NEW YORK – The US Centers for Disease Control and Prevention issued new guidance for laboratories for the detection of Treponema pallidum, the spirochete bacteria that causes syphilis.
Disclosed in a Morbidity and Mortality Weekly Report on Thursday, the new recommendations clarify terminology and offer algorithms for testing and screening using extant serology assays. The report also suggests that point-of-care and nucleic acid amplification tests should be developed in the future to help curb rising infection rates.
"A syphilis epidemic is occurring" in the US, the report states, "with sustained increases in primary and secondary syphilis from 5,979 cases reported in 2000 to 133,945 cases reported in 2020, a 2,140 percent increase." The epidemic is being amplified by gender- and race-related health disparities in the US, the CDC says, as well as interacting with ongoing HIV and substance use epidemics.
Syphilis infections are typically contracted through sexual activity and can progress through three stages comprising different symptoms. Primary syphilis usually presents as skin lesions, called chancres, while secondary and tertiary stages include rashes and involvement of internal organs, respectively, separated by a decades-long latent period. In the early stages, the T. pallidum swim freely in the blood while in the final stage spirochetes that have burrowed into capillaries and internal organs provoke a severe immune response.
Infections at any stage can be passed from a pregnant person to their unborn child. Known as congenital syphilis, these infections can cause deformed bones, anemia, brain and nerve problems, and skin rashes, as well as miscarriage and stillbirth.
In 2022, rates of primary syphilis in the US increased 17 percent compared to the previous year, with the highest number of cases reported since 1950, according to the CDC. Rates of congenital syphilis more than tripled, with more than 3,750 cases in 2022, including 282 stillbirths and infant deaths.
A MMWR issued in November noted that nearly 90 percent of these cases could have been prevented by timely testing and adequate treatment with penicillin.
Screening and testing for primary syphilis is critical to reversing these trends.
In the new recommendations, the CDC noted that currently available US Food and Drug Administration-cleared serological tests either detect antibodies to T. pallidum or detect antibodies that react to so-called lipoidal antigens presented by T. pallidum as well as by the host's immune system as it attacks the infection.
These nontreponemal and treponemal tests must be used together to distinguish between an untreated infection and a past infection that has been successfully treated, the recommendations state. The traditional algorithm for syphilis serologic screening begins with a nontreponemal test, with reactive samples confirmed by a treponemal test. The CDC report says this workflow was based on cost and labor requirements, but that automated treponemal testing has since allowed labs to use a "reverse algorithm," as well.
Newer serologic tests have an advantage of being amenable to lab automation, the recommendations state, but must be used in an algorithm which also can involve older, manual serologic tests. The recommendations note that at the start of 2022 there were a total of 12 FDA-cleared automated treponemal immunoassays.
The CDC notes that 2,360 laboratories participating in a 2015 College of American Pathologists syphilis serology proficiency testing program were using one or both of these algorithms.
"Each algorithm has advantages and disadvantages and both are acceptable," the report says.
The report also offers testing recommendations for different stages of infection, different specimen types and sites of infection, pregnant people, and people living with HIV.
Detecting T. pallidum directly with a microscope is tricky; the bug is tiny and thin, does not take up typical stains, and is extremely difficult to culture. The recommendations state that use of darkfield microscopy should be maintained if it is already established in clinics where a POC test for primary or secondary syphilis diagnosis would be beneficial for timely patient treatment.
The recommendations also comment on direct detection using nucleic acid amplification tests for the diagnosis of primary T. pallidum infection.
"Although NAATs hold great promise for syphilis diagnosis, especially for primary syphilis, no FDA-cleared NAATs are available for syphilis," the report states.
The recommendations state that laboratory-developed NAATs are based on the tp47 (tp074) or polA (tp0105) genes and have varying sensitivities depending on the stage of syphilis and specimen type. These can be used for primary or possible secondary syphilis lesions in seronegative patients, "provided that laboratories establish performance specifications to satisfy CMS regulations for CLIA compliance."
The report notes that the CDC's Sexually Transmitted Infections Treatment Guidelines of 2021 suggest that examination of the placenta, umbilical cord, suspicious lesions, nasal discharge, or other body fluids with a CLIA-validated NAAT could be considered in aiding the diagnosis of congenital syphilis.
Furthermore, "Increased availability of point-of-care tests that are sensitive and specific could facilitate expansion of screening programs and reduce the time from test result to treatment," the agency said.
As previously reported, there are currently two FDA-cleared, CLIA-waived 15-minute syphilis immunoassays. Syphilis Health Check from Diagnostics Direct detects both IgG and IgM antibodies to the bacteria, while DPP HIV-Syphilis is a combination HIV and syphilis rapid test from Chembio Diagnostics.
The recommendations comment on the two tests, noting that more evidence is needed that they are helpful for the specific populations they intend to serve and that data are insufficient to recommend when and where to use these tests.
"Additional POC tests and data are needed to increase understanding of their performance in clinical and outreach settings," the report also states.
NowDx recently submitted an at-home lateral flow immunoassay syphilis test to the FDA via the de novo pathway. A diagnostic technology from SD Biosensor was recently licensed by the World Health Organization and the Medicines Patent Pool and is available for sublicensing to develop rapid tests. QuidelOrtho plans to add a syphilis target to its Savanna herpes panel.