What is the diagnostic approach for syphilis?

Diagnostic Approach for Syphilis

Diagnose syphilis using a two-step serologic approach: screen with either a nontreponemal test (VDRL or RPR) or treponemal test (FTA-ABS, TP-PA, or EIA), then confirm reactive results with the complementary test type. 1

Direct Detection Methods (Early Lesions)

For patients presenting with suspicious mucocutaneous lesions, direct organism detection provides definitive diagnosis:

• Darkfield microscopy of lesion exudate or tissue remains the gold standard for diagnosing primary syphilis when lesions are present 1
• Direct fluorescent antibody staining (DFA-TP) of lesion material serves as an alternative to darkfield examination 1
• These methods are most useful during the primary stage when chancres are present, before serologic tests become reactive 1

Serologic Testing Algorithm

Traditional Approach (Screen with Nontreponemal Tests)

• Screen with nontreponemal tests: VDRL or RPR 1
• Confirm all reactive nontreponemal tests with treponemal tests: FTA-ABS, TP-PA, or MHA-TP 1
• Report nontreponemal test results quantitatively as titers correlate with disease activity 1

Reverse Sequence Algorithm (Emerging Approach)

• Some laboratories now screen with treponemal-based EIA, then confirm with nontreponemal testing 1
• This strategy identifies both active infections and previous treated infections more frequently 1

Critical Interpretation Points

• Fourfold titer changes (two dilution difference, e.g., 1:16 to 1:4) represent clinically significant differences in nontreponemal test results 1
• Use the same testing method (VDRL or RPR) and preferably the same laboratory for sequential tests, as RPR titers often run slightly higher than VDRL 1
• Treponemal tests typically remain reactive for life regardless of treatment and should not be used to assess treatment response 1

Special Diagnostic Considerations

HIV-Infected Patients

• Standard serologic tests remain accurate and reliable for most HIV-infected patients 1
• False-positive nontreponemal tests not confirmed by treponemal tests occur more commonly in HIV-infected persons 1
• Nontreponemal test responses may be atypical (higher, lower, or delayed titers) 1
• If clinical suspicion is high despite negative serology, pursue alternative diagnostics: biopsy, darkfield examination, repeat serology in 1-2 weeks, or exclude prozone phenomenon 1

Neurosyphilis Diagnosis

Diagnose neurosyphilis based on CSF examination showing reactive CSF-VDRL plus CSF WBC >10 cells/µL. 1, 2

CSF Analysis Components

• CSF-VDRL: Highly specific but insensitive—a reactive test confirms neurosyphilis, but a nonreactive test does not exclude it 1, 2
• CSF white blood cell count: Typically elevated at 10-200 cells/µL with mononuclear predominance 1, 2
• CSF protein: Normal or mildly elevated; elevated protein alone without reactive VDRL or elevated WBC should never be used as sole diagnostic criterion 1, 2
• CSF treponemal tests (FTA-ABS): Sensitive but not specific—a nonreactive test excludes neurosyphilis, but a reactive test does not confirm it 1, 2

Indications for CSF Examination

Perform lumbar puncture in patients with: 1

• Neurologic or ocular signs/symptoms
• Active tertiary syphilis
• Treatment failure
• HIV infection with late-latent syphilis or syphilis of unknown duration
• HIV infection with serum RPR ≥1:32 or CD4+ count <350 cells/µL (per some specialists)

Latent Syphilis Staging

• Early latent: Documented infection <1 year, serologic evidence without clinical manifestations 1
• Late latent: Documented infection >1 year or unknown duration 1
• Staging requires normal CSF profiles by definition 1

Common Diagnostic Pitfalls

• Prozone phenomenon: False-negative nontreponemal tests can occur with very high antibody titers; dilute serum if clinical suspicion is high 1
• Seronegative window: Primary syphilis has a period before serologic tests become reactive; use darkfield microscopy during this phase 1
• Blood contamination: Can cause false-positive CSF-VDRL results; interpret carefully 2
• HIV-related CSF pleocytosis: HIV itself causes mild mononuclear pleocytosis (5-15 cells/µL), particularly with CD4+ >500 cells/µL, complicating neurosyphilis diagnosis 1, 2
• Umbilical cord blood testing: Never use for newborn screening as maternal blood contamination causes false-positives; always test infant serum 1

Pregnancy and Congenital Syphilis Screening

• Screen all pregnant women at first prenatal visit 1, 3
• In high-risk populations, repeat screening at 28 weeks gestation and at delivery 1, 3
• No infant should leave the hospital without documented maternal serologic status 1
• Evaluate all infants born to seropositive mothers with quantitative nontreponemal test on infant serum (not cord blood) 1