Serologic Testing/Screening for Syphilis

When on consults, we are commonly called to interpret the meaning of serologic testing for syphilis (and other diseases like RMSF and Lyme as well). When evaluating the results of testing, a clinical history is imperative to interpretation. Does the patient have a history of syphilis, to their knowledge? Treated or untreated? If treated, how were they treated?

The following is taken directly from PPID Online (Mandell's), but explains testing well:

Confusion surrounds interpretation of the serologic tests for syphilis, principally because two different types of antibodies are measured: the nonspecific nontreponemal reaginic antibody and the specific anti-treponemal antibody. The test for the former is inexpensive, rapid, and convenient for screening large numbers of sera (e.g., donated blood) and as an indication of disease activity. Specific antibody tests establish the high likelihood of a treponemal infection, either currently or at some time in the past. To establish a diagnosis of syphilis, the two types of serologic tests are most often used together, although attempts to improve the single tests are ongoing. It should be emphasized that serologic test results for syphilis on rare occasions may be negative in active cases, especially in older patients.

Non-Treponemal Tests

A fourfold change in titer using the same test method, either VDRL or RPR, is necessary to demonstrate a clinically significant difference, preferably being performed in the same laboratory at the same time. Nontreponemal antibody tests vary during the course of untreated disease. They reach their highest prevalence and titer during the secondary and early latent stages and decline thereafter, usually to less than 1:4. Over time, at least 25% of untreated persons become VDRL or RPR negative, even without treatment. A persistently high-titered RPR or VDRL result is more common in HIV-infected persons because of the polyclonal antibody stimulation, a manifestation of immune dysfunction often seen in these patients, especially in early HIV disease.

The quantitative VDRL/RPR test should become nonreactive 1 year after successful therapy in primary syphilis and 2 years after successful therapy in secondary syphilis. Most patients with late syphilis should be nonreactive by the fifth year after treatment. The time required for the test to become negative correlates with the interval between contact and institution of therapy and with the severity of illness, especially with the type of skin lesions manifested in the secondary stage (i.e., a patient with a macular rash reverts to a negative titer sooner than does a patient with a papular rash). Therefore, a positive VRDL or RPR response after 1 year in a patient treated for primary syphilis or after 2 years in a patient treated for secondary syphilis suggests persistent infection, reinfection, or a biologically false-positive reaction. A patient with adequately treated late syphilis should have a negative response after 5 years. As with all quantitative serologic tests, only a fourfold or greater change in titer is meaningful.

Specific Treponemal Tests

These tests measure antibodies against specific T. pallidum antigens. The principal specific anti-treponemal antibody tests performed today are the FTA-abs and T. pallidum agglutination tests (TPHA and MHA-TP). These tests would be relatively expensive as screening tests, and if they were applied to a low-risk population, the number of false-positive reactions would increase proportionately. Therefore, their principal use is to verify a positive nontreponemal reaginic test result. Once positive, the patient usually remains positive for life. However, reversion to a nonreactive status may occur in up to 10% of patients, especially in those who are treated early.

When the diagnosis of syphilis is being seriously considered in an individual patient, the TPHA, MHA-TP, or FTA-abs test should be done. Once these have become positive and the diagnosis is established, the usefulness of these tests is limited because they can remain positive for life. A nontreponemal antibody test is very helpful for monitoring the efficacy of therapy. The failure to fall more than fourfold or become negative suggests a persistent infection, reinfection, or a false-positive test.

False Positive Testing

The likelihood of a biological false-positive (BFP) reaction depends on the population being studied. Acute or transient false-positive nontreponemal reaginic test reactions may occur whenever there is a strong immunologic stimulus (e.g., acute bacterial or viral infection, vaccination, intravenous drug abuse, HIV infection). Positive reactions persisting for months occur in the presence of continued parenteral drug abuse; with autoimmune or connective tissue diseases, especially systemic lupus erythematosus; with aging (in up to 10% of those older than 70 years of age); in hypergammaglobulinemic states; and in HIV coinfection. A false-positive nontreponemal reaginic test in this setting tends to be associated with other serum factors frequently associated with autoimmune diseases, such as antinuclear, antithyroid, or antimitochondrial antibodies, rheumatoid factor, and cryoglobulins.

A false-positive nontreponemal reaginic test can usually be verified (and syphilis excluded) by obtaining a negative specific treponemal antibody test (FTA-abs, TPHA, MHA-TP). However, at times the same illnesses that produce a false-positive nontreponemal reaginic test (e.g., systemic lupus erythematosus) also result in a positive or borderline-positive FTA-abs test reaction. Also, the FTA-abs may be positive when the VDRL is negative and vice versa. This false reaction can often be suggested by noting a beaded pattern of immunofluorescence on the treponemes, but the best definitive way to make the distinction is to obtain the functional but rarely available TPI test, PCR or immunoblotting using specific T. pallidum antigens such as 17-kDa, and so forth. Other spirochetal illnesses, such as relapsing fever (Borrelia spp.), yaws, bejel, pinta, leptospirosis, or rat-bite fever (Spirillum minor), also yield positive nontreponemal and treponemal tests. Infection with Borrelia burgdorferi (Lyme disease) results in a positive FTA-abs test but does not cause a positive nontreponemal reaginic reaction (VDRL or RPR).

Yvonne Carter, MD
http://www.ppidonline.com/content/default.cfm