VA Boston Medical Forum

A Veteran Presenting With Leg Swelling, Dyspnea, and Proteinuria

Fed Pract. 2019 September;36(9):420-424

References

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2. Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol. 2016;12(12):768-776.

3. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.

4. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47(2):643-656.

5. Nawaz FA, Larsen CP, Troxell ML. Membranous nephropathy and nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 2013;62(5):1012-1017.

6. Pillay A. Centers for Disease Control and Prevention Syphilis Summit—Diagnostics and laboratory issues. Sex Transm Dis. 2018;45(9S)(suppl 1):S13-S16.

7. Levett PN, Fonseca K, Tsang RS, et al. Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiol. 2015;26(suppl A):6A-12A.

8. Oliver SE, Aubin M, Atwell L, et al. Ocular syphilis—eight jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep. 2016;65(43):1185-1188.

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10. US Centers for Disease Control and Prevention. Clinical advisory: ocular syphilis in the United States. https://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm. Updated March 24, 2016. Accessed August 12, 2019.

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Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?

► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.⁶ The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.⁷ Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.

If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.

► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?

► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.⁸ Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.^9,10

► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?

► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.^11,12Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.^13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.¹⁵ As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).¹⁶ This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.

► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?

► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.⁹