How to Interpret Discordant Results From the RSA Screening Method for Syphilis

With the number of syphilis cases rising at a steady pace in the United States across almost all demographics, the Centers for Disease Control and Prevention (CDC) recently issued a call to action encouraging a heightened awareness among health care providers and asking them to take specific steps to help reduce the spread of the disease. These steps include:

• Taking complete sexual histories
• Following CDC testing recommendations
• Treating diagnosed patients immediately, per CDC guidelines
• Working with health departments to report all cases of syphilis by stage (including suspected or confirmed congenital syphilis)

Laboratories across the country are increasingly transitioning from the traditional algorithm to the reverse sequence algorithm (RSA) as a more efficient way to screen for syphilis. However, interpreting the results can be confusing for clinicians.

Meredith Edwards Clement, MD, a Duke infectious disease fellow who has studied syphilis screening methods extensively, offers insights into interpreting the results from RSA and determining the best course of action.

Question: What is the difference between traditional syphilis screening and the RSA?
Clement: Traditional screening starts with a nontreponemal antibody test, such as the Venereal Disease Research Laboratory (VDRL), followed by confirmation of positive results with a treponemal antibody-specific assay, such as the Treponema pallidum enzyme immunoassay (TP-EIA).

Conversely, the RSA starts with a screening treponemal test, and, if that test is positive, a reflexive nontreponemal test is performed. If the second test is reactive, syphilis is confirmed, but if it's nonreactive, that is, discordant with the results of the first test, a second, confirmatory treponemal test is performed. If the second treponemal test is also nonreactive, the initial treponemal test is generally considered to be a false positive, and the results are interpreted as negative for syphilis. However, if the second treponemal test is reactive, the provider should take further action. (Download a PDF of the RSA depicting a discordant result.)

Question: What further actions should be taken by the provider for patients who have discordant results?
Clement: Actions are based on the patient's history. Thus, the provider should first ask whether the patient has a history of syphilis diagnosis or treatment. If the patient has been treated appropriately in the past and hasn't engaged in any recent high-risk behavior, the results likely represent the patient's history of syphilis (as treponemal tests are thought to remain reactive for life). Additional treatment is therefore not indicated.

Question: What if the patient is certain they have never been treated for syphilis?
Clement: If the patient has not been treated previously, the provider should initiate treatment for syphilis. For patients who are asymptomatic, treatment is usually for late latent syphilis with penicillin-G injections weekly for 3 weeks. Non-treponemal titers can diminish over time even without treatment, which can explain why non-treponemal results might be negative in the setting of positive treponemal screening.

Question: What about patients with discordant results who are symptomatic?
Clement: A discordant result could also indicate early primary syphilis. If a patient presents with a painless chancre, that is, evidence of primary syphilis, but the nontreponemal test is nonreactive, it may be because antibodies have yet to develop. In this case, the provider should repeat non-treponemal testing—the Rapid Plasma Reagin (RPR) or VDRL titer—and treat the patient empirically for primary syphilis. Another situation in which a false negative may occur is the prozone reaction, which happens when an overabundance of antibodies interferes with laboratory testing. This is more common in secondary syphilis. If the provider has a strong clinical suspicion for syphilis but RPR or VDRL testing is non-reactive, he or she should alert the lab, and dilutions can be done to reveal the expected agglutination.

Question: What else should providers be aware of?
Clement: All cases of syphilis should be reported to local health departments. In addition, it is important that providers be aware of the resources offered by local health departments, which include extensive records of patients' syphilis history and treatment. Health departments can and should be contacted to confirm a patient's syphilis history or obtain further information when history is unclear.