Influenza Antivirals in Pediatrics: Why Aren’t We Using All the Available Tools?

Although attention to influenza was diverted during the coronavirus disease 2019 pandemic, it remains essential to ensure we are prepared to deal with upcoming influenza seasons. Four antiviral agents are now available for treatment and/or prophylaxis against influenza infection, including oseltamivir, zanamivir, peramivir, and baloxavir. Yet, these influenza antiviral agents remain significantly underutilized in children.

In this issue of Pediatrics, Antoon et al present contemporary findings on real-world outpatient prescribing of antiviral agents for the treatment and prevention of influenza infection in children.¹  The authors reviewed commercial insurance claims data for all outpatient and emergency department encounters in children from birth to 18 years across all 50 US states between 2010 and 2019. The results emphasize the under-prescribing of antiviral agents despite their proven importance in decreasing disease severity and accelerating resolution of influenza infections.

Both treatment and prophylaxis prescriptions varied widely by year and seasonal severity, age, and geographic location.¹  Rates encouragingly increased over the years of study, with the highest rate of antiviral agents dispensed during the most severe influenza season in 2017 to 2018. However, only 49.4% to 67.3% of children with an influenza diagnosis filled an antiviral prescription within 48 hours of diagnosis. A study of hospitalized children with laboratory-confirmed influenza in Canada over the same 9-year study period also showed under-utilization with only 41.3% receiving antiviral agents, whereas 72.8% received antibiotics.²  National influenza guidelines from the Centers for Disease Control and Prevention, Infectious Diseases of America, and the American Academy of Pediatrics recommend treatment of all high risk individuals and any individual with severe, complicated, or progressive influenza disease in both outpatient and inpatient settings regardless of duration of symptoms.³  In addition, treatment may be considered for any child with suspected or confirmed influenza disease, including those who are not at high risk for influenza complication, if treatment can be initiated within 48 hours of symptom onset.³ 

Of greatest concern, Antoon et al showed the lowest rate of antiviral treatment occurred in children <5 years of age, for whom only 37% of children <2 years and 34% of children 2 to 5 years with an influenza diagnosis received treatment.¹  Children <5 years are the pediatric age group who suffer the most influenza complications.⁴  In particular, healthy children <2 years are at highest risk of developing complications with hospitalization rates similar to older children with chronic underlying conditions and adults >65 years of age.^4,5  For these reasons, the American Academy of Pediatrics guidelines identify children <5 years and especially those <2 years as high risk groups for whom antiviral treatment should be offered as early as possible, regardless of influenza vaccination status and duration of symptoms.³ 

The rationale for influenza treatment was recently reviewed and published in the Recommendations for Prevention and Control of Influenza in Children, 2023 to 2024.⁵  Cochrane reviews and meta-analyses of multiple randomized controlled trials to evaluate the efficacy of influenza antiviral agents for uncomplicated influenza in outpatients found that timely treatment within 48 hours of symptom onset shortens median duration of illness by 17.6 to 36 hours.^5–8  Treatment with oseltamivir also reduces incidence of otitis media.^7–9  Furthermore, an influenza transmission model projects that antiviral treatment of children aged 5 to 19 years has the highest impact on reducing community transmission.¹⁰  Observational studies and clinical trial data suggest that prompt treatment with neuraminidase inhibitors may reduce transmission to close contacts.¹¹  A controlled trial to examine baloxavir efficacy to reduce transmission is currently underway.¹¹ 

A greater understanding of the various factors contributing to suboptimal adherence to the antiviral treatment guidelines is urgently needed. Although hesitancy toward vaccines among providers and patients have been studied with resulting ongoing interventions, much less is known about provider and patient attitudes toward antiviral agents. A principal issue remains that providers and patients may perceive that influenza infection in children is not serious. Most healthy children experience 4 to 7 days of fever, cough, and coryza that spontaneously recover with rest and fluids. Unfortunately, not all healthy children can anticipate an uncomplicated course. Bacterial infections of the upper respiratory tract, such as otitis media and sinusitis, can occur in 20% to 50% of healthy individuals, and complications of the lower tract, including bronchitis and pneumonia, can lead to hospitalizations.⁵  Importantly, it is underrecognized that 50% of pediatric influenza deaths occur in otherwise healthy children.¹² 

Additional questions about antiviral utilization remain. What leads providers to prescribe antiviral agents more frequently in adolescents when younger children are more likely to present with symptoms and require hospitalization?^1,4,13  Are providers and parents concerned about adverse effects? Of note, the only reported adverse effect from clinical trials was vomiting in a small percentage above those who received placebo.⁵  No link has been established between oseltamivir and neurologic or psychiatric events with ongoing surveillance despite initial reports in Japanese teenagers nearly 2 decades ago.⁵  What are the reasons for the lowest prescribing rates in the Pacific region of the United States?¹  Are there factors related to cost, insurance coverage, knowledge of antiviral options, perception of benefit, antiviral shortages, regional climate, culture, media coverage, and/or social media on clinical practices? Do these factors also affect patient and parental acceptance? Studies are desperately needed to further evaluate the implementation of antiviral treatment and chemoprophylaxis for influenza in children. The use of antiviral agents against influenza and adherence to national treatment guidelines in both outpatient and inpatient settings must be highlighted as important targets for improvement.^5,14 

As life and human behavior have returned to prepandemic norms, influenza will circulate at higher rates in the community once again. Influenza vaccine effectiveness is known to vary greatly each season, and vaccination rates in children decreased during the coronavirus disease 2019 pandemic.¹⁵  Thus, although we must improve influenza vaccination rates, antiviral agents also must play a larger role in the prophylaxis and treatment of influenza infection. When it comes to influenza, we should be using all the tools in our toolbox.