False positive reactions in confirmatory tests for syphilis in presence of antiphospholipid antibodies: misdiagnosis with prognostic and social consequences
- Author(s): Larrañaga, Gabriela de;
- Trombetta, Luis;
- Wingeyer, Silvia Perés;
- Remondino, Graciela
- et al.
Published Web Locationhttps://doi.org/10.5070/D354f9m4sr
False positive reactions in confirmatory tests for syphilis in presence of antiphospholipid antibodies: misdiagnosis with
prognostic and social consequences1. Hemostasis and Thrombosis Laboratory, Hospital of Infectious Diseases F. J. Muñiz, Buenos Aires, Argentina. firstname.lastname@example.org
Gabriela de Larrañaga1, Luis Trombetta2, Silvia Perés Wingeyer1, Graciela Remondino3
Dermatology Online Journal 12 (4): 22
2. Infectology Department, Hospital of Infectious Diseases F. J. Muñiz, Buenos Aires, Argentina
3. Autoimmunity and Serology Sections, Fernández Hospital, Buenos Aires, Argentina
False-positive reactions in the Venereal Disease Research Laboratory test are well known, whereas a positive fluorescent treponemal antibody absorption assay is rarely thought to be a false positive. The non-recognition of serological false-positive tests for syphilis may have negative prognostic and social implications.
Serologic tests for syphilis are based upon the detection of several different antibodies that are produced following treponeme infection. Tests are classified by the type of antigen used: nontreponemal or treponemal. Nontreponemal tests use a mixture of cardiolipin with lipids to detect reagin, which is present in the sera of patients with syphilis. The most widespread nontreponemal assay is the Venereal Disease Research Laboratory test (VDRL). Treponemal tests use Treponema pallidum as the antigen source; the Fluorescent Treponemal Antibody Absorption Assay (FTA-ABS) and the Microhemagglutination Assay (MHA-TP) are examples of this type .
Unfortunately, the cardiolipin antigens used in the detection of reaginic antibodies yield a large number of false-positive tests in many conditions other than syphilis, such as viral infections or autoimmune diseases (as a result of damage in the host's tissue). Because the VDRL has a high sensitivity but low specificity, it is used as a screening test. Today, treponemal FTA-ABS or MHA-TP tests are considered confirmatory assays with high specificity and sensitivity. Although the FTA-ABS test has an overall high specificity (98 %), false-positive reactions have also been reported in a variety of acute and chronic diseases, such as mixed connective tissue disease, autoimmune disease, diabetes mellitus, alcoholic cirrhosis, viral infections, and pregnancy [2, 3, 4, 5, 6]. For example, in various autoimmune diseases, specificity falls to 67.7 percent because of a high number of false-positive results . False-positive reactions in VDRL are well known, whereas a positive FTA-ABS is rarely thought to be a false positive. Without clinical or epidemiological situations for syphilis, the most commonly studied and reported as false-positive cases are based on VDRL. In contrast, FTA-ABS false positive cases are less often reported. In general, a false positive VDRL may necessitate a search for an alternative disease rather than syphilis. But a false-positive test for FTA-ABS is less expected, less studied, and consequently, directly leads to a diagnosis of syphilis.
We present a patient diagnosed mistakenly as syphilis because of a false-positive FTA-ABS related to antiphospholipid antibodies (APL).
A 58-year-old woman presented with a reactive VDRL for the first time when she was donating blood in 1996. She was examined in the infectious disease department. FTA-ABS proved to be reactive. The patient received treatment with penicillin although she had no evidence of clinical symptoms of syphilis or evidence of autoimmune manifestations. Her husband's serological studies for syphilis were negative. Despite having denied any possible risk behaviors, the diagnosis of syphilis was maintained, which resulted in considerable conflict in her family environment. Over the following 6 years her VDRL remained positive, with values between 2 and 16 dilutions, FTA-ABS was alternatively read as reactive and non-reactive; she continued receiving treatment. In view of these discrepancies in the diagnostic tests over those 6 years, complementary studies were performed. MHA-TP, FTA-ABS, rheumatoid factor, Rose-Ragan test and HIV test were all negative, whereas lupus anticoagulant was strongly positive (screening and confirmatory procedures based upon APTT, dRVVT and dPT). Anticardiolipin antibodies (IgG 16 GPL and IgM 130 MPL,) and anti-mitochondrial antibodies (AMA) of M2 type (strong positive) were also found. VDRL was 2 dilutions. The patient continued follow-up and eventually manifested primary biliary cirrhosis, noted to be associated with AMA, M2 type.
In the case presented, infectious diseases specialists, who rarely suspect a false positive FTA-ABS, treated the patient for syphilis. Our patient may never have had syphilis; she neither had clinical evidence of syphilis infection nor a social or sexual history compatible with the disease. Her only sexual partner had corresponding negative tests.
Most reported false-positive cases of syphilis have been published in the context of autoimmune diseases, but few in the context of autoantibodies alone as presented here. The finding of antiphospholipid antibodies in this patient allowed her to be rid of the misdiagnosis of syphilis that had resulted in her significant family problems. In addition she will now be followed appropriately for other clinical consequences of antiphospholipid syndrome .
AMA are a heterogeneous group of autoantibodies classified according to their mitochondrial antigen specificity and disease association . Currently, 9 types of AMA have been identified and each of them is associated with different clinical entities. The presence of antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant) is closely associated with autoimmune disease. Although anticardiolipin antibodies are frequently described during a syphilis infection, lupus anticoagulant is not [9, 11]. Our reported case showed anticardiolipin antibodies but also strong lupus anticoagulant tests.
In conclusion, our patient never had syphilis. We believe that her positive FTA-ABS resulted from cross reactions with the two recognized autoantibodies (AMA and APL). In fact, the final diagnosis of our patient was primary biliary cirrhosis.
A search for autoantibodies is required when epidemiological data is not suggestive for syphilis, serological tests present discrepancies, or the treatment seems to fail. Being labeled incorrectly as having syphilis has substantially negative clinical and social implications and may delay recognition of the correct diagnosis.
References1. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev. 1995 Jan; 8(1):1-21. PubMed
2. Carlsson B, Hanson HS, Wasserman J, Brauner A. Evaluation of the fluorescent treponemal antibody-absorption (FTA-Abs) test specificity. Acta Derm Venereol. 1991; 71(4):306-11. PubMed
3. Alegre A, Alberca I, Herraez J, Vicente V. Lupus anticoagulant and false positive serological test for syphilis. Haematologia. 1987; 20(2):117-9.PubMed
4. McKenna CH, Schroeter AL, Kierland RR, Stilwell GG, Pien FD. The fluorescent treponemal antibody absorbed (FTA-ABS) test beading phenomenon in connective tissue diseases. Mayo Clin Proc. 1973 Aug; 48(8):545-8. PubMed
5. Kraus SJ, Haserick JR, Lantz MA. Fluorescent treponemal antibody-absorption test reactions in lupus erythematosus. Atypical beading pattern and probable false-positive reactions. N Engl J Med. 1970 Jun; 282(23):1287-90. PubMed
6. Mackey DM, Price EV, Knox JM, Scotti A. Specificity of the FTA-ABS test for syphilis. JAMA. 1969 March; 207(9):1683-5. PubMed
7. Murphy FT, George R, Kubota K, Fears M, Pope V, Howards RS, Dennis GJ. The use of western blotting as the confirmatory test for syphilis in patients with rheumatic disease. J Rheumatol. 1999 Nov; 26(11):2448-53. PubMed
8. Marangoni A, Sambri V, Storni E, D`Antuono A, Negosanti M, Cevenini R. Treponema pallidum surface immunofluorescence assay for serologic diagnosis of syphilis. Clin Diagn Lab Immunol. 2000 May; 7(3):417-21. PubMed
9. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I, Galeazzi M, Meroni PL, Derksen RHWM, de Groot PG, Gromnica-Ihle E, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quéré I, Hachulla E, Vasconcelos C, Roch B, Fernández-Nebro A, Boffa MC, Hughes GRV, Ingelmo M. Antiphospholipid syndrome. Arthritis Rheum 2002 April; 46(4):1019-27. PubMed
10. La Rosa L, Covini G, Galperin C, Catelli L, Del Papa N, Reina G, Morabito A, Balestrieri G, Tincani A, Gershwin ME, Meroni PL. Anti-mitochondrial M5 type antibody represents one of the serological markers for anti-phospholipid syndrome distinct from anti-cardiolipin and anti-β2-glycoprotein I antibodies. Clin Exp Immunol 1998 Apr; 112(1):144-51. PubMed
11. Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to β2-Glycoprotein I Clearly Differentiates Anticardiolipin Antibodies from Antiphospholipid Syndrome and Syphilis. Thromb Haemost 1996 May; 75(5): 717-20. PubMed
© 2006 Dermatology Online Journal