Clinical Information

Syphilis is a disease caused by infection with the spirochete Treponema pallidum. The infection is systemic, and the disease is characterized by periods of latency. These features, together with the fact that T pallidum cannot be isolated in culture, mean that serologic techniques play a major role in the diagnosis and follow-up of treatment for syphilis.

Historically, the serologic testing algorithm for syphilis included an initial non-treponemal screening test, such as the rapid plasma reagin (RPR) or VDRL tests. Because these tests measure the host's antibody response to non-treponemal antigens, they lack specificity. Therefore, a positive result by RPR or VDRL requires confirmation by a treponemal-specific test, such as the fluorescent treponemal antibody-absorbed (FTA-ABS) or microhemagglutination assay (MHA-TP). Although the FTA-ABS and MHA-TP are technically simple to perform, they are labor intensive and require subjective interpretation by testing personnel.

As an alternative to the traditional syphilis screening algorithm as described above, many laboratories utilize the reverse syphilis screening algorithm. This algorithm starts with an automated treponemal assay, such as an enzyme immunoassay and multiplex flow immunoassay (MFI), to detect antibodies specific to T pallidum. If the screening assay is positive, the sample is reflexed to a RPR assay, which, if positive, is reported with a titer and is indicative of active or recent syphilis infection. If the RPR is negative, the sample is reflexed to a second treponemal assay, such as the T pallidum particle agglutination (TP-PA) assay. If the TP-PA is positive, this would indicate previously treated or late stage syphilis infection. Alternatively, if the TP-PA is negative, the initial positive screen is interpreted as a false positive result.

Syphilis screening at Mayo Clinic is performed by using the reverse algorithm, which first tests sera for T pallidum specific IgG/IgM antibodies using an automated MFI. A positive treponemal test suggests infection with T pallidum, but does not distinguish between recent or past, or treated and untreated infection. This is because treponemal tests may remain reactive for life, even following adequate therapy. Therefore, the results of a non-treponemal assay, such as RPR, are needed to provide information on a patient's disease state and history of therapy.(Table 1)

In some patients, the results of the treponemal screening test and RPR may be discordant (eg, syphilis IgG/IgM positive and RPR negative). To discriminate between a falsely reactive screening result and past syphilis, a second treponemal-specific antibody test is recommended using a method that is different from the initial screen test (eg, -TP-PA).

In the setting of a positive syphilis IgG/IgM screening result and a negative RPR, a positive TP-PA result is consistent with either 1) past, successfully treated syphilis, 2) early syphilis with undetectable RPR titers, or 3) late/latent syphilis in patients who do not have a history of treatment for syphilis. Further historical evaluation is necessary to distinguish between these scenarios.(Table 1)

In the setting of a positive syphilis IgG/IgM screening result and a negative RPR, a negative TP-PA result is most consistent with a falsely reactive syphilis IgG/IgM screen.(Table 1) If syphilis remains clinically suspected, a second specimen should be submitted for testing.

Table 1. Interpretation and follow-up of reverse screening results: