A new reflex testing algorithm for syphilis screening

Methodist and Children’s Hospitals, Omaha, NE, changed its screening protocol from using a non-treponemal test (RPR) first to instead using a treponemal test (a syphilis IgG enzyme immunoassays [EIA]) first (see Table 1). The change was made for three reasons: 1) the hospital has a low-prevalence population, so most of the results are negative; 2) the EIA produces an objective result with clear end points and is more reproducible; and 3) the automation and interface with the computer system reduce the amount of technologist time needed not only for running the test but also for recording results in the system, and it decreases the risk of transcription errors. Making this change was comfortable because the treponemal syphilis IgG EIA had equal sensitivity and greater specificity for Treponema pallidum compared to the non-treponemal rapid plasma reagin (RPR) test. Additionally, the RPR test has a high false-positive rate in a low-prevalence population.

Types of syphilis tests

There are two categories of tests for syphilis: non-treponemal tests and treponemal tests. Treponemal tests detect antibodies specific for T pallidum, the spirochete which causes syphilis.^1-3 Non-treponemal tests (RPR) detect anticardiolipin antibodies and are not specific for syphilis.^1-3 A positive test for syphilis is not by itself diagnostic of the disease, as false-positives occur in all currently available laboratory tests.²

Non-treponemal tests: Non-treponemal tests can be used both qualitatively and quantitatively.^1-3 The RPR and venereal disease research laboratory, or VDRL, tests are common non-treponemal tests. These tests detect anticardiolipin antibodies and, thus, can have a high false-positive rate, especially in low prevalence populations.² False-positive results are usually, but not always, of low titer (<1:8) and occur due to autoimmune disease, drug addiction, acute viral infections, recent immunizations, or age (10% of people over 80 years of age have false-positive tests results).

Treponemal tests: Treponemal tests, including the FTA-Abs (fluorescent treponemal antibody absorption) test and syphilis immunoassays, detect antitreponemal antibodies and indicate exposure to syphilis during the patient’s lifetime.^1-3 A positive result, however, does not mean the patient currently has untreated syphilis.

Need for both types of tests to aid diagnosis

Treponemal tests have equivalent sensitivity but greater specificity for T pallidum infection compared to non-treponemal tests.² Non-treponemal tests also have higher false-positive rates in low-prevalence populations. Both tests are needed for aiding the diagnosis of syphilis. Positive results from both tests support a diagnosis of syphilis with a very high positive predictive value.^1-3 A treponemal test remains positive even after successful treatment of the disease and, thus, cannot be used to monitor therapy; non-treponemal tests, however, are negative when the disease is successfully treated.^1,1-3,3-5 Therefore, non-treponemal tests remain essential because they demonstrate active disease, indicate response to therapy, and detect reinfection. The algorithm currently in use includes both treponemal and non-treponemal tests (see Figure 1).

Special circumstances

Pregnancy: May result in an increase in RPR titers in women who have been adequately treated for syphilis. The increase is usually one or two dilutions and raises the question of whether or not to treat/retreat these women for active disease.

Neonatal syphilis: Newborn infants should not be discharged from the hospital without determination of the mother’s serologic status for syphilis. Testing of the infant’s blood is inadequate for screening because false-negative and false-positive results can occur. Maternal IgG antibodies are passively transferred across the placenta. Therefore, a positive syphilis IgG or FTA-Abs test (both treponemal tests) is not conclusive of active syphilis infection; the RPR (non-treponemal test) on the infant must be positive as well.³ The tests performed on the infant should be the same as those performed on the mother to enable comparison of titer results. A pediatric infectious-disease consult is strongly recommended in these cases.

Neurosyphilis: The qualitative VDRL, a non-trepomenal test, remains the screening test of choice for cerebrospinal fluid (CSF) to assist in the diagnosis of neurosyphilis.^6,7 VDRL is highly specific but insensitive, therefore, a positive can be used for diagnosis but a negative does not rule out neurosyphilis. The FTA-Abs treponemal test is another test that has been used to test CSF fluid.^6,7 This test has high sensitivity and low specificity; a negative test is consistent with the absence of neurosyphilis.⁶ False-positive CSF results are common with the FTA-Abs test and are thought to be due to passive diffusion of treponemal antibodies through disruptions in the blood-brain barrier.⁶

Summary

The laboratory diagnosis of syphilis is made possible through using a combination of non-treponemal and treponemal tests. The use of only one type of test when positive, without a confirmatory test being performed, is not sufficient for diagnosis because of false-positive results due to different medical conditions. All test results must be interpreted carefully, together with the patient’s clinical history and symptoms, to arrive at a clinical diagnosis of syphilis.

Nancy Cornish, MD, is affiliated with the Methodist and Children’s Hospitals in Omaha, NE.

References

1. Pope V. Use of Treponemal Tests to Screen for Syphilis. Infect Disease. 2004;21(8):399-404.
2. Jurado RL. Syphilis Serology: A Practical Approach Infectious Disease in Clinical Practice. Infect Diseases Clinical Pract. 1996;5:351-358. 1996.
3. American Public Health Association. A manual of tests for syphilis. 1998.
4. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev. 1995;8(1):1-21.
5. Fiumara NJ. The diagnosis and treatment of infectious syphilis. Compr Ther. 1995;21(11):639-644.
6. Kent ME, Romanelli F. Reexamining syphilis: an update on epidemiology, clinical manifestations, and management. Ann Pharmacother. 2008;42(2):226-236.
7. Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep. 2004.4(6):435-440.