Effectiveness of Oseltamivir in Hospitalized Children With Laboratory-Confirmed Influenza, 2014-2023

Kacie Rytlewski; Angela Dunn; Alissa O’Halloran; Jennifer Habeck; Isaac Armistead; Nisha B Alden; Darpun Sachdev; Pam Daily Kirley; James Meek; Kimberly Yousey-Hindes; Satoshi Kamidani; Kyle P Openo; Patricia A Ryan; Maya Monroe; Sue Kim; Elizabeth Urlaub; Ruth Lynfield; Melissa McMahon; Chad B Smelser; Yomei Shaw; Grant Barney; Jemma V Rowlands; Brenda Tesini; Christina Felsen; Krista Lung; Melissa Sutton; Ann Thomas; H Keipp Talbot; William Schaffner; Andrea George; Holly Staten; Jessica R Cataldi; Samuel R Dominguez; Catherine H Bozio; Suchitra Rao

doi:10.1001/jamapediatrics.2026.3376

. 2026 Aug 10:e263376. Online ahead of print. doi: 10.1001/jamapediatrics.2026.3376

Effectiveness of Oseltamivir in Hospitalized Children With Laboratory-Confirmed Influenza, 2014-2023

Kacie Rytlewski ¹, Angela Dunn ², Alissa O’Halloran ³, Jennifer Habeck ^3,⁴, Isaac Armistead ⁵, Nisha B Alden ⁵, Darpun Sachdev ⁶, Pam Daily Kirley ⁷, James Meek ⁸, Kimberly Yousey-Hindes ⁸, Satoshi Kamidani ^9,^10,¹¹, Kyle P Openo ^11,¹², Patricia A Ryan ¹³, Maya Monroe ¹³, Sue Kim ¹⁴, Elizabeth Urlaub ¹⁴, Ruth Lynfield ¹⁵, Melissa McMahon ¹⁵, Chad B Smelser ¹⁶, Yomei Shaw ¹⁶, Grant Barney ¹⁷, Jemma V Rowlands ¹⁷, Brenda Tesini ¹⁸, Christina Felsen ^18,¹⁹, Krista Lung ²⁰, Melissa Sutton ²¹, Ann Thomas ²¹, H Keipp Talbot ²², William Schaffner ²², Andrea George ²³, Holly Staten ²³, Jessica R Cataldi ¹, Samuel R Dominguez ¹, Catherine H Bozio ³, Suchitra Rao ^1,^✉

¹Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora

²Adult and Child Center for Outcomes Research and Delivery Science, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora

³Influenza Division, US Centers for Disease Control and Prevention, Atlanta, Georgia

⁴Goldbelt Professional Services, Chesapeake, Virginia

⁵Colorado Department of Public Health and Environment, Denver

⁶California Department of Public Health, Richmond

⁷California Emerging Infections Program, Oakland

⁸Connecticut Emerging Infections Program, Yale School of Public Health, New Haven

⁹Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia

¹⁰Children’s Healthcare of Atlanta, Atlanta, Georgia

¹¹Georgia Emerging Infections Program, Atlanta

¹²Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia

¹³Maryland Department of Health, Baltimore

¹⁴Michigan Department of Health and Human Services, Lansing

¹⁵Minnesota Department of Health, St Paul

¹⁶New Mexico Department of Health, Santa Fe

¹⁷New York State Department of Health, Albany

¹⁸University of Rochester Medical Center, Rochester, New York

¹⁹New York Emerging Infections Program, Albany

²⁰Ohio Department of Health, Columbus

²¹Public Health Division, Oregon Health Authority, Portland

²²Vanderbilt University Medical Center, Nashville, Tennessee

²³Salt Lake County Health Department, Salt Lake City, Utah

Accepted for Publication: June 15, 2026.

Published Online: August 10, 2026. doi:10.1001/jamapediatrics.2026.3376

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Rytlewski K et al. JAMA Pediatrics.

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Corresponding Author: Suchitra Rao, MBBS, MSCS, University of Colorado School of Medicine and Children’s Hospital Colorado, 13123 E 16th Ave, Box 090, Aurora, CO 80045 (suchitra.rao@childrenscolorado.org).

Author Contributions: Drs Rytlewski and Rao 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. Dr Rytlewski contributed as first author. Dr Rao contributed as senior author.

Concept and design: Rytlewski, Dunn, Armistead, Kamidani, Thomas, Schaffner, Cataldi, Dominguez, Bozio, Rao.

Acquisition, analysis, or interpretation of data: Rytlewski, Dunn, O'Halloran, Whitmill Habeck, Armistead, Alden, Sachdev, Daily Kirley, Meek, Yousey-Hindes, Kamidani, Openo, Ryan, Monroe, Kim, Urlaub, Lynfield, McMahon, Smelser, Shaw, Barney, Rowlands, Tesini, Felsen, Lung, Sutton, Thomas, Talbot, Schaffner, George, Staten, Dominguez, Bozio, Rao.

Drafting of the manuscript: Rytlewski, Dunn, Armistead, Monroe, Rowlands, Rao.

Critical review of the manuscript for important intellectual content: Rytlewski, Dunn, O’Halloran, Whitmill Habeck, Armistead, Alden, Sachdev, Daily Kirley, Meek, Yousey-Hindes, Kamidani, Openo, Ryan, Monroe, Kim, Urlaub, Lynfield, McMahon, Smelser, Shaw, Barney, Tesini, Felsen, Lung, Sutton, Thomas, Talbot, Schaffner, George, Staten, Cataldi, Dominguez, Bozio, Rao.

Statistical analysis: Rytlewski, Dunn, O'Halloran, Whitmill Habeck, McMahon, Bozio.

Obtained funding: Alden, Meek, Ryan, Monroe, Felsen, Sutton, Talbot, Schaffner, Bozio.

Administrative, technical, or material support: Rytlewski, Armistead, Alden, Sachdev, Meek, Kamidani, Openo, Monroe, Lynfield, Smelser, Barney, Tesini, Sutton, Thomas, Schaffner, Cataldi, Dominguez.

Supervision: Alden, Meek, Tesini, Felsen, Thomas, Schaffner, Dominguez, Rao.

Other - Emerging Infections Program New Mexico Principal Investigator: Smelser.

Other - provided cleaned data for conceptualization and analysis: Daily Kirley.

Conflict of Interest Disclosures: Dr Armistead reported grants from the US Centers for Disease Control and Prevention/Colorado Department of Public Health and Environment and received funding through the US Centers for Disease Control and Prevention Emerging Infections Program cooperative agreement during the conduct of the study. Dr Alden reported grants from the US Centers for Disease Control and Prevention Emerging Infections Program cooperative agreement during the conduct of the study. Dr Daily Kirley reported grants from the Heluna Health/California Emerging Infections Program and that the US Centers for Disease Control and Prevention provided funds for data collection during the conduct of the study. Dr Meek reported grants from the US Centers for Disease Control and Prevention funds the Connecticut Emerging Infections Program during the conduct of the study. Dr Yousey-Hindes reported grants from the US Centers for Disease Control and Prevention during the conduct of the study. Dr Kamidani reported grants to Emory from Pfizer, Moderna, Meissa, Sanofi, and Bavarian Nordic outside the submitted work. Dr Ryan reported a cooperative agreement from the US Centers for Disease Control and Prevention during the conduct of the study. Dr Monroe reported grants from the US Centers for Disease Control and Prevention Emerging Infections Program during the conduct of the study. Dr Kim reported grants from the Michigan Department of Health and Human Services Emerging Infections Program during the conduct of the study. Dr Urlaub reported grants from the US Centers for Disease Control and Prevention Emerging Infections Program during the conduct of the study. Dr Lynfield reported grants from Emerging Infections Program Cooperative Agreement from the US Centers for Disease Control and Prevention during the conduct of the study; and she is an Associate Editor for AAP Red Book (Report of the Committee on Infectious Diseases) and received a fee for this work. Dr Smelser reported grants from US Centers for Disease Control and Prevention Emerging Infections Program New Mexico Department of Health has been part of Emerging Infections Program for over 20 years during the conduct of the study. Dr Shaw reported grants from the US Centers for Disease Control and Prevention The New Mexico Department of Health for RESP-NET activities during the conduct of the study. Dr Tesini reported personal fees from the Merck Manuals Editorial Board outside the submitted work. Dr Sutton reported grants from the US Centers for Disease Control and Prevention Emerging Infections Program during the conduct of the study. Dr Talbot reported grants from the US Centers for Disease Control and Prevention during the conduct of the study and consulting from Bredenberg outside the submitted work. Dr Schaffner reported grants from the US Centers for Disease Control and Prevention during the conduct of the study. Dr George reported grants from Council of State and Territorial Epidemiologists funding to participate in RESP-NET during the conduct of the study. Dr Cataldi reported grants from US Centers for Disease Control and Prevention during the conduct of the study. Dr Dominguez reported grants from Karius Diagnostics, Delve Bio, Biofire, and Pfizer and personal fees from Karius Diagnostics outside the submitted work. Dr Rao reported grants from the US Centers for Disease Control during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported by the US Centers for Disease Control and Prevention through an Emerging Infections Program cooperative agreement (CK17-1701) and through a Council of State and Territorial Epidemiologists cooperative agreement (NU38OT000297-02-00). The Influenza Hospitalization Surveillance Network is a collaboration of state health departments, academic institutions and local partners and is funded by the US Centers for Disease Control and Prevention.

Role of the Funder/Sponsor: The funding organization was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

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Corresponding author.

PMCID: PMC13458948 PMID: 42573991

This study attempts to assess the association between oseltamivir receipt and intensive care unit admission and hospital length of stay among pediatric influenza-associated hospitalizations.

Key Points

Question

Does oseltamivir treatment reduce risk of intensive care unit (ICU) admission and hospital length of stay among pediatric patients hospitalized with influenza?

Findings

Using a cohort study from a population-based surveillance network in 13 states across 8 influenza seasons, oseltamivir treatment was found to decrease both the likelihood of ICU admission and hospital length of stay among pediatric patients hospitalized with laboratory-confirmed influenza.

Meaning

These findings support the current national recommendations from the American Academy of Pediatrics, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America that recommend antiviral treatment for children hospitalized with laboratory-confirmed influenza.

Abstract

Importance

National organizations recommend antiviral treatment for hospitalized children with influenza; however, use in this setting has recently declined. Studies of oseltamivir effectiveness in children are limited by misclassification bias, unknown symptom onset date, and incomplete capture of antiviral use prior to admission.

Objective

To assess the association between oseltamivir receipt and intensive care unit (ICU) admission and hospital length of stay (LOS) among pediatric influenza-associated hospitalizations.

Design, Setting, and Participants

This cohort study used data that were obtained from the Influenza Hospitalization Surveillance Network (FluSurv-NET), which conducts US population-based surveillance for laboratory-confirmed influenza hospitalizations for all ages across 13 states. The study data include seasons 2014 to 2015 through 2022 to 2023, excluding 2020 to 2021. Participants included children aged younger than 18 years who were hospitalized with laboratory-confirmed influenza and for whom a respiratory symptom onset date was available. These data were analyzed from October 2024 through May 2026.

Exposures

Oseltamivir receipt as a time-dependent exposure.

Main Outcome(s) and Measure(s)

The primary outcome was time from symptom onset to ICU admission. Secondary outcome was time from admission to discharge (LOS). Adjusted Cox proportional hazard models (aHR) with oseltamivir receipt as a time-dependent exposure were used.

Results

After exclusions, 6044 influenza cases were included in the primary ICU analysis, of whom 4240 (70.2%) received oseltamivir, and 7103 cases were included in the secondary LOS analysis, of whom 5746 (80.9%) received oseltamivir. In the ICU analysis, the median (IQR) age was 3 (1-7) years, 3382 (56%) were male and 3721 (44%) were female, and 2937 (49%) had 1 or more medical comorbidity—the most common of which was asthma in 1547 children (26%). In adjusted models, compared with untreated children, oseltamivir treatment reduced the hazard of ICU admission (aHR, 0.69; 95% CI, 0.60-0.80) and shortened LOS (analyzed as hazard of hospital discharge; aHR, 1.13; 95% CI, 1.06-1.21).

Conclusions and Relevance

In this cohort of children hospitalized with influenza, oseltamivir treatment was significantly associated with a reduced risk of ICU admission by 31% and decreased hospital LOS. These findings demonstrate the benefits of oseltamivir receipt and support current national recommendations for oseltamivir treatment as soon as possible in children hospitalized with suspected or laboratory-confirmed influenza.

Introduction

Antiviral treatment for children with influenza has been shown in observational studies to decrease symptom duration compared with untreated children and shorten hospital length of stay (LOS), particularly with early treatment. Antiviral treatment decreases the risk of death among critically ill children with influenza. This evidence led to recommendations from national organizations, including the US Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America, and the American Academy of Pediatrics, to initiate or continue antiviral treatment for all pediatric patients hospitalized with suspected or confirmed influenza, regardless of symptom duration. Additional observational studies using the Pediatric Health Information System (PHIS) database support these recommendations. Adverse effect concerns are one prohibitive factor to prescribing. Additionally, case reports of neuropsychiatric events with oseltamivir treatment led to the US Food and Drug Administration safety update in 2005, though recent studies refute this association.

Data from the Influenza Hospitalization Surveillance Network (FluSurv-NET) and New Vaccine Surveillance Network showed use of antivirals for hospitalized pediatric patients with laboratory-confirmed influenza has declined. According to FluSurv-NET data, only 63% of children hospitalized with influenza received antivirals during the 2024 to 2025 season, down from 86% in the 2017 to 2018 season. While patients at higher risk for influenza-associated complications were more likely to receive antiviral treatment than those at lower risk, patients at higher risk have also had declines in treatment. Across a US-based prospective surveillance network from 2016 through 2020, 67.4% of pediatric patients hospitalized with laboratory-confirmed influenza received an influenza antiviral, ranging widely from 26% to 74% across 7 sites. A multicenter survey study in the US showed that prescribing influenza antivirals varied among the included sites and medical specialties, and treatment decision factors included symptom duration, doubt about effectiveness, and adverse effect concerns.

This retrospective cohort study aims to evaluate whether oseltamivir treatment reduces risk of intensive care unit (ICU) admission and/or shortens hospital LOS using multistate influenza hospitalization surveillance network data. It is hypothesized that oseltamivir treatment for influenza is associated with decreased ICU admission and decreased inpatient LOS.

Methods

Data Source and Patient Population

This retrospective cohort study analyzed data from FluSurv-NET, a US population–based surveillance network for individuals of all ages hospitalized with laboratory-confirmed influenza across 13 states (California, Colorado, Connecticut, Georgia, Maryland, Minnesota, Mississippi, New Mexico, New York, Ohio, Oregon, Tennessee, and Utah). A case was defined as any resident of the FluSurv-NET catchment area hospitalized with laboratory-confirmed influenza (detected through molecular assay or rapid antigen testing at the clinician’s discretion) within 14 days before or during admission from October 1 through April 30. Data analyzed included the 2014 to 2015 through 2022 to 2023 seasons, excluding 2020 to 2021 due to low numbers during the COVID-19 pandemic. Trained surveillance staff abstracted data from medical records using a standard case report form (CRF). All pediatric FluSurv-NET cases from 2014 through 2021 had a CRF completed. Starting in 2022 to 2023, random sampling occurred for abstraction depending on site, admission month, age group, and outcome. Because sampling occurred in 1 of 8 seasons, the complex survey design was not accounted for and cases from 2022 to 2023 were assumed to be representative of the full cohort.

Patients included children younger than 18 years with a recorded respiratory symptom onset date. Cases with missing dates (positive influenza test, oseltamivir initiation, or symptom start), positive influenza test more than 7 days before or more than 3 days after admission, hospital-to-hospital transfers (due to incomplete data), observation encounters (due to short LOS and variable definition among hospitals), LOS of 1 day or less or more than 30 days, treatment more than 14 days before admission or prior to symptom onset, and receipt of antivirals other than oseltamivir were excluded. Patients who initiated oseltamivir on the same day as ICU admission were excluded from the ICU primary analysis. This activity was determined as nonresearch public health surveillance by the CDC and conducted consistent with federal laws (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.). State health departments and academic institutional review boards at participating FluSurv-NET sites reviewed and approved these activities as indicated. This study follows Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Exposures, Outcomes and Variable

The time-dependent exposure in the main analysis was oseltamivir treatment with anchor at symptom onset, accounting for both exposed and unexposed time. The primary outcome was ICU admission and the secondary outcome was hospital LOS. Symptoms of influenza infection were grouped into respiratory (congested/runny nose, cough, hemoptysis/bloody sputum, shortness of breath/respiratory distress, sore throat, upper respiratory tract infection/influenza-like illness, wheezing), gastrointestinal (diarrhea, abdominal pain, nausea/vomiting), neurological (altered mental status/confusion, headache, seizures), constitutional (muscle aches/myalgias, fever/chills, fatigue), and other (chest pain, rash, conjunctivitis/pink eye). Vaccination was defined as having at least 1 influenza vaccine that season at least 2 weeks prior to positive influenza test. To account for influenza subtypes, seasons were grouped by predominant influenza A virus subtype circulating into 3 groups: A(H3N2) in the 2014 to 2015, 2016 to 2017, 2017 to 2018, 2021 to 2022, and 2022 to 2023 seasons; A(H1N1)pdm09 in the 2015 to 2016 and 2019 to 2020 seasons; and cocirculation of A(H1) and A(H3) in the 2018 to 2019 season. Medical comorbidities included asthma, autoimmune disease, cardiovascular disease, chronic lung disease, gastrointestinal/liver disease, hypertension, immune suppression, metabolic disease, neurologic disease, obesity, pregnancy, and kidney disease.

Statistical Analyses

Descriptive characteristics were summarized using frequencies (percentages) and medians (IQR), by binary oseltamivir treatment status within the ICU and LOS cohorts. Unadjusted Kaplan-Meier curves with time-invariant treatment were generated to compare probability of remaining outside of the ICU over time from symptom onset and probability of remaining in the hospital over days of admission in those treated with oseltamivir vs those who were not treated. Multivariable Cox proportional hazard modeling was used to mitigate immortal time bias, in which oseltamivir receipt was a time-dependent variable. Covariates were selected a priori based on clinical relevance and prior literature.

Bivariate Cox analyses were used as a secondary screening step with a liberal threshold (P < .20) to avoid excluding potentially important confounders. A priori covariates included age, influenza vaccination status, predominant influenza A virus subtype, and race and ethnicity. Days of illness before hospitalization and ICU admission were additional a priori covariates in the LOS model. Models were used to estimate the association of oseltamivir treatment as a time-dependent exposure anchored at respiratory symptom onset with the hazard of ICU admission and the hazard of hospital discharge after admission. Patients without ICU admission were censored at discharge for the ICU model. Death during hospitalization occurred infrequently. Therefore, deaths were treated as censoring events, as they were unlikely to meaningfully influence the association between treatment and outcome.

We presented hazard ratios with 95% CIs after testing the proportional hazards assumption with Shoenfeld residual correlations and plots. Spearman correlations between covariates were assessed for multicollinearity. All statistical tests were 2-sided, with P values <.05 deemed statistically significant. All data were analyzed in SAS version 9.4 (SAS Institute). LOS was estimated using a counting-process approach to account for time-varying oseltamivir exposure. Mean LOS was derived from model-based survival curves with covariates fixed at reference values, with 95% CIs estimated using bootstrap resampling.

Subgroup and Sensitivity Analyses

Sensitivity analyses were performed for both ICU and LOS models to: (1) reincorporate cases with oseltamivir initiated on the same day as ICU admission and classify these as untreated (ICU model), (2) exclude patients with oseltamivir treatment on same day of discharge (LOS model), (3) exclude cases with oseltamivir received before hospitalization, and (4) include cases with LOS of less than or equal to 1 day. Interaction analyses compared the hazard of ICU admission and discharge (LOS) by age (≤5 years vs >5 years) and presence of medical comorbidity (yes vs no) in both models and by ICU admission status (yes vs no) in the LOS model. The Wald χ² test was used to test the significance of the interaction term.

A time-varying categorized treatment variable was created to compare treatment effect for both ICU and LOS outcomes based on early (≤2 days from symptom onset), late (≥3 days from symptom onset), or no oseltamivir treatment.

Results

Across 8 seasons, 13 127 hospitalized cases of laboratory-confirmed influenza within the FluSurv-NET catchment area were reported among children younger than 18 years; of these, 10 066 (76.7%) received oseltamivir. After exclusions, 7103 cases were included for the LOS analysis as a secondary outcome, 5746 (80.9%) of whom received oseltamivir. Additional exclusions were applied for the primary ICU analysis which included 6044 cases, of whom 4240 (70.2%) received oseltamivir (Figure 1).

Flowchart of pediatric influenza hospitalizations and analysis inclusion counts. Light gray flow diagram with dark text in stacked rectangular boxes connected by vertical arrows, with side boxes connected by rightward arrows indicating exclusions. Top box: 13127 children aged less than 18 years hospitalized with laboratory confirmed influenza within FluSurv N E T during 2014 to 2015 through 2022 to 2023 seasons, excluding 2020 to 2021; within this box, 10066 received oseltamivir and 3061 did not receive oseltamivir. A vertical arrow leads to an exclusion box on the right listing 6024 excluded with the following lines: 2688 length of stay less than or equal to 1 day; 1920 missing influenza test date or symptom start date; 1112 observation encounters; 116 transfers or missing or unknown transfer data; 67 length of stay greater than 30 days; 39 tested greater than 7 days before admission or greater than 3 days after; 37 developed symptoms after influenza test; 30 developed symptoms after admission; 10 treated prior to symptom onset and admission; 5 treated greater than 14 days before admission. The main vertical arrow continues to a centered box: 7103 included in length of stay outcome analysis; 5746 received oseltamivir; 1357 did not receive oseltamivir. Another vertical arrow leads to a second exclusion box on the right: 1059 excluded; 1035 treated on same day as I C U admission; 13 missing date of I C U admission; 10 missing or unknown I C U admission status. The main vertical arrow continues to a lower centered box: 6044 included in I C U admission outcome analysis; 4240 received oseltamivir prior to I C U admission; 1804 did not receive oseltamivir prior to I C U admission. — ICU indicates intensive care unit; LOS, length of stay.

Among the 7103 cases in the LOS analysis, median (IQR) age was 3 (1-7) years, 3982 (56%) were male and 3721 (44%) were female, and 3563 (50%) had medical comorbidities, the most common being asthma in 1914 children (27%) (Table 1). Oseltamivir was initiated prior to admission in 1609 (22.7%) patients. Compared with those not receiving oseltamivir, a higher percentage of oseltamivir recipients were admitted 2 days or less after symptom onset (2799 [49%] vs 381 [28%]), were 2 years of age or younger (2557 [45%] vs 541 [40%]), had underlying medical comorbidity (2998 [52%] vs 565 [42%]), and had preexisting asthma (1608 [28%] vs 306 [23%]). Compared with those not receiving oseltamivir, a higher percentage of oseltamivir recipients were admitted to the ICU (1774 [31%] vs 200 [15%]) and received mechanical ventilation (369 [6%] vs 42 [3%]). The median LOS was 3 days for all children.

Table 1. Demographic and Clinical Characteristics of Laboratory-Confirmed Influenza Hospitalizations Among Children Younger Than 18 Years.

Variable	No. (%)
Variable	Total cases (n = 7103)	Oseltamivir (n = 5746)^a	No oseltamivir (n = 1357)
Symptom onset to hospitalization, d
0	550 (8)	492 (9)	58 (4)
1-2	2630 (37)	2307 (40)	323 (24)
3-5	2458 (35)	1891 (33)	567 (42)
>5	1465 (21)	1056 (18)	409 (30)
Age, y
≤2	3098 (44)	2557 (45)	541 (40)
3-5	1378 (19)	1049 (18)	329 (24)
6-12	1862 (26)	1497 (26)	365 (27)
>12	765 (11)	643 (11)	122 (9)
Sex
Male	3982 (56)	3241 (56)	741 (55)
Female	3121 (44)	2505 (44)	616 (45)
Caregiver-reported race and ethnicity
American Indian/Alaska Native (non-Hispanic)	100 (1)	91 (2)	9 (1)
Asian/Pacific Islander (non-Hispanic)	384 (5)	320 (6)	64 (5)
Black (non-Hispanic)	2076 (29)	1748 (30)	328 (24)
Hispanic	1669 (23)	1364 (24)	305 (22)
Multiracial	102 (1)	85 (1)	17 (1)
White (non-Hispanic)	2200 (31)	1719 (30)	481 (35)
Unknown	572 (8)	419 (7)	153 (11)
Any medical comorbidity^b
No	3536 (50)	2744 (48)	792 (58)
Yes	3563 (50)	2998 (52)	565 (42)
Missing	4 (0)	4 (0)	0
Asthma
Yes	1914 (27)	1608 (28)	306 (23)
No/unknown	5181 (73)	4132 (72)	1049 (77)
Missing	8 (0)	6 (0)	2 (0)
Receipt of current season’s influenza vaccination
No	3880 (55)	3126 (54)	754 (56)
Yes	2316 (33)	1914 (33)	402 (30)
Unknown	590 (8)	434 (8)	156 (11)
Ineligible (age <6 mo)	317 (4)	272 (5)	45 (3)
Influenza type
Unknown	10 (0)	6 (0)	4 (0)
Influenza A	5450 (77)	4451 (77)	999 (74)
Influenza B	1559 (22)	1230 (21)	329 (24)
Other	84 (1)	59 (1)	25 (2)
Predominant influenza A virus subtype circulating across seasons^c
A(H3N2)	4141 (58)	3303 (57)	838 (62)
A(H1N1)pdm09	1838 (26)	1467 (26)	371 (27)
Cocirculation of A(H3) and A(H1)	1124 (16)	976 (17)	148 (11)
Hospital LOS, median (IQR), d	3.0 (2.0-4.0)	3.0 (2.0-5.0)	3.0 (2.0-4.0)
ICU length of stay, median (IQR), d	2.0 (1.0-4.0)	2.0 (1.0-4.0)	2.0 (1.0-4.0)
ICU admission
Yes	1974 (28)	1774 (31)	200 (15)
No	5118 (72)	3962 (69)	1156 (85)
Unknown/missing	11 (0)	10 (0)	1 (0)
Invasive mechanical ventilation
Yes	411 (6)	369 (6)	42 (3)
No	6676 (94)	5363 (94)	1313 (97)
Missing	16 (0)	14 (0)	2 (0)
In-hospital death
Died during hospitalization	33 (0)	25 (0)	8 (1)
Discharged alive	7070 (100)	5721 (100)	1349 (99)

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Abbreviations: ICU, intensive care unit; LOS, length of stay.

^{^a}

Any oseltamivir treatment administered from the time of respiratory symptom onset to hospital discharge.

^{^b}

Medical comorbidities include asthma, autoimmune disease, cardiovascular disease, chronic lung disease, gastrointestinal/liver disease, hypertension, immune suppression, metabolic disease, neurologic disease, obesity, pregnancy, and kidney disease.

^{^c}

Seasons were grouped by predominant influenza A subtype circulating in a given season: A(H3N2) (2014-2015, 2016-2017, 2017-2018, 2021-2022, 2022-2023); A(H1N1)pdm09 (2015-2016, 2019-2020); cocirculation of A(H1); and A(H3) (2018-2019).

Primary Outcome of ICU Admission

In the unadjusted Kaplan-Meier analysis, any oseltamivir treatment was associated with longer time to ICU admission (log rank P < .001; eFigure 1A in Supplement 1). In the adjusted model for ICU admission, oseltamivir treatment as a time-dependent exposure reduced the hazard of ICU admission (aHR, 0.69; 95% CI, 0.60-0.80) compared with no treatment (Figure 2). In the sensitivity analysis in which cases starting oseltamivir on the same day as ICU admission were included as untreated, a stronger association was observed (aHR, 0.30; 95% CI, 0.26-0.34). Overall, 19 patients (0.31%) died during hospitalization, all occurring after the outcome of ICU admission. As a result, no deaths were censored in the ICU model.

Forest plot of adjusted hazard ratios for I C U admission across covariates. Left side table headed Covariate and Adjusted hazard ratio (95% C I). Right side forest plot with a vertical dotted reference line at hazard ratio 1, and headings above the plot reading Favors no I C U admission on the left and Favors I C U admission on the right. Each row has a dark teal square marker with a horizontal black line for the 95 percent confidence interval. Oseltamivir treatment: Yes, zero point six nine (zero point six zero to zero point eight zero); No, 1 Reference. Age, y: zero to 2, one point one nine (zero point nine nine to one point four three); 3 to 5, 1 Reference; 6 to 12, zero point nine seven (zero point eight zero to one point one nine); greater than or equal to 12, one point zero two (zero point eight zero to one point three zero). Race and ethnicity: American Indian or Alaska Native, one point seven five (one point zero one to three point zero two); Asian or Pacific Islander, zero point eight five (zero point six one to one point one nine); Black, zero point nine four (zero point seven eight to one point one two); Hispanic, one point zero six (zero point eight eight to one point two seven); Multiracial, zero point six zero (zero point three zero to one point two two); Unknown, zero point eight one (zero point six two to one point zero seven); White, 1 Reference. Medical comorbidity: Yes, one point six two (one point four zero to one point eight seven); No, 1 Reference. Vaccination status: Ineligible, one point zero one (zero point seven one to one point four six); Unknown, zero point eight nine (zero point six nine to one point one five); Vaccinated, zero point nine five (zero point eight two to one point one zero); Not vaccinated, 1 Reference. Constitutional symptoms: Yes, zero point five one (zero point four three to zero point six one); No, 1 Reference. Neurological symptoms: Yes, one point one six (zero point eight zero to one point six nine); No, 1 Reference; Unknown, one point six two (one point three six to one point nine four). Strain circulation: H 1 predominant, 1 Reference; H 3 predominant, zero point nine six (zero point eight two to one point one two); H 1 and H 3 cocirculation, zero point nine six (zero point seven seven to one point one nine). Bottom horizontal axis labeled Adjusted hazard ratio (95% C I) with tick labels at zero point two, 1, and 4. — Multivariable model with adjusted hazard ratios and P values for ICU outcome. An adjusted hazard ratio less than 1 (toward the left) indicates lower likelihood of ICU admission. Oseltamivir treatment is the primary exposure of interest. Other covariates are shown to illustrate the multivariable adjustment. State was an additional covariate used in the model not shown in the figure. The unadjusted hazard ratio for oseltamivir treatment was 0.72 (95% CI, 0.62-0.83). Both unadjusted and adjusted models treated oseltamivir treatment as a time-dependent exposure, with the unadjusted model including no additional covariates.

Additional sensitivity analyses including patients with a LOS of 1 day or less and excluding patients with oseltamivir treatment prior to admission also showed a decreased hazard of ICU admission for those treated (aHR, 0.71; 95% CI, 0.61-0.82 and aHR, 0.56; 95% CI, 0.47-0.66, respectively) (eTable 1 in Supplement 1). Interaction analyses for this model showed no significant difference in treatment effect for age 5 years or younger vs older than 5 years (aHR, 0.78; 95% CI, 0.65-0.93 and aHR, 0.59; 95% CI, 0.46-0.74; P = .06) or presence vs absence of medical comorbidities, including obesity, asthma, and neurologic condition, specifically (aHR, 0.64; 95% CI, 0.53-0.77 and aHR, 0.78; 95% CI, 0.63-0.98; P = .16) (eTable 2 in Supplement 1).

Both early and late treatment categories showed decreased hazard of ICU admission compared with no treatment (aHR, 0.74; 95% CI, 0.63-0.86 and aHR, 0.55; 95% CI, 0.41-0.73, respectively (Table 2). This effect persisted with treatment more than 5 days from symptom onset (aHR, 0.41; 95% CI, 0.22-0.77) (eTable 3 in Supplement 1). A higher percentage of children treated early had a medical comorbidity (913 [52%] vs 1190 [48%]), received influenza vaccination for that season (624 [36%] vs 777 [31%]), and had influenza A virus infection (1405 [80%] vs 1858 [75%]) (eTable 4 in Supplement 1).

Table 2. Model Estimates for Multivariable Cox Proportional Hazards Models With Time-Varying Treatment Categories.

Outcome^a^,^b	Adjusted hazards ratio (95% CI)	P value
ICU
Early vs no treatment	0.74 (0.63-0.86)	<.001
Late vs no treatment	0.55 (0.41-0.73)	<.001
Early vs late treatment	1.34 (0.99-1.81)	.06
Hospital length of stay
Early vs no treatment	1.15 (1.08-1.23)	<.001
Late vs no treatment	1.08 (0.98-1.20)	.13
Early vs late treatment	1.06 (0.97-1.17)	.22

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Abbreviation: ICU, intensive care unit.

^{^a}

Early treatment defined as oseltamivir treatment 2 days or less from respiratory symptom onset.

^{^b}

Late treatment defined as oseltamivir treatment 3 days or more from respiratory symptom onset.

Secondary Outcome of Hospital LOS

In the unadjusted Kaplan-Meier analysis, oseltamivir treatment was associated with a slightly longer duration of hospitalization, although the effect was small, it was statistically significant (log-rank P < .001) (eFigure 1B in Supplement 1). In the adjusted model for LOS analysis, oseltamivir treatment was associated with a decreased hospital LOS (increased hazard of discharge, 1.13; 95% CI, 1.06-1.21), compared with no treatment (Figure 3). This persisted in a sensitivity analysis excluding those who were treated on the same day as discharge (aHR, 1.07; 95% CI, 1.00-1.14) (eTable 5 in Supplement 1). Estimated LOS was 3.72 days (95% bootstrap CI, 3.2-4.34) for untreated patients and 3.33 days (95% bootstrap CI, 2.91-3.87) for treated patients, corresponding to a 9.4-hour reduction in hospital LOS with oseltamivir treatment (95% bootstrap CI, 4.3-14.6). Additional sensitivity analyses including children with LOS 1 day or less and excluding those who received oseltamivir prior to admission also showed shortened LOS in the oseltamivir treatment group (aHR, 1.18; 95% CI, 1.12-1.24, and aHR, 1.15; 95% CI, 1.08-1.22, respectively) (eTable 5 in Supplement 1). Interaction analyses for the LOS model showed no significant difference in treatment effect for cases with age 5 years or younger vs older than 5 years (aHR, 1.11; 95% CI 1.03-1.20 and aHR, 1.16; 95% CI 1.04-1.28; P = .53), admission to ICU vs no ICU (aHR, 1.14; 95% CI, 0.98-1.32 and aHR, 1.13; 95% CI, 1.06-1.21; P = .94), or presence vs absence of medical comorbidities (aHR, 1.10; 95% CI, 1.00-1.21 and aHR, 1.16; 95% CI, 1.07-1.26; P = .39) (eTable 6 in Supplement 1). When differentiating early and late treatment in the LOS analysis, those who received early treatment had a shorter LOS compared with those untreated (aHR, 1.15; 95% CI, 1.08-1.23). No significant impact was seen when comparing late treatment with no treatment (aHR, 1.08; 95% CI, 0.98-1.20) (Table 2).

Forest plot of adjusted hazard ratios for hospital discharge across covariates. Left side table headed Covariate and Adjusted hazard ratio with 95 percent C I. Right side forest plot with a vertical dotted reference line at hazard ratio 1. Upper right header text: Favors longer L O S on the left of the line and Favors discharge and shorter L O S on the right. Bottom horizontal axis labeled Adjusted hazard ratio with 95 percent C I, with tick labels from about zero point four to 2. Each row has a dark teal square marker and a horizontal black line for the 95 percent C I. Oseltamivir treatment: Yes, 1 point 13 (1 point 06 to 1 point 21); No, 1 reference. Age, years: 0 to 2, 0 point 90 (0 point 84 to 0 point 96); 3 to 5, 1 reference; 6 to 12, 0 point 89 (0 point 83 to 0 point 95); greater than or equal to 12, 0 point 84 (0 point 76 to 0 point 92). Race and ethnicity: American Indian or Alaska Native, 0 point 87 (0 point 70 to 1 point 07); Asian or Pacific Islander, 1 point 08 (0 point 97 to 1 point 21); Black, 1 point 07 (1 point 00 to 1 point 14); Hispanic, 1 point 01 (0 point 94 to 1 point 08); Multiracial, 0 point 96 (0 point 78 to 1 point 18); Unknown, 1 point 02 (0 point 93 to 1 point 13); White, 1 reference. Medical comorbidity: Yes, 0 point 81 (0 point 77 to 0 point 86); No, 1 reference. Vaccination status: Ineligible, 1 point 03 (0 point 91 to 1 point 17); Unknown, 1 point 04 (0 point 95 to 1 point 15); Vaccinated, 0 point 97 (0 point 92 to 1 point 02); Not vaccinated, 1 reference. Constitutional symptoms: Yes, 1 point 17 (1 point 09 to 1 point 26); No, 1 reference. Strain circulation: H 1 predominant, 1 reference; H 3 predominant, 1 point 01 (0 point 96 to 1 point 07); H 1 and H 3 cocirculation, 1 point 02 (0 point 94 to 1 point 10). Symptoms: 0 days before admission, 1 reference; 1 to 2 days before admission, 1 point 08 (0 point 98 to 1 point 19); 3 to 5 days before admission, 1 point 00 (0 point 90 to 1 point 10); greater than 5 days before admission, 0 point 95 (0 point 86 to 1 point 06). Admitted to I C U: Yes, 0 point 43 (0 point 40 to 0 point 45); No, 1 reference. — Multivariable model with adjusted hazard ratios and P values for hospital length of stay (LOS) outcome. Adjusted hazard ratio more than 1 signifies a higher likelihood of discharge and shorter LOS. Oseltamivir treatment is the primary exposure of interest. Other covariates are shown to illustrate the multivariable adjustment. State was an additional covariate used in the model not shown in the figure. The unadjusted hazard ratio for oseltamivir treatment was 0.97 (95% CI, 0.92-1.03). Both unadjusted and adjusted models treated oseltamivir treatment as a time-dependent exposure, with the unadjusted model including no additional covariates. ICU indicates intensive care unit.

Discussion

In our retrospective cohort study of US children hospitalized with laboratory-confirmed influenza across 8 seasons, oseltamivir treatment significantly reduced the likelihood of ICU admission by 31%; treatment effects remained significant regardless of time to treatment initiation from symptom onset. Oseltamivir receipt was also significantly associated with decreased hospital LOS. This study has important treatment implications and adds to the existing literature supporting oseltamivir benefits for all hospitalized children with laboratory-confirmed influenza, including otherwise healthy children and those treated beyond 2 days of respiratory illness onset.

Randomized clinical trials (RCTs) have demonstrated the efficacy of oseltamivir in outpatient children with influenza regarding decreased illness duration and prevention of secondary infections, but no sufficiently powered RCTs have been published for hospitalized children. Given the strong evidence in support of oseltamivir use in hospitalized children, placebo-controlled RCTs are unlikely to be conducted. Therefore, we are reliant on observational studies to assess treatment benefit. Though existing studies demonstrate the effectiveness of oseltamivir against death, ICU admission, and hospital LOS, the methodology of some of these studies has been questioned. For example, in studies using the PHIS database, both influenza infection and antiviral treatment receipt may have been misclassified by relying on International Classification of Diseases codes and not accounting for antiviral use prior to hospitalization, respectively. Bias concerns from these observational studies, along with the perceived unfavorable adverse effect profile of oseltamivir, lack of awareness of national recommendations, and decreased prescribing of antivirals more than 48 hours from symptom onset have likely contributed to the recent decline in antiviral use in hospitalized children with influenza.

Our study aimed to overcome these limitations in several ways. We analyzed data from a multistate surveillance system of influenza hospitalizations, including thousands of cases over 8 seasons with wide geographic and sociodemographic representation. All influenza cases were laboratory-confirmed, overcoming misclassification bias observed in other studies. Abstractors were trained to complete a standardized FluSurv-NET CRF, which collected robust clinical data, including receipt of oseltamivir prior to hospitalization. Anchoring the time at respiratory symptom onset allowed for effectiveness to be measured in the context of illness duration rather than from admission, which was a limitation in other studies. Lastly, a time-to-event analysis, rather than a propensity-based analysis was used to mitigate immortal time bias, which can result in overestimating intervention impact by including time in which an outcome cannot occur.

Our main finding was a significant decrease in ICU admission risk among hospitalized children with laboratory-confirmed influenza treated with oseltamivir compared with those not treated. The association persisted after excluding patients who received oseltamivir prior to admission. The association of oseltamivir with decreased odds of ICU admission has been shown in prior retrospective cohort studies in children. Importantly, our additional analyses of age, underlying medical comorbidity, and timing of oseltamivir initiation from symptom onset showed consistent benefit for all hospitalized pediatric patients with influenza.

Our analyses also demonstrated a significant decrease in the hospital LOS among those receiving oseltamivir, reflected as an increased hazard of discharge; this is notable particularly given that cases had a relatively short LOS (median, 3 days). This finding persisted in our sensitivity analyses. There was no evidence of effect modification by age or medical comorbidity. We observed the reduction in LOS most prominently with early treatment, which has been observed previously. Our findings suggest that health care professionals should encourage caregivers of children to seek care early in the course of influenza-like illness and also urgently consider oseltamivir treatment for all children and adolescents hospitalized with suspected or confirmed influenza.

Limitations

There are several limitations. As this study is retrospective, it relies on data captured over multiple sites and seasons, which has some inherent variation. This is mitigated by the uniform training of abstractors, standardization of CRFs, adjusting for surveillance site, and stable definitions for key variables during the analytic period. Testing at each FluSurv-NET site is at the clinician’s discretion or by facility practice, so patients with influenza-like illness without laboratory confirmation would not be included. The FluSurv-NET surveillance platform includes data from 13 states covering approximately 9% of the US population, so may not be generalizable throughout the entire US. In this time-to-event analysis, time was measured in days as dates. Because the date of respiratory symptom onset was utilized, the symptom start date might be delayed if fever was the presenting symptom. Oseltamivir receipt prior to hospitalization may be incompletely captured, which may lead to exposure misclassification. We hypothesize that this misclassification would be nondifferential, and thus, our observed associations could be underestimated. We did not account for the complex survey design used in selecting cases for CRF completion since it only applied to 1 season, and we do not expect that this has introduced bias. Lastly, given the observational nature of our study, we were unable to account for all potential confounders.

Conclusions

In this analysis of children hospitalized with laboratory-confirmed influenza, oseltamivir treatment significantly reduced the likelihood of ICU admission and decreased hospital LOS. These findings support current national recommendations to treat all children hospitalized with laboratory-confirmed influenza with oseltamivir as soon as possible, regardless of time from symptom onset or underlying risk factors for severe disease.

Supplement 1.

eFigure 1. Kaplan-Meier curves comparing oseltamivir treatment to no treatment evaluating the outcomes of a) intensive care unit admission and b) hospital length of stay

eTable 1. Sensitivity analyses for multivariable Cox models with time-varying exposure of oseltamivir receipt for the outcome of ICU admission

eTable 2. Evaluation of interaction of age and medical comorbidities in the association of time-varying oseltamivir receipt on the hazard of ICU admission

eTable 3. Model estimates for multivariable Cox proportional hazards in the ICU model with time-varying treatment categories of oseltamivir receipt ≤2 days, 3-5 days, and > 5 days from symptom onset

eTable 4. Demographic and clinical characteristics of laboratory-confirmed influenza hospitalizations among children aged <18 years, overall and by oseltamivir receipt for ICU analysis cohort

eTable 5. Sensitivity analyses for multivariable Cox models with time-varying exposure of oseltamivir receipt for the outcome of hospital length of stay

eTable 6. Evaluation of interaction of age and medical comorbidity in the association of time-varying oseltamivir receipt on the hazard of hospital length of stay

eTable 7. Model estimates for multivariable Cox proportional hazards in the ICU model with associated E-values

eTable 8. Model estimates for multivariable Cox proportional hazards in the LOS model with associated E-values

jamapediatr-e263376-s001.pdf^{(455.1KB, pdf)}

Supplement 2.

Data sharing statement

jamapediatr-e263376-s002.pdf^{(16.2KB, pdf)}

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