Amid Surge, CDC Unveils New Syphilis Testing Guidance

The CDC has published its first comprehensive laboratory recommendations for syphilis testing.

Published in the Morbidity and Mortality Weekly Report, the new recommendations include approaches for laboratory-based tests, point-of-care tests, sample processing, and how laboratories should report test results to clinicians and health departments.

The recommendations are primarily for clinical laboratory or disease control personnel, but also for clinicians to understand how to collect and process specimens, interpret test results, and counsel and treat patients, according to CDC researchers led by John Papp, PhD, of the agency’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention in Atlanta.

For Joseph Cherabie, MD, of the Washington University School of Medicine in St. Louis who serves as associate medical director at both the St. Louis County Sexual Health Clinic and the St. Louis STI/HIV Prevention Training Center, the new recommendations are the first-ever “one-stop shopping” resource for syphilis testing. Previously, recommendations for syphilis testing were embedded in the CDC’s Sexually Transmitted Infection (STI) Treatment Guidelines, he told MedPage Today.

The U.S. is currently in the midst of a syphilis epidemic. According to the CDC, syphilis cases rose nearly 80% from 2018 through 2022 and congenital cases are up a staggering 183% over the same period. Laboratories play a critical role in the public health response to the epidemic. Accurate and timely laboratory testing is critical for clinicians to make clinical diagnoses and begin disease management, and for local health departments and the CDC to monitor disease trends.

Testing for syphilis has traditionally been based on serologic algorithms to detect a humoral immune response to Treponema pallidum. These tests have been divided into nontreponemal tests (which detect antibodies that are broadly reactive to lipoidal antigens shared by both host and T. pallidum) and treponemal tests (which detect antibodies specific to T. pallidum). Both types of tests must be used together to distinguish between an untreated infection or a past infection that has been successfully treated, the authors noted.

Newer serologic tests allow for laboratory automation but must be used in an algorithm, which can also involve older manual serologic tests. Direct detection of T. pallidum continues to evolve from microscopic examination of samples from lesions to molecular detection of the organism.

Some point-of-care syphilis tests are available in the U.S. More widespread availability of point-of-care tests with high sensitivities and specificities could allow for expansion of screening programs and reduce the time from test result to treatment, Papp and co-authors noted.

Cherabie is happy to see that the recommendations include emerging technologies — such as point-of-care testing — that have come out in recent years and how those tests fit into the diagnostic algorithms. The new recommendations, he said, are “a place where people can now go and find out, what are the serologic tests, what are the algorithms, what are the pros and cons of each algorithm?”

The new recommendations also suggest updating syphilis serologic laboratory terminology that was developed at the beginning of the 20th century and modified according to WHO recommendations in 1954. Current terminology no longer reflects the evolving scientific understanding of the immunobiology of T. pallidum, said Papp and colleagues. For example, nontreponemal tests should be more accurately called lipoidal antigen tests because antigens used in nontreponemal tests are, in fact, found in T. pallidum membranes and host membranes.

The new key recommendations for laboratory syphilis testing are:

Endpoint titers (the highest dilution yielding a reactive result) should be clearly reported when testing serum with nontreponemal (lipoidal antigen) assays that detect antibodies to lipoidal antigens (i.e., rapid plasma reagin and Venereal Disease Research Laboratory). Reports should not contain mathematical symbols such as > or < signs.

Serologic tests that measure antibodies to both nontreponemal (lipoidal) and treponemal antigens related to syphilitic infections should be used in combination, when the primary test is reactive, to aid in the diagnosis of syphilis. Sole reliance on one reactive serologic test result can misclassify a patient’s syphilis status. Both the traditional syphilis screening algorithm (initial screening with nontreponemal [lipoidal antigen] assays) and the reverse syphilis screening algorithm (initial screening with treponemal immunoassays) are acceptable.

Nontreponemal (lipoidal antigen) tests (e.g., rapid plasma reagin or Venereal Disease Research Laboratory) are not interchangeable when used to determine antibody titers. Testing on follow-up samples must be performed using the same type of test. The T. pallidum particle agglutination test is the preferred manual treponemal test.

Nontreponemal (lipoidal antigen) and treponemal tests should be interpreted in the same manner regardless of pregnancy status.

Nontreponemal (lipoidal antigen) and treponemal tests should be interpreted in the same manner regardless of HIV status.

Darkfield microscopy for detection of T. pallidum should be maintained if already in use or established in STI clinics where a point-of-care test for primary or secondary syphilis diagnosis would be beneficial for timely patient treatment.

For direct detection of T. pallidum by immunohistochemistry and silver staining, immunohistochemistry is preferred over silver staining for formalin-fixed, paraffin-embedded tissue sections regardless of anatomic site.

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