Limited and Variable Use of Antivirals for Children Hospitalized With Influenza

The US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommend that all children hospitalized with influenza receive an antiviral medication, with a particular emphasis for those children with comorbid conditions that increase their risk of complications.^1,2 Despite these recommendations, previous studies have shown that antivirals are underused for children with influenza.³ In addition, although pediatric antimicrobial stewardship programs are widespread, few have focused on the appropriate use of antivirals for hospitalized children with influenza.⁴ The objective of this study was to characterize the patterns of antiviral use among hospitalized children with influenza, including those with high-risk conditions.

We conducted a retrospective cohort study of children younger than 18 years of age who were hospitalized at 46 freestanding children’s hospitals during the 2007-2015 influenza seasons (October 1 through May 15) and the 2009 H1N1 pandemic (April 1 through September 30, 2009). Participating hospitals are members of the Pediatric Health Information System network. Institutional review board approval was waived for all studies using this database from the University of Utah because the data are deidentified.

The proportion of children whose influenza was diagnosed using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis codes (487.x and 488.x) and who received an anti-influenza neuraminidase inhibitor (oseltamivir phosphate, zanamavir, or peramivir) was calculated for each influenza season. Children at high risk for influenza-related complications were identified using ICD-9-CM codes according to the criteria of the Advisory Committee on Immunization Practices (Table).¹

Descriptive statistics were used to characterize the seasonal frequency of prescribing antivirals. The χ² test was used to compare the frequency of prescribing antivirals among children with high-risk conditions with the frequency of prescribing antivirals among children without high-risk conditions. Temporal trends in prescribing antivirals were evaluated using joinpoint regression. Analysis of covariance was used to quantify the variability in prescribing antivirals at the hospital level. The results of the joinpoint regression and analysis of covariance are presented following adjustment for differences in case mix using all patient refined–diagnosis related group scores. P < .05 was considered to be statistically significant.

There were 35 909 pediatric inpatient admissions with an influenza discharge diagnosis code during the study period. Of these, 24 795 (69% [range, 38%-83%]) had an antiviral prescribed (>99% oseltamivir). During the prepandemic influenza seasons, 20% of children received an antiviral. In the seasons following the pandemic, this proportion increased sharply to 69% and remained relatively stable (P < .001) (Figure, A). During the 2014-2015 influenza season, antiviral use ranged from 42% to 90% across the 46 Pediatric Health Information System hospitals. Case-mix differences did not account for the variability across the study hospitals (R² < 0.001).

A high-risk condition was noted for 25 125 of the 35 909 admissions (70%). Antiviral use among children with high-risk conditions varied widely across the 46 Pediatric Health Information System hospitals (Figure, B), and children with a high-risk condition were only slightly more likely to receive an antiviral (70%) than those without a high-risk condition (67%; P < .001).

Published guidelines recommend the use of antivirals for all patients hospitalized with influenza, based on observational data showing decreased complications and mortality rates.^1,2,6 However, randomized clinical trials among otherwise healthy outpatients demonstrated only modest benefits, as well as adverse events, including nausea,⁷ which may lead to some hesitancy to prescribe antivirals universally. Other investigators have shown the underuse of antivirals and the overuse of antibiotics among outpatients with influenza. Our data demonstrate that both a high level of variation and the suboptimal use of antivirals extend to hospitalized children, with only a slight difference in the rate of prescribing antivirals for children with high-risk conditions. These children are the most likely to benefit from the prompt administration of antivirals.

The limitations of this study include use of ICD-9-CM codes to identify cases of influenza (limited sensitivity may result in underdetection) and children with high-risk conditions (which have not been validated). Antiviral use prior to hospital admission is not captured in the Pediatric Health Information System. Although it is not recommended to withhold antivirals based on the preceding duration of symptoms for hospitalized children, some clinicians may not prescribe antivirals if the duration of illness has exceeded several days. Antimicrobial stewardship strategies aimed at identifying and promptly treating children hospitalized with high-risk conditions could help to maximize the potential benefits of antivirals for seasonal influenza.

Corresponding Author: Adam L. Hersh, MD, PhD, Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT 84108 (adam.hersh@hsc.utah.edu).

Published Online: January 23, 2017. doi:10.1001/jamapediatrics.2016.3484

Author Contributions: Dr Stockmann and Mr Wilkes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Stockmann, Byington, Pavia, Ampofo, Korgenski, Hersh.

Acquisition, analysis, or interpretation of data: Stockmann, Pavia, Ampofo, Wilkes, Korgenski, Hersh.

Drafting of the manuscript: Stockmann, Byington.

Critical revision of the manuscript for important intellectual content: Byington, Pavia, Ampofo, Wilkes, Korgenski, Hersh.

Statistical analysis: Stockmann, Pavia, Wilkes.

Administrative, technical, or material support: Byington, Ampofo, Wilkes, Korgenski.

Study supervision: Byington, Pavia, Hersh.

Conflict of Interest Disclosures: Dr Byington has intellectual property in and receives royalties from BioFire Diagnostics, Inc. Dr Stockmann received grant support from the Thrasher Research Fund, the Primary Children’s Hospital Foundation, and Merck for work unrelated to this project. No other disclosures are reported.

Funding/Support: Dr Byington receives support through the H.A. and Edna Benning Presidential Endowment and the National Center for Advancing Translational Sciences of the National Institutes of Health (award 1ULTR001067).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: This paper was presented at the annual IDWeek meeting of the Infectious Diseases Society of America; October 8, 2015; San Diego, California.