OBJECTIVES

Antivirals are recommended for children hospitalized with influenza but are underutilized. We describe antiviral prescribing during influenza admissions in Canadian pediatric centers and identify factors associated with antiviral use.

METHODS

We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from 2010–2011 to 2018–2019. Logistic regression analyses were used to identify factors associated with antiviral use.

RESULTS

Among 7545 patients, 57.4% were male; median age was 3 years (interquartile range: 1.1–6.3). Overall, 41.3% received antiviral agents; 72.8% received antibiotics. Antiviral use varied across sites (range, 10.2% to 81.1%) and influenza season (range, 19.9% to 59.6%) and was more frequent in children with ≥1 chronic health condition (52.7% vs 36.7%; P < .001). On multivariable analysis, factors associated with antiviral use included older age (adjusted odds ratio [aOR] 1.04 [95% confidence interval (CI), 1.02–1.05]), more recent season (highest aOR 9.18 [95% CI, 6.70–12.57] for 2018–2019), admission during peak influenza period (aOR 1.37 [95% CI, 1.19–1.58]), availability of local treatment guideline (aOR 1.54 [95% CI, 1.17–2.02]), timing of laboratory confirmation (highest aOR 2.67 [95% CI, 1.97–3.61] for result available before admission), presence of chronic health conditions (highest aOR 4.81 [95% CI, 3.61–6.40] for cancer), radiographically confirmed pneumonia (aOR 1.39 [95% CI, 1.20–1.60]), antibiotic treatment (aOR 1.51 [95% CI, 1.30–1.76]), respiratory support (1.57 [95% CI, 1.19–2.08]), and ICU admission (aOR 3.62 [95% CI, 2.88–4.56]).

CONCLUSIONS

Influenza antiviral agents were underused in Canadian pediatric hospitals, including among children with high-risk chronic health conditions. Prescribing varied considerably across sites, increased over time, and was associated with patient and hospital-level characteristics. Multifaceted hospital-based interventions are warranted to strengthen adherence to influenza treatment guidelines and antimicrobial stewardship practices.

What’s Known on This Subject:

Observational studies suggest that early antiviral therapy in patients hospitalized with influenza is associated with improved outcomes; however, pediatric data are scarce. Despite guidelines recommending treatment, it is unknown why many children admitted to pediatric centers do not receive antiviral agents.

What This Study Adds:

Antiviral use was limited and variable among Canadian children hospitalized for influenza. Over time, use increased overall and in children at high risk. Patient- and hospital-level characteristics influenced antiviral use. Early antiviral initiation was strongly associated with rapidity of influenza test results.

Seasonal influenza epidemics are an important cause of pediatric hospitalization and mortality.1  Annual hospitalization rates are highest in young children, ranging from ∼250 per 100 000 children <6 months old to ∼4.6 to 42.1 per 100 000 for those 5 to 17 years old.27  Hospitalization risk is ∼4 to 21 times greater in children with chronic medical conditions8  and they accounted for ∼50% of pediatric influenza deaths during 2010–2016 in the United States.9,10  The neuraminidase inhibitors oseltamivir and zanamivir are the only influenza antiviral agents recommended for pediatric use in Canada.11  Randomized controlled trials show that early treatment with neuraminidase inhibitors (ie, within 48 hours of symptom onset) reduces illness duration and frequency of complications in adults and healthy children with influenza in the outpatient setting,1214  and a recent meta-analysis of observational studies showed that preadmission neuraminidase inhibitor treatment was associated with decreased odds of hospitalization,15  but efficacy in “at-risk” children remains to be proven. Despite a paucity of trial data in the hospital setting,16  clinical practice guidelines, including those from Canada, recommend antiviral treatment of hospitalized children with suspected or confirmed influenza, especially those with chronic health conditions.17,18  Observational studies in hospitalized adults support this guidance, with early antiviral therapy associated with decreased disease severity outcomes (length of stay [LoS], ICU admission, and mortality).1922  However, data on antiviral use among hospitalized children are scarce and have primarily focused on the 2009 H1N1 pandemic period or earlier.2325  Furthermore, despite availability of guidelines recommending treatment, many children admitted to pediatric centers for influenza do not receive antiviral agents,26,27  although recent studies have suggested increasing use.28 

We describe influenza antiviral use in children hospitalized with laboratory-confirmed influenza between 2010–2011 and 2018–2019 in Canadian pediatric centers and identify factors associated with antiviral treatment in this population. We hypothesized that antiviral use would vary considerably across sites, increase over time, and be associated with patient and hospital-level variables.

The study population comprised patients aged 0–16 years ascertained through active surveillance for laboratory confirmed influenza admissions from September 1, 2010, to June 30, 2019, at the 12 tertiary care pediatric hospitals participating in the Canadian Immunization Monitoring Program, ACTive (IMPACT).29  These centers admit >75 000 children annually, account for ∼90% of pediatric tertiary care beds in the country, receive referrals from all provinces and territories, and serve a population of ∼50% of Canada’s children.30  During the study period, all centers tested children admitted with acute respiratory infection for influenza, guided by their local policies and test availability. Patients with hospital LoS <1 day, receipt of antiviral agents before admission to the IMPACT hospital, and nosocomial cases (symptom onset ≥72 hours after admission) were excluded from this study. Institutional ethics approval was obtained at each center.

Trained nurse monitors prospectively screened daily laboratory results and admission lists for eligible cases. Audits of hospital discharge abstract databases were performed yearly to ensure case ascertainment completeness. Data were abstracted from medical charts.

The primary outcome was receipt of anti-influenza antiviral treatment during hospitalization. The secondary outcome was timing of antiviral receipt during admission. Exposure variables included demographics, health status (by chronic conditions known to be risk factors for complicated infection31 ), influenza season (eg, 2010–2011), admitting center, availability of local influenza treatment guidelines during that season at the admitting center, timing of admission within influenza season (screening for influenza at IMPACT centers occurs year-round, and we defined “peak” season as the period during which the national influenza test positivity proportion was at least 15%, as reported by the Public Health Agency of Canada7 ), test method used for diagnosis, timing of availability of laboratory confirmation of influenza infection in relation to admission, influenza vaccination status for that season, antibiotic prescription, and measures of illness severity (mortality, ICU admission, respiratory support [continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), conventional or high-frequency ventilation, and extracorporeal membrane oxygenation (ECMO)], ICU, and hospital LoS).

Data were analyzed by using R, version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was assessed by using 2-tailed tests, with an α of 0.05. Descriptive statistics were calculated, medians of continuous variables were compared across strata using the Wilcoxon rank test, and proportions were compared by using the Pearson’s χ2 test. The Mann-Kendall test was used to analyze temporal trends in antiviral use. Correction for multiple hypothesis testing was not performed. Logistic regression analyses were used to determine crude and adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) for factors associated with antiviral use, and for factors associated with early (during first 2 days of admission) versus late (after first 2 days of admission) initiation of antiviral agents. Given the substantial proportion of missing data for ethnicity (47%) and vaccination status (16.8%), no inferential statistics were performed on these variables. For the multivariable models, we considered variables that were statistically significant on univariable analyses, and, a priori, included plausible confounders based on literature or clinical experience. Model selection was guided by using the Akaike Information Criteria, using backward selection.

During the study period, 7946 laboratory-confirmed influenza admissions were recorded. Among these, 276 had a hospital LoS <1 day, 103 had received antiviral agents before hospitalization at the IMPACT center, and for 22 cases, data regarding receipt of antiviral agents were unknown. After these exclusions, we included 7545 cases (Fig 1).

FIGURE 1

Study flow diagram: antiviral use among Canadian children aged between 0 and 16 years, hospitalized for influenza between 2010–2019.

FIGURE 1

Study flow diagram: antiviral use among Canadian children aged between 0 and 16 years, hospitalized for influenza between 2010–2019.

Close modal

Median patient age was 3.0 years (interquartile range [IQR]: 1.1–6.3) and 57.4% were male (Table 1). Median number of cases admitted per influenza season was 680 (range 561–1298). The total number of cases at each IMPACT center during the study ranged from 185 to 1132. Eight IMPACT centers (75%) had local influenza treatment guidelines (adapted from national guidance documents), and onset of guideline availability ranged from before 2010–2011 to 2016–2017. Among patients ≥6 months of age with known vaccination status, only 690 of 5402 (12.8%) had documented receipt of influenza vaccine that season. Influenza A virus was detected in 5345 cases (70.8%), and influenza B was detected in 2165 (28.6%). Among the 1926 type A isolates subtyped, 50.3% were A/H3N2 and 45.9% A/H1N1 2009.

TABLE 1

Characteristics of Children Admitted for Influenza Across 12 Canadian IMPACT Pediatric Hospital Centers, 2010–11 to 2018–19 (n = 7545)

Characteristicsn (%)
Demographic data  
 Age, y  
  Mean ± SD 4.30 ± 4.10 
  Median (IQR) 3.0 (1.08–6.33) 
 Age group  
  0–5 mo 1053 (13.9) 
  6–23 mo 1841 (24.4) 
  24–59 mo 2100 (27.8) 
  ≥5 y 2551 (33.9) 
 Sex  
  Male 4332 (57.4) 
 Ethnicity  
  White 2141 (28.3) 
  Asian American 418 (5.5) 
  Middle Eastern or Arabic 333 (4.4) 
  Black 390 (5.1) 
  Latin, Central, and South American 111 (1.4) 
  North American Indigenous 472 (6.2) 
  Other or mixed 129 (1.7) 
  Unknown 3551 (47.0) 
 Influenza season  
  2010–2011 636 (8.4) 
  2011–2012 561 (7.4) 
  2012–2013 836 (11.0) 
  2013–2014 675 (8.9) 
  2014–2015 680 (9.0) 
  2015–2016 1298 (17.2) 
  2016–2017 563 (7.4) 
  2017–2018 1011 (13.3) 
  2018–2019 1285 (17.0) 
 Timing of admission within influenza season  
  Admitted during “peak” seasona 4845 (64.2) 
 IMPACT center  
  A 218 (2.8) 
  B 1132 (15.0) 
  C 1068 (14.1) 
  D 494 (6.5) 
  E 492 (6.5) 
  F 679 (8.9) 
  G 682 (9.0) 
  H 657 (8.7) 
  I 185 (2.4) 
  J 853 (11.3) 
  K 762 (1.0) 
  L 323 (4.2) 
 Availability of a local influenza antiviral treatment guidelineb  
  Treatment guideline available 3978 (52.7) 
 Vaccination status (n = 6492)c  
  Received influenza vaccine for that season 690 (10.6) 
  Did not receive influenza vaccine for that season 4712 (72.6) 
  Vaccination status unknown 1090 (16.8) 
Laboratory data  
 Influenza virus type  
  A 5345 (70.8) 
  B 2165 (28.6) 
  Both A and B 35 (4.6) 
 Test used to make the diagnosis  
  PCR 5512 (73.1) 
  EIA 234 (3.1) 
  DFA 1082 (14.3) 
  Viral culture 693 (9.2) 
  Unknown 24 (0.3) 
 Timing of availability of report of laboratory confirmation of influenza infection  
  Result available before IMPACT center admission 782 (10.4) 
  Result available on first day of admission 4660 (61.8) 
  Result available within second day of admission 1632 (21.6) 
  Result available after second day of admission 471 (6.2) 
Clinical data  
 Presence of underlying chronic health condition  
  Any underlying risk factor 3434 (45.4) 
  Chronic heart disorders 365 (4.8) 
  Chronic lung disorders 1403 (18.5) 
  Diabetes mellitus or other metabolic disorders 263 (3.4) 
  Cancer 318 (4.2) 
  Immunodeficiency 270 (3.5) 
  Immunosuppression 297 (3.9) 
  Chronic renal disease 169 (2.2) 
  Chronic anemia 102 (1.3) 
  Hemoglobinopathy 256 (3.3) 
  Chronic acetylsalicylic acid therapy 16 (0.2) 
  Residence in institutional setting and other chronic care facilities 28 (0.3) 
  Neurologic or neurodevelopment disorders 855 (11.3) 
  Pregnancy 2 (0.0) 
  Obesity 41 (0.5) 
  Prematurity (if <1 y old) 140 (1.8) 
 Duration of symptoms before admission at IMPACT hospital, d  
  Mean ± SD 3.68 ± 3.10 
  Median (IQR) 3 (2–5) 
 Presence of radiographically confirmed pneumonia 2212 (29.3) 
 Presence of a laboratory-confirmed bacterial infection 508 (6.7) 
 Coreceipt of antibiotic therapy 5494 (72.8) 
 Need for intensive care 1252 (16.5) 
 Need for respiratory supportd 795 (10.5) 
 Hospital LoS, d  
  Mean ± SD 4.81 ± 7.51 
  Median (IQR) 3 (2–5) 
 Outcome at hospital discharge  
  Survived 7501 (99.4) 
  Died of reported influenza infection 42 (0.5) 
  Died of other cause 2 (0) 
Characteristicsn (%)
Demographic data  
 Age, y  
  Mean ± SD 4.30 ± 4.10 
  Median (IQR) 3.0 (1.08–6.33) 
 Age group  
  0–5 mo 1053 (13.9) 
  6–23 mo 1841 (24.4) 
  24–59 mo 2100 (27.8) 
  ≥5 y 2551 (33.9) 
 Sex  
  Male 4332 (57.4) 
 Ethnicity  
  White 2141 (28.3) 
  Asian American 418 (5.5) 
  Middle Eastern or Arabic 333 (4.4) 
  Black 390 (5.1) 
  Latin, Central, and South American 111 (1.4) 
  North American Indigenous 472 (6.2) 
  Other or mixed 129 (1.7) 
  Unknown 3551 (47.0) 
 Influenza season  
  2010–2011 636 (8.4) 
  2011–2012 561 (7.4) 
  2012–2013 836 (11.0) 
  2013–2014 675 (8.9) 
  2014–2015 680 (9.0) 
  2015–2016 1298 (17.2) 
  2016–2017 563 (7.4) 
  2017–2018 1011 (13.3) 
  2018–2019 1285 (17.0) 
 Timing of admission within influenza season  
  Admitted during “peak” seasona 4845 (64.2) 
 IMPACT center  
  A 218 (2.8) 
  B 1132 (15.0) 
  C 1068 (14.1) 
  D 494 (6.5) 
  E 492 (6.5) 
  F 679 (8.9) 
  G 682 (9.0) 
  H 657 (8.7) 
  I 185 (2.4) 
  J 853 (11.3) 
  K 762 (1.0) 
  L 323 (4.2) 
 Availability of a local influenza antiviral treatment guidelineb  
  Treatment guideline available 3978 (52.7) 
 Vaccination status (n = 6492)c  
  Received influenza vaccine for that season 690 (10.6) 
  Did not receive influenza vaccine for that season 4712 (72.6) 
  Vaccination status unknown 1090 (16.8) 
Laboratory data  
 Influenza virus type  
  A 5345 (70.8) 
  B 2165 (28.6) 
  Both A and B 35 (4.6) 
 Test used to make the diagnosis  
  PCR 5512 (73.1) 
  EIA 234 (3.1) 
  DFA 1082 (14.3) 
  Viral culture 693 (9.2) 
  Unknown 24 (0.3) 
 Timing of availability of report of laboratory confirmation of influenza infection  
  Result available before IMPACT center admission 782 (10.4) 
  Result available on first day of admission 4660 (61.8) 
  Result available within second day of admission 1632 (21.6) 
  Result available after second day of admission 471 (6.2) 
Clinical data  
 Presence of underlying chronic health condition  
  Any underlying risk factor 3434 (45.4) 
  Chronic heart disorders 365 (4.8) 
  Chronic lung disorders 1403 (18.5) 
  Diabetes mellitus or other metabolic disorders 263 (3.4) 
  Cancer 318 (4.2) 
  Immunodeficiency 270 (3.5) 
  Immunosuppression 297 (3.9) 
  Chronic renal disease 169 (2.2) 
  Chronic anemia 102 (1.3) 
  Hemoglobinopathy 256 (3.3) 
  Chronic acetylsalicylic acid therapy 16 (0.2) 
  Residence in institutional setting and other chronic care facilities 28 (0.3) 
  Neurologic or neurodevelopment disorders 855 (11.3) 
  Pregnancy 2 (0.0) 
  Obesity 41 (0.5) 
  Prematurity (if <1 y old) 140 (1.8) 
 Duration of symptoms before admission at IMPACT hospital, d  
  Mean ± SD 3.68 ± 3.10 
  Median (IQR) 3 (2–5) 
 Presence of radiographically confirmed pneumonia 2212 (29.3) 
 Presence of a laboratory-confirmed bacterial infection 508 (6.7) 
 Coreceipt of antibiotic therapy 5494 (72.8) 
 Need for intensive care 1252 (16.5) 
 Need for respiratory supportd 795 (10.5) 
 Hospital LoS, d  
  Mean ± SD 4.81 ± 7.51 
  Median (IQR) 3 (2–5) 
 Outcome at hospital discharge  
  Survived 7501 (99.4) 
  Died of reported influenza infection 42 (0.5) 
  Died of other cause 2 (0) 

DFA, direct fluorescent antibody test; EIA, enzyme immunoassay test; PCR, polymerase chain reaction.

a

Admitted when the national testing positivity proportion was at least 15%, as reported by the Public Health Agency of Canada.

b

Availability of a local guideline at the admitting IMPACT center for the season of the admission.

c

1053 children were <6 mo of age, and therefore not eligible to receive the influenza vaccine.

d

Includes CPAP, BiPAP, conventional and high-frequency ventilation, and ECMO.

The median duration of symptoms before presentation was 3 days (IQR: 2–5). At least 1 chronic health condition was found in 3434 (45.4%) children. Seventy-two percent received antibiotics; laboratory confirmed bacterial infections (positive tissue, aspirate, blood, cerebrospinal fluid, and/or urine culture) were noted in only 508 (6.7%) patients. ICU admission occurred in 1252 (16.5%) cases, and 795 (63.5%) of these required respiratory support. Forty-two patients (0.5%) died from influenza-related complications.

Overall, 3122 patients (41.3%) were prescribed antiviral agents; 3118 (99.9%) received oseltamivir. Antiviral use increased from 19.9% in the 2010–2011 season to 59.6% in 2018–2019 (P for trend = .001) (Fig 2). Prescribing varied widely across sites (range 10.2% to 81.1%). Almost all cases (93%) had influenza test results available within 48 hours of admission. Among patients who received antiviral agents, 2551 (81.7%) received them within 2 days of admission (Supplemental Fig 5). The proportion treated decreased with time from symptom onset to admission (<2 days, 48.3%; 2–4 days, 44%; >4 days, 35%). Antiviral use increased with age, from 32% in those 0 to 5 months old to 48.6% in those >5 years old. Children with ≥1 chronic health condition were more likely to receive antiviral agents (52.7% vs 36.7%; P < .001); this was also seen across most individual medical conditions (Table 2). Median time to treatment after admission did not differ significantly between those with or without an underlying chronic health condition (2 ± 1.32 vs 2 ± 1.02 days; P = .06). Antiviral prescribing increased similarly over time for patients with or without a chronic health condition (Fig 3) and across age groups (Fig 4). Prescription of antibiotics was more frequent in children who received antiviral agents (77.3% vs 69.6%; P < .001). Patients who received antiviral agents had increased markers of disease severity (median hospital LoS, 4 vs 2 days, P < .001; ICU admission, 27.8% vs 8.68%, P < .001; median ICU LoS, 3 vs 2 days, P < .001; influenza-related mortality, 0.9% vs 0.2%, P < .001).

FIGURE 2

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–1011 to 2018–2019 (n = 7545).

FIGURE 2

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–1011 to 2018–2019 (n = 7545).

Close modal
FIGURE 3

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–2011 to 2018–2019 (n = 7545), stratified by the presence/absence of an underlying chronic health condition.

FIGURE 3

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–2011 to 2018–2019 (n = 7545), stratified by the presence/absence of an underlying chronic health condition.

Close modal
FIGURE 4

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–2011 to 2018–2019 (n = 7545), stratified by age group.

FIGURE 4

Percentage of patients treated with antiviral agents across 12 Canadian IMPACT pediatric hospital centers by influenza season, 2010–2011 to 2018–2019 (n = 7545), stratified by age group.

Close modal
TABLE 2

Factors Associated With Antiviral Use Among Children Hospitalized With Influenza Across 12 Canadian IMPACT Pediatric Hospital Centers, 2010–2011 to 2018–2019 (n = 7545)

Exposure VariableReceived Antiviral Agents (n = 3122), n (%)Did Not Receive Antiviral Agents (n = 4423), n (%)OR (95% CI)aORa (95% CI)
Demographic data     
 Age,b    
  Mean ± SD 4.96 ± 4.38 3.83 ± 3.83 P < .05 1.04 (1.02–1.05) 
  Median (IQR) 3.66 (1.41–7.41) 2.58 (0.91–5.75)   
 Age group     
  0–5 mo 337 (32.0) 716 (68.0) Reference NIc 
  6–23 mo 674 (36.6) 1167 (63.4) 1.22 (1.04–1.44) NIc 
  24–59 mo 870 (41.4) 1230 (58.6) 1.50 (1.28–1.75) NIc 
  ≥5 y 1241 (48.6) 1310 (51.4) 2.01 (1.73–2.34) NIc 
 Sex     
  Male 1783 (41.1) 2549 (58.9) 0.97 (0.89–1.07) 0.94 (0.83–1.06) 
 Influenza season     
  2010–2011 127 (20.0) 509 (80.0) Reference Reference 
  2011–2012 102 (18.2) 459 (81.8) 0.89 (0.66–1.18) 1.27 (0.89–1.81) 
  2012–2013 230 (27.5) 606 (72.5) 1.52 (1.18–1.94) 1.79 (1.32–2.43) 
  2013–2014 249 (36.9) 426 (63.1) 2.34 (1.82–3.00) 2.97 (2.15–4.10) 
  2014–2015 246 (36.2) 434 (63.8) 2.27 (1.77–2.91) 2.76 (2.00–3.81) 
  2015–2016 597 (46.0) 701 (54.0) 3.41 (2.73–4.26) 4.46 (3.27–6.07) 
  2016–2017 271 (48.1) 292 (51.9) 3.71 (2.88–4.80) 4.34 (3.07–6.13) 
  2017–2018 534 (52.8) 477 (47.2) 4.48 (3.56–5.64) 5.83 (4.24–8.01) 
  2018–2019 766 (59.6) 519 (40.4) 5.91 (4.72–7.40) 9.18 (6.70–12.57) 
 Timing of admission within influenza season     
  Admitted during “peak” seasond 2249 (46.4) 2596 (53.6) 1.81 (1.64–2.00) 1.37 (1.19–1.58) 
 Availability of a local influenza antiviral treatment guidelinee     
  Treatment guideline available 2097 (52.7) 1881 (47.3) 2.76 (2.51–3.04) 1.54 (1.17–2.02) 
Laboratory data     
 Influenza virus type     
  A 2363 (44.2) 2982 (55.8) Reference Reference 
  B 746 (34.4) 1419 (65.5) 0.66 (0.59–0.73) 0.81 (0.70–0.94) 
  Both A and B 13 (37.1) 22 (62.9) 0.74 (0.37–1.48) 0.65 (0.25–1.68) 
 Timing of availability of report of laboratory confirmation of influenza infection     
  Result available before IMPACT center admission 295 (37.7) 487 (62.3) 1.04 (0.82–1.32) 2.67 (1.97–3.61) 
  Result available on first day of admission 1972 (42.3) 2688 (57.7) 1.26 (1.03–1.53) 2.63 (2.06–3.37) 
  Result available within second day of admission 682 (41.8) 950 (58.2) 1.23 (1.00–1.52) 1.78 (1.37–2.31) 
  Result available after second day of admission 173 (36.7) 298 (63.3) Reference Reference 
Clinical data     
 Presence of underlying chronic health condition     
  Chronic heart disorders 205 (56.2) 160 (43.8) 1.87 (1.51–2.31) 1.82 (1.39–2.38) 
  Chronic lung disorders 709 (50.5) 694 (49.5) 1.57 (1.40–1.77) 1.51 (1.30–1.77) 
  Diabetes mellitus or other metabolic disorders 121 (46.0) 142 (54.0) 1.21 (0.94–1.55) NIf 
  Cancer 197 (61.9) 121 (38.1) 2.39 (1.90–3.01) 4.81 (3.61–6.40) 
  Immunodeficiency 186 (68.9) 84 (31.1) 3.27 (2.51–4.25) 2.74 (1.98–3.80) 
  Immunosuppression 212 (71.4) 85 (28.6) 3.71 (2.87–4.80) 3.52 (2.54–4.86) 
  Chronic renal disease 101 (59.7) 68 (40.3) 2.14 (1.56–2.92) 1.50 (1.01–2.21) 
  Chronic anemia 50 (49.0) 52 (51.0) 1.36 (0.92–2.02) NIf 
  Hemoglobinopathy 147 (57.4) 109 (42.6) 1.95 (1.51–2.51) 2.33 (1.70–3.20) 
  Chronic acetylsalicylic acid therapy 3 (18.7) 13 (81.3) 0.32 (0.09–1.14) NIf 
  Residence in institutional setting and other chronic care facilities 17 (60.7) 11 (39.3) 2.19 (1.02–4.69) 2.14 (0.84–5.45) 
  Neurologic or neurodevelopment disorders 482 (56.4) 373 (43.6) 1.98 (1.71–2.28) 1.22 (1.01–1.47) 
  Pregnancy 1 (50.0) 1 (50.0) 1.41 (0.08–22.66) NIf 
  Obesity 17 (41.4) 24 (58.6) 1.00 (0.53–1.87) NIf 
  Prematurity (if <1 y old) 62 (44.2) 78 (55.8) 1.12 (0.80–1.58) NIf 
 Duration of symptoms before admission at IMPACT hospital,b    
  Mean ± SD 3.34 ± 3.04 3.92 ± 3.11 P < .05 0.92 (0.90–0.94) 
  Median (IQR) 3 (1–5) 3 (2–5)   
  Presence of radiographically confirmed pneumonia 1074 (48.5) 1138 (51.5) 1.51 (1.36–1.67) 1.39 (1.20–1.60) 
  Presence of a laboratory-confirmed bacterial infection 228 (44.9) 280 (55.1) 1.16 (0.97–1.39) NIf 
  Coreceipt of antibiotic therapy 2413 (43.9) 3081 (56.1) 1.48 (1.33–1.64) 1.51 (1.30–1.76) 
  Need for intensive care 868 (69.3) 384 (30.7) 4.05 (3.55–4.61) 3.62 (2.88–4.56) 
  Need for respiratory supportg 559 (70.3) 236 (29.7) 3.86 (3.29–4.54) 1.57 (1.19–2.08) 
 Hospital LoS,b    
  Mean ± SD 6.41 ± 9.69 3.68 ± 5.18 P < .05 NIh 
  Median (IQR) 4 (2–7) 2 (1–4)   
Outcome at hospital discharge     
 Survived 3903 (52.0) 4408 (48.0) Reference NIh 
 Died of reported influenza infection 29 (69.0) 13 (31.0) 3.17 (1.65–6.12) NIh 
 Died of other cause 0 (0.0) 2 (100.0) NA NIh 
Exposure VariableReceived Antiviral Agents (n = 3122), n (%)Did Not Receive Antiviral Agents (n = 4423), n (%)OR (95% CI)aORa (95% CI)
Demographic data     
 Age,b    
  Mean ± SD 4.96 ± 4.38 3.83 ± 3.83 P < .05 1.04 (1.02–1.05) 
  Median (IQR) 3.66 (1.41–7.41) 2.58 (0.91–5.75)   
 Age group     
  0–5 mo 337 (32.0) 716 (68.0) Reference NIc 
  6–23 mo 674 (36.6) 1167 (63.4) 1.22 (1.04–1.44) NIc 
  24–59 mo 870 (41.4) 1230 (58.6) 1.50 (1.28–1.75) NIc 
  ≥5 y 1241 (48.6) 1310 (51.4) 2.01 (1.73–2.34) NIc 
 Sex     
  Male 1783 (41.1) 2549 (58.9) 0.97 (0.89–1.07) 0.94 (0.83–1.06) 
 Influenza season     
  2010–2011 127 (20.0) 509 (80.0) Reference Reference 
  2011–2012 102 (18.2) 459 (81.8) 0.89 (0.66–1.18) 1.27 (0.89–1.81) 
  2012–2013 230 (27.5) 606 (72.5) 1.52 (1.18–1.94) 1.79 (1.32–2.43) 
  2013–2014 249 (36.9) 426 (63.1) 2.34 (1.82–3.00) 2.97 (2.15–4.10) 
  2014–2015 246 (36.2) 434 (63.8) 2.27 (1.77–2.91) 2.76 (2.00–3.81) 
  2015–2016 597 (46.0) 701 (54.0) 3.41 (2.73–4.26) 4.46 (3.27–6.07) 
  2016–2017 271 (48.1) 292 (51.9) 3.71 (2.88–4.80) 4.34 (3.07–6.13) 
  2017–2018 534 (52.8) 477 (47.2) 4.48 (3.56–5.64) 5.83 (4.24–8.01) 
  2018–2019 766 (59.6) 519 (40.4) 5.91 (4.72–7.40) 9.18 (6.70–12.57) 
 Timing of admission within influenza season     
  Admitted during “peak” seasond 2249 (46.4) 2596 (53.6) 1.81 (1.64–2.00) 1.37 (1.19–1.58) 
 Availability of a local influenza antiviral treatment guidelinee     
  Treatment guideline available 2097 (52.7) 1881 (47.3) 2.76 (2.51–3.04) 1.54 (1.17–2.02) 
Laboratory data     
 Influenza virus type     
  A 2363 (44.2) 2982 (55.8) Reference Reference 
  B 746 (34.4) 1419 (65.5) 0.66 (0.59–0.73) 0.81 (0.70–0.94) 
  Both A and B 13 (37.1) 22 (62.9) 0.74 (0.37–1.48) 0.65 (0.25–1.68) 
 Timing of availability of report of laboratory confirmation of influenza infection     
  Result available before IMPACT center admission 295 (37.7) 487 (62.3) 1.04 (0.82–1.32) 2.67 (1.97–3.61) 
  Result available on first day of admission 1972 (42.3) 2688 (57.7) 1.26 (1.03–1.53) 2.63 (2.06–3.37) 
  Result available within second day of admission 682 (41.8) 950 (58.2) 1.23 (1.00–1.52) 1.78 (1.37–2.31) 
  Result available after second day of admission 173 (36.7) 298 (63.3) Reference Reference 
Clinical data     
 Presence of underlying chronic health condition     
  Chronic heart disorders 205 (56.2) 160 (43.8) 1.87 (1.51–2.31) 1.82 (1.39–2.38) 
  Chronic lung disorders 709 (50.5) 694 (49.5) 1.57 (1.40–1.77) 1.51 (1.30–1.77) 
  Diabetes mellitus or other metabolic disorders 121 (46.0) 142 (54.0) 1.21 (0.94–1.55) NIf 
  Cancer 197 (61.9) 121 (38.1) 2.39 (1.90–3.01) 4.81 (3.61–6.40) 
  Immunodeficiency 186 (68.9) 84 (31.1) 3.27 (2.51–4.25) 2.74 (1.98–3.80) 
  Immunosuppression 212 (71.4) 85 (28.6) 3.71 (2.87–4.80) 3.52 (2.54–4.86) 
  Chronic renal disease 101 (59.7) 68 (40.3) 2.14 (1.56–2.92) 1.50 (1.01–2.21) 
  Chronic anemia 50 (49.0) 52 (51.0) 1.36 (0.92–2.02) NIf 
  Hemoglobinopathy 147 (57.4) 109 (42.6) 1.95 (1.51–2.51) 2.33 (1.70–3.20) 
  Chronic acetylsalicylic acid therapy 3 (18.7) 13 (81.3) 0.32 (0.09–1.14) NIf 
  Residence in institutional setting and other chronic care facilities 17 (60.7) 11 (39.3) 2.19 (1.02–4.69) 2.14 (0.84–5.45) 
  Neurologic or neurodevelopment disorders 482 (56.4) 373 (43.6) 1.98 (1.71–2.28) 1.22 (1.01–1.47) 
  Pregnancy 1 (50.0) 1 (50.0) 1.41 (0.08–22.66) NIf 
  Obesity 17 (41.4) 24 (58.6) 1.00 (0.53–1.87) NIf 
  Prematurity (if <1 y old) 62 (44.2) 78 (55.8) 1.12 (0.80–1.58) NIf 
 Duration of symptoms before admission at IMPACT hospital,b    
  Mean ± SD 3.34 ± 3.04 3.92 ± 3.11 P < .05 0.92 (0.90–0.94) 
  Median (IQR) 3 (1–5) 3 (2–5)   
  Presence of radiographically confirmed pneumonia 1074 (48.5) 1138 (51.5) 1.51 (1.36–1.67) 1.39 (1.20–1.60) 
  Presence of a laboratory-confirmed bacterial infection 228 (44.9) 280 (55.1) 1.16 (0.97–1.39) NIf 
  Coreceipt of antibiotic therapy 2413 (43.9) 3081 (56.1) 1.48 (1.33–1.64) 1.51 (1.30–1.76) 
  Need for intensive care 868 (69.3) 384 (30.7) 4.05 (3.55–4.61) 3.62 (2.88–4.56) 
  Need for respiratory supportg 559 (70.3) 236 (29.7) 3.86 (3.29–4.54) 1.57 (1.19–2.08) 
 Hospital LoS,b    
  Mean ± SD 6.41 ± 9.69 3.68 ± 5.18 P < .05 NIh 
  Median (IQR) 4 (2–7) 2 (1–4)   
Outcome at hospital discharge     
 Survived 3903 (52.0) 4408 (48.0) Reference NIh 
 Died of reported influenza infection 29 (69.0) 13 (31.0) 3.17 (1.65–6.12) NIh 
 Died of other cause 0 (0.0) 2 (100.0) NA NIh 

Data are n (row %) unless otherwise indicated. NA, not applicable; NI, not included.

a

Multivariable logistic regression model included age, sex, influenza season, IMPACT center, timing of admission relative to peak influenza activity within season, availability of local guideline, presence of underlying chronic health conditions shown above, influenza virus type, timing of availability of influenza laboratory test result relative to hospital admission, duration of symptoms before admission, presence of radiographically confirmed pneumonia, coreceipt of antibiotic therapy, need for ICU admission and respiratory support. Odd ratios for IMPACT center are not shown in the table above.

b

Medians compared by using Wilcoxon rank test.

c

Age treated as a continuous variable in the multivariable logistic regression model.

d

Admitted when the national testing positivity rate was at least 15%, as reported by the Public Health Agency of Canada.

e

Availability of a local guideline at the admitting IMPACT center for the season of the admission.

f

Not included in the multivariable model because not significantly associated in univariable analysis.

g

Includes CPAP, BiPAP, conventional and high-frequency ventilation, and ECMO.

h

Not included in the multivariable model because these variables necessarily occurred after antiviral treatment decisions (ie, at the end of the hospitalization).

Multivariable logistic regression identified increased odds of receipt of antiviral therapy with advancing age (aOR 1.04 [95% CI, 1.02–1.05]), more recent season (highest aOR 9.18 [6.70–12.57] for 2018–2019), admission during peak season (aOR 1.37 [1.19–1.58]), local treatment guideline availability during that season at that center (aOR 1.54 [1.17–2.02]), timing of availability of laboratory confirmation of infection (highest aOR 2.67 [1.97–3.61] for result availability before admission), radiographic pneumonia (aOR 1.39 [1.20–1.60]), coreceipt of antibiotic therapy (aOR 1.51 [1.30–1.76]), ICU admission (aOR 3.62 [2.88–4.56]), and respiratory support (aOR 1.57 [1.19–2.08]). Among chronic health conditions, cancer was most strongly associated with antiviral therapy, (aOR 4.81 [3.61–6.40]). Influenza B virus infection demonstrated lower odds (aOR 0.81 [0.70–0.94]) of receiving antiviral therapy. In a model restricted to children that received antiviral agents, early (during first 2 days of admission) initiation of treatment was strongly associated with timing of availability of laboratory confirmation of infection and inconsistently associated with more recent seasons (Supplemental Table 3).

North American influenza clinical practice guidelines, including those of the Infectious Diseases Society of America,18  American Academy of Pediatrics,32  and the Canadian Pediatric Society,33  recommend antiviral treatment of all children hospitalized with influenza. Despite this, our country-wide hospital-based active surveillance study comprising >7500 pediatric admissions for laboratory confirmed influenza during 9 postpandemic seasons found that the overall use of antiviral agents was only 41%. Prescribing increased over time, demonstrated wide variation across participating centers, and was associated with the timing of admission relative to peak influenza circulation, timing of availability of influenza test results, and availability of local influenza treatment guidelines. Furthermore, we identified patient-level factors associated with antiviral use which included older age, presence of underlying chronic health conditions that are risk factors for severe illness, infecting virus type, radiographic pneumonia, coreceipt of antibiotics, and need for intensive care and respiratory support.

The use of neuraminidase inhibitors in adults and children in randomized placebo-controlled trials of the treatment of influenza in outpatients has been demonstrated to reduce duration of illness and viral shedding, and risk of influenza-associated complications.12,34  The evidence base for antiviral treatment of influenza in the hospital setting is weaker. The only published trial in which researchers evaluated neuraminidase inhibitors among children admitted with influenza was terminated early with only 21% of the targeted population enrolled.16  However, mounting evidence from observational studies in hospitalized children and adults suggests clinical benefit (including decreased LoS, health care costs, ICU admission, and mortality) of treatment with neuraminidase inhibitors, especially in high-risk populations and when initiated early (within 48 hours of illness onset or of hospitalization).21,23,35  Despite this, our study and others show that a substantial number of hospitalized children with influenza do not receive antiviral treatment. In a retrospective cohort of ∼36 000 children hospitalized with influenza during 2007–2015 in the United States, 69% received antiviral treatment; 30% of children at high risk were not treated.27  Among influenza hospitalizations (adults and children) in Ontario from 2004–2005 to 2013–2014, the percentage treated increased from 29% before the 2009 pandemic to 74% during the pandemic, and 55% to 65% thereafter.36  Similarly, we found that use rates increased over time, climbing to almost 60% during 2018–2019; this trend was observed across centers and patient subpopulations. Antiviral use among children most likely to benefit from treatment, those with chronic health conditions, more than doubled over the study period to nearly 70% in 2018–2019.

Guidelines recommend initiation of antiviral treatment within 48 hours of onset of illness in outpatients, because optimal benefits are obtained with early treatment.17,18,37  In this study, only a quarter of children presented within this time interval; delayed presentation (ie, >48 hours) may have led some clinicians not to use antiviral agents. However, antiviral agents are recommended for all patients hospitalized for influenza, even if treatment is started >48 hours after onset of illness.17,18,37  Like others, we observed that likelihood of antiviral use increased with rapidity of influenza testing38 ; moreover, prompt availability of test results was strongly associated with earlier initiation of antiviral therapy. These findings suggest that integrating novel rapid and accurate molecular assays to emergency department diagnostic algorithms, especially for at-risk children being hospitalized, would facilitate early diagnosis and treatment.39  Furthermore, although >80% of children treated with antiviral agents received them within 48 hours of admission, only 42% received them on the day of admission. Given the benefits of earlier treatment, antiviral agents should be initiated empirically for children hospitalized with suspected influenza and not delayed while awaiting the results of laboratory testing. Additionally, considering that only a quarter of patients in our study presented to an IMPACT hospital within 48 hours of symptom onset, primary care clinicians of at-risk children should counsel parents to seek care early if their child develops influenza-like symptoms.

We observed wide variation of antiviral use across IMPACT centers (range, 10.2% to 81.1%). Similarly, Stockmann et al27  found that antiviral use ranged from 42% to 90% across 46 freestanding US children’s hospitals. Although most IMPACT centers had local antiviral guidelines, such guidelines were not always in place during earlier seasons. We found that the availability of local treatment guidelines was significantly associated with antiviral use, strengthening the call for local treatment protocols to improve adherence to national recommendations. Furthermore, quality improvement methods such as awareness modules, biweekly flyers, failure tracking, and similar approaches have also been shown to increase antiviral use among children hospitalized with influenza.40 

Additional hospital-level factors not evaluated in this study, such as the population served, referral patterns, and the presence of an antimicrobial stewardship program, may also influence local prescribing cultures. Moreover, recommendations for treatment of children hospitalized with influenza are based only on observational data. Randomized clinical trials of neuraminidase inhibitors among outpatients have shown modest benefits but with accompanying risk of adverse events, primarily gastro-intestinal side-effects, which may be transient and mitigated when oral oseltamivir is taken along with food.41  However, the perception of a questionable risk/benefit profile may lead to hesitancy to prescribe antiviral agents among some clinicians.27,42 

It is concerning that antibiotics were used almost twice as frequently as antiviral agents in this cohort of children admitted with laboratory-confirmed influenza. Although the IMPACT data set is limited in its ability to provide antibiotic treatment details (spectrum of activity; timing and duration of use; complete versus incomplete courses), only 6.7% of children had a laboratory-confirmed concomitant or secondary bacterial infection and we presume that most physicians were empirically treating pneumonia and/or acute otitis media, which rarely have a laboratory-confirmed etiology. Our findings are similar to those from other studies evaluating antimicrobial use in hospitalized influenza cases36,43  and highlight the difficulty clinicians face distinguishing bacterial versus viral causes of severe lower respiratory tract infections because of overlap in presentations, risk of bacterial superinfection, and challenges in obtaining samples from the lower respiratory tract for microbiologic testing.44,45  Multifaceted interventions using combinations of education, rapid viral testing, biomarkers, and audit with feedback may be needed to reduce antibiotic overuse in influenza-associated hospitalizations.4648 

We found that older age was associated with antiviral use. More “classic” presentation among older children,49  lack of approval of oseltamivir use by Health Canada in infants <12 months of age, and evolving guidance on oseltamivir use in younger children43  could be reasons for antiviral use increasing with older age. Reports of neurotoxicity from animal models when oseltamivir was used in the infant rats50  had raised concerns for its use in young children; however, no such neurotoxicity has been observed in human studies.17  Neuraminidase inhibitors are not currently authorized in Canada for the treatment of seasonal influenza in infants aged younger than 1 year, and oseltamivir use in infants is recommended on a case-by-case basis, based on illness severity.17 

The presence of chronic conditions known to be risk factors for complicated infection were significantly associated with antiviral use in a multivariable logistic regression model. Children with these comorbidities may present more severe disease, which may partly explain greater antiviral use in this population; nevertheless, after adjustment for requirement for ICU and respiratory support, these conditions remained associated with antiviral prescription. This suggests that clinicians recognize that these children are at greater risk of severe outcomes and potentially benefit most from antiviral treatment. However, earlier treatment was not observed in patients with comorbidities, reinforcing the need for rapid diagnostics or prompt empirical therapy while awaiting influenza test results for at-risk children.

Our study is limited by its retrospective design. Although case reporting was conducted prospectively by nurse monitors using a standardized reporting form, data were collected from the medical chart and could not capture clinical decision-making processes. Data regarding the receipt of influenza vaccine and ethnicity were frequently missing. Furthermore, although site investigators are questioned annually on testing practices, we cannot ascertain whether all children admitted with acute respiratory infection received influenza tests. Clinical data were limited regarding the timing of appearance of specific signs or symptoms during the course of illness. Moreover, although we were not able to include or control for measures of severity at presentation or admission to hospital, we attempted to overcome this limitation by including need for ICU admission and respiratory support as proxies for disease severity in our multivariable model. Finally, the external validity of this study is limited by the fact that IMPACT conducts surveillance in tertiary care centers in Canada; the management of pediatric influenza associated admissions in community hospitals may be different. Despite these limitations, our study is strengthened by its representation of a nationwide active surveillance cohort of children hospitalized with laboratory confirmed influenza admitted over almost a decade, and it is one of the largest such studies in the postpandemic period.

Antiviral medications are underused among children hospitalized for influenza in Canadian pediatric hospitals. Moreover, nearly half of children with chronic health conditions placing them at risk for severe outcomes were not treated. However, an increase in use overall, and in children at high risk, was observed over time. Despite national clinical practice guidelines, there was wide variation in antiviral prescribing practices across the country, and a high rate of antibiotic use was noted. We also identified patient and hospital-level characteristics independently associated with antiviral prescribing. Prompt availability of influenza test results was strongly associated with earlier initiation of antiviral therapy. Taken together, these findings call for multifaceted interventions to strengthen adherence to local and national influenza treatment guidelines and antimicrobial stewardship practices.

We acknowledge the IMPACT nurse monitors, Annick Audet (IMPACT Nurse Monitor Liaison), the staff of the data center, including Kim Marty (Data Manager) and Jennifer Mark (Data Research Assistant), and Melanie Laffin Thibodeau (Manager, Surveillance, Canadian Paediatric Society).

Investigators and centers participating in this IMPACT project included: Natalie Bridger, Cheryl Foo Janeway Children’s Health & Rehabilitation Centre, St. John’s, NL; Scott A. Halperin, Karina Top, IWK Health Centre, Halifax, NS; Roseline Thibeault, Centre Mere-Enfant de Quebec, CHUL, Quebec City, QC; Dorothy L. Moore, Marie-Astrid Lefebvre, Jesse Papenburg, The Montreal Children’s Hospital, Montreal, QC; Marc Lebel, Centre hospitalier universitaire Sainte-Justine, Montreal, QC; Nicole Le Saux, Children’s Hospital of Eastern Ontario, Ottawa, ON; Dat Tran, Shaun K. Morris, The Hospital for Sick Children, Toronto, ON; Joanne Embree, Winnipeg Children’s Hospital, Winnipeg, MB; Ben Tan, Athena McConnell, Rupeena Purewal, Royal University Hospital, Saskatoon, SK; Taj Jadavji, Cora Constantinescu, Alberta Children’s Hospital, Calgary, AB; Wendy Vaudry, Catherine Burton, Stollery Children’s Hospital, Edmonton, AB; Julie Bettinger, Laura Sauvé, Manish Sadarangani, BC Children’s Hospital, Vancouver, BC.

We thank Chelsea Caya and Ian Schiller (Research Institute of the McGill University Health Centre) for helpful feedback on statistical programming.

Dr Mehta participated in the design of the study, conducted the analysis, and drafted the initial manuscript; Drs Vaudry, Bettinger, Halperin, Jadavji, Sadarangani, Bancej, and Morris contributed to study conception and design and reviewed and revised the manuscript; Dr Dendukuri contributed to the study design, oversaw the analysis, and reviewed and revised the manuscript; Dr Papenburg conceptualized and designed the study, oversaw the analysis, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: This surveillance activity is conducted as part of the Canadian Immunization Monitoring Program Active (IMPACT), a national surveillance initiative managed by the Canadian Pediatric Society and conducted by the IMPACT network of pediatric investigators on behalf of the Public Health Agency of Canada’s Center for Immunization and Respiratory Infectious Diseases. Public Health Agency of Canada provided input into the study design and was involved in the review and approval of the manuscript.

     
  • AIC

    Akaike Information Criteria

  •  
  • aOR

    adjusted odds ratio

  •  
  • BiPAP

    bilevel positive airway pressure

  •  
  • CI

    confidence interval

  •  
  • CPAP

    continuous positive airway pressure

  •  
  • ECMO

    extracorporeal membrane oxygenation

  •  
  • IMPACT

    Canadian Immunization Monitoring Program, ACTive

  •  
  • IQR

    interquartile range

  •  
  • LoS

    length of stay

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Papenburg reports grants from MedImmune, grants from Sanofi Pasteur, grants and personal fees from Seegene, and grants and personal fees from AbbVie, outside the submitted work. Dr Sadarangari has been an investigator on projects funded by GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo, and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. Dr Halperin has been an investigator on projects funded by Sanofi-Pasteur, GlaxoSmithKline, and Seqirus.

Supplementary data