What is the differential diagnosis and treatment approach for a patient presenting with a suspected syphilis lesion?

Differential Diagnosis of Syphilis Lesions

Primary Differential Considerations

When evaluating a suspected syphilis lesion, all patients must be tested for syphilis serology, genital herpes, and HIV, with additional testing for Haemophilus ducreyi (chancroid) in endemic areas. 1

The key differential diagnoses for genital lesions that may mimic syphilis include:

Primary Syphilis Chancre Mimics

• Genital herpes (HSV-1 or HSV-2) - Most common alternative diagnosis; presents with painful vesicles or ulcers (versus painless chancre in syphilis), diagnosed via NAAT (preferred), viral culture, or DFA testing 1
• Chancroid (H. ducreyi) - Painful ulcer with tender inguinal adenopathy; one-third of patients present with painful ulcer plus tender adenopathy, and when accompanied by suppurative inguinal adenopathy, this combination is almost pathognomonic for chancroid 1
• Lymphogranuloma venereum - Can present with genital ulceration followed by painful inguinal lymphadenopathy 1
• Traumatic ulceration - History of injury, irregular borders, no associated adenopathy 2

Secondary Syphilis Rash Mimics

• Pityriasis rosea - Herald patch followed by diffuse rash, but typically spares palms and soles (unlike secondary syphilis) 2
• Drug eruptions - Medication history is key; can present with similar diffuse rash 2
• Viral exanthems - Associated with acute viral illness symptoms 2
• Psoriasis - Chronic course, characteristic silvery scale 2

Diagnostic Algorithm

Step 1: Direct Examination (When Lesions Present)

• Darkfield microscopy of lesion exudate or tissue is the gold standard for diagnosing primary syphilis when lesions are present 3, 4
• Direct fluorescent antibody (DFA) staining serves as alternative to darkfield examination 4
• These methods allow immediate diagnosis before serologic tests become positive 1

Step 2: Serologic Testing (All Suspected Cases)

• Screen with nontreponemal test (RPR or VDRL) - quantitative titers correlate with disease activity 3, 4
• Confirm all reactive nontreponemal tests with treponemal test (FTA-ABS, TP-PA, or MHA-TP) 3, 4
• Both test types are required for diagnosis - using only one type is insufficient 3

Critical timing consideration: Treponemal antibodies appear 1-4 weeks after infection, while nontreponemal antibodies appear slightly later but are reliably positive by 4-6 weeks in primary syphilis 5

Step 3: HIV and STI Co-Testing

• HIV testing is mandatory in all patients with genital lesions, as inflammatory epithelium enhances HIV transmission 1
• Simultaneous testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas is optimal for detecting the most common treatable STIs 1
• High-risk individuals (especially MSM) require extragenital site evaluation (rectal, oropharyngeal) for GC and CT 1

Step 4: Stage-Specific Evaluation

• For suspected neurosyphilis - CSF examination showing reactive CSF-VDRL plus CSF WBC >10 cells/µL confirms diagnosis 3, 4
• For HIV-infected patients with late latent syphilis - CSF examination is recommended to rule out neurosyphilis 5, 4

Treatment Approach by Stage

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment 1, 5, 6

• Treatment should be initiated immediately if clinical suspicion is high, especially in patients at high risk for loss to follow-up 5
• Do not wait for serologic confirmation if characteristic lesions are present and patient may not return 5

Early Latent Syphilis (< 1 year)

Benzathine penicillin G 2.4 million units IM as a single dose 5, 3

Late Latent Syphilis or Unknown Duration

Benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1, 5, 3

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day (administered as 3-4 million units IV every 4 hours or continuous infusion) for 10-14 days 5

• Alternative for penicillin-allergic patients: Ceftriaxone 2 grams daily IM or IV for 10-14 days, though cross-reactivity risk exists 1

Special Population Considerations

HIV-Infected Patients

• Standard benzathine penicillin G regimen remains first-line treatment 1
• Some specialists recommend additional weekly doses (3 total) for early syphilis in HIV-infected patients 1
• More frequent monitoring required: Clinical and serologic evaluation at 3,6,9,12, and 24 months (versus 6 and 12 months in HIV-negative patients) 1, 5
• CSF examination recommended before treatment of early syphilis in HIV-infected patients by some specialists 1
• Higher risk for neurologic complications and treatment failure, though magnitude is likely minimal 1

Pregnant Patients

• Only penicillin regimens are acceptable for treating syphilis during pregnancy 5, 7
• Penicillin-allergic pregnant women must be desensitized before treatment 1, 5
• Screen at first prenatal visit, at 28 weeks in high-risk populations, and at delivery 1, 3, 4
• Adequate treatment during pregnancy prevents congenital syphilis; up to 40% of fetuses with in-utero exposure are stillborn or die from infection during infancy without treatment 6

Penicillin-Allergic Patients (Non-Pregnant)

• For early syphilis: Doxycycline 100 mg orally twice daily for 14 days 5, 2
• For late latent syphilis: Penicillin desensitization is preferred over alternatives 5
• For neurosyphilis: Desensitization is required; ceftriaxone may be considered with caution due to cross-reactivity risk 1

Follow-Up and Treatment Success Monitoring

Primary and Secondary Syphilis

• Clinical and serologic evaluation at 6 and 12 months after treatment 5
• Treatment success: Fourfold decline in RPR titer within 6-12 months 5, 2
• Use same testing method (RPR vs VDRL) preferably by same laboratory - titers are not interchangeable 5

Late Latent Syphilis

• Serologic evaluation at 6,12,18, and 24 months after treatment 5
• Treatment success: Fourfold decline in RPR titer within 12-24 months 5

Treatment Failure Indicators

• Clinical signs or symptoms persist or recur (new chancre, rash, neurologic symptoms) 5
• Sustained fourfold increase in RPR titer compared to post-treatment baseline 5
• Failure of RPR titer to decline fourfold within expected timeframe 5

Management of treatment failure:

1. Re-evaluate for HIV infection if not previously tested 5
2. Perform CSF examination to rule out neurosyphilis 5
3. Re-treat with three additional weekly doses of benzathine penicillin G 2.4 million units IM unless neurosyphilis is confirmed 5

Critical Pitfalls to Avoid

• Never rely on single test type - both nontreponemal and treponemal tests are required for diagnosis 3
• Never use treponemal test titers to monitor treatment - they remain positive for life regardless of cure 5, 3
• Beware of prozone phenomenon - false-negative nontreponemal tests can occur with very high antibody titers; dilute serum if clinical suspicion is high 4
• Do not compare titers between different test types (VDRL vs RPR) - they are not directly comparable 5
• Do not assume persistent low-titer reactivity indicates treatment failure - many patients remain "serofast" with stable low titers (generally <1:8) for extended periods or life 5
• In children with genital lesions, do not assume HSV only - consider atypical presentation of VZV 1

Partner Management

• For secondary syphilis: Identify and notify sexual contacts from past 6 months plus duration of symptoms 5
• Partner testing and/or treatment of positive index cases is essential to prevent reinfection 1
• All positive tests for syphilis require public health reporting 1