What is the recommended approach for diagnosing syphilis in adults, particularly those with high-risk behaviors or suspected neurosyphilis?

Diagnosing Syphilis in Adults with High-Risk Behaviors or Suspected Neurosyphilis

The diagnosis of syphilis requires both a nontreponemal test (RPR or VDRL) AND a treponemal test (FTA-ABS, TP-PA, or enzyme immunoassay) performed together—a single test type is insufficient for accurate diagnosis. 1, 2

Initial Diagnostic Algorithm

For Suspected Early Syphilis (Primary/Secondary)

• When lesions are present, darkfield microscopy or direct fluorescent antibody (DFA) testing of lesion exudate provides immediate definitive diagnosis without waiting for antibody development 1, 3
• Order both test types simultaneously: nontreponemal (RPR or VDRL) quantitatively with titers (e.g., 1:4,1:16,1:64) plus treponemal confirmation (FTA-ABS, TP-PA, or treponemal EIA/CLIA) 4, 1, 2
• Nontreponemal tests have 88.5% sensitivity in primary syphilis and 97-100% sensitivity in secondary syphilis 1, 2
• Critical pitfall: If clinical suspicion is high (characteristic chancre, diffuse rash with mucocutaneous lesions, lymphadenopathy) but initial serology is negative, pursue repeat serology in 1-2 weeks, exclude prozone phenomenon, or perform biopsy/darkfield examination 4

For Suspected Latent or Late Syphilis

• Both nontreponemal and treponemal tests are required, but sensitivity of nontreponemal tests decreases significantly: 85-100% in early latent, 61-75% in late latent, and only 47-64% in tertiary syphilis 1, 2
• Up to 25-39% of late latent cases can have non-reactive RPR despite active infection 1
• A positive treponemal test with negative nontreponemal test in late disease does not exclude active infection—clinical context and symptoms must guide management 1

Screening High-Risk Populations

Who to Screen

• Men who have sex with men (MSM): Screen at least annually, or every 3-6 months if multiple/anonymous partners, sex with illicit drug use, or partners engaging in these activities 4
• People with HIV: Screen at initial evaluation and at least annually; HIV-infected individuals comprised significant proportions of syphilis cases and require heightened surveillance 4, 5
• Pregnant women: Screen at first prenatal visit, at 28 weeks in high-risk populations, and at delivery 4, 2
• Other high-risk groups: Adults in correctional facilities, commercial sex workers, people exchanging sex for drugs, contacts of infectious syphilis cases 4

Diagnosing Neurosyphilis

Indications for CSF Examination

Perform lumbar puncture with CSF examination in the following scenarios:

• Any neurologic symptoms (meningitis, cranial nerve dysfunction, auditory symptoms) or ocular symptoms (uveitis) 4
• Active tertiary syphilis (aortitis, gummatous disease) 4
• Treatment failure (persistent symptoms or fourfold increase in nontreponemal titers) 4
• All HIV-infected patients with late-latent syphilis or syphilis of unknown duration 4
• Some specialists recommend CSF examination for all HIV-infected patients with syphilis regardless of stage, particularly if serum RPR ≥1:32 with CD4 count <350 cells/µL 4

CSF Diagnostic Criteria

• Reactive CSF-VDRL plus CSF WBC >10 cells/µL confirms neurosyphilis 4
• CSF-VDRL is specific but not sensitive—a reactive test establishes diagnosis, but nonreactive test does not exclude it 4
• CSF treponemal tests (FTA-ABS) are sensitive but not specific—a nonreactive test excludes neurosyphilis 4
• Typical CSF findings include mild mononuclear pleocytosis (10-200 cells/µL) and normal or mildly elevated protein 4
• Important caveat: HIV infection itself can cause mild CSF pleocytosis (5-15 cells/µL), particularly with CD4 counts >500 cells/µL, making neurosyphilis diagnosis more challenging 4

Special Considerations for HIV-Infected Patients

• Standard serologic tests remain accurate for most HIV-infected patients, though atypical responses (unusually high, low, delayed, or fluctuating titers) can occur 4
• False-negative serologic tests have been reported in HIV-infected patients with documented T. pallidum infection 4
• If clinical suspicion is high and serology is negative, pursue darkfield examination, biopsy, or direct fluorescent antibody staining 4
• HIV-infected patients have higher rates of concomitant uveitis and meningitis with syphilis 4
• More frequent monitoring is required (every 3 months instead of 6 months) after treatment 4

Critical Interpretation Principles

Understanding Test Results

• A fourfold change in nontreponemal titer (two dilutions, e.g., 1:16 to 1:4 or 1:64) represents clinically significant difference 4, 1, 2
• Treponemal tests remain positive for life in 75-85% of patients regardless of treatment and should never be used to monitor treatment response 1, 2
• Nontreponemal test titers correlate with disease activity and are used for monitoring treatment response 1, 2
• Never compare titers between different test types (VDRL vs. RPR)—use the same method, preferably by the same laboratory 1, 2

Common Diagnostic Pitfalls

• Never rely on a single test type—both nontreponemal and treponemal tests are mandatory for diagnosis 1, 2
• False-positive nontreponemal tests occur in 0.6-1.3% of the general population, with higher rates in autoimmune diseases, pregnancy, HIV, hepatitis B/C, and IV drug use 1
• In secondary syphilis with very high antibody titers, the prozone phenomenon can cause false-negative nontreponemal tests—request dilution if clinical suspicion is high 4
• PCR-based methods are not currently recommended as standard diagnostic tests for neurosyphilis 4

Concurrent Testing Requirements

• All patients diagnosed with syphilis must be tested for HIV 4
• In areas with high HIV prevalence, patients with primary syphilis should be retested for HIV after 3 months 4
• Consider evaluation for other sexually transmitted infections, as presence of any STI increases risk for others 4