Acyclovir and ganciclovir exposure and short-term outcomes in hospitalized children with EBV-associated mononucleosis-like illness: a retrospective cohort study using inverse probability of treatment weighting.

Background: Epstein-Barr virus (EBV)-associated mononucleosis-like illness in children involves marked immune activation and variable clinical severity. Although supportive care remains standard for immunocompetent children, acyclovir and ganciclovir are frequently used in hospitalized patients with severe manifestations. However, their real-world effectiveness remains uncertain. This study aimed to characterize real-world antiviral treatment patterns and evaluate the associations of acyclovir and ganciclovir exposure with short-term clinical outcomes in hospitalized children with EBV-associated mononucleosis-like illness. Methods: This single-center retrospective cohort study included 1,059 hospitalized children with EBV-associated mononucleosis-like illness at the Children's Hospital of Soochow University from January 2019 to December 2023. Patients were categorized into no antiviral therapy (n=371), acyclovir (n=526), and ganciclovir (n=162) groups. Eligibility required compatible symptoms, EBV serologic evidence, detectable EBV DNA, atypical lymphocytosis, and acute-phase immunophenotyping. Antiviral exposure was analyzed as a time-varying variable, and stabilized inverse probability of treatment weighting (IPTW) was applied using baseline clinical, laboratory, virological, and immunological variables. Results: Before weighting, antiviral-treated children had greater disease severity, including higher alanine aminotransferase (ALT), aspartate aminotransferase (AST), EBV DNA levels, and CD4/CD8 ratio inversion. After IPTW, covariate balance was achieved [all standardized mean difference (SMD) <0.10]. Median time to defervescence was 5.2, 6.1, and 5.6 days in the no-antiviral, acyclovir, and ganciclovir groups, respectively. IPTW-weighted Cox analysis showed lower fever-resolution hazard with acyclovir [hazard ratio (HR) 0.78, 95% confidence interval (CI): 0.69-0.89], whereas ganciclovir showed no significant association (HR 0.91, 95% CI: 0.76-1.09). The prediction model integrating clinical and immune indicators achieved an area under the curve (AUC) of 0.69. Conclusions: Antiviral use mainly reflected disease severity and was not associated with improved short-term outcomes after adjustment. Supportive care and individualized risk stratification remain important.