The burden and clinical manifestation of hospitalized influenza among different pediatric age‐groups in the tropics

Abstract Introduction In tropical Singapore, influenza occurs all year‐round. This study of influenza‐confirmed hospitalized pediatric patients compared clinical characteristics and complications by age‐group and differences between influenza A and B. Methods This was a retrospective study of pediatric inpatients from January 2013 to December 2014. Patients were grouped into: <6 months, 6 months to <5 years, 5‐ to <10‐year and ≥10 years. Complications were classified into neurologic, pulmonary, and other. We also calculated the incidence of hospitalized influenza cases per 100 000 age‐related population. Results There were a total of 1272 patients with a median age of 37 months. The highest hospitalization rates were in the <6 months age‐group. Majority (75.2%) had no comorbidity; 25.6% had complications: neurologic 11.9%, pulmonary 9.6%, other 4.1%. Patients with other complications were older, male, and had the highest influenza B rates and the longest length of stay. Influenza A comprised 76.9% of cases and had higher complication rates especially neurologic, compared to influenza B. Influenza B patients were older and were more likely to develop other complications. The 6‐month to <5‐year‐age‐group had the highest complication rate (30.6%), especially neurologic. However, ≥10 years old had the highest other complications, ICU/ high‐dependency admissions and influenza B Victoria rates. Conclusions Infants <6 months had the highest hospitalization rates for influenza. The 6‐month to <5‐year‐age‐group had the highest complication rate especially neurologic. Influenza A patients were younger, had higher seizure rates and complications compared to influenza B.

cases were defined as upper respiratory tract manifestations and influenza-unrelated illness, for example, urinary tract infection (UTI).
High dependency (HD) is a unit that caters for more severely ill patients requiring closer monitoring or non-invasive ventilation without needing ICU admission. Obesity was defined as BMI > 25 kg/m 2 .
Immunosuppression was defined as non-malignancy related immunosuppressive therapy, for example, steroids, biological modifying agents. Pneumonia was defined as fever and cough with chest Xray (CXR) changes of lobar/broncho-pneumonia or focal infiltrates.
Positive bacterial tests were either culture-positive from any site or positive mycoplasma PCR or serology (particle agglutination IgG antibody ≥320 single titer). C-reactive protein was the result on admission. Criteria for treating influenza with oseltamivir were as follows: age <2 years or any high-risk factor for complicated disease within 3 days of onset, or severe disease based on clinician assessment independent of duration since onset.
Statistical analysis was performed using the spss 19.0 statistical software program. Student's t test or one-way ANOVA were used to compare continuous data; chi-square test or Fisher's exact test was used to compare categorical data, using P < .05 as statistical significance. This study was approved by the internal review board for waiver of consent.
Incidence of influenza hospitalization was derived using 56.8% market share for admissions in children and calculated as per 100 000 population based on the number of children in that agegroup (information from MOH and Singapore government statistics).

| RE SULTS
There were a total of 1272 influenza-positive patients admitted with a median age of 37 months (IQR 13-76 months); males constituted 56.5%. Majority were positive for influenza by IF (96.5%) compared to PCR (3.5%). The median length of stay (LOS) was 3 days (IQR 2-4 days). C-reactive protein and chest X-ray were performed in 28.8% and 31.1% of patients, respectively. Figure 1 shows the burden of influenza hospitalizations by year, age-groups, and subtypes/lineages (excluding unknown subtypes/lineages). Incidence of hospitalized influenza was highest for <6 months, followed by 6-month to <5-year-age-group and lowest in ≥10-year-age-group. Figure 2 shows the monthly incidence of  The 6-month to <5-year-age-group (54.0%) and ≥10-year-agegroup (11.6%) constituted the largest and smallest proportion, respectively. The 5-to <10-year and ≥10-year-age-groups had the highest rates of influenza B, while <6-month-age-group had the highest rates of influenza A. The <6-month-age-group had the influenza-related complication rates but the highest bacterial infection rates and antibiotic usage. The 6-month to <5-year-age-group had the highest seizure rates, cough duration, CRP, and complication rates. The 5-to <10-year-age-group had the highest influenza B Yamagata rates and prior seizure history. The ≥10-year-age-group had the highest rates of comorbidity, other complications, ICU/HD admissions, and mean LOS.
The seven complicated cases with confirmed bacterial coinfection were as follows: two pneumococcal bacteremia, two S pyogenes bacteremia, one each for P aeuginosa pneumonia, Mycoplasma pneumonia, and campylobacter gastroenteritis (admitted for febrile seizure).
The mortality rate in our cohort was 0.2%. The three deaths were as follows: Acute necrotizing encephalitis, invasive pneumococcal disease, decompensated liver failure in a biliary atresia patient post-Kasai procedure. One cerebral palsy patient with no prior seizures developed sequelae of epilepsy.

| D ISCUSS I ON
The main findings from our study were that the highest burden of influenza hospitalizations was in the <6-month-age-group, followed by the 6-month to <5-year-age-group. Majority (75.2%) of pediatric inpatients had no comorbidity and 25.6% had complications: neurologic 11.9%, pulmonary 9.6%, and other 4.1%. The 6-month to <5-year-age-group suffered the highest complication rate (30.6%).
Influenza A patients were younger, had higher seizure rates and complications compared to influenza B.
In our study, the highest hospitalization rate occurred in the <6-month-age-group. This is similar to Hong Kong but different from temperate countries where the highest rates occurred in the 6-to 23-month-age-group. [10][11][12] Patients who were ≤6 weeks or <3 months old were likely admitted for neonatal or infantile pyrexia workup, this can explain the high UTI rates and antibiotic usage in this age-group. At the average rate of 881.68 per 10 5 population for <6 months old, it is higher than temperate countries. 3,13 This could be due to all year-round influenza with bimodal peaks, similar to Malaysia. 14 Studies have shown that maternal influenza vaccination can prevent influenza in infants; therefore, pregnant women should receive influenza vaccination to protect their infants. 15,16 The age-group 6 month to <5 years was the largest cohort (54%) with the second-highest hospitalization rate and the highest complication rate (30.6%) especially neurologic, similar to another study. 17 In other studies, the age-group 6-35 months or the lowest agegroups had the highest incidence of complications. 11,18,19 However, the ≥10-year-old-age-group had the highest other complications, ICU/high-dependency admissions, and influenza B Victoria rates. This is unlike other studies which had higher ICU admissions in the youngest age-groups <12 months. 20  Abbreviation: SD, standard deviation. especially pneumonia and asthma exacerbation. 11,16

| CON CLUS IONS
Infants <6 months had the highest hospitalization rates for influenza. The 6-month to <5-year-age-group had the highest complication rate especially neurologic. Influenza A patients were younger, had higher seizure rates and complications compared to influenza B.

ACK N OWLED G EM ENTS
We thank Yixiang Ng, Senior Statistician, Epidemiology & Disease Control Division, Ministry of Health, Singapore, for providing data on KKH market share and pediatric hospitalizations by age-group.