Syphilis: Clinical Manifestations and Treatment
Clinical Manifestations by Stage
Primary Syphilis
Primary syphilis presents as a painless ulcer (chancre) at the infection site with regional lymphadenopathy. 1 The chancre typically appears at the site where T. pallidum entered the body, most commonly on the genitals, anus, or mouth. 2 In HIV-infected individuals, multiple or atypical chancres may occur, and primary lesions might be absent or easily missed. 1
Secondary Syphilis
Secondary syphilis develops weeks to months after the primary stage and is characterized by:
- Diffuse rash that can involve the palms and soles 2
- Mucocutaneous lesions including condyloma latum in genital or perineal areas 3
- Generalized lymphadenopathy 4
- Constitutional symptoms including fever, malaise, and headache 1, 3
Secondary syphilis can mimic acute primary HIV infection with similar constitutional symptoms and CSF abnormalities. 1
Latent Syphilis
Latent syphilis is characterized by positive serologic tests without any clinical manifestations. 1
- Early latent syphilis is defined as infection acquired within the preceding year, based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 5
- Late latent syphilis occurs more than one year after infection 2
Tertiary Syphilis
Tertiary syphilis occurs in approximately 25% of untreated patients after 3-12 years of latency and includes: 1
- Gummatous lesions (granulomatous lesions affecting skin, bones, and organs) 1, 4
- Cardiovascular syphilis (aortitis, aortic aneurysm) 1, 4
- Neurologic involvement (tabes dorsalis, general paresis) 1
Neurosyphilis
Neurosyphilis can occur at any stage of syphilis and may present with: 2
- Meningitis 2
- Uveitis and ocular manifestations 2
- Hearing loss 2
- Stroke 2
- Psychiatric manifestations including psychosis, mania, depression, anxiety, and personality changes 6
The diagnosis of neurosyphilis requires a combination of reactive serologic tests, CSF abnormalities (elevated cell count >5 WBCs/mm³ or protein), and/or reactive VDRL-CSF with or without clinical manifestations. 7, 1
Treatment Regimens
Primary and Secondary Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment for primary and secondary syphilis. 1, 5
For penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 14 days is the alternative regimen. 5, 8
Early Latent Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose is recommended for early latent syphilis. 5
Late Latent Syphilis and Tertiary Syphilis
Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals is recommended for late latent syphilis, latent syphilis of unknown duration, and tertiary syphilis. 1, 5
For penicillin-allergic non-pregnant adults with late latent syphilis, doxycycline 100 mg orally twice daily for 28 days is the alternative. 5, 8
Neurosyphilis
Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or by continuous infusion for 10-14 days is the first-line treatment for neurosyphilis. 1, 9
An alternative regimen is procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days. 9
Penicillin remains the only proven effective therapy for neurosyphilis; patients with penicillin allergy must undergo desensitization. 7, 5, 9
Special Populations
Pregnant Women
Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission and treating syphilis during pregnancy. 7, 5 Pregnant women with penicillin allergy must undergo desensitization before treatment. 7, 5 Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy if untreated. 2
HIV-Infected Patients
HIV-infected patients should receive the same treatment regimens as non-HIV-infected patients. 5 However, they may have:
- More apparent clinical lesions and accelerated disease progression 1
- Atypical serologic responses (unusually high, low, or fluctuating titers) 7
- Multiple or atypical chancres 1
All patients with syphilis should be tested for HIV. 1
Follow-Up and Monitoring
Quantitative nontreponemal tests (VDRL or RPR) should be repeated at 3,6,12, and 24 months after treatment. 1, 5
Expected serologic response:
- A fourfold decline in titer is expected within 6 months for primary/secondary syphilis 1, 5
- A fourfold decline in titer is expected within 12-24 months for late syphilis 5
Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis. 1, 5 If treatment failure is suspected, patients should be re-evaluated for HIV infection and undergo CSF examination. 5
Management of Sex Partners
Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative. 7, 5 Persons exposed more than 90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 5
Important Clinical Considerations
Jarisch-Herxheimer Reaction
The Jarisch-Herxheimer reaction is an acute febrile reaction that may occur within 24 hours after any syphilis therapy, particularly in early syphilis. 7, 5, 9 Patients should be informed about this possible adverse reaction, which includes fever, headache, and myalgia. 7, 5 Antipyretics may be recommended, but no proven methods prevent this reaction. 7 In pregnant women, this reaction may induce early labor or fetal distress but should not prevent or delay therapy. 7
Critical Pitfalls to Avoid
- Do not use oral penicillin preparations for syphilis treatment as they are ineffective 5
- Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 5
- Do not switch between different nontreponemal testing methods (VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 7, 5
- Use the same testing method and preferably the same laboratory for serial monitoring 7