What are the tests for syphilis?

Diagnostic Tests for Syphilis

The diagnosis of syphilis requires both nontreponemal and treponemal tests for accurate detection, with darkfield microscopy and direct fluorescent antibody tests of lesion exudate being the definitive methods when lesions are present. 1

Types of Diagnostic Tests

Nontreponemal Tests

• Rapid Plasma Reagin (RPR) - detects antiphospholipid antibodies, correlates with disease activity, and should be reported quantitatively 2, 1
• Venereal Disease Research Laboratory (VDRL) - can be performed on both serum and cerebrospinal fluid (CSF) for neurosyphilis diagnosis 2, 1
• Toluidine Red Unheated Serum Test (TRUST) - less commonly used alternative nontreponemal test 2
• Unheated Serum Reagin (USR) - another less common nontreponemal test option 2

Treponemal Tests

• Fluorescent Treponemal Antibody Absorption (FTA-ABS) - highly sensitive treponemal test that can be used on serum or CSF 1, 3
• T. pallidum Particle Agglutination (TP-PA) - specific treponemal test that typically remains reactive for life 1, 4
• Enzyme immunoassays (EIAs) and chemiluminescence immunoassays (CLIAs) - automated treponemal tests increasingly used in reverse screening algorithms 5, 4

Testing Algorithms

Traditional Algorithm

• Initial screening with a nontreponemal test (RPR or VDRL)
• If reactive, confirm with a treponemal test (FTA-ABS or TP-PA) 5, 6

Reverse Algorithm

• Initial screening with an automated treponemal test (EIA or CLIA)
• If reactive, confirm with a nontreponemal test (RPR or VDRL)
• If discordant (treponemal positive, nontreponemal negative), perform a second different treponemal test 5, 7

The reverse algorithm offers increased automation, throughput, and can detect more cases in early primary and late latent stages when nontreponemal tests may be nonreactive, but may increase false positives 5, 6.

Direct Detection Methods

• Darkfield microscopy - definitive method for diagnosing early syphilis when lesions are present 1
• Direct fluorescent antibody tests of lesion exudate or tissue - another definitive method for early diagnosis 1
• Nucleic acid amplification tests (NAATs) - newer molecular methods that can detect T. pallidum DNA 7, 4

Special Considerations

Neurosyphilis Diagnosis

• Requires combination of reactive serologic test results, abnormal CSF cell count or protein, and reactive VDRL-CSF 1, 3
• VDRL-CSF is the standard test for CSF and is diagnostic when reactive (sensitivity 49-87%, specificity 74-100%) 3
• A negative VDRL-CSF does NOT rule out neurosyphilis due to limited sensitivity 3
• FTA-ABS on CSF is highly sensitive and could exclude neurosyphilis when negative 3

Point-of-Care Testing (POCT)

• Rapid treponemal and dual treponemal/nontreponemal POCTs are available for resource-limited settings 7, 4
• These tests offer quick results but may have limitations in sensitivity and specificity compared to laboratory-based tests 7

Monitoring Treatment Response

• Sequential serologic tests should use the same testing method, preferably by the same laboratory 1
• A fourfold change in nontreponemal test titer (two dilutions) indicates a clinically significant difference in treatment response 1
• For neurosyphilis, CSF leukocyte count is a sensitive measure of treatment effectiveness 3

Common Pitfalls

• Using only one type of test can lead to misdiagnosis 1, 5
• Failure to report nontreponemal test results quantitatively limits ability to monitor treatment response 1
• Comparing titers between different test types (e.g., VDRL and RPR) can lead to incorrect conclusions 1
• Relying solely on treponemal tests to assess treatment response is inappropriate as they typically remain positive for life 1, 8
• In prozone phenomenon, high antibody titers can cause false-negative results in nontreponemal tests unless the sample is diluted 2