October 2021 – Clinical Microbiology and Infectious Disease Pathology

Treponema pallidum

Treponema pallidum is the infectious agent causing syphilis. T. pallidum is a stealthy pathogen due to its ability to evade the host immune system and cause disseminated infection (1). Historians believed that the “sailor’s handshake” served as a way to assess the presence of epitrochlear lymphadenopathy associated with syphilis, but it is nonspecific and frequently observed in non-syphilis infections (2). 

Syphilis has four distinct stages of disease, presenting with different signs and symptoms at each stage (3). Primary syphilis generally presents with painless lesions at the original site of infection, referred to as ‘chancres,’ typically around the genitals, anus or in and around the mouth. Symptoms of primary syphilis can be relatively mild and go unnoticed (1). Symptoms of secondary syphilis include a maculopapular skin rash, swollen lymph nodes, and fever (1,3). When infections with T. pallidum are left untreated, syphilis can progress to a latent stage, during which time patients are entirely asymptomatic, but years later may develop tertiary syphilis (1). Tertiary syphilis can present with disseminated symptoms and can affect the heart, brain, and other organs. Tertiary syphilis can occur 10-30 years after initial infection (1). 

There are two types of serologic tests used to diagnose syphilis: nontreponemal and treponemal-specific tests (1). Nontreponemal tests detect antibodies to cardiolipin and lecithin antigens that are released from infected host cells and are thus considered nonspecific biomarkers of infection (1). Nontreponemal tests are semi-quantitative and are reported with an endpoint titer. Changes in this titer are followed after treatment to monitor for therapeutic response. In contrast, treponemal tests detect antibodies against specific treponemal antigens and are thus considered more specific (1). Once a patient has a positive treponemal test, they can remain positive for life, making serial testing for these antibodies not useful as a monitor for response to therapy or for confirming diagnosis in a patient with previously treated disease. 

There are two algorithms for diagnosis of syphilis infections: the traditional and the reverse syphilis screening algorithms (3). The traditional algorithm begins with a non-treponemal assay, which if positive is followed with a treponemal assay to confirm the result. In contrast, the reverse screening algorithm begins with a treponemal, T. pallidum specific immunoassay as the initial screen, which if positive is followed by the rapid plasma reagin (RPR) as the confirmatory test. If the results are discordant results for these tests, the T. pallidum particle agglutination assay (TTPA) is performed. The advantage of the reverse algorithm over the traditional version is multi-fold, including the ability to screen samples initially using high-throughput automated assays rather than manual nontreponemal methods, and the reverse algorithm has been associated with higher sensitivity during primary disease. Nucleic acid amplification tests (NAATs) have also been developed and evaluated for detection of T. pallidum DNA, but to date none are currently available commercially (3). NAATs are highly specific, but sensitivity of the assay is largely dependent on the specimen source (3). 

For diagnosis of neurosyphilis, additional testing on cerebrospinal fluid needs to be performed (1). A positive cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) is highly specific for neurosyphilis but is associated with lower sensitivity. T. pallidum is a thin, tightly coiled, microaerophilic spirochete that does not grow well on standard culture media. Darkfield microscopy was utilized in the past to identify the organisms directly from the chancre, however, it is infrequently used today (3). T. pallidum can also be visualized by histopathology as was done in this case (3). Although the spirochetes cannot be seen on H&E, they can be highlighted by silver impregnation methods, specific immunohistochemistry (IHC), or immunofluorescence (3). Silver impregnation methods are nonspecific but T. pallidum IHC is recommended for optimal sensitivity (3). 

References

1. Henao-Martinez, A F., Johnson, S C. Diagnostic tests for syphilis. Neurol Clin Pract. 2014 Apr; 4(2): 114-122.
2. O’Glasser, A Y., Kent C. M., J Med. 2016; 129(4): 379-381.
3. Theel, E. S., Katz, S., Pillay, A. Molecular and direct detection tests for Treponema pallidum subspecies pallidum: A review of the literature, 1964-2017. CID. 2020 June; 71(1): S4-S12.