Introdution There may be a difference in the immune and inflammatory response to repeat as compared to initial syphilis.

Methods Prospective study: We prospectively recruited patients with a new diagnosis of syphilis, described their clinical and demographic characteristics and tested their plasma for IFNa, IFNg, IL-1b, IL-12p40, IL-12p70, IP-10, MCP-1, MIP-1a, MIP-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-17A (Luminex multiplex assay (EMD Millipore) and their serum with a quantitative Rapid Plasma Reagin (RPR) test (Macrovue, Becton, Dickinson) at baseline pre-treatment and 6 months following therapy. The Mann-Whitney U-test was used to assess if cytokine levels and RPR titres differed between those with initial and repeat syphilis sampled at baseline and 6 month time points. Retrospective study: We compared RPR response kinetics between initial and repeat syphilis in persons attending our HIV/STI clinic.

Results Prospective study: 91 individuals, 36 with initial- and 55 with repeat syphilis, were included in the study. At baseline visit those with initial syphilis were more likely to be symptomatic and had higher levels of IL-8, IL-10 and MIP-1β. By the 6 month visit IL-10 remained higher in those with initial syphilis. Median RPR titres were higher at baseline in the repeat compared to the initial infection groups in those with symptomatic (primary and/or secondary) syphilis (1/128 [IQR 1/64-1/256] vs. 1/64 [IQR 1/16-1/128], p=0.016) but not those with latent syphilis. Retrospective study: Syphilis was diagnosed in 1 027/12 520 individuals tested. Repeaters had higher RPR titres at diagnosis and a stepwise increase in RPR titre with number of previous syphilis episodes. They had a different RPR response kinetic: they were less likely to be serofast and less likely to serorevert than initial syphilis. Not one of those with 4 or more episodes of syphilis seroreverted.

Conclusion Repeat syphilis has a different clinical presentation and immunological response than initial infection. We discuss the implications for clinicians and epidemiologists.