Syphilis Serology

The causative organism of syphilis, Treponema pallidum, cannot be cultured in the clinical microbiology lab. Therefore, serologic tests are necessary for the diagnosis of the disease in any stage. Serologic tests for syphilis are classified as either nontreponemal or treponemal.

Nontreponemal tests include RPR and VDRL. These tests detect IgM and IgG anti-cardiolipin antibody, which is produced in response to host cell damage and cardiolipins released from treponemes. Consequently, false positive nontreponemal tests occur in the presence of other anti-cardiolipin antibody-producing conditions including autoimmune disease, various other infections, pregnancy, and previous transfusions. All reactive nontreponemal tests should be followed up with treponemal testing. Titers of reactive nontreponemal tests can be monitored for effectiveness of therapy—a fourfold decrease in titer indicates therapeutic response.

RPR titers are negative or low early in primary syphilis. As the disease progresses, titers increase and a greater percentage of patients develop a reactive RPR. RPR titers may decrease after several years, even without therapy. RPR titers drop rapidly after treatment of primary or secondary syphilis, while the FTA-ABS remains reactive, irrespective of treatment.

RPR is not highly specific. Biological false positive reactions (BFP) occur in about 1 in 4,000 persons in the general population and 1 in 2,000 pregnant women. Both acute and chronic biologic false positive reactions occur. Viral and bacterial infections, immunizations, and pregnancy may cause acute BFP. The titers are usually low and decrease with time. Autoimmune diseases, senescence, cirrhosis, metastatic cancer, lymphomas, myeloma, drug abuse, and anti-cardiolipin antibody syndromes cause chronic BFP. Reactivity usually persists more than six months and the titer remains fixed at a low level. All specimens with reactive RPR’s have confirmatory testing performed by FTA-ABS.

Treponemal tests include FTA-ABS and TP-PA. These tests are not used for initial screening, due to slightly higher (1%) false positive rates than nontreponemal tests in the general population. The FTA-ABS test measures treponemal antibodies by indirect fluorescence, while TP-PA is a particle agglutination test that has widely replaced MHA-TP. The FTA-ABS is reactive earlier in primary syphilis than the RPR and remains reactive in 98% of patients with latent syphilis. A reactive treponemal test in addition to a reactive nontreponemal test is highly specific for infection. Treponemal tests may remain reactive indefinitely, and are not useful for monitoring therapy.

Clinically, syphilis has four defined stages. The primary stage is defined by the presence of a chancre at the site of infection. In secondary syphilis, the organism disseminates to multiple sites, causing rashes & lymphadenopathy. Primary and secondary syphilis generally occur in the first 6 months of untreated infection. Latent syphilis is asymptomatic infection, occurring after or between primary & secondary stages. Tertiary syphilis consists of late complications of the disease, including aortic aneurysm and neurosyphilis, usually occurring years or decades after primary infection. Serologic tests have variable sensitivity at each stage of disease. The % sensitivity of each serologic test by stage of infection is:

























Syphilis IgG





The specificity for all tests in all stages of infection is 96-99%. Of note, nontreponemal tests have low sensitivity (70%) in tertiary syphilis. Therefore, treponemal tests should be performed regardless of RPR/VDRL results when late complications of the infection, such as aortic aneurysm or neurosyphilis, are suspected.

VDRL testing on CSF for the diagnosis of neurosyphilis is highly specific (99.8%), but has low sensitivity (50%), therefore a reactive CSF VDRL is diagnostic, but a non-reactive result does not rule out neurosyphilis. FTA-ABS can also be performed on CSF, and has 100% sensitivity, but lower specificity than VDRL (94%).

Syphilis IgG antibodies are useful when primary infection is suspected and other serologic tests are negative, and when false positive results are suspected.

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