Serologic testing for syphilis: missing the point

You may have seen several news sources touting the recent CDC finding that nearly one in five positive reactions with a newer syphilis test are wrong.  These headlines may grab the reader's attention, but the press took the finding out of context and failed to deliver the real message that the CDC was trying to convey.  Worse, the press reports may needlessly confuse and worry those who are being treated for syphilis.

Serological tests for syphilis are grouped into two categories.  Nontreponemal tests such as the VDRL and RPR are based on antibody generated against the lipid cardiolipin.  Presumably cardiolipin is released from damaged tissue in syphilis patients and gets incorporated into the membrane of Treponema pallidum.  The reason that these tests are "nontreponemal" is that antibodies to cardiolipin accompany many other conditions.  On the other hand, treponemal tests use T. pallidum proteins or even the entire spirochete as antigen to detect antibodies against the spirochete.  Although the classic treponemal tests such as the FTA-ABS (fluorescent treponemal antibody-absorption) and TP-PA (Treponema pallidum particle agglutination) are still used, the newer automated EIA (enzyme immunoassay) and CIA (immunochemiluminescence) treponemal tests enable clinical laboratories to rapidly screen a large number of sera.

The traditional approach to syphilis testing is to first screen the patient's serum with a nontreponemal test.  Since nontreponemal tests can give false positive reactions, reactive sera are retested with one of the treponemal tests.  However, the low cost of executing the automated treponemal tests have led some high-volume clinical laboratories to reverse the order of the assays:  they screen with the EIA/CIA treponemal test and confirm positive results with a nontreponemal test.  The CDC report in the Morbidity and Mortality Weekly Report deals with this so-called "reverse sequence" testing.

So where did the "nearly one in five" figure come from?  From 2006 to 2010, five large clinical laboratories screened 140,176 sera specimens with the reverse sequence procedure.  Of the 4,834 reactive with the EIA/CIA treponemal test, 2,743 gave negative results with the nontreponemal RPR test.  When the samples that gave discrepant results were tested further with one of the classic treponemal tests, 866 of the 2,743 samples were negative.  Overall, among the 4,834 samples that were reactive with the newer treponemal test, 866 or 18% were nonreactive with two subsequent tests.  These 866 were assumed to be false positives.

The news media pounced on the 18% figure and declared that hundreds may have been given antibiotics to treat a disease that they didn't have.  But they ignored the fact that doctors don't diagnose syphilis on the basis of a single lab test.  It is standard practice to perform a second test when the first comes back positive and to do even a third one if warranted.  Doctors also take into account the physical exam and the sexual and medical history of the patient before making the decision to treat with antibiotics.

Here's how the CDC responded to the assertion that those among the 18% may have been falsely diagnosed and treated unnecessarily with antibiotics:

There are two problems with this assertion. First, the current report does not document whether or not treatment was provided. Second, in those cases where treatment was provided, it may have been justified based on sexual risk and findings on clinical evaluation. It is also important to note that syphilis is not diagnosed on the basis of a single blood test. Many labs routinely will do additional testing when the first test is positive, without notifying the patient. Doctors diagnose syphilis after considering at least two syphilis tests, the patient's history, the physical exam, and a review of past syphilis test results. The MMMR analysis, while important, does not allow us to conclude that the newer tests led to inaccurate syphilis diagnosis or inappropriate treatment.

So what was the message that the CDC was trying to communicate to readers of the MMMR report?  Their intention was to provide guidance in the management of cases for which the reverse sequence screening is performed instead of the traditional sequence, which is still recommended by the CDC.  Specifically, when conflicting results occur (positive with the treponemal test, negative with the nontreponemal test), a third test should be done with the TP-PA.  (The CDC does not recommend the FTA-ABS because it is less specific and probably less sensitive.)  A positive reaction with the TP-PA indicates past or present syphilis; a negative reaction indicates that syphilis is unlikely.  As always, the clinical observations and medical history of the patient should also be considered in making an informed treatment decision.


Reference

Centers for Disease Control and Prevention (February 11, 2011).  Discordant results from reverse sequence syphilis screening -- five laboratories, United States, 2006-2010.  MMMR. Morbidity and Mortality Weekly Report 60(5):133-137.  link