Early syphilis in a man with a negative Treponema pallidum enzyme immunoassay-IgM

A 44-year-old man who has sex with men (MSM) attended our genitourinary medicine clinic in September 2009 with a two-week history of generalized rash and a mouth ulcer. He reported unprotected insertive and receptive oral sex with a casual male partner two months prior to the onset of symptoms. His last other sexual partner was another casual male contact six months before, with whom he had unprotected insertive and receptive oral, and protected receptive anal intercourse. On examination, a snail track ulcerated lesion was noted on the right mucosal aspect of his cheek. He had a generalized maculopapular rash involving the palms and soles. Condylomata lata were present perianally and a primary chancre was still evident on the shaft of his penis. A swab was taken from the chancre for dark field microscopy but no treponemes were visible. The condylomata lata were not swabbed, although these may have been more likely to yield treponemes. A presumptive diagnosis of secondary syphilis was made and the patient was given an intramuscular injection of 2.4 MU benzathine penicillin. He tolerated this well and did not experience a Jarisch–Herxheimer reaction. His syphilis serology at the time was positive, although not in keeping with the clinical presentation. Treponema pallidum total antibody (Architect Syphilis TP CLIA, Abbott Diagnostics, Wiesbaden, Germany) was positive and T. pallidum particle agglutination (TPPA; Serodia, Fujirebio Inc, Tokyo, Japan) test titre was >1280. Surprisingly the T. pallidum enzyme immunoassay (EIA)-IgM (Enzywell Treponema IgM, Diesse Diagnostica Senese SpA, Siena, Italy) and Venereal Disease Research Laboratory (VDRL; Immutrep, Omega Diagnostics, Alva, UK) tests were both negative. The serum was not titrated to exclude the prozone phenomenon; however, at no stage during serological follow-up did his VDRL become positive. Hepatitis B serology showed past resolved infection. Of note, he had previously attended our clinic in November 2008, which was six months prior to this presentation, and at this time his T. pallidum total antibody screening test was negative.

On discussing the results with the patient, he revealed that he had been diagnosed with common variable immunodeficiency (CVID) syndrome in 2004 after many years of recurrent sinusitis, chest and urinary tract infections. At the time of diagnosis he had profound hypogammaglobulinaemia (immunoglobulin G [IgG] 1.5; normal range 7–16 g/L); his IgA and IgM were also significantly below the normal range. He remains under regular follow-up with the immunology department and self-administers subcutaneous IgG weekly. His serum immunoglobulins had last been checked the week prior to his recent presentation at our clinic and showed IgG within normal limits but markedly reduced levels of IgA and IgM. This provided an interesting explanation as to why the T. pallidum EIA-IgM was negative, despite the multiple clinical features of secondary syphilis. On the basis of his immunodeficiency he was given a second dose of benzathine penicillin one week later.

DISCUSSION

CVID was first recognized in 1973 ¹ and is the second most common syndrome causing primary immunodeficiency. ² Its prevalence is reported to be between one in 10,000–200,000 individuals. ³ The mean age of diagnosis is 30 years, although there is often a significant delay to diagnosis. ¹ CVID is characterized by impaired B-cell differentiation and diminished immunoglobulin production, which results in increased susceptibility to infection. Typically IgG and IgA levels are diminished, although approximately 50% of patients will also have reduced IgM levels and T-lymphocyte dysfunction. Notably there is poor or absent response to vaccination in those with CVID. ¹ This has implications for hepatitis vaccination in individuals who have this immune deficiency and who fall into certain risk groups.

This patient had markedly reduced levels of IgM due to his inability to produce adequate immunoglobulin. His T. pallidum EIA-IgM was therefore negative despite presenting clinically with primary/secondary syphilis. The reported sensitivity and specificity of the assay used (Enzywell Treponema IgM) is 98.2% and 100%, respectively. ⁴ This case highlights the importance of recognizing the many clinical symptoms and signs of syphilis, as certain antibody tests for treponemal infection may fail to detect early infection in patients with this unusual immunodeficiency.

CONCLUSION

Syphilis serology may be difficult to interpret especially in the context of primary immunodeficiency. It is therefore important to manage patients with consideration to their symptoms and the findings of clinical examination.