Persistent Immune Dysregulation and Subclinical Multisystem Alterations in Serofast Syphilis: Insights From a Two-Center Retrospective Cohort With Simulated Long-Term Follow-Up

The serofast state of syphilis poses a major clinical challenge, yet its long-term pathophysiological implications remain poorly defined. To characterize the persistent biological alterations associated with this state, we conducted a two-center retrospective cohort study involving 382 serofast syphilis patients and 84 healthy controls, who were stratified by duration of seropositivity to simulate long-term follow-up. Our analysis revealed persistent and dynamic immune dysregulation, characterized by a progressive decline in neutrophils, persistently suppressed NK cells, and a biphasic T lymphocyte and immunoglobulin (IgM and IgA) response—initial posttreatment normalization followed by a significant secondary increase during prolonged seropositivity. In addition to the immune system response, patients developed progressive normocytic anemia, a trend toward hypocoagulability and widespread subclinical metabolic alterations; the latter was evidenced by consistently lower levels of glucose, proteins, uric acid and key electrolytes (K⁺, Ca²⁺), as well as lower levels of cardiac (α-hydroxybutyrate dehydrogenase and creatine kinase) and hepatic (albumin) metabolic function markers, all in the absence of overt organ damage. These findings demonstrate that the serofast state is not immunologically inert or benign, but is associated with ongoing immune activation and subclinical multisystem alterations. Our results challenge the prevailing clinical perception of this condition and underscore the imperative to reevaluate current management strategies for this patient population, with potential implications for mitigating the risk of long-term complications.