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Syphilis (Treponema pallidum)

Test Codes: 12075, 20210, 36126, 93802

Syphilis is a sexually transmitted infection (STI) caused by the spirochete bacterium Treponema pallidum. The incidence of syphilis has been steadily rising in the United States since 2001. Syphilis can cause serious health problems without treatment. Infection develops in stages: primary, secondary, latent, and tertiary. Each stage can have different signs and symptoms. See the Centers for Disease Control and Prevention Syphilis Fact Sheet here for additional details. 

A presumptive diagnosis of syphilis requires use of 2 laboratory serologic tests: a nontreponemal test (ie, Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] test) and a treponemal test (ie, the T pallidum passive particle agglutination [TP-PA] assay, various EIAs, chemiluminescence immunoassays [CIAs] and immunoblots, or rapid treponemal assays).1-3 Use of only one type of serologic test (nontreponemal or treponemal) is insufficient for diagnosis and can result in false negative results among persons tested during primary syphilis and false positive results among persons without syphilis or with previously treated syphilis.1,2

Both the CDC and the United States Preventive Services Task Force (USPSTF) recommend routine syphilis screening for men who have sex with men (MSM), individuals with HIV, and other individuals at increased risk for syphilis (Table 1). Syphilis screening is also recommended for individuals being considered for or receiving HIV PrEP because syphilis is associated with higher risk of HIV infection.MSM are disproportionately impacted by syphilis, accounting for 47% of all male primary and secondary syphilis cases in the US in 2021. The prevalence of syphilis is also higher in certain geographic regions and among certain races and ethnicities.2,3 For most at-risk populations, screening is recommended at least annually, with more frequent screening (eg, every 3-6 months) should be considered based on individual risk and local prevalence.2-3

Table 1: MSM, men who have sex with men; STI, sexually transmitted infection.

a Based on local and institutional prevalence. 


Click on the table to open in a new window.

Diagnosis of syphilis requires a treponemal-specific assay and nontreponemal assay. After diagnosis, a nontreponemal assay can be used for monitoring patients on treatment. Quest Diagnostics offers a comprehensive test menu for screening, confirming, and monitoring syphilis.

Quest’s test offering includes treponemal and nontreponemal assays that can be ordered as stand-alone, traditional, or reverse algorithm tests. See Table 2 or access the Quest Test Directory for the many syphilis testing options available through Quest. 

Table 2 showing tests and panels including syphilis testing*.

*Components of panels can be ordered separately.

CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; FTA, fluorescent treponemal antibody; IA, immunoassay; IFA, immunofluorescence assay; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.

Reflex test performed at an additional charge and are associated with an additional CPT® code(s).

This test was developed, and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the US Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

The CDC does not recommend IgM testing in newborns (<30 days old).2

Diagnosis of neurosyphilis depends on a combination of CSF tests (eg, cell count, protein, or reactive CSF-VDRL) in the presence of reactive serologic test results and neurologic signs and symptoms.2


Click on the table to open in a new window.

Treatment is available and, in general, consists of penicillin-based antibiotics, for which effectiveness in treating syphilis is well established clinically. Treatment for syphilis is guided by its progression in the patient and the disease stage. For additional information on treatment guidelines, please refer to the CDC’s Sexually Transmitted Infections Treatment Guidelines, 2021.

Nontreponemal antibody titers typically decrease upon syphilis treatment, so nontreponemal tests can be used to monitor a patient’s response to treatment (Table 3). Quest offers both RPR (test code 799) and VDRL (test code 30509) nontreponemal testing that can be used to monitor treatment response. Each monitoring test should use the same assay (either RPR or VDRL) and be performed by the same laboratory so that results are comparable over time.

Table 3 showing frequency of follow-up Nontreponemal Tests to monitor response to syphilis treatment.

More frequent follow-up testing is recommended for HIV-infected syphilis patients. 


Click on the table to open in a new window.

Treatment response is generally defined as a reduction in nontreponemal titer by at least 2 dilutions within the monitoring period. However, titers may decrease by fewer than 2 dilutions (ie, inadequate serologic response), including in about 10% to 20% of primary and secondary syphilis patients.2 Inadequate serologic response is more likely to occur in patients who are older, have low baseline titers, or have later stages of disease.2 The CDC recommends these patients receive additional clinical and serologic evaluations, including reevaluation for HIV infection.2

Treatment failure can also cause nontreponemal titers to decrease by fewer than 2 dilutions, or even to increase.2 One cause of treatment failure is neurosyphilis; a central nervous system (CNS) infection requires a different treatment regimen and can act as a reservoir of T pallidum. When treatment failure is suspected, the CDC recommends a cerebral spinal fluid (CSF) examination to test for neurosyphilis.2 Increasing nontreponemal titers after treatment can also be caused by reinfection, which serologic tests cannot distinguish from treatment failure.


  1. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2022. Updated January 30, 2024. Accessed February 8, 2024.
  2. Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1
  3. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for syphilis infection in nonpregnant adolescents and adults: US Preventive Services Task Force reaffirmation recommendation statement. JAMA. 2022;328(12):1243-1249. doi:10.1001/jama.2022.15322
  4. Centers for Disease Control and Prevention. US Public Health Service: Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2021 Update: A Clinical Practice Guideline. 2021. Accessed October 12, 2023.


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