Serological Response After Shorter Durations of Therapy for Syphilis of Late Latent or Unknown Duration: What Does It Mean?

To the Editor—We read with interest the retrospective cohort by Pugsley et al comparing serological response after different regimens for late latent syphilis or syphilis of unknown duration [1]. Using public health data, the authors assembled 18 027 cases and found no significant differences in the proportion achieving a 4-fold decline in lipoidal (nontreponemal) antigen titers by 24 months after 1 or 3 doses of benzathine penicillin G (BPG) or 28 days of doxycycline. Other retrospective studies report similar findings [2]. We urge caution in interpreting these results and consider what serological response truly reflects in late latent disease. Syphilis treatment outcomes can be conceptualized as 3 forms of “cure.” Microbiological cure—the eradication of Treponema pallidum—is the desired endpoint but cannot be directly confirmed in routine practice. Clinical cure denotes resolution of signs and symptoms but may not indicate microbiological cure (latent infection is asymptomatic yet persistent). Serological cure is defined as at least a 4-fold decline in lipoidal antigen titers (historically, seroreversion). Serological response can be an indirect marker of microbiological cure, but the overlap depends on context and disease stage.