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Serum, CSF, swabs and tissue

Clinical background

In recent years, increased cases of syphilis (infection caused by the spirochete Treponema pallidum subsp. pallidum) have been reported worldwide, including Australia, and particularly in men who have sex with men. Indigenous Australians continue to have significantly higher incidence rates than non-indigenous.

Clinical stages of syphilis

​​​​​​​Primary syphilis: Transmission usually occurs via direct contact with an infectious lesion during sex. The median incubation period before clinical manifestations is 21 days (range 3–90 days). After this time, an ulcerated lesion (chancre), usually painless, with a raised indurated margin, appears at the site of inoculation, for example, genitalia, posterior pharynx, anus. Regional lymphadenopathy may be present. Chancres heal spontaneously within 3–6 weeks, even in the absence of treatment. Dissemination of the spirochete also occurs during this primary stage of infection.

​​​​​​​Secondary syphilis: Weeks to a few months later, approximately 25% of those with untreated infection develop a systemic illness, secondary syphilis. Manifestations may include rash, fever, lymphadenopathy, alopecia, hepatitis, nephritis or nephrotic syndrome, gastrointestinal ulceration and uveitis.

​​​​​​​Latent syphilis (early latent and late latent): This describes a phase of infection without signs or symptoms and which is detected by blood test. Early latent syphilis is defined as less than two years duration and during which the individual remains infectious. Late latent syphilis is when the infection is likely to have been acquired more than two years ago, is no longer infectious to other people, but treatment is very important to prevent long-term consequences.

Most sexual transmission occurs during primary, secondary syphilis and early latent syphilis. However, vertical transmission from mother to baby can occur up to nine years after the initial infection.

​​​​​​​Late syphilis: This refers to the stage beyond 2 years of infection and includes asymptomatic (late latent) as well as symptomatic infection (tertiary syphilis).

​​​​​​​Tertiary syphilis: This includes cardiovascular and neuro-syphilis and can present 20–30 years after infection.

T. pallidum readily crosses the placenta. Vertical transmission can occur at any time during pregnancy and at any stage of the disease. Perinatal transmission occurs in 50% of patients with primary or secondary syphilis, with fewer congenital infections among women with early latent (40%), late latent (10%), and tertiary disease (10%).


Direct detection

Nowadays, dark ground illumination (DGI) of specimens collected from chancres is rarely performed. Syphilis PCR is available and can be performed on a swab (taken from a chancre or mucosal lesion), tissue biopsy (for example, condylomata) or cerebrospinal fluid (CSF).

Treponemal serology

Serology is the commonest laboratory method used for diagnosing syphilis. There are two types of serological tests:

  • Non-treponemal tests, for example, VDRL, RPR – these identify antibodies related to infection but which are not specific for the bacterium itself.
  • Treponemal tests, for example, TPHA (T. pallidum haemagglutination assay), TPPA (T. pallidum particle agglutination assay), treponemal EIA/CLIA and western blot. Specific IgM testing is also available and is applicable in the neonatal setting.

Tests currently used in Australia

Screening tests

The usual screening test performed is an immunoassay (EIA or CLIA) for treponemal antibody. If the result is non-reactive, that result is reported without any further testing and with repeat testing recommended if possible recent exposure has occurred. If the result of the treponemal antibody screening test is reactive, further testing (RPR and TPHA or TPPA) is performed reflexively. The combination of results obtained is usually able to establish if there is serological evidence of infection and to identify it as past or current.

Automated assays are generally used to screen for syphilis due to their rapid turn-around time and high sensitivity. False-positive screening tests occur relatively frequently but additional testing (RPR, TPPA) and/or repeat testing can identify them as such.

Rapid plasma reagin (RPR)

RPR is an example of a non-treponemal test. This measures IgM and IgG antibodies that react with a cardiolipin-cholesterol-lecithin antigen. These anti-lipoidal antibodies can be produced not only as a consequence of treponemal infection, but also during autoimmune diseases or other diseases where tissue damage occurs. RPR is usually in high titre with recent infection and falls over time, either in response to treatment or during late syphilis. VDRL is another non-treponemal test, usually performed only on CSF.

Treponema pallidum haemagglutination assay (TPHA) or T. pallidum particle agglutination assay (TPPA)

The TPHA/TPPA is a specific treponemal antibody and should be detectable in all patients with secondary and late syphilis. During primary syphilis, as with the EIA, treponemal antibodies may take 1–4 weeks to appear after the chancre develops. After infection, the TPHA/TPPA and initial screening EIA stay positive indefinitely, regardless of treatment. Fluorescent treponemal antibody (FTA-AB) and western blot are available as second-line confirmatory tests in reference laboratories, and may be helpful in difficult cases.

Treponemal tests do not differentiate syphilis from infection with T. pallidum subsp. pertenue, which causes yaws, T. pallidum subsp. endemicum, the cause of non-venereal endemic syphilis, or T. carateum, which causes pinta.

Molecular testing

Treponemal PCR has replaced dark-field examination of suspected chancres. PCR can also be performed on CSF, although, as the sensitivity of the test is undetermined, a negative result does not rule out CNS involvement.

Interpretation of syphilis serology tests

Other issues

​​​​​​​CSF examination is indicated in those with reactive treponemal serology and suspected neurosyphilis, ophthalmic syphilis, treatment failure (failure of RPR to fall after treatment for primary, secondary or early latent syphilis) or HIV-infected patients with latent syphilis. A positive VDRL, or positive treponemal PCR are both specific for tertiary syphilis.

​​​​​​​Pregnancy – If treponemal serology is reactive during pregnancy, the likelihood of fetal infection depends on the stage of syphilis and gestational age when the mother is treated. Paediatric assessment of the newborn is essential. FTA-AB (fluorescent treponemal antibody) IgM testing is available for infants, and correlation of the infant’s (not cord blood) RPR titre and the mother’s RPR titre at delivery is important (see Australian Society of Infectious Diseases Perinatal Infection Guidelines, cited in references).

​​​​​​​Co-infection with other STIs needs to be excluded, particularly HIV. Partners should be assessed and treated and follow-up undertaken to monitor response to therapy.

​​​​​​​Notification – Syphilis is a nationally notifiable disease (refer to NNDS).


Treatment of choice is penicillin. Dosage and duration is dependent on the stage of the infection. Therefore, it is important to properly stage the infection prior to commencing treatment.


For further information on the epidemiology and treatment of syphilis, refer to:

  1. Management of Perinatal Infections [Internet]. Australasian Society for Infectious Diseases, 2014. [Accessed Jun 2022] <>
  2. Syphilis [Internet]. Australian Government Department of Health, 2021. [Accessed Jun2022] <>
  3. Syphilis [Internet]. Centers for Disease Control and Prevention (CDC), 2022. [Accessed Jun 2022] <>
  4. eTG complete [Internet]. Therapeutic Guidelines, 2022. [Accessed Jun 2022] <> (Keyword syphilis)