Syphilis is a sexually transmitted infection (STI) that the CDC reports is rising at alarming rates in the US. It is caused by the spirochete Treponema pallidum and if left untreated can cause serious health concerns. Syphilis is associated with a spectrum of symptoms and recognizing its presentation can sometimes be challenging. Additionally, screening tests can often be difficult to interpret especially in individuals with multiple exposures. In this article we break down the various stages of syphilitic disease presentation and outline a general approach for diagnosis and treatment.

T. pallidum has been associated with various at-risk populations who require routine screening including men who have sex with men (MSM), and those who have high-risk sexual behavior, HIV, persons who inject drugs (PWID), other STIs and/or pregnancy.

Syphilis is divided into multiple stages (primary, secondary, latent, and tertiary), with different signs and symptoms associated with each stage. A person with primary syphilis generally develops a painless chancre or ulcer at the original site of infection. These sores usually occur on or around the genitals, but can also be present in a perirectal distribution or around the mouth.

Secondary syphilis may include a non-pruritic rash involving the palms and soles (Figure 1), swollen lymph nodes and fever. Also known as the great imitator, primary and secondary syphilis can also be accompanied by periostitis, hepatitis and nephritis. In the early stages of disease, Treponema is predominantly transmitted through sexual contacts.

The latent stage is often asymptomatic and can overlap with secondary as in early latent (< 1 year of infection) or late latent (> 1 year of infection). Because this stage is usually discovered serendipitously a good sexual history is often the hallmark of establishing the correctly timed diagnosis (important as they are treated differently – see below).

Tertiary syphilis is associated with more severe disease occurring 2 to 50 years after infection and characterized as gummatous, cardiovascular, ocular, otic or neurosyphilis. The neurologic manifestations of syphilis can be either meningo-vascular(hemiplegia, aphasias, and seizures) or parenchymatous(paresis or tabes dorsalis). The CNS invasion of syphilis however has the potential to involve any stage of the disease spectrum.

A diagnosis of syphilis is generally obtained by serological testing. Although dark field microscopy can be used to identify the Treponeme it is often not available at the point of care. The most common testing algorithms available use a two-staged serological approach. This algorithm uses a highly sensitive and specific Treponemal test plus a Nontreponemal test (e.g., RPR or VDRL). This approach allows for reflex to the nontreponemal tests which provide quantitative titers that are necessary for clinical management.

A few important properties to consider when interpreting syphilis testing is that up to 30% of serological tests are negative in primary syphilis – so, if syphilis is strongly suspected, the test should be repeated in two weeks. And, a positive Treponemal test will remain positive irrespective of treatment whereas Nontreponemal tests decline with appropriate therapies. If CNS disease is suspected, a CSF VDRL test should be performed.

Penicillin (Bicillin – LA) is highly effective for the treatment of syphilis. The various regimens according to stage include:

1. Primary or Secondary Syphilis

a. Penicillin G benzathine (Bicillin- LA) 2.4 million units IM once

b. Doxycycline 100 mg PO bid for 14 days (alternatively)

2. Early-Latent Syphilis

a. Penicillin G benzathine (Bicillin- LA) 2.4 million units IM once

b. Doxycycline 100 mg PO bid for 28 days (alternatively)

3. Late-Latent Syphilis

a. Penicillin G benzathine (Bicillin- LA) 2.4 million units IM – 3 doses over 1-week intervals

b. Doxycycline 100 mg PO bid for 28 days (alternatively)

4. Neuro-Syphilis

a. Penicillin G infusions 18-24 million units/day for 10-14 days

Follow up is mandatory to document response to therapy and quantitative non-treponemal titers should be evaluated at 0, 3 ,6 ,12, and 24 months. In primary and secondary syphilis the RPR titer should decrease by 4-fold at 6 months, 8-fold at 12 months and 16-fold by 24 months. As such, the goal of an appropriate syphilis diagnosis and treatment is clinical and serological cure.

References:

1. IDSA Guidelines: Clinical Infectious Diseases. 43:1089, 2006
2. New Eng J Med. Neurosyphilis. 381:1358, 2019
3. New Eng J Med. Epidemic of Syphilis. 382:845, 2020
4. Pictures from UpToDate