What are the clinical presentation, staging, recommended treatment, and follow‑up for primary, secondary, and latent syphilis?

Syphilis: Clinical Presentation, Staging, Treatment, and Follow-Up

Clinical Presentation by Stage

Primary Syphilis

Primary syphilis presents as a painless, indurated ulcer (chancre) at the site of inoculation, typically accompanied by regional lymphadenopathy. 1

• The chancre appears 10-90 days after exposure and heals spontaneously within 3-6 weeks without treatment 2
• HIV-infected individuals may present with multiple or atypical chancres, and primary lesions might be absent or missed 1
• The lesion is highly infectious during this stage 3

Secondary Syphilis

Secondary syphilis develops weeks to months after the primary chancre and is characterized by systemic dissemination with constitutional symptoms and mucocutaneous manifestations. 1

• Classic presentation includes non-pruritic rash involving palms and soles, generalized lymphadenopathy, fever, and malaise 2
• Condylomata lata (broad, flat, moist papules in anogenital areas) and mucous patches in the oral cavity are highly characteristic 2
• Can mimic acute HIV infection with constitutional symptoms and CSF abnormalities 1
• Symptoms resolve spontaneously but may relapse with decreasing intensity 2

Latent Syphilis

Latent syphilis is defined by positive serologic tests without clinical manifestations and is subdivided into early latent (<1 year) and late latent (>1 year or unknown duration). 1

• Early latent: infection acquired within the past year 4
• Late latent: infection acquired more than one year ago or of unknown duration 4
• Patients remain infectious during early latent stage but less so in late latent stage 4

Tertiary Syphilis

Tertiary syphilis occurs in approximately 25% of untreated patients after 3-12 years of latency, manifesting as gummatous lesions, cardiovascular syphilis, or neurosyphilis 1

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Diagnostic Approach

Serologic Testing

Diagnosis relies on both nontreponemal tests (VDRL, RPR) and treponemal tests (FTA-ABS, MHA-TP), with a fourfold change in nontreponemal titer considered clinically significant. 1

• Nontreponemal tests are used for screening and monitoring treatment response 1
• Treponemal tests confirm the diagnosis but remain positive for life 1
• Titers ≥1:32 are considered indicative of early syphilis for partner notification purposes 5

Direct Detection Methods

• Darkfield examination and direct fluorescent antibody tests of lesion exudate are definitive for diagnosing early syphilis 1
• Alternative tests (biopsy, darkfield, DFA staining) are useful when serologic tests are nonreactive but clinical findings suggest syphilis 4

CSF Examination Indications

• Not routinely recommended for primary or secondary syphilis unless neurologic or ophthalmic symptoms are present 4
• Required for HIV-infected patients with late latent syphilis or syphilis of unknown duration 4
• Should be performed when treatment failure is suspected 4

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Treatment Recommendations

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

• This regimen provides adequate treponemicidal blood levels and prevents progression to later stages 6
• Some specialists recommend additional treatments for HIV-infected patients (three weekly doses of 2.4 million units IM) 4

For penicillin-allergic, non-pregnant patients: Doxycycline 100 mg orally twice daily for 14 days 1

• Alternative: Tetracycline 500 mg orally four times daily for 14 days (though compliance is typically better with doxycycline) 4
• Ceftriaxone 1 gram daily IM or IV for 8-10 days may be considered, though optimal dosing is not well-defined 4
• Close follow-up is essential with alternative regimens as efficacy is less well-documented 4

Late Latent Syphilis or Latent Syphilis of Unknown Duration

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals. 1

• HIV-infected patients with late latent syphilis should have CSF examination before treatment 4

For penicillin-allergic patients: Doxycycline 100 mg orally twice daily for 28 days 1

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days. 1

• Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons 4
• Alternative: Procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times daily, both for 10-14 days 1

Special Populations

Pregnant Women:

• Must be treated with penicillin regimens appropriate for their stage of syphilis 1
• Penicillin-allergic pregnant women must be desensitized and treated with penicillin, as it is the only effective option 1

HIV-Infected Patients:

• Treat with same regimens as HIV-negative patients, though some specialists recommend enhanced therapy 4
• More frequent follow-up required (3-month intervals instead of 6-month intervals) 4
• May be at increased risk for neurologic complications and treatment failure 4

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Follow-Up and Monitoring

Serologic Monitoring Schedule

Quantitative nontreponemal tests should be repeated at 6 and 12 months after treatment for primary and secondary syphilis, with a fourfold decline expected within 6 months. 4

• More frequent evaluation at 3,6,9,12, and 24 months for HIV-infected patients 4
• For late syphilis, fourfold decline expected within 12-24 months 7

Treatment Failure Criteria

Treatment failure is defined as:

• Persistent or recurrent signs/symptoms 4
• Sustained fourfold increase in nontreponemal test titer 4
• Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 4

Management of Treatment Failure

Patients meeting treatment failure criteria should undergo CSF examination and be re-treated. 4

• Re-treatment regimen: Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (unless CSF indicates neurosyphilis) 4
• HIV-infected patients whose titers do not decrease fourfold within 6-12 months should undergo CSF examination and re-treatment 4

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Partner Management

Exposure-Based Treatment Algorithm

Sexual partners exposed within 90 days of diagnosis should receive presumptive treatment with benzathine penicillin G 2.4 million units IM, even if seronegative. 8

• Partners may be infected but not yet showing serologic evidence of disease 8

Time periods for identifying at-risk partners: 4

• Primary syphilis: 3 months plus duration of symptoms
• Secondary syphilis: 6 months plus duration of symptoms
• Early latent syphilis: 1 year before diagnosis

Partners exposed >90 days before diagnosis:

• Should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 4
• Otherwise, treat based on serologic test results 4

Additional Partner Management Considerations

• All partners should be tested for HIV, as co-infection is common 1
• Repeat serologic testing at 6,12, and 24 weeks after exposure, as initial negative tests do not exclude early infection 8

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Important Clinical Caveats

Jarisch-Herxheimer Reaction

An acute febrile reaction with headache, myalgia, and other symptoms may occur within 24 hours after any therapy for syphilis. 4

• Patients should be advised of this possibility before treatment 4
• Antipyretics may be recommended, but no proven methods prevent this reaction 4
• May induce early labor or fetal distress in pregnant women but should not delay therapy 4

HIV Testing

All patients with syphilis should be tested for HIV. 1

• Co-infection is common and affects management and follow-up 4
• HIV-infected patients may have unusual serologic responses (higher titers, false-negatives, delayed seroreactivity) 4

CSF Invasion

• T. pallidum invasion of CSF with abnormalities is common in primary and secondary syphilis, but neurosyphilis develops in only a limited number after standard treatment 4
• Detection of T. pallidum in CSF before therapy does not predict treatment failure 9

Penicillin Allergy

Pregnant women and patients with neurosyphilis who are penicillin-allergic must be desensitized and treated with penicillin. 1

• Penicillin is the only therapy with documented efficacy for neurosyphilis and syphilis during pregnancy 4
• Skin testing for penicillin allergy may be useful but minor determinants are unavailable commercially 4