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The Ins and Outs of Serologic Testing for Syphilis

Roberts, James R. MD

doi: 10.1097/01.EEM.0000831224.17224.03
    syphilis, serologic testing, CME:
    Secondary syphilis is one of only a few rashes that occur on the palms and soles. The rash has many characteristics, but is usually multiple raised erythematous lesions or scaly brown macules.

    Syphilis has not received much attention over the past few years despite the number of U.S. cases soaring by 74 percent since 2015, largely because health news has been consumed with the COVID-19 pandemic. But the Centers for Disease Control and Prevention said the rate of primary and secondary syphilis rose 11 percent during 2018 and 2019 alone, following historic lows in 2000 and 2001. (

    It is certainly a complicated disease, and the varied clinical presentations can challenge even the most experienced physician. The ED is often the place where patients with syphilis first have contact with the medical community.

    The disease occurs in primary, secondary, and tertiary stages, and each has protean manifestations, from open sores to rashes to CNS involvement. Syphilis is spreading because the disease and its presentations are so complex that many physicians just don't understand it.


    Many of the intricacies of diagnosis and treatment cannot be handled in the ED because of this. A one-time physician visit is not the answer, and referral for follow-up, consultation with specialists, and additional testing and possible treatments are mandatory. The task of the emergency physician is to identify the disease, institute basic therapy, and provide necessary follow-up care, not an easy task, to say the least.

    Sexually Transmitted Diseases Treatment Guidelines, 2015

    Workowski KA, Bolan GA

    Centers for Disease Control and Prevention

    MMWR Recomm Rep.


    This review article is a good reference for diagnosing and treating syphilis, which is done using a number of serologic tests that are quite complicated. Treponema pallidum, the organism causing syphilis, cannot be grown in the laboratory, so no culture tests are available. Essentially, no test directly detects the organism. A test looking for the organism in an ulcer, called the dark field microscopic examination, was previously used, but is no longer available.

    Diagnosing syphilis with serologic tests can be confusing, and it is best to contact a consultant for help in interpreting results. Both available blood tests should be used, and treatment can be initiated in the ED if syphilis is suspected even if testing is ambiguous. At-risk patients should also be tested for HIV and screened for other sexually transmitted infections. The hospital laboratory can perform both syphilis blood tests, but it often takes a lot of cajoling to have these laboratory tests performed while the patient is still in the ED.

    Two types of serologic tests are available for syphilis: nontreponemal tests (rapid plasma reagin test [RPR] and the venereal disease research laboratory test [VDRL]) and treponemal-specific tests (treponemal enzyme immunoassay [TP-EIA], fluorescent treponemal antibody absorption test [FTA-ABS]). Using only one test is insufficient for diagnosis because serologic testing, especially nontreponemal tests, can be associated with false-positive and false-negative results.

    Treatment is indicated when the first test, such as the RPR test, is positive while waiting for a confirmatory test, such as the FTA-ABS. Either test can be used as the initial screening test, but most EDs perform the RPR test. The VDRL test is most often used on spinal fluid. Confirmatory testing of the first test is necessary due to the potential for a false-positive screening test result. False-negative results can also occur because initial serologic testing relies on antibody production, a humoral immune response to infection that requires time to be positive. Testing may be of limited value in patients with advanced immunosuppression or early disease.

    Nontreponemal Tests: The nontreponemal RPR and VDRL tests do not measure the presence or number of the bacteria that cause syphilis but the protein antibodies produced when someone is infected with syphilis. Nontreponemal assays are semiquantitative, and the amount of antibody present generally reflects the activity of the infection. The RPR results reflect the number of antibodies produced and their concentration, and are reported as a ratio, such as 1:8 or 1:32.

    How well the RPR test can detect syphilis depends on the stage of the infection. The test is most sensitive (almost 100%) during the middle stages. It is less sensitive, 70 to 90 percent, during the earlier stages of the infection. The RPR ratio declines as the disease is treated, and it can be used to assess the response to therapy. Some conditions may cause a false-positive RPR test, including IV drug use, Lyme disease, certain types of pneumonia, malaria, pregnancy, lupus, and tuberculosis.

    This test can be repeated in 10 to 14 days if the results are small titers or absent in a patient with a suspected clinical diagnosis. About 20 to 30 percent of those presenting with only a chancre will have a negative nontreponemal test, likely because the test was performed before sufficient antibodies had developed. These titers decrease with treatment but tend to wane over time even without treatment. Successful therapy accelerates the pace of antibody decline. Changes in titer can be followed after treatment to detect a therapeutic response.

    Treponemal Tests: All positive RPR test results should prompt follow-up with the FTA-ABS or Treponema pallidum particle agglutination (TP-PA) test. Treponemal tests are qualitative only, and are reported as reactive or nonreactive. This test usually remains positive for life, so these tests alone are generally not useful for confirming active syphilis in a patient with prior treated disease. This test result will also be positive even if a patient was previously diagnosed with syphilis and treated successfully.

    The normal FTA-ABS test result is a negative reading, indicating no antibodies to the T. pallidum bacterium. This means that a patient is not currently and never has been infected with syphilis. The damage to organs and tissues from syphilis is irreversible, and treatment is likely to be ineffective.

    Diagnostic testing for syphilis should be performed on patients with signs and symptoms of infection. All pregnant women should be routinely tested in early pregnancy. Asymptomatic patients should also be screened for syphilis if they are at high risk for having acquired disease or transmitting it to others. Patients who have a positive nontreponemal test (RPR) followed by a negative treponemal test (FTA-ABS) are generally considered to have a false-positive syphilis result.

    Primary syphilis is a chancre at the site of contact with an infected individual. Because this is a sexually transmitted infection, the chancre usually occurs on the penis, as shown here, and on the genitalia, rectum, or lips. Serologic tests are usually but not always positive when a chancre appears. The chancre is painless, has an indurated border, and is loaded with spirochetes that readily transmit syphilis. Treatment cures the chancre, but it will heal even without treatment prior to the development of secondary syphilis. Adenopathy is common during this phase of syphilis.

    Lumbar puncture VDRL is used to detect CNS involvement (neurosyphilis), and should be performed in patients with positive serology findings and evidence of neurologic or ophthalmologic involvement and in patients with HIV infection who also have syphilis of an unknown or more than one-year duration. Patients with possible neurosyphilis should always be referred to a specialist.

    Syphilis and HIV Infection: Syphilis is a major problem in patients with HIV infection. Syphilis and HIV have similar modes of transmission, and infection with one may enhance acquiring and transmitting the other. Syphilis may have a negative impact on the immunologic and virologic status of patients with HIV infection, and serologic testing for syphilis can be interpreted in the same manner regardless of HIV status.

    The rise in the rate of reported syphilis cases has been primarily attributed to increased cases among men who have sex with men, high-risk sexual behavior, unprotected sex including oral and anal sex, sex with multiple partners, and sex under the influence of drugs, especially methamphetamine.

    Approximately 42 percent of men having sex with men with primary and secondary syphilis are infected with HIV, compared with eight percent of men who have sex with women and four percent of women. (Sexually Transmitted Disease Surveillance 2018. Centers for Disease Control and Prevention, 2019;

    Individuals with HIV should be followed by a specialist because they are at high risk for complications. HIV infection may modulate the clinical presentation of syphilis. Those with syphilis and HIV may have greater organ involvement, atypical and florid skin rashes, more rapid progression to neurosyphilis, and altered clinical and serologic response to syphilis treatment. Syphilis may also have the impact of increasing the HIV viral load.

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    Learning Objectives for This Month's CME Activity: After participating in this CME activity, readers should be better able to explain how serological testing diagnoses syphilis.

    Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read his past columns at

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