Pseudo-Pseudo Syphilis?
ABSTRACT & COMMENTARY
Synopsis: Biological false-positive tests for syphilis may not always be false.
Source: Erbelding EJ, et al. Syphilis serology in human immunodeficiency virus infection: Evidence for false-negative fluorescent treponemal testing. J Infect Dis 1997;176: 1397-1400.
Erbelding and colleagues in baltimore and Dallas examined the occurrence of falsely negative FTA-ABS (fluorescent treponemal antibody absorption) tests in a cohort of 1117 injection drug users who had undergone, among other things, serological testing for HIV infection and syphilis. Subjects were initially placed into one of three groups: 10% were biological false-positive reactors (BFP: positive RPR at > 1:4; negative FTA-ABS), 80% were RPR-negative, and 10% had serological evidence of syphilis (both RPR and FTA-ABS positive).
Among the 112 BFP reactors, 68 (61%) had a reactive RPR that remained less than 1:8, with persistently negative FTA-ABS. Thirty-five (31%) of the BFP reactors had, on at least one occasion, an RPR greater than 1:8 at the same time the FTA-ABS was negative. An additional five (4.5%) patients converted from FTA-ABS negative to positive, while four (3.6%) were initially RPR and FTA-ABS positive but subsequently lost reactivity in the latter test.
Serum samples from selected BFP reactors who were also HIV infected were evaluated for the presence of antibody to 17 kDa and 47 kDa antigens (as recombinant fusion proteins) of Treponema pallidum membrane proteins by immunoblotting. Selection was based on the absence of a history of syphilis but a rise in RPR over time. Of three subjects with consistently non-reactive FTA-ABS tests, one had a positive immunoblot.
One subject, who had had an RPR reactive at 1:1 and a borderline FTA-ABS two years prior to the study and was never treated, had an RPR as high as 1:64 during the study with a completely negative FTA-ABS. This subject had a positive immunoblot. A fifth subject had been treated for syphilis one year prior to study entry, at which time his RPR was 1:16 and his FTA-ABS was negative. During the study, the latter remained negative, but the RPR rose to as high as 1:256 and his immunoblot for T. pallidum membrane antigens was positive. In another subject, immunoblotting was positive at a time when a low titer RPR had reverted to negative. The subject subsequently had a rising RPR and a positive FTA-ABS and was treated for syphilis.
COMMENT BY STAN DERESINSKI, MD, FACP
This prospective study found that several selected HIV-infected subjects who would otherwise have been classified as having a biological false reaction to non-specific tests for syphilis nonetheless had strong serological evidence of infection with this spirochete. Unfortunately, it is unclear from the report how many subjects were selected for immunoblot testing. Thus, we cannot determine the frequency of this phenomenon. Furthermore, the interpretation of these results relies upon confidence in the accuracy of the immunoblotting procedure used in this study. While the available evidence indicates that it is accurate, that evidence is limited.
Nonetheless, the observations reported here are important ones. The serological diagnosis of syphilis is fraught with potential error, nowhere more so than in the HIV-infected patient. There is no true gold standard for the diagnosis of this infection, and we are forced to rely upon imperfect reflections of an often imperfect host response. Until we have a test that reliably detects the presence of the organism, rather than antibodies to it, we are bound to be frequently befuddled in managing some of our patients. It is hard to believe that the closest thing we have to a gold standard for the diagnosis of syphilis remains rabbit testicular injection. Detection of the organism by PCR may be effective in the diagnosis of congenital syphilis, but it has not yet been demonstrated to be reliable in other circumstances.
The diagnosis of neurosyphilis is often even more puzzling than that of other forms of this infection, both in HIV- and non-HIV-infected subjects. There are many reports in the literature of putative neurosyphilis in the absence of a positive CSF VDRL test. On the other hand, we injected CSF from 30 HIV-infected patients with serological evidence of syphilis in serum, but not CSF, into rabbit testicles and failed to recover T. pallidum in any. In some instances, the diagnosis of neurosyphilis is based upon a positive CSF FTA-ABS test. Unfortunately, there is, to my knowledge, no available confirmation of the validity of the use of the FTA-ABS test for this purpose. Perhaps the application of immunoblotting or better PCR tests will help solve this problem.
In the meantime, all we can do is suspect the possibility that, in some cases ordinarily classified as BFP reactors, particularly those with rising RPR titers who are HIV infected, subjects may actually be infected with T. pallidum. As Erbelding and colleagues state, "Pending the development of more sensitive syphilis diagnostic tests, the decision to treat for syphilis in HIV disease should be based on the presence of behavioral risks for syphilis and the community prevalence of disease in addition to test results, as with treatment algorithms for tuberculin reactivity."
Which of the following is correct?
a. A patient with a positive FTA-ABS test and a negative RPR is considered to be a biologic false-positive reactor.
b. HIV-infected patients may, in some instances, have falsely negative FTA-ABS tests.
c. Biological false reactors should all be considered to have syphilis and receive treatment.
d. A negative FTA-ABS eliminates the possibility that a patient has syphilis.
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