Syphilis: A rapid review

Syphilis is on the rise. Across North America, we are seeing syphilis rates unheard of since we abandoned the lambskin condom. (OK, I have no idea if that is factually accurate, but I always imagined syphilis and lambskin going hand in hand.) In Canada, there were 96 cases of congenital syphilis in 2021, as compared to 7 in 2017, a 1271% increase! (CCDR 2022) Numbers are similar in the United States, with 2677 cases of congenital syphilis reported in 2021 as compared to 332 in 2012. (Dyer 2022) Among adults in Canada, there were 11,268 cases of syphilis diagnosed in 2021, and there are definitely more cases than diagnoses. (CCDR 2022) Although I am sure there are some emergency departments with significant expertise in the topic, this is not a diagnosis I have seen regularly in my career, and so I figured it was time for a brief review.

Etiology

Syphilis is a sexually transmitted infection caused by the bacteria Treponema pallidum. Transmission is either through intimate contact (vaginal, anal, and oral sex) or vertical transmission from mother to baby.

Presentation

Syphilis can be a difficult diagnosis to make, with a variety of presentations. Approximately 50% of people will not develop or notice symptoms (at least in the early stages). When there are symptoms, they are often non-specific (aside from the chancre). Syphilis has been called the “great imitator” because the signs and symptoms can be difficult to distinguish from other diseases. Therefore, the diagnosis relies heavily on sexual history, STI risk factors, and screening tests. (Salazar 2022)

There are 3 classically described stages (although it’s really 4 if you count latent syphilis):

• Primary syphilis presents with a usually painless ulcer or chancre, which typically has a well-defined margin and indurated base. (Don’t be fooled, because a large percentage of these turn out to be painful). These can occur on the cervix, in the mouth, and in the rectum, and so are often missed or ignored. The typical incubation period is 3-6 weeks. In other words, the chancre will typically occur 3-6 weeks after the sexual activity leading to infection. (Ramchandani 2023; Salazar 2022)
• Secondary syphilis is caused by hematogenous spread of T pallidum, leading to widespread vasculitis. The presentation is highly varied, and dependent on the organ systems involved. There are often flu-like symptoms with malaise, fever, myalgias, and arthralgias. There can be generalized lymphadenopathy. The classic rash, if present, is a symmetrical diffuse maculopapular or pustular rash, typically involving the soles and palms. Condylomata lata are wart-like manifestations of secondary syphilis. Vasculitis due to secondary syphilis may cause a nephrotic syndrome, glomerulonephritis, or hepatitis. About 25% of patients will develop relapsing episodes. (Ramchandani 2023; Salazar 2022)
• Latent syphilis is a period of ongoing asymptomatic infection, often divided into early and late latent syphilis at a cutoff of 1 or 2 years depending on which guideline you follow.
• Tertiary syphilis (aka late symptomatic disease) occurs in 10-40% of patients with untreated syphilis, and is characterized by chronic end-organ complications, usually occurring 10-20 years after the onset of infection. Neurosyphilis of the spine (aka tabes dorsalis) can cause ataxia, incontinence, dorsal column loss (vibration and proprioception), the Argyll-Robertson pupil, and areflexia. Neurosyphilis of the brain can cause a wide range of symptoms including behavioral changes, memory impairment, altered mood, seizures, and tremor. Visual symptoms, such as  iritis, uveitis, and chorioretinitis, are manifestations of neurosyphilis. (Neurosyphilis can also present earlier, during the secondary stage.) Cardiovascular syphilis usually affects the aortic root, causing aortitis and aortic regurgitation. Gummatous syphilis causes granulomatous rubbery tissue with a necrotic center in the skin or visceral organs. 

Congenital syphilis

Syphilis can cause a number of pregnancy complications, including congenital malformations, miscarriage, stillbirth, or neonatal death. Children born with syphilis usually (but not always) develop symptoms in the first 3 months of life. A highly infectious purulent and persistent rhinitis is often the earliest sign. Other presentations include hepatosplenomegaly, a morbilliform rash, glomerulonephritis and nephrotic syndrome, generalized lymphadenopathy, and CNS involvement. A rash, similar to the rash of secondary syphilis, can also occur. Necrotising funisitis (inflammation of the umbilical cord) is virtually diagnostic of congenital syphilis.

Congenital syphilis probably requires an entire write up on its own, but the primary medical focus is on screening all pregnant women. (Ramchandani 2023; Salazar 2022)

Diagnosis/ Testing

Serology testing is broken down into treponemal tests, which are specific, and non-treponemal tests, which are non-specific.

Treponemal tests are antigen-based tests that detect antibodies against T pallidum. These tests remain positive for life, and therefore cannot distinguish between active and past infections. There are false positives (generally from non-STI treponemal infections). There are also false negatives (usually early in the disease course, before the antibody reaction occurs.)

Treponemal tests include:

• Treponemal enzyme immunoassay (EIA)
• T pallidum particle agglutination assay (TPPA)
• T pallidum haemagglutination assay (TPHA)
• Fluorescent antibody absorption (FTA-ABS)
• Immunocapture assay (ICA).

Non-treponemal tests (VDRL and RPR) work by detecting the antibody response to the release of cardiolipin during syphilis infection. They can provide a quantitative measure, and can be used to measure response to therapy. RPR is generally recommended over VDRL.

These tests all have moderate to poor sensitivity in primary syphilis (as low as 46%), but generally have high sensitivities for secondary and tertiary syphilis. (Ramchandani 2023) In other words, don’t rely on the test if you are working up a chancre – just treat empirically.

Co-infection

Co-infection with HIV and other sexually transmitted infections is very common, and so screening tests for multiple STIs is recommended. 

Treatment

Depending on suspicion, local testing practices, and reliability of follow-up, empiric treatment of early disease (chancre or classic rash) is reasonable.

The first line treatment is penicillin. Doxycycline is an alternative in patients with penicillin allergy.

Primary, secondary, and early latent disease are treated with a single intramuscular dose of benzathine benzylpenicillin. Late latent and tertiary disease with normal CSF is treated with 3 weekly intramuscular doses of benzathine benzylpenicillin. Neurosyphilis is usually treated with intravenous penicillin, and I would defer to my ID colleagues at this point for length of treatment, as guidelines seem to vary. 

• Antibiotics (from Clement 2014; Ramchandani 2023)
  • Early syphilis
    • Benzathine benzylpenicillin 2.4 million units IM x1
    • Alternate options:
      • Doxycycline 100 mg PO BID for 14 days
      • Ceftriaxone 1 gram daily for 10-14 days
      • Tetracycline 500 mg QID for 14 days
  • Late syphilis
    • Benzathine benzylpenicillin 2.4 million units IM x3 weekly doses
    • Alternate options:
      • Doxycycline 100 mg PO BID for 28 days
      • Tetracycline 500 mg QID for 28 days
  • Neurosyphilis
    • Aqueous penicillin G, 3-4 million units q4h for 14 days
    • Alternate options:
      • Ceftriaxone 2 grams daily for 10-14 days

Counseling about safe sex practices, and treatment strategies such as pre-exposure prophylaxis in high risk populations, is really important, and can be started in the emergency department. Screening for other STIs is important, and don’t forget to suggest assessment and screening of medical contacts.

The Jarisch-Herxheimer reaction

Within the first 24 hours after starting therapy, patients can develop fever, headache, and myalgias. This usually resolves within 24 hours, and the treatment is supportive (NSAIDs, tylenol, fluids). 

Historical acknowledgement

It is impossible to discuss syphilis without acknowledging one of the darkest chapters in the history of medicine (although there are certainly many to choose from): the Tuskegee experiment. This was a longitudinal study of the effects of untreated syphilis in Black men. These men were left untreated until the 1970s, despite penicillin being available and widely used to treat syphilis in the 1940s. Most importantly, this was not an isolated incident, but rather a marker of the extremely immoral and racist treatment of Black Americans by the medical community for centuries, with a profound ongoing legacy.

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References

CCDR 2022. Infectious syphilis includes the primary, secondary and early latent (less than one year after infection) stages of infection, during which syphilis is transmissible. Early congenital syphilis is defined as a laboratory confirmation of infection by Treponema pallidum occurring within the first 2 years of birth. Case definitions for diseases under national surveillance. Can Comm Dis Rep 2000;26(S3). http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/00vol26/26s3/index.html

Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014 Nov 12;312(18):1905-17. doi: 10.1001/jama.2014.13259. PMID: 25387188

Dyer O. Syphilis and gonorrhoea cases soar in US. BMJ. 2022 Sep 30;378:o2355. doi: 10.1136/bmj.o2355. PMID: 36180090

Ramchandani MS, Cannon CA, Marra CM. Syphilis: A Modern Resurgence. Infect Dis Clin North Am. 2023 Jun;37(2):195-222. doi: 10.1016/j.idc.2023.02.006. Epub 2023 Mar 31. PMID: 37005164

Salazar J and Cruz A. Syphilis infection. BMJ Best Practice. 2022. Available at: https://bestpractice.bmj.com/topics/en-gb/50