Influenza hospitalizations in Australian children 2010–2019: The impact of medical comorbidities on outcomes, vaccine coverage, and effectiveness

Abstract Background Children with comorbidities are at greater risk of severe influenza outcomes compared with healthy children. In Australia, influenza vaccination was funded for those with comorbidities from 2010 and all children aged <5 years from 2018. Influenza vaccine coverage remains inadequate in children with and without comorbidities. Methods Children ≤16 years admitted with acute respiratory illness and tested for influenza at sentinel hospitals were evaluated (2010–2019). Multivariable regression was used to identify predictors of severe outcomes. Vaccine effectiveness was estimated using the modified incidence density test‐negative design. Results Overall, 6057 influenza‐confirmed hospitalized cases and 3974 test‐negative controls were included. Influenza A was the predominant type (68.7%). Comorbidities were present in 40.8% of cases. Children with comorbidities were at increased odds of ICU admission, respiratory support, longer hospitalizations, and mortality. Specific comorbidities including neurological and cardiac conditions increasingly predisposed children to severe outcomes. Influenza vaccine coverage in influenza negative children with and without comorbidities was low (33.5% and 17.9%, respectively). Coverage improved following introduction of universal influenza vaccine programs for children <5 years. Similar vaccine effectiveness was demonstrated in children with (55% [95% confidence interval (CI): 45; 63%]) and without comorbidities (57% [(95%CI: 44; 67%]). Conclusions Comorbidities were present in 40.8% of influenza‐confirmed admissions and were associated with more severe outcomes. Children with comorbidities were more likely experience severe influenza with ICU admission, mechanical ventilation, and in‐hospital morality. Despite demonstrated vaccine effectiveness in those with and without comorbidities, vaccine coverage was suboptimal. Interventions to increase vaccination are expected to reduce severe influenza outcomes.


| BACKGROUND
Seasonal influenza is a leading cause of pediatric morbidity and mortality globally. 1 Young children have the highest risk of influenzaassociated 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 2011 5,6 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)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(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.

| 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 (χ 2 ) 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.

| 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.

| 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).

| Vaccine coverage and effectiveness
For vaccine coverage and VE estimates, 4262 influenza cases and 2488 eligible influenza test-negative controls were included (supporting information Figure S1).   15 Cardiac, hepatic, and neurological conditions were significantly associated with mechanical ventilation, consistent with our findings. 16 We observed that children with immunosuppression and/or malignancies were at lower odds of ICU admission and mechanical ventilation than children without immunosuppression and/or malignancies. Pre-emptive hospitalization, more aggressive management of children with fever, and greater proactive influenza management in this patient group may account for these differences. 17 T A B L E 2 Characteristics of hospitalized influenza-confirmed cases with and without comorbidities As observed previously, 7,10 antiviral use was low in Australian children relative to other similar high-income settings. 18 Currently, national guidelines recommends that any child hospitalized with confirmed influenza should be given antiviral treatment as well as outpatients such as those with comorbidities at risk of severe outcomes. 16 Further research on the modifiable factors associated with ongoing low use of antivirals in Australian pediatric hospitals is urgently required. It should be noted that antiviral use was associated with ICU admission, mechanical ventilation, extended hospitalization length, and increased ICU stay, likely due to residual confounding with increased antiviral prescriptions in those with very severe influenza infections.
Children with comorbidities were significantly more likely to have nosocomial influenza than children without comorbidities. Nosocomial infections were independently associated with severe influenza outcomes. Pediatric nosocomial respiratory viral infections have previously been shown to lead to more severe clinical outcomes including mortality and extended hospitalization length. 19 Further efforts to reduce nosocomial acquisition from family and staff are required for this vulnerable cohort.
Aboriginal children were overrepresented in the influenzapositive cohort (7.9% of this cohort compared with 3.3% of the general Australian population) 20  Clinical trials are currently underway to assess the safety and immunogenicity of an influenza vaccine given earlier in infancy. 29 In this analysis, children 6 to 11 months were shown to have a lower VE compared with older children. Although there is some evidence that younger children producing a poorer immune response to inactive influenza vaccines compared with older children, 30  supervision.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.