Antoon James W, Williams Derek J, Bruce Jean, Sekmen Mert, Zhu Yuwei, Grijalva Carlos G
Division of Hospital Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
Division of Pharmacoepidemiology, Departments of Health Policy and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
JAMA Neurol. 2025 Aug 4. doi: 10.1001/jamaneurol.2025.1995.
Reports of pediatric neuropsychiatric events during influenza treatment with oseltamivir have prompted public concerns. However, whether oseltamivir or influenza infection is associated with increased risk of neuropsychiatric events remains unclear.
To determine the association between influenza, oseltamivir, and serious neuropsychiatric events.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted in a population-based ambulatory setting during the 2016 to 2017 and 2019 to 2020 influenza seasons. Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study. Children aged 5 to 17 years enrolled in Tennessee Medicaid were for eligible for inclusion. Data analysis was completed from July 2023 to March 2025.
Each person-day of follow-up was assigned to 1 of the following 5 mutually exclusive exposure groups: (1) untreated influenza; (2) treated influenza; (3) posttreatment period (period between oseltamivir completion and end of influenza period); (4) influenza prophylaxis; and (5) no exposure.
The primary outcome was a neuropsychiatric event requiring hospitalization, and events were identified using a validated algorithm. Poisson regression estimated incidence rate ratios (IRRs) while accounting for relevant covariates measured on each person-day. Sensitivity analyses examined robustness of findings to alternate exposure and outcome definitions, time-varying outcome risk, negative control outcome, and unmeasured confounding.
Among 692 975 eligible children, a total of 692 295 children (median [IQR] age, 11 [7-14] years; 50.3% female) experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric) during 19 688 320 person-weeks of follow-up. Among the 151 401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were dispensed oseltamivir (60.1% [95% CI, 59.6%-60.6%] among those at high risk for influenza complications). The most common events overall were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%). Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza periods (IRR, 0.53; 95% CI, 0.33-0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24-0.74). Subanalyses suggest that this finding is driven more by a reduction in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings.
In this cohort study, oseltamivir treatment during influenza episodes was associated with a reduced risk of serious neuropsychiatric events. These findings support oseltamivir use for prevention of these influenza-related complications.
在使用奥司他韦治疗流感期间出现小儿神经精神事件的报告引发了公众关注。然而，奥司他韦或流感感染是否与神经精神事件风险增加相关仍不清楚。
确定流感、奥司他韦与严重神经精神事件之间的关联。
设计、背景和参与者：这项回顾性队列研究在2016至2017年以及2019至2020年流感季节的基于人群的门诊环境中进行。随访从流感季节的第一天开始，持续到最早出现结局事件、失访、死亡、年满18岁、季节结束或研究结束。田纳西州医疗补助计划登记的5至17岁儿童符合纳入条件。数据分析于2023年7月至2025年3月完成。
每个随访人日被分配到以下5个相互排斥的暴露组之一：（1）未治疗的流感；（2）接受治疗的流感；（3）治疗后时期（奥司他韦疗程结束至流感期结束之间的时期）；（4）流感预防；（5）无暴露。
主要结局是需要住院治疗的神经精神事件，事件通过经过验证的算法识别。泊松回归估计发病率比（IRR），同时考虑每个随访人日测量的相关协变量。敏感性分析检验了研究结果对替代暴露和结局定义、随时间变化的结局风险、阴性对照结局以及未测量的混杂因素的稳健性。
在692975名符合条件的儿童中，共有692295名儿童（中位年龄[四分位间距]，11[7 - 14]岁；50.3%为女性）在19688320人周的随访期间经历了1230起严重神经精神事件（898起神经事件和332起精神事件）。在151401次流感发作中，66.7%（95%CI，66.5% - 67.0%）使用了奥司他韦（流感并发症高危人群中为60.1%[95%CI，59.6% - 60.6%]）。总体上最常见的事件是情绪障碍（36.3%）和自杀或自残行为（34.2%）。与未治疗的流感相比，在奥司他韦治疗的流感期间（IRR，0.53；95%CI，0.33 - 0.88）和治疗后时期（IRR，0.42；95%CI，0.24 - 0.74）事件发生率较低。亚组分析表明，这一发现更多是由神经事件的减少（IRR，0.45；95%CI，0.25 - 0.82）而非精神事件（IRR，0.80；95%CI，0.34 - 1.88）驱动的。敏感性分析表明，错误分类或未测量的混杂因素无法解释这些结果。
在这项队列研究中，流感发作期间使用奥司他韦与严重神经精神事件风险降低相关。这些发现支持使用奥司他韦预防这些与流感相关的并发症。
