be non-reactive in cases of early primary, late latent syphilis or tertiary syphilis. If these diagnoses are suspected, it is appropriate to add a TT to the initial screen or, in the case of primary syphilis, to repeat both the TT and NTT after two (2) to four (4) weeks, when testing may have been done before seroconversion(incubation period).

Refer to the follow-up section for recommendations related to monitoring of NTT results post treatment.

Syphilis serodiagnostic interpretation

Note: The following information is provided for general guidance. Health care professionals should consider yaws, pinta, bejel and Lyme disease in the differential diagnosis when NTT and/or TT are positive. Interpret syphilis serology results in consultation with an experienced colleague. People with reactive syphilis serology should be tested for HIV, as HIV infection may affect treatment and recommended follow-up.

Traditional algorithm
Initial screen with NTT RPR First TT TP-PA Second TT FTA-ABS Possible interpretation
Non-reactive Non-reactive Reactive
  • Primary syphilis with compatible history/clinical findings
Reactive
(dilutions can vary)
Reactive Reactive
  • Syphilis, any stageFootnote *
  • Previously treated syphilis
Non-Reactive Reactive Reactive
  • Previously treated syphilis
  • Early primary syphilis
  • Late latent/tertiary syphilis
Reactive Non-reactive Non-reactive
  • False positive
Table 1 - Footnote *

Note: RPR titre ≥ 8 are more likely to be infectious syphilis.

Return to Table 1 - Footnote * referrer

Reverse algorithm
Initial screen with TT: EIA NTT: RPR Second TT: TP-PA, FTA-ABS or INNO-LA Possible interpretation
Table 2 - Footnote *

Note: RPR titre ≥ 8 are more likely to be infectious.

Return to Table 2 - Footnote * referrer

Negative Not done Not done
  • Not a case. Repeat serology if at risk for syphilis
Borderline/ indeterminate Non-reactive Non-reactive or indeterminate
  • Repeat serology as seroconversion may not have occurred yet (incubation period)
  • If repeat serology remains unchanged, it is not a case of syphilis
Borderline/ indeterminate Non-reactive Reactive
  • Early primary syphilis
  • Late latent/tertiary syphilis
  • Previously treated syphilis
  • If laboratory does not do the confirmatory test, repeat serology to determine if the person is seroconverting
  • If repeat serology remains unchanged it is not a case of syphilis
Positive Reactive
or
non-reactive
Non-reactive
  • False positive
  • EIA without 2nd TT:
    • Early primary syphilis
    • Late latent/tertiary syphilis
    • Previously treated syphilis
Positive Reactive
or
non-reactive
Indeterminate
  • Repeat serology to determine if it is early primary, late latent/tertiary or previously treated syphilis
  • If repeat serology is unchanged this is likely to be a false positive
  • EIA without 2nd TT:
    • Syphilis, any stage, except with non-reactive NTT, then all but secondary stageFootnote *
    • Previously treated syphilis
Positive Non-reactive Reactive
  • Early primary syphilis
  • Late latent/tertiary syphilis
  • Previously treated syphilis
Positive Reactive Reactive
  • Syphilis, any stageFootnote *
  • Previously treated syphilis

Direct tests (Non-serological)

Non-serological tests are done on primary and secondary lesions. Contact your laboratory to determine the type and availability of direct tests for syphilis from suspect lesions (e.g. chancres, condylomata lata).

When latent or tertiary syphilis are suspected, conduct a physical and neurologic examination to evaluate for the presence of signs of tertiary syphilis. Chest radiographs for the evaluation of cardiovascular syphilis in asymptomatic people is not routinely recommendedFootnote 8.

Additional investigation, including long bone x-ray and lumbar puncture may be indicated when congenital syphilis is suspected. Work with a paediatric specialist to evaluate and test.

Lesions samples

Nucleic Acid Amplification Tests (NAAT) are very sensitive and specific. They can be used to detect T. pallidum in mucosa and skin from lesions of suspected primary and secondary syphilis and may be an option for oral/rectal lesions.

Dark-field microscopy is an older test that can detect the characteristic morphology and movement of T. pallidum spirochetes from genital lesions of early syphilis.
Note: Very few laboratories continue to offer dark-field microscopy in Canada.

The direct fluorescent antibody test (DFA) is another older test that can detect T. pallidum from genital lesions: it is not reliable for oral or rectal lesions as they may cross-react with specimens of non-pathogenic treponemes.

When ulcers are present, consider herpes simplex virus and (if epidemiologically appropriate) chancroid and/or lymphogranuloma venereum in the differential diagnosis.

Cerebrospinal fluid (CSF)

A diagnosis of neurosyphilis is usually based on a combination of reactive serologic results, abnormalities of CSF cell count or protein or a reactive CSF-VDRL with or without clinical manifestationsFootnote 9.

Indications for CSF examination in all people (including those who are HIV-positive) with suspected or confirmed syphilis, include:

Some experts also recommend CSF examination in HIV-positive persons with infectious syphilis and a CD4 ≤ 350 cells/µL and VDRL/RPR ≥ 1:32 dilutionsFootnote 11, Footnote 12. CSF abnormalities in people with HIV-positive (e.g. elevated WBC and elevated protein) are common in persons with HIV, even without syphilis. It is unclear whether these findings are significant in people without neurologic symptoms.

While some studies have reported CSF abnormalities in people with CD4 ≤ 350 cells/µL and VDRL/RPR ≥ 1:32 dilutionsFootnote 12, CSF examination has not been associated with improved outcomes if the neurologic evaluation is normal.  

CSF for cell count and differential, protein, VDRL and/or FTA-ABSFootnote 10 tests should be performed. CSF-VDRL is highly specific but not sensitive. The CSF FTA-ABS is highly sensitive but non-specific for neurosyphilis.
Note: A negative CSF FTA-ABS result may help to exclude a diagnosis of neurosyphilisFootnote 10.

CSF examination is not recommended in late latent syphilis unless other criteria for CSF examination are met. In asymptomatic adults and youth co-infected with HIV, a detailed neurological evaluationFootnote 12, close serologic and clinical follow-up post treatment is recommended.

References

Footnote 1

Solomon MM, Mayer KH, Glidden DV, et al. Syphilis predicts HIV incidence among men and transgender women who have sex with men in a preexposure prophylaxis trial. Clinical Infectious Diseases. 2014;59(7):1020-1026.

Return to footnote 1

Footnote 2

Wendel Jr GD, Sheffield JS, Hollier LM, Hill JB, Ramsey PS, Sánchez PJ. Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clinical Infectious Diseases. 2002;35(Supplement_2):S200-S209.

Return to footnote 2

Footnote 3

Klein VR, Cox SM, Mitchell MD, Wendel GD,Jr. The jarisch-herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75(3 Pt 1):375-380.

Return to footnote 3

Footnote 4

Sheffield JS, Sánchez PJ, Morris G, et al. Congenital syphilis after maternal treatment for syphilis during pregnancy. Obstet Gynecol. 2002;186(3):569-573.

Return to footnote 4

Footnote 5

Sheffield JS, Wendel Jr GD. Syphilis in pregnancy. Clin Obstet Gynecol. 1999;42(1):97-106.

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Footnote 6

Tsang RS, Radons SM, Morshed M. Laboratory diagnosis of syphilis: A survey to examine the range of tests used in canada. Canadian Journal of Infectious Diseases and Medical Microbiology. 2011;22(3):83-87.

Return to footnote 6

Footnote 7

Singh AE, Romanowski B. Syphilis: Review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev. 1999;12(2):187-209.

Return to footnote 7

Footnote 8

Dabis R, Radcliffe K. Is it useful to perform a chest X-ray in asymptomatic patients with late latent syphilis? Int J STD AIDS. 2011;22(2):105-106.

Return to footnote 8

Footnote 9

Dumaresq J, Langevin S, Gagnon S, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early syphilis. J Clin Microbiol. 2013;51(12):4060-4066. doi: 10.1128/JCM.01989-13 [doi].

Return to footnote 9

Footnote 10

Golden MR, Marra CM, Holmes KK. Update on syphilis: Resurgence of an old problem. JAMA. 2003;290(11):1510-1514. doi: 10.1001/jama.290.11.1510 [doi].

Return to footnote 10

Footnote 11

Libois A, De Wit S, Poll B, et al. HIV and syphilis: When to perform a lumbar puncture. Sex Transm Dis. 2007;34(3):141-144. doi: 10.1097/01.olq.0000230481.28936.e5 [doi].

Return to footnote 11

Footnote 12

Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: Association with clinical and laboratory features. J Infect Dis. 2004;189(3):369-376. doi: JID30874 [pii].

Return to footnote 12

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