Treatment during influenza was associated with nearly half the risk of serious neuropsychiatric events compared with no treatment, according to a recent study. However, the absolute risk was low: the overall incidence was 6.25 events per 100,000 person-weeks.
Researchers conducted a retrospective cohort study to evaluate the association between oseltamivir use and serious neuropsychiatric events—defined as those that required hospitalization—in pediatric and adolescent patients with influenza. "Whether oseltamivir is truly associated with neuropsychiatric events remains unclear. Influenza infection itself is associated with encephalitis, seizures, altered mental status, and other neuropsychiatric events," lead author James W. Antoon, MD, PhD, MPH, of the Division of Hospital Medicine, Department of Pediatrics at Vanderbilt University Medical Center in Nashville, Tennessee wrote with colleagues to introduce their study. To explore associations that have been reported in case reports, they analyzed Tennessee Medicaid data from the 2016 through 2017 and 2019 through 2020 influenza seasons.
Oseltamivir treatment was associated with a reduced risk of serious neuropsychiatric events during influenza episodes. Most events occurred earlier in the untreated group (median = 1 day after diagnosis) than in the treated group (median = 2.5 days), which suggested a possible temporal protective effect. Compared with untreated influenza, the adjusted incidence rate ratio (aIRR) for treated influenza was 0.53 and 0.42 for the post-treatment period. Subgroup analyses demonstrated a greater reduction in neurologic events (aIRR = 0.45) than in psychiatric events (aIRR = 0.80), although the reduction in psychiatric events was not statistically significant.
The findings were consistent across multiple sensitivity analyses, which included alternate outcome definitions, excluded follow-up covariates, and incorporated time-varying outcome risk models. A negative control outcome analysis using appendicitis yielded no association, and the calculated E-value of 3.2 indicated that substantial unmeasured confounding would be required to explain away the observed effect.
Methods, Limitations, and Future Research
The cohort included 692,295 pediatric and adolescent patients, aged 5 to 17 years, who contributed more than 19 million person-weeks of follow-up. Each person-day was categorized into one of five mutually exclusive exposure groups: untreated influenza, oseltamivir-treated influenza, post-treatment period, influenza prophylaxis, or no exposure. The primary outcome was defined as a hospitalization involving a serious neuropsychiatric event, which was identified through a validated diagnostic algorithm with high predictive accuracy.
During the study period, 151,401 influenza episodes were recorded, of which 67% were treated with oseltamivir. Among the patients who were at high risk for influenza complications, 60% received treatment. A total of 1,230 serious neuropsychiatric events occurred, including 898 neurologic and 332 psychiatric events. The most frequently observed events were mood disorders (36%) and suicidal or self-harm behaviors (34%), followed by seizures (14%).
The researchers employed methods, including validated measures to identify influenza cases and neuropsychiatric events and use of a strict definition of influenza seasons, to limit misclassification and confounders. Still, healthy user bias, not accounting for influenza strain or symptom duration, and excluding milder neuropsychiatric events that could be managed in an outpatient setting were possible limitations.
"Findings from this study should inform both caregivers and clinicians on the safety of oseltamivir and its role in preventing influenza-associated complications," they concluded.
Full disclosures can be found in the published study.
Source: JAMA Neurology