College of American Pathologists



Recent Changes to Syphilis Screening Algorithms

Posted July 1, 2011

Suzanne Tucker, MD, and
Josh A. Hanson, MD

A growing number of laboratories in the United States have reversed the long-established, traditional algorithm for laboratory diagnosis of a syphilis infection. Instead of screening with a non-treponemal test, such as the rapid plasma reagin (RPR) and confirming reactive results with a direct treponemal test, such as the fluorescent treponemal antibody absorption (FTA-ABS), these laboratories screen with an automated direct treponemal test and confirm with a non-treponemal test, often the RPR. This reversal of traditional syphilis testing was primarily initiated by the decreased cost, improved sensitivity and specificity, and improved efficiency of automated treponemal testing.1,2

The adoption of the new algorithm has resulted in cases of discordant laboratory results (a reactive treponemal test and negative RPR) that would not otherwise have been identified in the traditional method. In a study performed by the Centers for Disease Control and Prevention (CDC), 3,664 (3%) of 116, 822 total specimens or 56% of total initial reactive specimens had a reactive treponemal test and negative RPR.1 From a laboratory standpoint, a reactive direct treponemal test indicates only that a treponemal infection has occurred sometime in a patient’s lifetime, regardless of whether the patient has been adequately treated in the past. This is a common occurrence, as antibodies often persist in patients long after the infectious agent has been eliminated; and therefore a positive treponemal test may not indicate an active infection, but only a previous exposure.2 The RPR, however, usually becomes non-reactive following successful treatment, thus a negative RPR in this setting often indicates previous treatment. Unfortunately, there are no standardized algorithms on how these results should be interpreted or how these patients should be managed.1

If the patient knows his or her treatment history and there are no clinical symptoms of a recurrent or inadequately treated initial syphilis infection, a positive direct treponemal test and negative RPR results are often attributed to previous treatment. However, if the patient has no recollection of previous treatment, the patient can be tested with a second, different treponemal test, such as the FTA-ABS or the TP-PA. If that result is also negative, clinical suspicion must be assessed to decide whether treatment is indicated or if a third treponemal test should be used to resolve the discrepancy between the two treponemal test results. A thorough history and physical exam are necessary to determine the clinical suspicion of a syphilis infection in cases of discrepant results.

Despite these new clinical dilemmas, the sensitivity and specificity of the automated direct treponemal tests are improved over the RPR. For instance, the laboratory at Fletcher Allen Heath Care at the University of Vermont recently began using an automated antigen-based chemiluminescence immunoassay, which has a sensitivity of 99.2% for the detection of syphilis. This is an improvement over the RPR, which has an overall sensitivity of 96.3% for the detection of non-treated syphilis.4 RPR sensitivity drops significantly to 6.5% in cases of previously treated, latent syphilis, limiting its use as a diagnostic test for an inadequately treated syphilis infection.4 In addition, the RPR suffers from poor specificity as it can be reactive in patients with common diseases such as infectious mononucleosis, Streptococcus pyogenes infection, viral infections, and autoimmune diseases.

In conclusion, automated direct treponemal testing has an improved sensitivity and specificity compared to the RPR in the detection of primary, secondary and latent syphilis.3,4,5 These automated tests are less expensive to perform than the RPR and remove operator bias since many treponemal tests are objective rather than subjective. However, they often result in discordant results when used with a confirmatory non-treponemal test, such as the RPR. Standardized follow-up algorithms have not yet been established to guide clinicians when the direct treponemal test and RPR disagree. Understanding the clinical situations in which these tests were performed is essential for the correct interpretation of the results.


  1. Centers for Disease Control and Prevention (CDC). Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006. MMWR. 2008;57(32);872–875.
  2. Association of Public Health Laboratories (APHL) and CDC. Laboratory diagnostic testing for Treponema pallidum: expert consultation meeting summary report, Atlanta, GA: CDC, US Dept of Health and Human Services; January 13–15, 2009.
    . Accessed September 9, 2010.
  3. McClatchey KD, Amin HM, Curry JL. Clinical Laboratory Medicine, 2nd Edition. Philadelphia, PA: Lippincott, Williams and Wilkins; 2002.
  4. Marangoni A Sambri V, Accardo S. Evaluation of LIAISON Treponema Screen, a novel recombinant antigen-based chemiluminescence immunoassay for laboratory diagnosis of syphilis. Clin Diagn Lab Immunol. 2005;12(10):1231–1234.
  5. Schmidt BL, Edjlalipour M, Luger A. Comparative evaluation of nine different enzyme-linked immunosorbent assays for determination of antibodies against Treponema pallidum in patients with primary syphilis. J Clin Microbiol. 2000;38(3): 1279–1282.

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NewsPath® Editor: C. Leilani Valdes, MD
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and the NewsPath Editorial Board and may be reproduced in whole or in part as a service to the medical community. Copyright © 2011 by the College of American Pathologists.
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