https://orcid.org/0000-0001-6188-2658
Abstract
Guidelines state that all hospitalized children with suspected or confirmed influenza receive prompt treatment with influenza-specific antivirals. We sought to determine the frequency of, and factors associated with, antiviral receipt among hospitalized children.
We conducted active surveillance of children presenting with fever or respiratory symptoms from 1 December 2016 to 31 March 2020 at 7 pediatric medical centers in the New Vaccine Surveillance Network. The cohort consisted of children hospitalized with influenza A or B confirmed by clinical or research testing. The primary outcome was frequency of antiviral receipt during hospitalization. We used logistic regression to obtain adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for factors associated with antiviral receipt.
A total of 1213 children with laboratory-confirmed influenza were included. Overall, 652 children (53.8%) received an antiviral. Roughly 63.0% of children received clinical influenza testing. Among those with clinical testing, 67.4% received an antiviral. Factors associated with higher odds of antiviral receipt included hematologic (aOR = 1.76; 95% CI = 1.03–3.02) or oncologic/immunocompromising (aOR = 2.41; 95% CI = 1.13–5.11) disorders, prehospitalization antiviral receipt (aOR = 2.34; 95% CI = 1.49–3.67), clinical influenza testing (aOR = 3.07; 95% CI = 2.28–4.14), and intensive care unit admission (aOR = 1.53; 95% CI = 1.02–2.29). Symptom duration >2 days was associated with lower odds of antiviral treatment (aOR = 0.40; 95% CI = .30–.52). Antiviral receipt varied by site with a 5-fold difference across sites.
Almost half of children hospitalized with influenza did not receive antivirals. Additional efforts to understand barriers to guideline adherence are crucial for optimizing care in children hospitalized with influenza.
Influenza illness accounts for up to 10% of all pediatric hospitalizations during the winter season in the United States [1, 2]. While young children and those with comorbidities are at increased risk for influenza complications, the majority of children hospitalized for influenza are otherwise healthy [3]. Complications of influenza include conditions that require hospitalization, such as pneumonia, myocarditis, myositis, and encephalitis; influenza can also lead to multiorgan failure and even death [2, 4–8].
Meta-analyses of clinical trials demonstrate that influenza antiviral use results in shorter symptom duration and lower risk of developing subsequent pneumonia, sinusitis, and otitis media infections [2, 9–11]. Observational studies also support outpatient use of influenza-specific antivirals, with antiviral use associated with decreased hospitalizations and influenza-related complications [12–15]. Among hospitalized children, early use of antivirals may decrease the length of hospital stay, use of mechanical ventilation, and intensive care unit (ICU) admission [16–18].
The American Academy of Pediatrics (AAP), Infectious Diseases Society of America (IDSA), and Centers for Disease Control and Prevention (CDC) recommend initiation of influenza antiviral treatment as soon as possible in all children hospitalized with confirmed or suspected influenza, regardless of symptom duration, vaccination status, or underlying risk factors [19–21]. However, recent evidence suggests that the use of antivirals in the pediatric inpatient setting is highly variable and suboptimal, with a substantial number of children not receiving guideline-concordant antiviral treatment [4, 22–24]. Prior studies that sought to determine factors that contribute to variable antiviral use lacked laboratory confirmation of influenza and did not account for important factors such as outpatient antiviral use, vaccination status, and symptom duration [22, 24].
A better understanding of the drivers of influenza antiviral use will inform future efforts to improve the clinical management of children hospitalized with influenza illness. Therefore, the objectives of this study were to determine the prevalence of and factors associated with influenza antiviral receipt among children hospitalized with laboratory-confirmed influenza illness in a multicenter, prospective surveillance cohort in the United States.
METHODS
Study Design and Population
Data from the CDC-funded New Vaccine Surveillance Network (NVSN) were used for this study. The NVSN is a prospective, active, population-based surveillance platform of children with acute respiratory illness across 7 pediatric medical centers in the following US cities: Cincinnati, Ohio; Houston, Texas; Kansas City, Missouri; Nashville, Tennessee; Pittsburgh, Pennsylvania; Rochester, New York; and Seattle, Washington [25, 26]. Children were eligible for enrollment if they were aged <18 years and had an illness duration of <14 days, had at least 1 qualifying acute respiratory illness sign or symptom (eg, apnea, cough, earache, fever, myalgia, nasal congestion, runny nose, sore throat, vomiting after coughing, shortness of breath [rapid or shallow breathing]), wheezing, or apparent life-threatening event or brief resolved unexplained event), and resided in a surveillance site area. Data for this study were restricted to the dates of 1 December 2016 to 31 March 2020. Children with fever and neutropenia associated with malignancy, those readmitted within 4 days, or those transferred from another hospital after an admission of >48 hours were excluded from NVSN enrollment. Written informed consent was obtained from the parent or guardian, and assent was obtained when applicable. The institutional review boards at the CDC and each of the 7 surveillance sites approved this study. This report was prepared in compliance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines [27].
Definition of Influenza Virus Infection
Influenza cases were defined as those with laboratory-confirmed influenza, which included either a positive clinical or research test for influenza virus A or B. Clinical testing included antigen-based and molecular assays reported in the electronic medical record at each of the 7 sites. In addition to clinical testing, study personnel collected mid-turbinate nasal or oropharyngeal swabs from all enrolled children for research testing (results not reported to providers). For intubated patients, tracheal aspirates were accepted as an alternative specimen source. When nasal, oropharyngeal, or tracheal aspirate specimens were not collected, clinically salvaged respiratory specimens were obtained. These research specimens were tested at each site using commercial or institution-specific in-house reverse-transcription polymerase chain reaction (RT-PCR) assays for influenza. Diagnostic assay methods varied by site and included the Luminex NxTAG Respiratory Pathogen Panel (Cincinnati and Kansas City), BioFire FilmArray Respiratory Panel (Seattle), Applied Biosystems TaqMan Array Microfluidic Card (Rochester), and in-house RT-PCR assays (Houston, Pittsburgh, and Nashville) [28]. All sites conducted CDC-sponsored proficiency testing to ensure valid and consistent respiratory viral detection [28, 29].
Children at Increased Risk for Influenza Complications
Children at increased risk for influenza complications were identified using the 2018 IDSA Clinical Practice Guidelines definition for children at increased risk of influenza and included age <5 years (especially <2 years), underlying chronic pulmonary (including asthma), cardiovascular, renal, hepatic, gastrointestinal, hematologic (including sickle cell disease), oncologicor immunosuppressive, metabolic (including diabetes mellitus), and neurologic and neuromuscular conditions [30]. Underlying conditions were collected from electronic medical records at each site. Other conditions at high risk for influenza complications, including children with long-term aspirin use, those living in a chronic care facility, and pregnant children, were not included as part of the increased risk definition as these conditions were either uncommon in our dataset or the necessary data were unavailable for assessment.
Outcomes
The primary outcome was proportion of antiviral use, defined as the number of children with with influenza confirmed by research or routine clinical laboratory testing who received an influenza antiviral (oseltamivir, peramivir, baloxavir, or zanamivir) during hospitalization divided by the total number of children hospitalized with influenza. Our secondary outcomes were factors associated with in-hospital influenza antiviral receipt.
Statistical Analyses
Descriptive statistics are presented as medians (interquartile ranges [IQRs]) for continuous variables and frequencies (percentages) for categorical variables. The proportion of children with antiviral receipt was calculated by dividing the number of hospitalized children who received an antiviral by the total number of children hospitalized with influenza confirmed by research or routine clinical laboratory testing. To account for missing data in the regression model, we used multiple imputation by chained equations with M = 20 iterations as implemented in the “mice” package in R. Adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) for factors potentially associated with antiviral receipt were generated using mixed-effects logistic regression that included the following fixed-effects covariates: age; sex; comorbidities; symptom duration at presentation, defined as time between self-reported symptom onset and admission; presence of gastrointestinal symptoms; seasonal influenza vaccination status; receipt of antivirals in the outpatient setting prior to hospitalization; clinical testing for influenza; clinical influenza co-detection; early admission to the ICU; influenza season; and admission during peak influenza season. Individuals were captured at the encounter level, allowing for multiple encounters for each individual across influenza seasons. However, outcomes of encounters that come from the same individual may be correlated due to patient-specific factors not accounted for by the model. To account for this, we included patient-level identifiers (to account for repeat encounters across influenza seasons) and study site as random effects in the model. Influenza season was defined as the period spanning the first Sunday in July for a given calendar year until the day before the first Sunday in July of the subsequent year. Peak influenza season was defined as the 13 consecutive weeks (with Sunday as the index day) with the highest cumulative number of influenza cases at each site [7, 31]. All analyses were performed using R, version 4.4.1.
To compare heterogeneity in antiviral receipt by those at increased risk for influenza complications (defined based on 2018 IDSA Clinical Practice Guidelines as age <5 years or presence of an underlying condition) [30], we used our mixed-effects logistic regression model to obtain patient-specific predicted values (or expected receipt) for the probability of antiviral use to compare with actual receipt. We used descriptive statistics to compare the distribution of predicted probabilities between those at increased risk for influenza complications and those not at increased risk for influenza complications.
RESULTS
Study Population
Of 17 109 hospitalized children enrolled over the study period, 17 051 (99.7%) underwent influenza testing, 1213 (7.1%, representing 1195 children with 1 encounter and 9 with 2 encounters) of whom were positive for influenza A or B (Figure 1). A total of 162 (13.4%) children were identified by clinical testing only, 602 (49.6%) by clinical and research testing, and 449 (37.0%) by research testing only. The median age of confirmed cases was 3.7 years (IQR, 1.3–8.1). Most were male (55.6%), had public insurance (64.3%), and did not receive antivirals prior to admission (89.9%); 41.2% were non-Hispanic white, 27.7% were non-Hispanic Black, 20.4% were Hispanic, and 10.7% were another race (Table 1).
Flowchart of study participants.
Demographic and Clinical Characteristics of Hospitalized Children Who Tested Positive for Influenza A or B by Clinical or Research Assays Stratified by Influenza-Specific Antiviral Receipt, New Vaccine Surveillance Network, 1 December 2016 to 31 March 2020
| Characteristic | All (N = 1213) | No Antiviral Receipt (n = 561) | Antiviral Receipt (n = 652) |
|---|---|---|---|
| Age at presentation, median (IQR), y | 3.7 (1.3–8.1) | 3.7 (1.3–7.8) | 3.6 (1.2–8.4) |
| Age group at presentation, n (%), y | |||
| 0–1 | 415 (34.2) | 179 (31.9) | 236 (36.2) |
| 2–4 | 289 (23.8) | 152 (27.1) | 137 (21.0) |
| 5–17 | 509 (42.0) | 230 (41.0) | 279 (42.8) |
| Sex, n (%) | |||
| Female | 538 (44.4) | 240 (42.8) | 298 (45.7) |
| Male | 675 (55.6) | 321 (57.2) | 354 (54.3) |
| Race and Hispanic origin, n (%) | |||
| Hispanic | 246/1205 (20.4) | 81/560 (14.5) | 165/645 (25.6) |
| Non-Hispanic Black | 334/1205 (27.7) | 154/560 (27.5) | 180/645 (27.9) |
| Non-Hispanic White | 496/1205 (41.2) | 265/560 (47.3) | 231/645 (35.8) |
| Non-Hispanic other | 129/1205 (10.7) | 60/560 (10.7) | 69/645 (10.7) |
| Insurance status, n (%) | |||
| Private | 348/1191 (29.2) | 172/551 (31.2) | 176/640 (27.5) |
| Public | 766/1191 (64.3) | 351/551 (63.7) | 415/640 (64.8) |
| Both | 20/1191 (1.7) | 9/551 (1.6) | 11/640 (1.7) |
| Self-pay | 57/1191 (4.8) | 19/551 (3.4) | 38/640 (5.9) |
| Risk factor for influenza complications, n (%) | |||
| Any risk factor | 1073 (88.5) | 473 (84.3) | 600 (92.0) |
| Aged 0–4 y | 704 (58.0) | 331 (59.0) | 373 (57.2) |
| Respiratory disorder | 362 (29.8) | 151 (26.9) | 211 (32.4) |
| Cardiovascular disorder | 99 (8.2) | 34 (6.1) | 65 (10.0) |
| Neurologic or neuromuscular disorder | 187 (15.4) | 77 (13.7) | 110 (16.9) |
| Hematologic disorder | 91 (7.5) | 23 (4.1) | 68 (10.4) |
| Oncologic or immunocompromising disorder | 56 (4.6) | 11 (2.0) | 45 (6.9) |
| Endocrine disorder | 62 (5.1) | 25 (4.5) | 37 (5.7) |
| Renal or urologic disorder | 26 (2.1) | 11 (2.0) | 15 (2.3) |
| Gastrointestinal or hepatic disorder | 148 (12.2) | 50 (8.9) | 98 (15.0) |
| Genetic or metabolic disorder | 202 (16.7) | 80 (14.3) | 122 (18.7) |
| Signs and symptoms | |||
| Days symptomatic at presentation, median (IQR) | 3.0 (2.0–5.0) | 4.0 (3.0–6.0) | 3.0 (2.0–4.0) |
| 1 or 2, n (%) | 439/1207 (36.4) | 137/559 (24.5) | 302/648 (46.6) |
| 3 or more, n (%) | 768/1207 (63.6) | 422/559 (75.5) | 346/648 (53.4) |
| Fever, n (%) | 1129/1206 (93.6) | 525/555 (94.6) | 604/651 (92.8) |
| Cough, n (%) | 1139 (93.9) | 531 (94.7) | 608 (93.3) |
| Congestion or runny nose, n (%) | 1061/1210 (87.7) | 487/559 (87.1) | 574/651 (88.2) |
| Sore throat, n (%) | 468/905 (51.7) | 216/429 (50.3) | 252/476 (52.9) |
| Dyspnea, n (%) | 811/1201 (67.5) | 365/553 (66.0) | 446/648 (68.8) |
| Myalgia, n (%) | 354/825 (42.9) | 165/392 (42.1) | 189/433 (43.6) |
| Chills, n (%) | 567/1101 (51.5) | 255/506 (50.4) | 312/595 (52.4) |
| Vomiting, n (%) | 419/1207 (34.7) | 188/556 (33.8) | 231/651 (35.5) |
| Diarrhea, n (%) | 371/1205 (30.8) | 194/557 (34.8) | 177/648 (27.3) |
| Antiviral receipt, n (%) | |||
| Prior receipt of influenza-specific antivirals | 122/1204 (10.1) | 46/554 (8.3) | 76/650 (11.7) |
| Receipt of in-hospital antivirals on day 1 or 2 | 598/649 (92.1) | 0/0 (NA) | 598/649 (92.1) |
| Received current season influenza vaccine, n (%) | 565 (46.6) | 249 (44.4) | 316 (48.5) |
| Clinical testing,an (%) | |||
| Not tested for influenza | 396 (32.6) | 263 (46.9) | 133 (20.4) |
| Tested negative for influenza | 53 (4.4) | 46 (8.2) | 7 (1.1) |
| Tested positive for influenza | 764 (63.0) | 252 (44.9) | 512 (78.5) |
| Research testing, n (%) | |||
| Not tested for influenza | 22 (1.8) | 5 (0.9) | 17 (2.6) |
| Tested negative for influenza | 140 (11.5) | 52 (9.3) | 88 (13.5) |
| Tested positive for influenza | 1051 (86.6) | 504 (89.8) | 547 (83.9) |
| Clinical influenza co-detection, n (%) | 85/760 (11.2) | 31/250 (12.4) | 54/510 (10.6) |
| Length of stay, median (IQR), d | 2.0 (1.0–3.0) | 1.0 (1.0–2.0) | 2.0 (1.0–3.0) |
| Intensive care unit admission, n (%) | |||
| Day 1 or 2 | 163 (13.4) | 51 (9.1) | 112 (17.2) |
| Day 3 or after | 13 (1.1) | 4 (0.7) | 9 (1.4) |
| Influenza season, n (%) | |||
| 2016–2017 | 215 (17.7) | 111 (19.8) | 104 (16.0) |
| 2017–2018 | 296 (24.4) | 128 (22.8) | 168 (25.8) |
| 2018–2019 | 285 (23.5) | 130 (23.2) | 155 (23.8) |
| 2019–2020 | 417 (34.4) | 192 (34.2) | 225 (34.5) |
| Peak influenza season, n (%) | 994 (81.9) | 453 (80.7) | 541 (83.0) |
| Study site, n (%) | |||
| A | 103 (8.5) | 76 (13.5) | 27 (4.1) |
| B | 193 (15.9) | 67 (11.9) | 126 (19.3) |
| C | 135 (11.1) | 73 (13.0) | 62 (9.5) |
| D | 105 (8.7) | 32 (5.7) | 73 (11.2) |
| E | 209 (17.2) | 55 (9.8) | 154 (23.6) |
| F | 100 (8.2) | 49 (8.7) | 51 (7.8) |
| G | 368 (30.3) | 209 (37.3) | 159 (24.4) |
| Characteristic | All (N = 1213) | No Antiviral Receipt (n = 561) | Antiviral Receipt (n = 652) |
|---|---|---|---|
| Age at presentation, median (IQR), y | 3.7 (1.3–8.1) | 3.7 (1.3–7.8) | 3.6 (1.2–8.4) |
| Age group at presentation, n (%), y | |||
| 0–1 | 415 (34.2) | 179 (31.9) | 236 (36.2) |
| 2–4 | 289 (23.8) | 152 (27.1) | 137 (21.0) |
| 5–17 | 509 (42.0) | 230 (41.0) | 279 (42.8) |
| Sex, n (%) | |||
| Female | 538 (44.4) | 240 (42.8) | 298 (45.7) |
| Male | 675 (55.6) | 321 (57.2) | 354 (54.3) |
| Race and Hispanic origin, n (%) | |||
| Hispanic | 246/1205 (20.4) | 81/560 (14.5) | 165/645 (25.6) |
| Non-Hispanic Black | 334/1205 (27.7) | 154/560 (27.5) | 180/645 (27.9) |
| Non-Hispanic White | 496/1205 (41.2) | 265/560 (47.3) | 231/645 (35.8) |
| Non-Hispanic other | 129/1205 (10.7) | 60/560 (10.7) | 69/645 (10.7) |
| Insurance status, n (%) | |||
| Private | 348/1191 (29.2) | 172/551 (31.2) | 176/640 (27.5) |
| Public | 766/1191 (64.3) | 351/551 (63.7) | 415/640 (64.8) |
| Both | 20/1191 (1.7) | 9/551 (1.6) | 11/640 (1.7) |
| Self-pay | 57/1191 (4.8) | 19/551 (3.4) | 38/640 (5.9) |
| Risk factor for influenza complications, n (%) | |||
| Any risk factor | 1073 (88.5) | 473 (84.3) | 600 (92.0) |
| Aged 0–4 y | 704 (58.0) | 331 (59.0) | 373 (57.2) |
| Respiratory disorder | 362 (29.8) | 151 (26.9) | 211 (32.4) |
| Cardiovascular disorder | 99 (8.2) | 34 (6.1) | 65 (10.0) |
| Neurologic or neuromuscular disorder | 187 (15.4) | 77 (13.7) | 110 (16.9) |
| Hematologic disorder | 91 (7.5) | 23 (4.1) | 68 (10.4) |
| Oncologic or immunocompromising disorder | 56 (4.6) | 11 (2.0) | 45 (6.9) |
| Endocrine disorder | 62 (5.1) | 25 (4.5) | 37 (5.7) |
| Renal or urologic disorder | 26 (2.1) | 11 (2.0) | 15 (2.3) |
| Gastrointestinal or hepatic disorder | 148 (12.2) | 50 (8.9) | 98 (15.0) |
| Genetic or metabolic disorder | 202 (16.7) | 80 (14.3) | 122 (18.7) |
| Signs and symptoms | |||
| Days symptomatic at presentation, median (IQR) | 3.0 (2.0–5.0) | 4.0 (3.0–6.0) | 3.0 (2.0–4.0) |
| 1 or 2, n (%) | 439/1207 (36.4) | 137/559 (24.5) | 302/648 (46.6) |
| 3 or more, n (%) | 768/1207 (63.6) | 422/559 (75.5) | 346/648 (53.4) |
| Fever, n (%) | 1129/1206 (93.6) | 525/555 (94.6) | 604/651 (92.8) |
| Cough, n (%) | 1139 (93.9) | 531 (94.7) | 608 (93.3) |
| Congestion or runny nose, n (%) | 1061/1210 (87.7) | 487/559 (87.1) | 574/651 (88.2) |
| Sore throat, n (%) | 468/905 (51.7) | 216/429 (50.3) | 252/476 (52.9) |
| Dyspnea, n (%) | 811/1201 (67.5) | 365/553 (66.0) | 446/648 (68.8) |
| Myalgia, n (%) | 354/825 (42.9) | 165/392 (42.1) | 189/433 (43.6) |
| Chills, n (%) | 567/1101 (51.5) | 255/506 (50.4) | 312/595 (52.4) |
| Vomiting, n (%) | 419/1207 (34.7) | 188/556 (33.8) | 231/651 (35.5) |
| Diarrhea, n (%) | 371/1205 (30.8) | 194/557 (34.8) | 177/648 (27.3) |
| Antiviral receipt, n (%) | |||
| Prior receipt of influenza-specific antivirals | 122/1204 (10.1) | 46/554 (8.3) | 76/650 (11.7) |
| Receipt of in-hospital antivirals on day 1 or 2 | 598/649 (92.1) | 0/0 (NA) | 598/649 (92.1) |
| Received current season influenza vaccine, n (%) | 565 (46.6) | 249 (44.4) | 316 (48.5) |
| Clinical testing,an (%) | |||
| Not tested for influenza | 396 (32.6) | 263 (46.9) | 133 (20.4) |
| Tested negative for influenza | 53 (4.4) | 46 (8.2) | 7 (1.1) |
| Tested positive for influenza | 764 (63.0) | 252 (44.9) | 512 (78.5) |
| Research testing, n (%) | |||
| Not tested for influenza | 22 (1.8) | 5 (0.9) | 17 (2.6) |
| Tested negative for influenza | 140 (11.5) | 52 (9.3) | 88 (13.5) |
| Tested positive for influenza | 1051 (86.6) | 504 (89.8) | 547 (83.9) |
| Clinical influenza co-detection, n (%) | 85/760 (11.2) | 31/250 (12.4) | 54/510 (10.6) |
| Length of stay, median (IQR), d | 2.0 (1.0–3.0) | 1.0 (1.0–2.0) | 2.0 (1.0–3.0) |
| Intensive care unit admission, n (%) | |||
| Day 1 or 2 | 163 (13.4) | 51 (9.1) | 112 (17.2) |
| Day 3 or after | 13 (1.1) | 4 (0.7) | 9 (1.4) |
| Influenza season, n (%) | |||
| 2016–2017 | 215 (17.7) | 111 (19.8) | 104 (16.0) |
| 2017–2018 | 296 (24.4) | 128 (22.8) | 168 (25.8) |
| 2018–2019 | 285 (23.5) | 130 (23.2) | 155 (23.8) |
| 2019–2020 | 417 (34.4) | 192 (34.2) | 225 (34.5) |
| Peak influenza season, n (%) | 994 (81.9) | 453 (80.7) | 541 (83.0) |
| Study site, n (%) | |||
| A | 103 (8.5) | 76 (13.5) | 27 (4.1) |
| B | 193 (15.9) | 67 (11.9) | 126 (19.3) |
| C | 135 (11.1) | 73 (13.0) | 62 (9.5) |
| D | 105 (8.7) | 32 (5.7) | 73 (11.2) |
| E | 209 (17.2) | 55 (9.8) | 154 (23.6) |
| F | 100 (8.2) | 49 (8.7) | 51 (7.8) |
| G | 368 (30.3) | 209 (37.3) | 159 (24.4) |
Abbreviation: IQR, interquartile range.
Clinical tests performed >1 day after antiviral receipt were excluded.
Demographic and Clinical Characteristics of Hospitalized Children Who Tested Positive for Influenza A or B by Clinical or Research Assays Stratified by Influenza-Specific Antiviral Receipt, New Vaccine Surveillance Network, 1 December 2016 to 31 March 2020
| Characteristic | All (N = 1213) | No Antiviral Receipt (n = 561) | Antiviral Receipt (n = 652) |
|---|---|---|---|
| Age at presentation, median (IQR), y | 3.7 (1.3–8.1) | 3.7 (1.3–7.8) | 3.6 (1.2–8.4) |
| Age group at presentation, n (%), y | |||
| 0–1 | 415 (34.2) | 179 (31.9) | 236 (36.2) |
| 2–4 | 289 (23.8) | 152 (27.1) | 137 (21.0) |
| 5–17 | 509 (42.0) | 230 (41.0) | 279 (42.8) |
| Sex, n (%) | |||
| Female | 538 (44.4) | 240 (42.8) | 298 (45.7) |
| Male | 675 (55.6) | 321 (57.2) | 354 (54.3) |
| Race and Hispanic origin, n (%) | |||
| Hispanic | 246/1205 (20.4) | 81/560 (14.5) | 165/645 (25.6) |
| Non-Hispanic Black | 334/1205 (27.7) | 154/560 (27.5) | 180/645 (27.9) |
| Non-Hispanic White | 496/1205 (41.2) | 265/560 (47.3) | 231/645 (35.8) |
| Non-Hispanic other | 129/1205 (10.7) | 60/560 (10.7) | 69/645 (10.7) |
| Insurance status, n (%) | |||
| Private | 348/1191 (29.2) | 172/551 (31.2) | 176/640 (27.5) |
| Public | 766/1191 (64.3) | 351/551 (63.7) | 415/640 (64.8) |
| Both | 20/1191 (1.7) | 9/551 (1.6) | 11/640 (1.7) |
| Self-pay | 57/1191 (4.8) | 19/551 (3.4) | 38/640 (5.9) |
| Risk factor for influenza complications, n (%) | |||
| Any risk factor | 1073 (88.5) | 473 (84.3) | 600 (92.0) |
| Aged 0–4 y | 704 (58.0) | 331 (59.0) | 373 (57.2) |
| Respiratory disorder | 362 (29.8) | 151 (26.9) | 211 (32.4) |
| Cardiovascular disorder | 99 (8.2) | 34 (6.1) | 65 (10.0) |
| Neurologic or neuromuscular disorder | 187 (15.4) | 77 (13.7) | 110 (16.9) |
| Hematologic disorder | 91 (7.5) | 23 (4.1) | 68 (10.4) |
| Oncologic or immunocompromising disorder | 56 (4.6) | 11 (2.0) | 45 (6.9) |
| Endocrine disorder | 62 (5.1) | 25 (4.5) | 37 (5.7) |
| Renal or urologic disorder | 26 (2.1) | 11 (2.0) | 15 (2.3) |
| Gastrointestinal or hepatic disorder | 148 (12.2) | 50 (8.9) | 98 (15.0) |
| Genetic or metabolic disorder | 202 (16.7) | 80 (14.3) | 122 (18.7) |
| Signs and symptoms | |||
| Days symptomatic at presentation, median (IQR) | 3.0 (2.0–5.0) | 4.0 (3.0–6.0) | 3.0 (2.0–4.0) |
| 1 or 2, n (%) | 439/1207 (36.4) | 137/559 (24.5) | 302/648 (46.6) |
| 3 or more, n (%) | 768/1207 (63.6) | 422/559 (75.5) | 346/648 (53.4) |
| Fever, n (%) | 1129/1206 (93.6) | 525/555 (94.6) | 604/651 (92.8) |
| Cough, n (%) | 1139 (93.9) | 531 (94.7) | 608 (93.3) |
| Congestion or runny nose, n (%) | 1061/1210 (87.7) | 487/559 (87.1) | 574/651 (88.2) |
| Sore throat, n (%) | 468/905 (51.7) | 216/429 (50.3) | 252/476 (52.9) |
| Dyspnea, n (%) | 811/1201 (67.5) | 365/553 (66.0) | 446/648 (68.8) |
| Myalgia, n (%) | 354/825 (42.9) | 165/392 (42.1) | 189/433 (43.6) |
| Chills, n (%) | 567/1101 (51.5) | 255/506 (50.4) | 312/595 (52.4) |
| Vomiting, n (%) | 419/1207 (34.7) | 188/556 (33.8) | 231/651 (35.5) |
| Diarrhea, n (%) | 371/1205 (30.8) | 194/557 (34.8) | 177/648 (27.3) |
| Antiviral receipt, n (%) | |||
| Prior receipt of influenza-specific antivirals | 122/1204 (10.1) | 46/554 (8.3) | 76/650 (11.7) |
| Receipt of in-hospital antivirals on day 1 or 2 | 598/649 (92.1) | 0/0 (NA) | 598/649 (92.1) |
| Received current season influenza vaccine, n (%) | 565 (46.6) | 249 (44.4) | 316 (48.5) |
| Clinical testing,an (%) | |||
| Not tested for influenza | 396 (32.6) | 263 (46.9) | 133 (20.4) |
| Tested negative for influenza | 53 (4.4) | 46 (8.2) | 7 (1.1) |
| Tested positive for influenza | 764 (63.0) | 252 (44.9) | 512 (78.5) |
| Research testing, n (%) | |||
| Not tested for influenza | 22 (1.8) | 5 (0.9) | 17 (2.6) |
| Tested negative for influenza | 140 (11.5) | 52 (9.3) | 88 (13.5) |
| Tested positive for influenza | 1051 (86.6) | 504 (89.8) | 547 (83.9) |
| Clinical influenza co-detection, n (%) | 85/760 (11.2) | 31/250 (12.4) | 54/510 (10.6) |
| Length of stay, median (IQR), d | 2.0 (1.0–3.0) | 1.0 (1.0–2.0) | 2.0 (1.0–3.0) |
| Intensive care unit admission, n (%) | |||
| Day 1 or 2 | 163 (13.4) | 51 (9.1) | 112 (17.2) |
| Day 3 or after | 13 (1.1) | 4 (0.7) | 9 (1.4) |
| Influenza season, n (%) | |||
| 2016–2017 | 215 (17.7) | 111 (19.8) | 104 (16.0) |
| 2017–2018 | 296 (24.4) | 128 (22.8) | 168 (25.8) |
| 2018–2019 | 285 (23.5) | 130 (23.2) | 155 (23.8) |
| 2019–2020 | 417 (34.4) | 192 (34.2) | 225 (34.5) |
| Peak influenza season, n (%) | 994 (81.9) | 453 (80.7) | 541 (83.0) |
| Study site, n (%) | |||
| A | 103 (8.5) | 76 (13.5) | 27 (4.1) |
| B | 193 (15.9) | 67 (11.9) | 126 (19.3) |
| C | 135 (11.1) | 73 (13.0) | 62 (9.5) |
| D | 105 (8.7) | 32 (5.7) | 73 (11.2) |
| E | 209 (17.2) | 55 (9.8) | 154 (23.6) |
| F | 100 (8.2) | 49 (8.7) | 51 (7.8) |
| G | 368 (30.3) | 209 (37.3) | 159 (24.4) |
| Characteristic | All (N = 1213) | No Antiviral Receipt (n = 561) | Antiviral Receipt (n = 652) |
|---|---|---|---|
| Age at presentation, median (IQR), y | 3.7 (1.3–8.1) | 3.7 (1.3–7.8) | 3.6 (1.2–8.4) |
| Age group at presentation, n (%), y | |||
| 0–1 | 415 (34.2) | 179 (31.9) | 236 (36.2) |
| 2–4 | 289 (23.8) | 152 (27.1) | 137 (21.0) |
| 5–17 | 509 (42.0) | 230 (41.0) | 279 (42.8) |
| Sex, n (%) | |||
| Female | 538 (44.4) | 240 (42.8) | 298 (45.7) |
| Male | 675 (55.6) | 321 (57.2) | 354 (54.3) |
| Race and Hispanic origin, n (%) | |||
| Hispanic | 246/1205 (20.4) | 81/560 (14.5) | 165/645 (25.6) |
| Non-Hispanic Black | 334/1205 (27.7) | 154/560 (27.5) | 180/645 (27.9) |
| Non-Hispanic White | 496/1205 (41.2) | 265/560 (47.3) | 231/645 (35.8) |
| Non-Hispanic other | 129/1205 (10.7) | 60/560 (10.7) | 69/645 (10.7) |
| Insurance status, n (%) | |||
| Private | 348/1191 (29.2) | 172/551 (31.2) | 176/640 (27.5) |
| Public | 766/1191 (64.3) | 351/551 (63.7) | 415/640 (64.8) |
| Both | 20/1191 (1.7) | 9/551 (1.6) | 11/640 (1.7) |
| Self-pay | 57/1191 (4.8) | 19/551 (3.4) | 38/640 (5.9) |
| Risk factor for influenza complications, n (%) | |||
| Any risk factor | 1073 (88.5) | 473 (84.3) | 600 (92.0) |
| Aged 0–4 y | 704 (58.0) | 331 (59.0) | 373 (57.2) |
| Respiratory disorder | 362 (29.8) | 151 (26.9) | 211 (32.4) |
| Cardiovascular disorder | 99 (8.2) | 34 (6.1) | 65 (10.0) |
| Neurologic or neuromuscular disorder | 187 (15.4) | 77 (13.7) | 110 (16.9) |
| Hematologic disorder | 91 (7.5) | 23 (4.1) | 68 (10.4) |
| Oncologic or immunocompromising disorder | 56 (4.6) | 11 (2.0) | 45 (6.9) |
| Endocrine disorder | 62 (5.1) | 25 (4.5) | 37 (5.7) |
| Renal or urologic disorder | 26 (2.1) | 11 (2.0) | 15 (2.3) |
| Gastrointestinal or hepatic disorder | 148 (12.2) | 50 (8.9) | 98 (15.0) |
| Genetic or metabolic disorder | 202 (16.7) | 80 (14.3) | 122 (18.7) |
| Signs and symptoms | |||
| Days symptomatic at presentation, median (IQR) | 3.0 (2.0–5.0) | 4.0 (3.0–6.0) | 3.0 (2.0–4.0) |
| 1 or 2, n (%) | 439/1207 (36.4) | 137/559 (24.5) | 302/648 (46.6) |
| 3 or more, n (%) | 768/1207 (63.6) | 422/559 (75.5) | 346/648 (53.4) |
| Fever, n (%) | 1129/1206 (93.6) | 525/555 (94.6) | 604/651 (92.8) |
| Cough, n (%) | 1139 (93.9) | 531 (94.7) | 608 (93.3) |
| Congestion or runny nose, n (%) | 1061/1210 (87.7) | 487/559 (87.1) | 574/651 (88.2) |
| Sore throat, n (%) | 468/905 (51.7) | 216/429 (50.3) | 252/476 (52.9) |
| Dyspnea, n (%) | 811/1201 (67.5) | 365/553 (66.0) | 446/648 (68.8) |
| Myalgia, n (%) | 354/825 (42.9) | 165/392 (42.1) | 189/433 (43.6) |
| Chills, n (%) | 567/1101 (51.5) | 255/506 (50.4) | 312/595 (52.4) |
| Vomiting, n (%) | 419/1207 (34.7) | 188/556 (33.8) | 231/651 (35.5) |
| Diarrhea, n (%) | 371/1205 (30.8) | 194/557 (34.8) | 177/648 (27.3) |
| Antiviral receipt, n (%) | |||
| Prior receipt of influenza-specific antivirals | 122/1204 (10.1) | 46/554 (8.3) | 76/650 (11.7) |
| Receipt of in-hospital antivirals on day 1 or 2 | 598/649 (92.1) | 0/0 (NA) | 598/649 (92.1) |
| Received current season influenza vaccine, n (%) | 565 (46.6) | 249 (44.4) | 316 (48.5) |
| Clinical testing,an (%) | |||
| Not tested for influenza | 396 (32.6) | 263 (46.9) | 133 (20.4) |
| Tested negative for influenza | 53 (4.4) | 46 (8.2) | 7 (1.1) |
| Tested positive for influenza | 764 (63.0) | 252 (44.9) | 512 (78.5) |
| Research testing, n (%) | |||
| Not tested for influenza | 22 (1.8) | 5 (0.9) | 17 (2.6) |
| Tested negative for influenza | 140 (11.5) | 52 (9.3) | 88 (13.5) |
| Tested positive for influenza | 1051 (86.6) | 504 (89.8) | 547 (83.9) |
| Clinical influenza co-detection, n (%) | 85/760 (11.2) | 31/250 (12.4) | 54/510 (10.6) |
| Length of stay, median (IQR), d | 2.0 (1.0–3.0) | 1.0 (1.0–2.0) | 2.0 (1.0–3.0) |
| Intensive care unit admission, n (%) | |||
| Day 1 or 2 | 163 (13.4) | 51 (9.1) | 112 (17.2) |
| Day 3 or after | 13 (1.1) | 4 (0.7) | 9 (1.4) |
| Influenza season, n (%) | |||
| 2016–2017 | 215 (17.7) | 111 (19.8) | 104 (16.0) |
| 2017–2018 | 296 (24.4) | 128 (22.8) | 168 (25.8) |
| 2018–2019 | 285 (23.5) | 130 (23.2) | 155 (23.8) |
| 2019–2020 | 417 (34.4) | 192 (34.2) | 225 (34.5) |
| Peak influenza season, n (%) | 994 (81.9) | 453 (80.7) | 541 (83.0) |
| Study site, n (%) | |||
| A | 103 (8.5) | 76 (13.5) | 27 (4.1) |
| B | 193 (15.9) | 67 (11.9) | 126 (19.3) |
| C | 135 (11.1) | 73 (13.0) | 62 (9.5) |
| D | 105 (8.7) | 32 (5.7) | 73 (11.2) |
| E | 209 (17.2) | 55 (9.8) | 154 (23.6) |
| F | 100 (8.2) | 49 (8.7) | 51 (7.8) |
| G | 368 (30.3) | 209 (37.3) | 159 (24.4) |
Abbreviation: IQR, interquartile range.
Clinical tests performed >1 day after antiviral receipt were excluded.
Prevalence and Timing of Antiviral Receipt
Of 1213 hospitalized children with laboratory-confirmed influenza, 652 (53.8%) received an antiviral. Among the 561 (46.2%) children who did not receive an antiviral, 263 (46.9%) were not clinically tested for influenza. Among those who underwent a clinical influenza test, 519 of 817 (63.5%) received an antiviral, and among those who tested positive clinically, 512 of 764 (67.0%) received an antiviral. Among 153 infants aged <6 months (ineligible for vaccination), 96 (62.7%) received an antiviral. Compared with children not clinically tested, those clinically tested more frequently received antivirals (63.5% vs 33.6%), time between self-reported symptom onset and admission was ≤2 days (40.2% vs 28.4%), and a lower proportion of children clinically tested were non-Hispanic white (33.5% vs 57.0%; Supplementary Table 1).
Among those who received an antiviral, 1 child received peramivir only, 650 received oseltamivir only, and 1 received both peramivir and oseltamivir. The date of antiviral receipt was recorded for 649 children (99.5%): 598 (92.1%) received an antiviral on day 1 or 2 of presentation and 51 (7.9%) received an antiviral on or after day 3. Antiviral receipt was highest among Hispanic children (67.1%), and the site-specific frequency of antiviral receipt ranged from 26.2% to 73.7% (Figure 2). The proportion of antiviral receipt was generally higher with shorter time between self-reported symptom onset and admission (Supplementary Figure 1).
Frequency and timing of antiviral receipt in hospitalized children with influenza enrolled in the New Vaccine Surveillance Network (1 December 2016 to 31 March 2020), stratified by age group (A), race and Hispanic origin (B), influenza season (C), study site (D), clinical testing (E), and peak influenza season (F). Day refers to the day of hospitalization on which the first dose of antiviral was received. None refers to cases where no antiviral was received during the hospitalization.
Factors Associated With Antiviral Receipt Among Children With Influenza
Patient-level factors associated with higher odds of antiviral receipt included a hematologic disorder (aOR = 1.76; 95% CI = 1.03–3.02), an oncologic or immunocompromising disorder (aOR = 2.41; 95% CI = 1.13–5.11), receipt of antivirals for current illness prior to hospitalization (aOR = 2.34; 95% CI = 1.49–3.67), clinical testing for influenza (aOR = 3.07; 95% CI = 2.28–4.14), and ICU admission at presentation (aOR = 1.53; 95% CI = 1.02–2.29; Figure 3). Time between self-reported symptom onset and admission >2 days at presentation was associated with lower odds of antiviral receipt (aOR = 0.40; 95% CI .30–.52). System-level factors, such as study site, were also associated with receipt of an antiviral (Figure 3). We identified significant heterogeneity in odds of antiviral receipt by site, with the odds of receipt differing by an estimated 457% difference between the sites with the highest (Site E) and lowest (Site A) receipt (aOR = 5.57; 95% CI 3.30–9.41).
Factors associated with antiviral receipt among hospitalized children with influenza enrolled in the New Vaccine Surveillance Network (1 December 2016 to 31 March 2020) identified from a generalized linear mixed-effects model with a patient-level identifier and study site as random effects. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.
Figure 4 shows the distribution of the predicted probability of antiviral receipt based on the regression model, stratified by the risk for influenza complications (based on 2018 IDSA guidelines). While there was a higher tendency for those at increased risk for influenza complications to receive an antiviral compared with those not at increased risk, our model identifies a large proportion of children at increased risk as being unlikely to receive an antiviral. As shown in Figure 4, the median expected antiviral receipt among children deemed at increased risk was 58%. Among those not at increased risk for influenza complications, the median expected receipt was 42%. Additionally, Figure 4 illustrates that our model covariates selected a priori explain a large degree of variation in actual antiviral receipt within both groups defined by increased risk status.
Distribution of the predicted probability of antiviral receipt among children disaggregated by the risk of influenza complications (according to the 2018 Infectious Diseases Society of America Clinical Practice Guideline). The group-specific median and interquartile range are indicated in the top right corner of each subfigure.
We performed a secondary analysis of factors associated with antiviral receipt among 764 children with laboratory-confirmed influenza by rapid or RT-PCR clinical testing. Results were consistent with the primary analysis with the exception of prior antiviral testing, which was no longer a significant factor (Supplementary Figure 2).
DISCUSSION
In this large, multicenter, prospective study of antiviral use among hospitalized children with laboratory-confirmed influenza, we found that almost half did not receive antiviral therapy despite widely endorsed recommendations by national organizations and treatment guidelines. Importantly, almost 37% of hospitalized infants in our study aged <6 months who are ineligible for influenza vaccination and at highest risk for severe influenza and influenza-related complications [8, 31–33] did not receive an antiviral. Prescribing was also higher among those clinically tested for influenza, those who received antivirals prior to hospitalization, those with an underlying hematologic disorder or an oncologic/immunocompromising disorder, and those admitted to the ICU at presentation. Conversely, antiviral use was less frequent when symptoms had been present for >2 days at hospitalization and at some study sites. Our findings underscore the need for increased efforts to improve antiviral use in managing influenza disease among hospitalized children.
Our finding of limited use of antivirals in hospitalized children with influenza illness is concerning. The IDSA, CDC, and AAP recommend treatment as soon as possible for hospitalized children with suspected or confirmed influenza [20, 34, 35]. These guidelines also state that lack of influenza testing or delays in obtaining testing results should not delay empiric antiviral treatment in this population. Our results align with those from our previous study in which we used NVSN data from the 2015–2016 influenza season and found that 52% of hospitalized children with a positive clinical test for influenza received antiviral treatment [36]. Our current analysis indicates that there was minimal change in the subsequent years; adherence to guidelines for antiviral use in hospitalized children remains suboptimal. The reasons for lack of treatment of children hospitalized with symptomatic influenza illness are unclear. Oseltamivir allergy and serious adverse events (ie, neuropsychiatric events [7, 23] or Stevens–Johnson syndrome [35, 37]) are generally thought to be rare. However, if a child does have an oseltamivir allergy, an alternative antiviral such as peramivir (or potentially baloxavir) may be used. Given changes in healthcare utilization for influenza and influenza transmission following the coronavirus disease 2019 pandemic, continued monitoring of influenza antiviral use is warranted [38–40]. To date, the CDC recommends empiric treatment with influenza antivirals during influenza season for those who are at high risk of severe influenza, and treatment should not be delayed for clinical testing results despite other circulating virus strains (such as severe acute respiratory syndrome coronavirus 2) [41]. However, this guidance may change in the future based on epidemiologic trends of these viruses.
There was varied receipt of antivirals across the 7 geographically distinct study sites, ranging from 26.2% to 73.7%. Among those with clinical influenza testing, 67% received an antiviral. This is similar to findings from 36 academic children's hospitals between 2007 and 2020 that showed median oseltamivir use of 66% among those hospitalized with an influenza diagnosis [22]. In the most recent season of that study, oseltamivir use by hospital ranged from 56.5% to 90.1%. The reasons for this high variation are likely multifactorial. Differences in institutional cultures, presence of standardized care protocols, and location of medical training have all been shown to play a role in variation in care for other disease processes. It is also likely that, despite strong national recommendations for treatment, a misperception regarding evidence for antiviral treatment in hospitalized children is a factor in the variation of influenza treatment.
A recent meta-analysis of randomized trials in hospitalized adults suggests that antivirals shorten hospital length of stay (LOS) [42]. However, data for hospitalized children are primarily driven by observational studies. A study of a prospectively derived cohort of children hospitalized with laboratory-confirmed influenza found that early oseltamivir receipt was associated with a shorter LOS among children at increased risk for influenza complications and, separately, in those admitted to the ICU [17]. However, children who received oseltamivir ≥3 days after symptom onset did not have a significantly lower LOS compared with those who did not receive antiviral therapy. These data are supported by retrospective studies that have also shown that antiviral use is associated with a shortened hospital course in adults [43], as well as hospitalized children at increased risk of influenza complications [16] and those with severe disease admitted to the ICU [44–46]. A recent retrospective cohort study found that early oseltamivir treatment was associated with shorter LOS, transfer to the ICU, a composite outcome of death/extracorporeal membrane oxygenation use, and readmission among all children admitted with influenza. These findings were similar among those with and without underlying comorbidities [18]. However, that study could not account for confounding factors such as symptom duration, vaccination status, or antiviral receipt prior to hospitalization.
While observational studies suggest limited benefit in LOS with antivirals among those with symptoms that last <3 days, there are no randomized trials to confirm these findings. However, there is evidence of a clinical benefit of antivirals even when initiated after 48 hours of symptoms [8, 41–44, 47–52], and there are hospital outcomes other than LOS where antivirals may be beneficial to hospitalized patients, such as symptom severity, respiratory support, and development of influenza complications. Additional studies are needed on these outcomes to inform clinical decision-making. Most children hospitalized for influenza are otherwise healthy, and there are no randomized trials of antiviral treatment in this population. Rigorous studies are needed in healthy children hospitalized for influenza to determine the effectiveness of guideline treatment decisions, especially surrounding the timing of treatment in relation to disease onset.
We identified several factors associated with low antiviral use that may serve as targets for interventions to improve the care of children hospitalized with influenza. First, children with clinical influenza testing had 3-fold higher odds of antiviral receipt than those without clinical testing. In our cohort, approximately 47% of untreated children did not receive clinical influenza testing. However, almost 64% of those with a clinical influenza test and 67% of those with a positive clinical test for influenza received an antiviral. The IDSA guidelines recommend influenza testing in all hospitalized individuals with acute respiratory illness [30]. While establishing a diagnosis through testing is not a requirement for, and should not delay, antiviral treatment in hospitalized children, it is likely that efforts to improve appropriate clinical testing or to increase provider suspicion for influenza infection will result in more antiviral receipt.
Second, outpatient antiviral receipt prior to hospitalization was a strong predictor of inpatient antiviral receipt. Recent evidence suggests that the receipt of outpatient influenza-specific antivirals, including among children at increased risk for influenza complications and those aged <2 years, is low [53, 54]. Interventions to improve early antiviral receipt in the outpatient setting will likely aid in overcoming clinical inertia to treat in the inpatient setting.
Third, children who presented on or after day 3 of symptoms were significantly less likely to receive antivirals compared with those who presented on day 1 or 2. Qualitative research by the CDC on antiviral prescribing practices revealed that there is a wide range of physician perceptions as to the effectiveness of influenza-specific antivirals and that some clinicians may not prescribe antivirals after the 2-day window, which was found to be optimal treatment timing in clinical trials [55]. The low proportion of antiviral receipt in children with >2 days of symptoms may reflect either a misunderstanding of national recommendations or a belief that antiviral treatment is not effective after 2 days of symptoms in those with severe disease. Future interventions could focus on increasing antiviral use in hospitalized children with >2 days of symptoms regardless of duration of symptoms.
Our results must be considered in the context of several limitations. The study was performed at 7 academic children's hospitals, and findings may not be generalizable to community hospital settings. Clinical testing information was determined by chart review at the treating institution, and we may have underestimated clinical testing if it was performed at an outside facility and written documentation of the testing was not provided to the treating hospital. Additionally, receipt of an antiviral was well captured in our study, but we could not determine if an individual received the full antiviral treatment course or the time of day of individual doses. It is possible that some children were suboptimally treated with antivirals. Finally, time stamps (or clock times) were not available in our study to measure time in hours. Our approach of measuring symptom duration at presentation in days rather than hours may lead to an overestimation of the interval between symptom onset and presentation (as partial days are counted in full). Therefore, we may have overestimated the proportion of antiviral receipt in those with <48 hours of symptoms. Despite these limitations, our findings provide strong evidence that the management of children hospitalized for influenza can be improved through improving guideline-concordant antiviral treatment.
CONCLUSIONS
Among hospitalized children with laboratory-confirmed influenza, approximately half received guideline-recommended influenza-specific antivirals. Antiviral receipt varied according to several individual-and system-level factors, including specific underlying conditions, clinical testing, prior antiviral treatment, symptom duration, early ICU admission, and treatment site. Future studies could focus on identifying barriers to treatment and improving clinical influenza testing, providing antiviral treatment for children with influenza-associated hospitalizations with >2 days of symptoms, and standardizing care both within and across institutions.
Supplementary Data
Supplementary materials are available at Clinical 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.
Notes
Financial support. This study was supported by cooperative agreement IP16-004 with the Centers for Disease Control and Prevention. J. W. A. (K23 AI168496) was partially supported by the National Institute for Allergy and Infectious Diseases of the National Institutes of Health.
References
Author notes
J. W. A. and J. Z. A. contributed equally and are co-first authors. S. M. O. and N. B. H. contributed equally and are co-senior authors.
Potential conflicts of interest. J. W. A. previously served as a member of the AstraZeneca Scientific Advisory Board. G. A. W. has received honoraria from Merck & Company for writing and revising chapters in the Merck Manual Electrophysiologic Studies. M. A. S. has received research funding from Pfizer and honoraria from Sanofi Pasteur for vaccine consultation. J. A. E. reports work as a consultant to AbbVie, AstraZeneca, Meissa Vaccines, Pfizer, Moderna, and Sanofi Pasteur and research to support their university from AstraZeneca, GSK, Merck, and Pfizer. M. G. M. reports research to support their university from Merk Sharpe & Dohme and a nonfinancial research grant from Viracor. F. M. M. reports work as a consultant for Moderna, GSK, AstraZeneca, Sanofi, Novavax, and Merck; serving on the data and safety monitoring boards for Pfizer, Moderna, the National Institutes of Health (NIH), Meissa, and Dynavax; and grant and research support from Pfizer, Gilead, NIH, and CDC. J. E. S. reports work as a consultant at the Association of American Medical Colleges. J. V. W. previously served as a member of the Quidel Scientific Advisory Board and on an independent data monitoring committee for GSK. S. M. O. reports travel support from the Gates Foundation. N. B. H. received grant support from Sanofi and Quidel, receives current grant support from Merck, and served on an advisory board for CSL Seqirus. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
