Time Course of the Immune Response in a Preterm Infant With Congenital Syphilis Following Incomplete Maternal Treatment: A Case Report

To the Editors: Rising maternal syphilis infections have led to a surge in congenital syphilis (CS), which causes severe and permanent health issues leading to substantial social and economic burdens compared with adult infection.1,2 However, the immunopathogenesis of CS, especially the role of neonatal immunity, remains unclear. Here, we report a case of a preterm infant with CS following incomplete maternal treatment, providing a unique opportunity to observe fetal–neonatal immune responses to active Treponema pallidum infection. A female neonate was born at 27 weeks gestation (1024 g). Maternal syphilis screening at 8 weeks gestation was negative. However, seroconversion was confirmed at 26 weeks and 5 days following fetal ascites detection: rapid plasma reagin (56 units) and T. pallidum hemagglutination assay titers (259, cutoff index). Maternal amoxicillin treatment was initiated, but spontaneous delivery occurred 2 days later. At birth, she presented respiratory failure, hepatosplenomegaly, ascites, skeletal abnormalities, anemia and thrombocytopenia. Serological tests confirmed CS diagnosis (rapid plasma reagin: 76.8, T. pallidum hemagglutination assay: 28.7, cutoff index; fluorescent treponemal antibody-absorption immunoglobulin [Ig]M, 1:1,280). Administration of intravenous penicillin G improved CS symptoms. After surgical ligation for patent ductus arteriosus and initiation of home oxygen therapy for bronchopulmonary dysplasia, she was discharged from the hospital on day 114. Time course analysis of peripheral blood lymphocyte subsets revealed a polarization of T helper (Th)2 cells at birth, followed by gradual increase in Th1 cells, T follicular helper cells, memory B cells and regulatory T cells (Fig. 1A). Cytokine profiling revealed elevated interleukin (IL)-12, IL-8, IL-10 and IL-21 levels; however, pro-inflammatory or Th1 cytokines were not elevated: IL-1β, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma (Fig. 1B).FIGURE 1.: Temporal progression of the peripheral immunophenotype. A: Immune cell analyses in peripheral blood on days of life 0, 3, 7 and 11 using a LSRFortessa flow cytometer (Becton Dickinson, Franklin Lakes, NJ) and FlowJo software (version 10.6.2; Becton Dickinson). The proportions of Th1 cells (CCR6−CXCR3+), Th2 cells (CCR6−CXCR3−) within memory Th cells (CD4+CD45RO+); Treg cells (CD127dimCD25+) within Th cells (CD4+); Tfh cells (CD45RO+CXCR5+) within Th cells (CD4+) and memory B cells (CD19+CD27+IgD+) within B cells (CD19+) were assessed. B: Cytokine profiles in peripheral blood were evaluated on days of life 0, 1, 7 and 11 using a BD Cytometric Bead Array (Becton Dickinson). Tfh indicates T follicular helper; Treg, regulatory T cells.At primary infection sites in adult syphilis, pro-inflammatory cytokines, Th1-mediated immunity and humoral responses, which are all critical for bacterial clearance, are induced.3 As observed in the present case, infants with CS present with systemic infection at birth, resembling that of adult secondary syphilis.1,2 However, despite detectable humoral immune responses, pro-inflammatory cytokine production and Th1-mediated immunity were markedly reduced at birth, with T-cell differentiation skewed toward a Th2 phenotype. Th2 polarization and attenuated pro-inflammatory cytokine production and Th1-mediated immunity indicated developmentally distinct characteristics of the neonatal immunoregulatory immune system, which are essential for fetal–maternal tolerance.4 A previous report suggested that preterm infants with CS exhibit pro-inflammatory cytokine production and Th1 responses at birth, indicating that they possess pathogen clearance mechanisms similar to those in adults5; however, the infant was born to a mother who had completed syphilis treatment. Therefore, the reported immune profile may not represent the immune status during active T. pallidum infection and likely differs from that observed in our case, where maternal treatment was incomplete. Accordingly, the Th1 response in our case gradually developed following the initiation of antimicrobial treatment. These findings suggest that developmentally distinct features of the neonatal immune system contribute to impaired clearance of T. pallidum, leading to the severity of CS symptoms. Study limitations include the single-case design. Future research with larger cohorts is necessary to further elucidate the immunopathogenic features of CS.