Flu in Flux: The Evolving Controversy Over Oseltamivir for Children Who Are Hospitalized

The 2024 to 2025 influenza season marked the worst in 15 years, with at least 216 influenza-associated pediatric deaths.1 This severity was undoubtedly multifactorial. Although vaccine efficacy was similar to prior seasons, lower vaccination rates in pediatrics (less than 50%) likely played a notable role.2Given worsening public trust in vaccines, cancellation of the advisory meeting to select target influenza strains for vaccine development, and federal orders to halt the vaccine’s publicity campaign,3 pediatric hospitalists may face an even worse influenza season. If we cannot reliably prevent severe influenza cases, understanding the evidence behind available therapeutics becomes paramount. The American Academy of Pediatrics, Infectious Diseases Society of America, and Centers for Disease Control and Prevention strongly recommend every child hospitalized with influenza (regardless of risk, severity, or symptom duration) receive oseltamivir (a neuraminidase inhibitor) or another antiviral.4–6However, there is controversy among pediatric hospitalists regarding the use of oseltamivir in this setting. A recent survey of pediatric providers demonstrated wide variability in treatment preferences for children hospitalized with influenza, likely because of concerns surrounding the evidence of antiviral use in this population, particularly those presenting late into illness, and potential adverse effects.7This skepticism is not unfounded. For years, scholars raised concerns that recommendations favoring oseltamivir were unduly influenced by unpublished pharmaceutical data.8 Attempting to overcome publication bias, Jefferson et al obtained pharmaceutical clinical study reports to conduct a Cochrane systematic review.9 This 2014 review found oseltamivir was associated with shorter symptom duration for healthy children and increased vomiting but no association with symptom relief for children with asthma, pediatric hospitalizations, or complications including pneumonia, acute otitis media, and sinusitis. Additionally, despite case reports linking oseltamivir use to neuropsychiatric events like delirium or suicide attempts, the review found no association (but was underpowered for this outcome). However, a 2020 population-based study found no increased risk of neuropsychiatric events in children prescribed oseltamivir.10Since 2014, subsequent meta-analyses of predominantly adult populations have shown mixed benefits of oseltamivir use. The only pediatric-specific meta-analysis among these showed that healthy children who received oseltamivir in the outpatient setting within the first 48 hours of symptom onset (“early treatment”) had shorter illness courses and decreased risk of acute otitis media.11 Notably, most of these reviews were underpowered to investigate influenza-related complications, and none explored the effects of oseltamivir on children who are hospitalized.Unfortunately, there are no high-quality prospective studies in the pediatric inpatient setting. Therefore, to interpret the effectiveness of oseltamivir in this population, we are left to extrapolate from (1) trial data in outpatient children, (2) trial and observational data in adults who are hospitalized, and (3) observational data in children who are hospitalized.Outpatient pediatric trial data has shown children with mild to moderate disease benefit from early treatment. It may be reasonable to assume children who are hospitalized with moderate to severe disease would similarly benefit. However, the outpatient data have not shown benefits for children treated later in illness. Importantly, no studies have adequately explored adverse effects in children who are hospitalized, in which the 1.7-fold increased risk of vomiting from oseltamivir may have important implications, as dehydration is an important indication for continued hospitalization among children with viral illnesses.9 Newer antivirals, like baloxavir, may offer milder adverse effects but also lack prospective data in the inpatient pediatric setting.12Some trials and observational studies in adults who are hospitalized have shown benefits of early oseltamivir treatment, and some studies showed mortality benefits with treatment initiation as late as 5 days into illness.6 These latter studies likely provided some basis for the recommendation to treat all children who are hospitalized regardless of symptom duration. However, the US Food and Drug Administration’s position is that children “should be given medicines that have been appropriately evaluated for their use in those populations.” They state that extrapolation of adult data to pediatrics when disease course and response to treatment are presumed similar “may be possible.”13 We advise skepticism with direct extrapolation and suggest that the children we serve in the hospital, with unique susceptibilities to respiratory disease and adverse gastrointestinal effects, deserve pediatric-specific evidence.Finally, observational studies in children who are hospitalized are limited. Three studies using the Pediatric Health Information System (PHIS) administrative database reported associations between early oseltamivir treatment in children who are hospitalized and decreased length of stay (LOS).14–16 However, a subsequent study exploring the accuracy of influenza diagnoses and oseltamivir use in the “unexposed” cohort of the PHIS studies found 63% of patients were misclassified because they did not truly have influenza or were labeled unexposed despite receiving oseltamivir prior to hospitalization. As these misclassified patients had longer LOS, including them in the PHIS studies could have inappropriately skewed findings away from the null.17Other observational pediatric studies using different data sources with laboratory-confirmed influenza have demonstrated benefits of oseltamivir for certain high-risk populations. Louie et al used medical record data of critically ill children to show a mortality benefit of antiviral treatment, particularly with early treatment.18 Meanwhile, Campbell et al used data from the Influenza Hospitalization Surveillance Network to evaluate children with underlying medical conditions and critically ill children and found an association with decreased LOS only for those with early treatment.19 Taking the findings from all these studies together, the benefits of oseltamivir likely outweigh the risks for critically ill children, those with severe comorbidities, and those presenting within 48 hours of illness.Most children hospitalized with influenza are not critically ill, lack severe comorbidities, and present after 48 hours of illness.20 We need to shrink the knowledge gap around the benefits of antivirals for stable, children who are hospitalized presenting later in their illness course and the impact that gastrointestinal effects may have on populations particularly at risk for dehydration, including neonates and children with medical complexity. Ideally this would come from prospective, randomized, placebo-controlled, and comparative effectiveness trials of oseltamivir and baloxavir in children hospitalized for influenza.Such trials should capture family-centered outcomes including time to symptom resolution (with strict criteria for symptom onset/resolution), time to return to school/daycare/work, household transmission, and incidence of adverse effects. These trials would also ideally be powered to capture common influenza-related complications. Lastly, they should include operational outcomes such as LOS, hydration requirements, duration of respiratory support, escalation to intensive care, and revisit/readmission rates.In our opinion, prescribing oseltamivir for all children hospitalized with influenza, regardless of symptom duration, is not sufficiently supported by high-quality evidence, and professional societies should reconsider this recommendation. Although it remains unanimously recommended in national guidelines, a perceived lack of equipoise could make it challenging to compel funders to support a traditional patient-randomized efficacy trial. Alternative designs to obtain more definitive inpatient data could be a pragmatic cluster-randomized trial with a waiver of consent, instrumental variable analysis based on hospital-level oseltamivir utilization, or a hybrid effectiveness implementation approach, combining the evaluation of comparative clinical effectiveness while preparing for the implementation of best practices that derive from the results, whether supporting or refuting the use of antivirals. These approaches could allow us to reevaluate oseltamivir’s effectiveness for children hospitalized with influenza, compare outcomes and adverse effects of baloxavir with the current standard of care, and identify strategies to improve uptake of guidelines across clinical sites.Further, future research could also explore which pediatric patients are at highest risk for poor outcomes and who would most benefit from home testing for early detection and antiviral prophylaxis.Meanwhile, winter is coming. So, what are we, as pediatric hospitalists, to do? As rigorous clinical trials take time to design, fund, and conduct, we do not anticipate having clear answers for children who are hospitalized before influenza season.Presently, the most honest thing we can offer families is transparency for shared decision-making. In our practice, we share with all families that (1) oseltamivir is safe and recommended by national guidelines; (2) some research suggests it could shorten time with symptoms and lower the risk of associated ear infections; (3) there has been mixed evidence on how much it helps, particularly if your child has been sick for more than 2 days; and (4) there is an increased risk of vomiting.More critically, we must advocate for vaccination. This includes recommending influenza vaccination for all children aged 6 months and older at every clinical encounter, including in the hospital. In these conversations, we should emphasize the value of vaccination in preventing severe disease rather than infection itself. As the virus mutates rapidly with no guarantee of an ideal match for circulating strains, providing false reassurance that vaccination prevents all infections may worsen medical mistrust. Instead, reinforcing that vaccination prevents severe illness may be more compelling. Finally, we should call for the influenza campaign’s publicity strategies to be reinstated. If not, health systems should launch more comprehensive outreach to promote vaccine uptake in our communities.At the end of the day, we face many unknowns. We likely have another severe influenza season ahead of us, and it remains unclear whether we can rely on antivirals like oseltamivir to help all children who are hospitalized. Nevertheless, what remains certain is the importance of vaccination to prevent and mitigate severe influenza and fostering more prospective nonindustry-sponsored clinical antiviral trials to guide our treatment plans for all influenza seasons to come.We thank Dr Alan Schroeder for critically reviewing this manuscript prior to submission.