1 BACKGROUND

Seasonal influenza is a leading cause of pediatric morbidity and mortality globally.1 Young children have the highest risk of influenza-associated hospitalization.2 Children with medical comorbidities including neurological, cardiac, metabolic, and hematological conditions are known to be at greater risk for severe influenza disease compared with otherwise healthy children of similar ages.3

Seasonal influenza hospitalizations have been captured through the InFluenza Complications Alert Network (FluCAN) in Australia since 2009.4 Two tertiary pediatric hospitals from the Paediatric Active Enhanced Diseases Surveillance Network (PAEDS) contributed data from 20115, 6 expanding in 2017 with recruitment from pediatric tertiary hospitals in other states.7

Quadrivalent inactivated influenza vaccination is recommend for all Australian children aged ≥6 months.8 Live-attenuated influenza vaccines are not available in Australia. Influenza vaccination was funded in 2010 for children aged ≥6 months old with medical comorbidities through the National Immunization Program (NIP) and Aboriginal and/or Torres Strait Islander children (herein respectfully referred to as Aboriginal) aged 6 months to <5 years in 2015.8 Western Australia has provided state-based funding of influenza vaccination for children aged 6 months to <5 years old since 2008.9 All other Australian states and the Australian Capital Territory funded influenza vaccination for all children aged 6 months to <5 years old from 2018. Influenza vaccination for this age group was nationally funded through the NIP in 2020.8, 10

In this study, we describe the epidemiology and clinical outcomes of seasonal influenza hospitalizations in Australian children (2010–2019), focusing on children with medical comorbidities. Vaccine effectiveness (VE) against influenza-confirmed hospitalization was evaluated using the modified incidence density test-negative design.11 The impact of comorbidities on severe influenza hospitalization outcomes, vaccine coverage, and VE in Australian children is explored. These data are critical to inform the design of programs to improve vaccine coverage in those at greatest risk.

2 METHODS 2.1 Study design

Hospitalized children with an acute respiratory illness (ARI), testing positive for influenza, were enrolled from PAEDS-FluCAN sites (2010–2019: see supporting information Table S1). Cases were enrolled during each southern hemisphere influenza season from 2010 to 2019 (April to October, inclusive). A child was eligible for enrolment as a case if they were aged ≤16 years, hospitalized with an ARI, and tested positive for influenza type A and/or B. A hospitalized case of ARI was defined by inpatient admission of the patient excluding emergency department only care with the presence of new respiratory symptoms including shortness of breath, cough, and/or rhinorrhea with or without fever. Nosocomial influenza infections with positive influenza test result were included as hospitalized ARIs.

Cases were diagnosed using respiratory specimens tested with specific influenza assays, mostly nucleic acid testing, with a small number (<3% of total cases; all tested between 2011 and 2013) diagnosed by immunofluorescence or rapid antigen testing. Influenza A and B testing was performed on all participants; however, subtyping was not routinely performed. Patients were eligible for enrolment if admitted as inpatients to a PAEDS-FluCAN site excluding admission to the emergency department alone. Cases were classified as a nosocomial influenza infection if their first positive influenza test was dated ≥3-day postadmission. Contemporaneously tested hospitalized children who met enrolment criteria but tested negative for influenza A and/or B were enrolled as influenza-negative controls.

2.2 Assessing risk factors and outcomes

Patient demographics, age at time of hospital admission, comorbidities, clinical history, treatments, therapies, and hospitalization outcomes were collected. Comorbidities included chronic cardiac disease, chronic respiratory disease, neurological conditions, immunosuppression, malignancies, diabetes, hepatic disease, renal disease, genetic comorbidities, inborn errors of metabolism, obesity, and long-term aspirin therapy.12 Immunosuppression and malignancies were combined as a single variable (immunosuppression and/or malignancy), whereas long-term aspirin therapy and inborn errors of metabolism were grouped (other comorbidities) due to low case numbers.

Descriptive analyses of demographics, clinical characteristics, and outcomes were performed on children testing positive for influenza with grouping by influenza strains, presence of comorbidities, and comorbidity type. Categorical data were described using proportions and compared using chi-square (χ2) tests. Continuous data were described using medians and interquartile ranges with comparisons performed using Mann–Whitney U tests. Multivariable logistic regression models were used to determine the odds of intensive care unit (ICU) admission, mechanical ventilation, and mortality adjusted by age group (6–11 months, 12–23 months, 2–4 years, and ≥5 years), comorbidity, sex, Aboriginal status, antiviral treatment, and influenza type. Negative binomial regression models used the same independent variables to evaluate the impact on length of hospitalization and length of ICU stay. Variables within these models were grouped by Australian state as well as month and year of case admission.

2.3 Estimating vaccine coverage and effectiveness

Vaccine coverage and effectiveness estimates were undertaken using both influenza-positive cases and test-negative controls. Controls were patients ≤16 years old admitted to PAEDS-FluCAN hospitals with ARI but test-negative for influenza. Controls were randomly chosen as the most time-proximate influenza test-negative subjects at each site.6, 7 Influenza vaccination status was obtained through parental reporting and confirmed through the Australian Immunization Register (AIR).13 An immunized child was defined by receipt of at least one dose of a licensed influenza vaccine in the same calendar year and prior to date of hospital admissions. Cases and controls aged <6 months at admission, missing vaccination status, with nosocomial infection, or multiple influenza strains were removed from vaccine coverage and VE analyses (VE analysis cohort; supporting information Figure S1).

A modified incidence density test-negative design was used to determine VE. VE was estimated as 1 minus the adjusted odds ratio (aOR) of vaccination in influenza test-positive cases compared with test-negative controls.11 Conditional logistic regression models using influenza case status as the dependent outcome were constructed for influenza vaccination. The model was adjusted for potential confounders including age at time of admission, Aboriginal status, and comorbidities and was grouped by state, month, and year of admission. All analyses were performed using Stata 16®. Ethics approval was obtained from Monash University, Australia, with reciprocal ethics and governance approvals at each site.

3 RESULTS 3.1 Demographics and clinical outcomes

From 2010 to 2019, 6057 influenza-confirmed hospitalizations were evaluated from 20 hospital sites (supporting information Figure S1 and supporting information Table S1). The median age was 3.6 years (interquartile range [IQR]: 1.2; 7.2), 55.7% were male, and 481 (7.9%) identified as Aboriginal (Table 1). Influenza A was detected in 68.7% of cases (n = 4162) and Influenza B in 30.6% (n = 1855); 40 cases (0.7%) were positive with more than one influenza type/subtype. Most influenza A infections were not subtyped (n = 2866, 68.9%); however, when subtyped, influenza A/H1N1 (n = 647, 15.5%) and A/H3N2 (n = 649, 15.6%) were seen in near equal proportions. Influenza type B cases were significantly older than influenza type A cases (median age: 5.3 vs. 3.0 years, p < 0.001). Nosocomial influenza infection was identified in 395 cases (6.5%).

TABLE 1. Hospitalized influenza-confirmed cases: Demographics, clinical factors, comorbidities, outcomes, and treatments Variable Influenza type, no. (%) of children A/H1N1 (n = 647) A/H3N2 (n = 649) A/unknown (n = 2866) B (n = 1855) Multiple types (n = 40) Total (n = 6057) Demographics Male 374 (57.8%) 344 (53.0%) 1581 (55.2%) 1050 (56.7%) 23 (57.5%) 3372 (55.7%) Aboriginal 42 (6.5%) 78 (12.0%) 217 (7.6%) 142 (7.7%) 2 (5.0%) 481 (7.9%) Median age at admission, years (IQR) 2.8 (1.0; 5.7) 3.2 (1.1; 7.1) 3.0 (1.1; 6.5) 5.3 (2.0; 8.5) 3.0 (0.4; 6.5) 3.6 (1.2; 7.2) Clinical factors Current influenza vaccination 24 (3.7%) 68 (10.5%) 303 (10.6%) 209 (11.3%) 2 (5.0%) 606 (10.0%) Nosocomial infection 58 (9.0%) 37 (5.7%) 182 (6.4%) 115 (6.2%) 3 (7.5%) 395 (6.5%) Comorbidities Any comorbidities 267 (41.2%) 284 (43.8%) 1134 (39.6%) 766 (41.3%) 18 (45.0%) 2469 (40.8%) Respiratory comorbidity 81 (12.5%) 95 (14.6%) 410 (14.3%) 243 (13.1%) 5 (12.5%) 834 (13.9%) Neurological comorbidity 62 (9.6%) 79 (12.2%) 271 (9.5%) 203 (10.9%) 5 (12.5%) 620 (10.2%) Immunosuppression and/or malignancy 63 (9.7%) 70 (10.8%) 280 (9.8%) 197 (10.6%) 4 (10.0%) 614 (10.1%) Cardiac comorbidity 25 (3.9%) 38 (5.9%) 156 (5.4%) 109 (5.9%) 2 (5.0%) 330 (5.5%) Genetic comorbidity 14 (2.2%) 35 (5.4%) 128 (4.5%) 91 (4.9%) 3 (7.5%) 271 (4.5%) Renal comorbidity 17 (2.6%) 25 (3.9%) 71 (2.5%) 59 (3.2%) 1 (2.5%) 173 (2.9%) Hepatic comorbidity 7 (1.1%) 9 (1.4%) 64 (2.2%) 42 (2.3%) 0 (0.0%) 122 (2.0%) Diabetes 4 (0.6%) 11 (1.7%) 32 (1.1%) 29 (1.6%) 0 (0.0%) 76 (1.3%) Obesity 3 (0.5%) 5 (0.8%) 16 (0.6%) 13 (0.7%) 0 (0.0%) 37 (0.6%) Other comorbidities 4 (0.6%) 1 (0.2%) 23 (0.8%) 5 (0.3%) 0 (0.0%) 33 (0.5%) Number of distinct comorbidity types 0 380 (58.7%) 365 (56.2%) 1732 (60.4%) 1089 (58.7%) 22 (55.0%) 3588 (59.2%) 1 192 (29.7%) 157 (24.2%) 703 (29.7%) 480 (25.9%) 11 (27.5%) 1543 (25.5%) 2 56 (8.7%) 85 (13.1%) 281 (9.8%) 186 (10.0%) 4 (10.0%) 612 (10.1%) 3 17 (2.6%) 32 (4.9%) 99 (3.5%) 67 (3.6%) 3 (7.5%) 218 (3.6%) 4 1 (0.2%) 6 (0.9%) 38 (1.3%) 26 (1.4%) 0 (0.0%) 71 (1.2%) ≥5 1 (0.2%) 4 (0.6%) 13 (0.5%) 7 (0.4%) 0 (0.0%) 25 (0.4%) Treatments Antiviral use 155 (24.0%) 191 (29.4%) 566 (19.8%) 377 (20.3%) 13 (32.5%) 1302 (21.5%) Oxygen support 46 (7.1%) 56 (8.6%) 135 (4.7%) 71 (3.8%) 1 (2.5%) 309 (5.1%) Noninvasive support (CPAP/BiPAP) 14 (2.2%) 10 (1.5%) 87 (3.0%) 50 (2.7%) 1 (2.5%) 162 (2.7%) Mechanical ventilation 25 (3.9%) 20 (3.1%) 111 (3.9%) 52 (2.8%) 2 (5.0%) 210 (3.5%) ECMO 1 (0.2%) 1 (0.2%) 4 (0.1%) 7 (0.4%) 1 (0.3%) 14 (0.2%) Hospitalization outcomes Length of stay; median, days (IQR) 2 (1; 4) 2 (1; 4) 2 (1; 3) 2 (1; 3) 2 (1; 3) 2 (1; 3) ICU admission 81 (12.5%) 65 (10.0%) 333 (11.6%) 186 (10.0%) 4 (10.0%) 669 (11.1%) ICU length of stay: median, days (IQR) 2 (1; 6) 2 (1; 4) 2 (1; 6) 3 (1; 7) 11 (4; 33) 2 (1; 6) Mortality 2 (0.3%) 3 (0.5%) 9 (0.3%) 11 (0.6%) 0 (0.0%) 25 (0.4%) Abbreviations: BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; ECMO, extra-corporeal membrane oxygenation; ICU, intensive care unit; IQR, interquartile range.

The median length of hospitalization was 2 days (IQR: 1; 3). In total, 669 cases (11.0%) were admitted to ICU with 55.3% of ICU cases requiring respiratory support (mechanical ventilation: 31.4%; noninvasive respiratory support: 23.9%). Antiviral use was uncommon with only 1302 cases (21.5%) receiving antiviral therapy. Of the 25 children with test-positive influenza who died in hospital, 13 (52.0%) were male, 3 (12.0%) identified as Aboriginal, and 6 (24.0%) were younger than 6 months at time of hospital admission.

3.2 The prevalence and impact of comorbidities

In total, 2469 cases (40.8%) were reported to have at least one comorbidity with chronic respiratory comorbidities most prevalent (13.8%; Table 1). Of children with comorbidities, 37.5% (n = 926) reported more than one comorbidity. Influenza-confirmed cases with comorbidities were older, more likely to be vaccinated for influenza, and have nosocomial influenza compared with their otherwise healthy peers with influenza (Table 2). Those with comorbidities were more likely to experience severe influenza disease with higher rates of ICU admission (15.7% vs. 7.9%; p < 0.001), longer hospitalization (3 versus 1 day; p < 0.001), and higher in-hospital, all-cause mortality (0.7% vs. 0.3%; p = 0.02; Table 2). In addition, interventions were greater in those with comorbidities, including mechanical ventilation (5.0% vs. 2.4%; p < 0.001), noninvasive respiratory support (4.7% vs. 1.3%; p < 0.001), and antiviral use (33.7% vs. 13.1%; p < 0.001) (Table 2). Differences in demographics and clinical outcomes by comorbidity type are summarized in supporting information Table S2.

TABLE 2. Characteristics of hospitalized influenza-confirmed cases with and without comorbidities Variable Comorbidity status, no. (%) Chi-squarea or Mann–Whitney Ub test scores (χ2 and z) and p-values Children without comorbidities (n = 3588) Children with comorbidities (n = 2469) All hospitalized influenza-confirmed children (n = 6057) Demographics Male 2004 (56.0%) 1368 (55.4%) 3372 (55.7%) χ2 = 0.2; p = 0.68 Aboriginal 297 (8.4%) 184 (7.6%) 481 (8.1%) χ2 = 1. 5; p = 0.23 Median age at admission, years (IQR) 2.9 (1.0; 6.3) 4.7 (1.8; 8.5) 3.6 (1.2; 7.2)

z = −13.1;

p < 0.001

Clinical factors Current influenza vaccination 221 (6.2%) 385 (15.6%) 606 (10.0%)

χ2 = 146.3;

p < 0.001

Nosocomial infection 142 (4.0%) 253 (10.3%) 395 (6.5%) χ2 = 0.2; p < 0.001 Treatments Antiviral use 469 (13.1%) 833 (33.7) 1302 (21.5%) χ2 = 0.2; p < 0.001 Oxygen support 177 (4.9%) 132 (5.4%) 309 (5.1%) χ2 = 0.5; p = 0.47 Noninvasive support (CPAP/BiPAP) 46 (1.3%) 116 (4.7%) 162 (2.7%) χ2 = 65.5; p < 0.001 Mechanical ventilation 86 (2.4%) 124 (5.0%) 210 (3.5%) χ2 = 30.1; p < 0.001 ECMO 9 (0.3%) 5 (0.2%) 14 (0.2%) χ2 = 0.2; p = 0.70 Hospitalization outcomes Length of hospitalisation; median, days (IQR) 1 (1; 3 3 (1; 5) 2 (1; 3)

z = −20.1;

p < 0.001

ICU admission 282 (7.9%) 387 (15.7%) 669 (11.1%) χ2 = 90.9: p < 0.001 ICU LOS: median, days (IQR) 2 (1; 4) 3 (1; 7) 2 (1; 6) z = −3.2; p = 0.002 Mortality 9 (0.3%) 16 (0.7%) 25 (0.4%) χ2 = 5.6; p = 0.02 Note: Values in bold are statistically significant as is standard. Abbreviations: BiPAP, Bilevel Positive Airway Pressure; CPAP, Continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit. a Chi-square testing was used to evaluate significance differences between variables in children with and without comorbidities except for age, length of hospitalization and length of ICU stay. b Mann–Whitney U tests were used to evaluate differences in age, length of hospitalization, and length of ICU stay.

Comorbidities were an independent predictor of severe outcomes. Specifically, the odds of ICU admission were higher in those with any comorbidity (aOR: 1.36, 95% Confidence Interval [95% CI]: 1.05; 1.77) compared with cases without any comorbidity. Children with diabetes (aOR: 3.22, 95% CI: 1.25; 8.23), cardiac (aOR: 1.93, 95% CI: 1.23; 3.03), respiratory (aOR: 1.54, 95% CI: 1.08; 2.21), or neurological comorbidities (aOR: 1.57, 95% CI: 1.25; 1.98) were at greatest odds of ICU admission (Table 3). Of note, children with immunosuppression and/or malignancy were at lower odds of ICU admission (aOR: 0.28, 95% CI: 0.17; 0.45). Respiratory, neurological, cardiac, genetic, and hepatic comorbidities and diabetes were associated with prolonged hospitalization, whereas respiratory, renal, cardiac, and other comorbidities increased the length of ICU stay (supporting information Table S3). All-cause mortality was more likely in cases with neurological comorbidities (aOR: 3.31, 95% CI: 1.79; 6.13), immunosuppression and/or malignancies (aOR: 1.85, 95% CI: 1.10; 3.14), and genetic comorbidities (aOR: 1.97, 95% CI: 1.38; 2.83, supporting information Table S4).

TABLE 3. Factors associated with ICU admission and mechanical ventilation in influenza-positive children

Variable

(N = patient no. with variable)

ICU admission (n = 549) Mechanical ventilation (n = 210) n (% of children with variable and ICU admission) Crude odds ratio (95% CI) Adjusted odds ratio (95% CI) n (% of children with variable and mechanical ventilation) Crude odds ratio (95% CI) Adjusted odds ratio (95% CI) Comorbidities No comorbidities (N = 3588) 282 (7.9%) Reference Reference 86 (2.4%) Reference Reference Any comorbidity (N = 2469) 387 (15.7%) 2.18 (1.85; 2.56) 1.36 (1.05; 1.75) 124 (5.0%) 2.15 (1.63; 2.85) 1.08 (0.68; 1.71) Cardiac comorbidity (N = 330) 87 (26.4%) 3.17 (2.44; 4.10) 1.93 (1.23; 3.03) 40 (12.1%) 4.51 (3.13; 6.49) 2.46 (1.45; 4.17) Diabetic comorbidity (N = 76) 22 (29.0%) 3.36 (2.03; 5.55) 3.22 (1.25; 8.23) 2 (2.6%) 0.75 (0.18; 3.08) 0.68 (0.26; 1.77) Genetic comorbidity (N = 271) 42 (15.5%) 1.51 (1.07; 2.12) 0.80 (0.60; 1.06) 15 (5.5%) 1.68 (0.98; 2.88) 0.79 (0.58; 1.09) Hepatic comorbidity (N = 122) 17 (13.9%) 1.31 (0.78; 2.02) 1.01 (0.49; 2.11) 8 (6.6%) 1.99 (0.96; 4.13) 2.32 (1.12; 4.80) Immunosuppression and/or malignancies (N = 614) 48 (7.8%) 0.66 (0.48; 0.89) 0.28 (0.17; 0.45) 15 (2.4%) 0.67 (0.40; 1.15) 0.32 (0.14; 0.75) Neurological comorbidity (N = 620) 132 (21.3%) 2.47 (2.00; 3.05) 1.57 (1.25; 1.98) 1 (3.0%) 0.87 (0.12; 6.39) 1.93 (1.12; 2.64) Obesity (N = 37) 5 (13.5%) 1.26 (0.49; 3.25) 0.81 (0.30; 2.21) 50 (8.1%) 2.89 (2.08; 4.02) 0.51 (0.13; 2.05) Other comorbidities (N = 33) 4 (12.1%) 1.11 (0.39; 3.17) 0.67 (0.21; 2.11) 2 (5.4%) 1.60 (0.38; 6.68) 0.76 (0.09; 1.59) Renal comorbidity (N = 173) 22 (12.7%) 1.18 (0.75; 1.86) 0.72 (0.40; 1.32) 7 (4.1%) 1.18 (0.55; 2.55) 0.83 (0.24; 2.83) Respiratory comorbidity (N = 834) 171 (20.5%) 2.45 (2.02; 2.96) 1.54 (1.08; 2.21) 51 (6.1%) 2.07 (1.50; 2.87) 1.17 (0.61; 2.26) Influenza type Influenza A (N = 4162) 479 (11.5%) Reference Reference 156 (3.8%) Reference Reference Influenza B (N = 1855) 186 (10.0%) 0.86 (0.72; 1.02) 1.01 (0.90; 1.14) 52 (2.8%) 0.74 (0.54; 1.02) 0.82 (0.53; 1.25) Multiple influenza strains (N = 40) 4 (10.0%) 0.85 (0.30; 2.41)