Background
Influenza causes significant morbidity in young children and, each year, leads to hospitalisation of approximately 870,000 children under 5 years of age worldwide [
1]. Whereas annual influenza attack rates range from 5 to 10% in adults, they range from 20 to 30% in children [
2]. Young children are also important vectors for the spread of influenza in the community and within families because they are in close contact with each other in schools and day care, have close contact with adults and the elderly, have poor hygiene habits, have limited pre-existing immunity, and shed high virus titres [
3].
The World Health Organization (WHO) recommends that children 6 to 59 months of age be considered a priority for influenza vaccination, along with pregnant women, elderly adults, individuals with specific chronic medical conditions, and healthcare workers [
4]. Despite these recommendations, many countries do not have vaccination policies, and those that do often do not include young children as a target group [
5]. This may be because severe influenza has been thought to be a problem limited to children with underlying high-risk conditions [
6]. More information about the burden of influenza in young children is therefore needed to inform and support influenza vaccination policies.
A recent phase III placebo-controlled clinical trial conducted in several countries in the Northern and Southern Hemispheres examined the efficacy, immunogenicity, and safety of an inactivated quadrivalent influenza vaccine in healthy children aged 6 to 35 months [
7]. To provide additional understanding of the occurrence and burden of influenza in healthy young children, we examined data collected from participants randomised to the placebo arm of the trial. This analysis focused on the occurrence of laboratory-confirmed influenza, the virus types/subtypes, severe symptoms and complications of influenza, and influenza-related healthcare use.
Discussion
Although the WHO recommends including young children as a target group for influenza vaccination, many countries do not include them in their recommendations [
5], probably because severe influenza has not been considered a problem for children without underlying high-risk conditions [
6]. In this study we showed that 11.5% of 2210 healthy unvaccinated children 6 to 35 months of age contracted influenza during the influenza season. In many of these children, infection with influenza virus resulted in high fever, complications, medical visits, and use of antibiotics.
We found that more than one-third of influenza episodes were associated with grade 3 fever. AOM, also common in cases of influenza [
9], was reported for 6.1% of influenza episodes. This is lower than that found in another study of children aged < 3 years (39.7%) [
10] but close to rates reported in studies of children aged < 2 years (6.4%) and 2 to 4 years (4.9%) [
11]. Acute lower respiratory infections were documented for 8.7% of influenza episodes, which is lower than the combined rate of 13% for children < 5 years of age reported in a meta-analysis by Nair et al. [
12]. Finally, influenza was associated with pneumonia in just under 2% of episodes.
The rates of medication use, outpatient visits, and hospitalisations in the study generally agreed with a systematic review by Antonova et al. [
3] who reported that 76 to 99% of children aged < 18 years with laboratory-confirmed influenza received antipyretic or other medications for symptomatic relief and that 0.3 to 20% were hospitalised. Importantly, antibiotics were prescribed for more than 40% of the confirmed influenza episodes. A few of these antibiotic prescriptions could have been for influenza-associated AOM or acute lower respiratory infection, which were observed in 15% of influenza cases. We did not find other reports describing antibiotic use in young children with ILI, although the systematic review by Antonova et al. reported that influenza is associated with antibiotic prescriptions in 7 to 55% of cases in European children aged < 18 years [
3]. A retrospective analysis of the US Impact National Benchmark Database from 2005 to 2009 found that antibiotics were prescribed in about 22% of all patients with influenza and were used inappropriately in 79% of the cases because of an absence of secondary infection or comorbidity [
13]. Thus, unnecessary antibiotic use in influenza appears to be a continuing problem and may be contributing to the spread of antibiotic-resistant bacteria [
13,
14].
Strain circulation differed between consecutive seasons in the same region. For example, in the included European countries, A(H3N2) dominated during the 2014/2015 influenza season and A(H1N1) dominated during the 2015/2016 season. In the Philippines, B/Yamagata dominated during the 2014 season, whereas A(H3N2) dominated during the 2015 season. In both seasons in the European countries, the B lineage recommended by the WHO for the trivalent vaccine [
15,
16] did not match with the dominant circulating B lineage. Although the study included relatively few confirmed influenza episodes, strain circulation in this study population generally agreed with the WHO seasonal reports [
15‐
18].
A unique characteristic of our analysis is that the data resulted from active surveillance during a randomised, placebo-controlled vaccine efficacy trial. This favours systematic and complete data collection, and therefore would have reduced the chance of missing ILI episodes. Although active surveillance could have increased the rate of ILI compared to passive surveillance, the overall influenza attack rate (11.5%) was consistent with the rate described in a 2014 meta-analysis (15.2% [95% confidence interval, 11.4 to 18.9]) for unvaccinated children aged < 18 years [
19]. However, this overall attack rate is substantially lower than that described by the WHO (20 to 30% for children) [
2]. Similarly, the higher attack rate in the European countries (20.5%) compared to the other countries (6.7%–9.3%) cannot be explained by the surveillance procedures used to identify ILI cases, since these were identical in all participating countries. The burden of influenza between countries can vary widely and is determined by a number of factors including the characteristics of circulating viruses, and the timing and severity of the season [
4]. Our study included countries located in different regions with different latitudes, climates, and influenza seasonality that may partly explain the differences between the influenza attack rates observed. For example, in Europe, the 2014–2015 season was particularly severe [
20], which could partly explain the higher attack rate reported compared to other regions.
An important limitation of this analysis is that the population was selected for the phase III clinical trial and may not have been representative of the wider population in the included regions. Specifically, the trial included children without comorbidities who were presumed to be immunologically naïve to influenza. The inclusion of only children without comorbidities may explain why the attack rate was lower in this analysis than reported by the WHO [
2] and in the 2014 meta-analysis [
19].
A final limitation is that Honduras and the Dominican Republic were not included in this analysis because participants in this region had been recruited outside the influenza season – which is often difficult to define in the tropics and subtropics [
21] – resulting in no confirmed influenza cases.