December 17, 2021
The U.S. Food and Drug Administration (FDA) is alerting clinical laboratory staff and health care providers that false reactivity, or "false-positive", Rapid Plasma Reagin (RPR; non-treponemal) test results, when using the Bio-Rad Laboratories BioPlex 2200 Syphilis Total & RPR kit, can occur in some people who received a COVID-19 vaccine. Based on information provided by the manufacturer, Bio-Rad Laboratories, RPR false reactivity was observed in some individuals for at least five months following a COVID-19 vaccination.
More research is underway to determine the extent of the issue. It is not known if other RPR tests may be affected similarly. Treponemal testing for syphilis such as Treponema pallidum particle agglutination (TP-PA) and treponemal immunoassays do not appear to be impacted by this issue.
Health care providers should make patients who received a reactive RPR result using the Bio-Rad BioPlex 2200 Syphilis Total & RPR test kit aware that they may need to be retested for syphilis with another test to confirm results.
COVID-19 vaccines do not cause syphilis. Health care providers should continue to strongly encourage patients to get vaccinated against COVID-19 and be aware of their patients’ vaccination status when interpreting reactive RPR test results.
The FDA recommends clinical laboratory staff and health care providers who use the Bio-Rad BioPlex 2200 Syphilis Total & RPR kit should do the following:
- Perform confirmatory testing for all reactive results. Use of only one type of serologic test (non-treponemal or treponemal) for people without an earlier syphilis diagnosis is insufficient for diagnosis.
- In individuals with a negative treponemal test (e.g., TP-PA) but reactive RPR result on the BioPlex 2200 Syphilis Total & RPR kit, repeat RPR testing is not necessary unless otherwise clinically indicated.
- For people previously treated for syphilis in whom treponemal tests will remain persistently positive, and who are being evaluated for possible new syphilis infection, a reactive RPR should be interpreted in the context of the patient’s medical history (including COVID-19 vaccination status), risk factors and clinical presentation. In individuals previously treated for syphilis who received a COVID-19 vaccine and whose clinical presentation and epidemiologic considerations do not support syphilis re-infection, confirm reactive RPR results performed on the BioPlex 2200 Syphilis Total & RPR platform using a different RPR test. Sequential serologic tests for a patient should be performed using the same testing method (VDRL or RPR), preferably by the same laboratory, to minimize variability. However, if the previously used RPR test was the BioPlex 2200, a RPR test from a different manufacturer should be used at this time.
- Ensure your patients are aware of the importance of getting vaccinated against COVID-19 and are aware that the COVID-19 vaccines do not cause syphilis. Millions of people in the United States have already received a COVID-19 vaccine. Getting vaccinated to prevent COVID-19 will help protect your patients from COVID-19, and it may also protect the people around them. The FDA and the CDC have several systems in place to continually monitor COVID-19 vaccine safety.
- Encourage patients who are sexually active to get tested for sexually transmitted infections to protect their health.
A person is considered positive for syphilis when the non-treponemal (RPR) and treponemal antibody tests (e.g., TP-PA, or enzyme immunoassay) are both reactive. The Bio-Rad BioPlex 2200 Syphilis Total & RPR kit is a multiplex test used to detect (IgG/IgM) antibodies to Treponema pallidum (the bacteria that causes syphilis) and non-treponemal reagin antibodies in human serum or plasma.
The clinical community is aware that false-reactive RPR test results have been observed in people with systemic infections unrelated to syphilis, such as tuberculosis, rickettsial diseases, and endocarditis. False reactive RPR testing has been previously observed following immunization (specifically following smallpox vaccine). False reactivity with RPR can also occur during pregnancy.
The FDA will continue to work with Bio-Rad Laboratories to evaluate:
- Whether the Bio-Rad Laboratories’ recommendations to clinical laboratory staff and health care providers who use the Bio-Rad BioPlex 2200 Syphilis Total & RPR adequately mitigate the risk of false reactive results in individuals who have received a COVID-19 vaccine.
- How Bio-Rad Laboratories will further assess and investigate the adverse health consequences of false reactive results and any intended corrections or resolutions.
- Any additional complaints associated with the Bio-Rad BioPlex 2200 Syphilis Total & RPR false reactive results.
The FDA is continuing to investigate whether this issue is specific to the Bio-Rad BioPlex 2200 Syphilis Total & RPR test or if other tests may also be affected. The FDA will continue to keep clinical laboratory staff, health care providers, and the public informed of significant new information.
Reporting Problems to the FDA
The FDA encourages health care providers to report adverse events or suspected adverse events experienced with medical devices, including in vitro diagnostic tests.
- Voluntary reports can be submitted through MedWatch, the FDA Safety Information and Adverse Event Reporting program.
- Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations.
- Health care personnel employed by facilities that are subject to the FDA's user facility reporting requirements should follow the reporting procedures established by their facilities.
Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.
- National Overview - Sexually Transmitted Disease Surveillance, 2019: Syphilis
- Centers for Disease Control and Prevention - Sexually Transmitted Diseases: Syphilis
- Sexually Transmitted Infections Treatment Guidelines, 2021
- MedlinePlus: Syphilis
If you have questions about this letter, contact the Division of Industry and Consumer Education (DICE).