Syphilis is a bacterial infection caused by the agent Treponema pallidum that can result in a variety of symptoms and progressive complications if left untreated. Due to the fact that the symptoms of syphilis can be mistakenly attributed to a number of other diseases, it has been named “the great masquerader” (1). Sir William Osler, a pioneering physician of the 19th and 20th century, claimed that the later stage of syphilis could produce symptoms to simulate “almost every disease known to man” (2). It was especially important to develop diagnostic tools besides clinical assessments in order to definitively identify syphilis as the disease and prescribe the appropriate treatment. The blog post “A Brief History of Laboratory Diagnostics for Syphilis”, a post by Peera Hemarajata on the American Society for Microbiology blog, succinctly illuminates the challenges and innovations in the pursuit of this diagnostic tool (3).
Although syphilis as a disease has been characterized for 500 years, it wasn’t until the 20th century that the bacterial agent was observed and identified in diseased tissues by zoologist Fritz Schaudinn and dermatologist Erich Hoffman. This technique of observing T. pallidum in tissue was improved by the use of dark field microscopy, and high numbers of treponemes could be seen in tissue specimens. However, there were many limitations to this technique, including the fact that treponemes can only be seen in high numbers earlier in the infection and that they can only be specifically identified from certain tissues with careful preparation. For these reasons, dark field microscopy is no longer used as a diagnostic tool for syphilis (3).
After microscopic observation of treponemes, there was a shift to serological testing for confirmation of syphilis. At first, these tests were non-treponemal, as they were not T. pallidum specific. The test was simple: if the sera of patients contained certain antibodies, first called Wasserman antibodies and then “reagins”, immune complexes would form and complement factors would be depleted, leaving erythrocytes intact which could be seen by observing the red blood cells. However, it was later determined that the antibodies were anti-phospholipid, present in response to any tissue damage and not treponemal specific. Therefore, this test yielded many false positive results. Much later, in the 1940s, it was discovered that the antigen that had prompted production of the anti-phospholipid antibodies was a diphosphatidylglycerol called cardiolipin. Why would this cardiolipin be associated with the presence of T. pallidum, to the extent that antibodies to this molecule could be used as a diagnostic tool? This mystery baffled researchers until only very recently, when a study in 2018 showed that T. pallidum produced a cardiolipin with weak immunogenicity, and furthermore, that infection of this bacteria stimulated production of cardiolipin by the host. Therefore, although this serological diagnostic test was imperfect and not treponemal specific, it was somewhat successful as a clinical tool, and also led to the development of many more non-treponemal serological diagnostic tests, some of which are still used today (3).
There have been further advancements in the field, owing to the identification of T. pallidum as the causal agent, that allow for treponemal-specific diagnostic tests. Among these are enzyme immunoassays (EIA) and chemiluminescence assays (CIA) that detect treponemal-specific antibodies, which can be automated for high-throughput screening. Looking back at the history of diagnostic tests for syphilis, the field has significantly advanced, improving the chance of early diagnosis and treatment. When I worked at a multiple sclerosis research center, one of the projects I worked on involved identifying biomarkers for cognitive dysfunction in MS patients. It can be difficult to determine which patients will develop these symptoms, which will progress and become more difficult to treat. Although multiple sclerosis and syphilis are very different diseases, I found it interesting that effective diagnostic tools are necessary for both in order to improve patient outcomes.
- Gonzalez-Martinez, A., et al. (2020). "Diagnosis of Syphilitic Bilateral Papillitis Mimicking Papilloedema." Emerging Infectious Diseases 26(1): 171-173.
- Hemarajata, Peera. “Revisiting the Great Imitator, Part I: The Origin and History of Syphilis.” ASM.org, 17 June 2019, asm.org/Articles/2019/June/Revisiting-the-Great-Imitator,-Part-I-The-Origin-a?_ga=2.108552842.902210486.1578510385-1722949983.1578510385.
- Hemarajata, Peera. “A Brief History of Laboratory Diagnostics for Syphilis.” ASM.org, 6 Jan. 2020, www.asm.org/Articles/2020/January/A-Brief-History-of-Laboratory-Diagnostics-for-Syph.
