Influenza Antiviral Use in Patients Hospitalized With Laboratory-Confirmed Influenza in the United States, FluSurv-NET, 2015–2019 Open Access

Abstract

Influenza virus infections resulted in an estimated 140 000–710 000 hospitalizations and 12 000–52 000 deaths per year in the United States in the decade before the coronavirus disease 2019 (COVID-19) pandemic [1]. Influenza antiviral treatment is associated with improved outcomes, including in-hospital survival [2, 3]. Although treatment is recommended for hospitalized patients with suspected or confirmed influenza regardless of illness duration [4], greater clinical benefit is derived from early vs late initiation [3, 5, 6]. Further, most patients hospitalized for influenza have risk factors for severe influenza-associated complications and should receive antiviral treatment as outpatients [4, 7].

The use of antiviral treatment in individuals hospitalized with laboratory-confirmed influenza has increased over time [8–10]. Before the 2009 influenza pandemic, population-based surveillance data from the Centers for Disease Control and Prevention (CDC)–funded Emerging Infections Program (EIP) found that only about half of those hospitalized with laboratory-confirmed influenza received antiviral treatment [8]. From the Influenza Hospitalization Surveillance Network (FluSurv-NET) surveillance platform, which includes EIP sites and additional states [11], antiviral treatment increased from 72% during the 2010–2011 influenza season to 89% during the 2014–2015 season [9]. However, information on trends and timing of antiviral use since 2015 is lacking. Using data from FluSurv-NET, we evaluated more recent trends in antiviral treatment for patients hospitalized with laboratory-confirmed influenza during the 2015–2016 through 2018–2019 seasons. Second, we evaluated timing of antiviral therapy initiation and risk factors for late initiation to inform whether an opportunity exists to improve treatment timing.

METHODS

We included patients of all ages captured in FluSurv-NET surveillance during the 2015–2016 through 2018–2019 influenza seasons. FluSurv-NET performs prospective, population-based surveillance for hospitalized laboratory-confirmed influenza cases from October 1 to April 30, when seasonal influenza viruses typically circulate [11, 12]. Throughout the study period, the network was comprised of acute care hospitals and laboratories in 13 states, with a catchment area representing ∼9% of the US population. Cases included residents of a FluSurv-NET catchment area hospitalized within 14 days of a positive influenza test (including antigen, molecular, viral culture, and/or fluorescent antibody staining) performed at the discretion of local providers.

Trained surveillance officers identified cases by reviewing infection preventionist databases, laboratory logs, discharge summaries, and reportable condition databases [11]. Using a standardized case report form, information was collected on demographic characteristics, medical conditions, clinical details including illness onset date, and influenza treatment including start dates and drugs used. During the 2015–2016 and 2016–2017 influenza seasons, data were collected on all patients with laboratory-confirmed influenza. During the subsequent 2 seasons, data were collected for all younger patients (<50 years), with some sites implementing an age-stratified random sampling of patients age ≥50 years (during the 2017–2018 season) and age ≥65 years (during the 2018–2019 season) [13].

Baseline patient characteristics were summarized using descriptive statistics, including unweighted counts and weighted percentages. The weighted percentage of patients who received any influenza antiviral treatment by season was determined, stratified by age (0–17, 18–49, 50–64, 65–74, 75–84, and ≥85 years). Within each age group, trends in the percentage who received treatment by season were assessed using the Cochran-Armitage test, not accounting for sample design. Among patients who received treatment, we generated multivariable logistic regression models to assess factors associated with late initiation of therapy, defined as ≥3 days from the date of illness onset. Prespecified variables in the model included age, sex, race/ethnicity, number of categories of medical conditions associated with increased risk of severe influenza, surveillance site, influenza season, and continuous days from illness onset to hospitalization. Variance was calculated using 1000 replicate weights to account for the stratified sampling design during the last 2 seasons. For the regression model, we excluded patients with a missing date of illness onset, documented illness onset date ≥14 days before admission, or illness onset after admission. We also excluded patients documented as having received antiviral therapy before the date of illness onset as these patients may have received therapy for a different reason (eg, postexposure prophylaxis). A significance threshold was set at P < .05. Analyses were performed using SAS, version 9.4 (Cary, NC, USA).

Patient Consent

The CDC determined that this activity met the requirement for public health surveillance, and institutional review board (IRB) approval and patient consent were not required. FluSurv-NET sites obtained human subjects and ethics approvals from their respective state health departments and academic partner IRBs as indicated.

RESULTS

After excluding 0.7% (434/62 616) of patients for whom influenza antiviral use data could not be ascertained, we included 62 182 patients hospitalized with laboratory-confirmed influenza. A majority (76%) were ≥50 years of age, 54% were female, 59% were non-Hispanic White, 20% were non-Hispanic Black, and 9% were Hispanic of any race (Supplementary Table 1). Most (83%) had ≥1 high-risk condition, most commonly cardiovascular disease, diabetes mellitus, and nonasthma chronic lung disease.

Over the 4 seasons, 92% of patients received influenza antiviral therapy; 86% in 2015–2016, 90% in 2016–2017, 93% in 2017–2018, and 94% in 2018–2019. Across all age groups, the proportion of patients who received treatment increased over the 4 seasons (Cochran-Armitage P < .001) (Figure 1). Among those who received treatment, the most commonly used agent was oseltamivir (99%). Baloxavir marboxil, approved by the US Food and Drug Adminstration in October 2018 [14], was used in 1.8% of hospitalized patients who received influenza treatment during the 2018–2019 season. However, most use (97%) was at a single surveillance site.

Figure 1.

Percentage of hospitalized patients with laboratory-confirmed influenza who received influenza antiviral therapy by season and age,^a FluSurv-NET, 2015–2016 through 2018–2019. ^aWeighted percentages used to account for sampling methods; Cochran-Armitage test for trend suggested an increase in influenza antiviral use over time across all age groups (P < .001).

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Of patients who received antiviral treatment, 83% (47 425/56 617) had a documented number of days from illness onset to treatment initiation and met other inclusion criteria for the regression analysis. The median duration from illness onset to treatment initiation (interquartile range [IQR]) was 3 (2–5) days, which was the same across all seasons. The median number of days between illness onset and hospital admission (IQR) was 3 (2–5) days. Among treated patients, only 5% (2306/47 425) started treatment before the date of hospital admission, whereas 64% (30 071/47 425) started on hospital day 0, 26% (12 334/47 425) on hospital day 1, and 6% (2714/47 425) on day 2 or later. Adjusting for model covariates, for each additional day from illness onset to hospital admission, the odds of late initiation of therapy (≥3 days after illness onset) was 9.0 (95% CI, 8.2–9.8) (Supplementary Table 2). Being non-Hispanic Black vs non-Hispanic White was associated with late treatment (adjusted odds ratio [OR], 1.19; 95% CI, 1.09–1.30), as was having 3 or more medical conditions (adjusted OR, 1.23; 95% CI, 1.11–1.36).

DISCUSSION

Results from this population-based surveillance study found that most patients hospitalized with laboratory-confirmed influenza across 13 geographically dispersed states received influenza antiviral treatment over 4 influenza seasons. A trend was observed toward increases in the proportion treated over time across age groups, with most treated promptly on admission. Despite prompt in-hospital treatment, most patients did not receive treatment in the first 2 days of illness, almost certainly due to lack of treatment before admission. These findings suggest that influenza is not generally being recognized and treated quickly within the outpatient setting among priority groups at higher risk for influenza-associated complications. Higher-risk groups should be counseled to have a low threshold to seek care, providers should have a low threshold for evaluating and treating patients for suspected influenza, and strategies should be considered for reducing barriers to care (eg, by expanding telemedicine visits) in order to reduce the risk of influenza-related complications [7, 15].

Adjusting for other factors including days to hospitalization, medically complex patients (with ≥3 conditions) were at higher risk for late influenza treatment compared with those without documented underlying medical conditions. This may be due, in part, to the atypical presentation of influenza in medically complex patients, such as presentation with acute exacerbations of chronic conditions [16]. Black non-Hispanic populations were at higher risk of late treatment compared with non-Hispanic Whites, although the median number of days from admission to start of treatment was the same for each group (median, 0 days), which might be attributable to differential access to care. This was unchanged after adjusting for FluSurv-NET site, although this could not account for local differences by race/ethnicity in hospitals within a site.

This study is subject to several limitations. The number of days from illness onset to treatment was not known or outside of the included range for 17% of patients, and illness duration based on documentation from medical records may be subject to error. Further, there could be some undercapture of antiviral therapy started before hospital admission. Although FluSurv-NET includes 13 states and represents about 9% of the US population, it may not represent the entire population. The surveillance network also does not capture patients without laboratory-confirmed influenza, in whom influenza treatment is less likely [17]. Models assessing risk factors for late antiviral therapy may have residual confounding.

CONCLUSIONS

In patients hospitalized with influenza, most were treated with antivirals, but they were often admitted to the hospital too late in their course of illness to receive the most benefits from treatment, even when started promptly after admission. Opportunity exists for encouraging earlier testing, medical care, and treatment initiation to improve clinical outcomes and reduce disparities. Strategies might include increasing access to at-home testing and over-the-counter antivirals or telemedicine visits with empiric treatment initiation based on clinical judgment for high-risk groups.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Acknowledgments

We thank Jeremy Roland, MPH, Joelle Nadle, MPH, Susan Brooks, MPH, Ashley Coates, MPH, and Erin Parker, MPH, at the California Emerging Infections Program; Adam Misiorski, MPH, Amber Maslar, MPA, and Tamara Rissman, MPH, at the Connecticut Emerging Infections Program, Yale School of Public Health; Megan Lasure, MPH, Shelton Bartley MPH, Emily Fawcett, MPH, Andrew Martin, MPH, Kate Ward, MPH, and Jeremiah Williams, MPH, at the Foundation for Atlanta Veterans Education and Research, Georgia Emerging Infections Program, and Atlanta Veterans Affairs Medical Center; Patricia Ryan, MSc, David Blythe, MD, MPH, Alicia Brooks, MPH, Cindy Zerrlaut, Robert Sunkel, MPH, Brian Bachaus, MS, Emily Blake, MPH, Elisabeth Vaeth, MPH, and Molly Hyde, MA, MHS, at the Maryland Department of Health; Jim Collins, MPH, RS, Shannon Johnson, MPH, Justin Henderson, MPH, and Libby Reeg, MPH, at the Michigan Department of Health and Human Services; Ruth Lynfield, MD, Cynthia Kenyon, PhD, and the MN FluSurv-NET team at the Minnesota Department of Health; Sophrena Bushey, MHS, Christine Long, MPH, and RaeAnne Kurtz, BS, at the University of Rochester School of Medicine and Dentistry; Nicholas Fisher, BS, Maya Scullin, MPH, and Laurie Billing, MPH, at the Ohio Department of Health; Amanda Carter, BS, Andrea George, MPH, Andrew Haraghey, BS, Ashley Swain, CHES, Emily Roberts, MPH, Laine McCullough, MPH, Mary Hill, MPH, Melanie Crossland, MPH, Kristen Olsen, BS, and Holly Staten, CHES, at the Salt Lake County Health Department.

Financial support. This work was supported by the Centers for Disease Control and Prevention (CDC) through an Emerging Infections Program cooperative agreement (grant CK17-1701), the 2008–2013 Influenza Hospitalization Surveillance Project cooperative agreement (grant 5U38HM000414)), and the 2018–2023 Influenza Hospitalization Surveillance Project cooperative agreement (grant 5NU38OT0002970).

Disclaimer. The findings and conclusions of this report are those of the authors and do not necessarily reflect the official position of the Centers for Disease Control and Prevention.

References

Author notes