The results below represent studies of laboratory-confirmed influenza. Results from studies of ILI can be found in Additional file 1: Table S2 in the Online Appendix.

Articles included

Figure 1 presents the details of the literature search and review process. From the initial literature search (conducted in 2009), we identified 747 unique, potentially relevant articles. After Phase 1 screening of titles and abstracts and searches of relevant Web sites, 171 articles were considered for more detailed evaluation. Of these, three articles were duplicates, three articles could not be sourced, and a further 129 articles were excluded at Phase 2 screening. Another three articles were identified in the reference lists of the included articles. Therefore, a total of 39 articles were eligible for inclusion.

From the literature search update (conducted in 2011), we identified a total of 406 unique, potentially relevant articles. After Phase 1 screening and searches of relevant Web sites, 48 articles were considered for detailed evaluation, and of these, we excluded 41 articles at Phase 2 screening. Another four articles were identified from prior knowledge of one of the authors; thus, 11 additional articles were eligible for inclusion. In total, 50 articles were eligible for inclusion from the two stages of the review. Of those, 13 articles reported relevant data for children with laboratory-confirmed influenza, and the remaining 37 articles reported data on ILI.

Table 1 describes the study details, quality, and the risk of bias for the 13 articles that included data based on laboratory-confirmed influenza in children. Most studies investigated the burden of confirmed influenza in children 15 years of age or younger, and children’s ages varied among studies.

Table 1 Reviewed articles on culture-confirmed influenza in children Full size table

Study quality and types varied. The 13 articles were classified as follows: two were randomised, controlled trials that had placebo groups (therefore providing data on influenza burden); seven were prospective cohort studies with good follow-up; three were prospective cohort studies with poor follow-up; and one was an ecological study.

Clinical burden of influenza

Incidence of influenza

Studies reported influenza rates across a range of seasons and settings. Table 2 summarises influenza incidence and prevalence rates in various study settings. Annual incidence of influenza was 62 per 1,000 in full-term infants aged 1 year or younger [50]. Annual incidence of lower respiratory tract infection due to influenza was 1.1 per 100 children-years in children aged 36 months or younger [45]. During fall, winter, and spring, when infection risk is highest in European countries, influenza incidence rates were 167 per 1,000 in children aged 13 years or younger (9 October 2000 — 20 May 2001 and 1 October 2001 — 19 May 2002 in Finland [35]) and 96 per 1,000 children younger than 14 years (1 November 2008 — 30 April 2009 in Italy [37]).

Table 2 Incidence and prevalence rates of laboratory-confirmed influenza in children Full size table

Influenza was a common culture-confirmed pathogen in children seeking health care due to ILI. In a randomised, controlled trial of children with ILI, influenza was confirmed in 25% of children aged 1 through 3 years during an active epidemic period (14 January — 9 April 2008) in Finland [42]. In children presenting to the emergency department (ED) with ILI, influenza was identified in 33% (0-11 months old) and 49% (≤ 36 months old) during a 4-week local influenza peak (weeks 3 – 6 in 2002) in France [36, 43]. In Italy, influenza was identified in children presenting to the ED during 5 winter months: 15% in those younger than 15 years (1 November 2002 — 31 March 2003 [46, 47]) and in 8.7% of those younger than 14 years (1 November 2001 —31 March 2002 [38, 48]). Among children hospitalised with ILI during 37 days of a local influenza epidemic 1 January — 6 February 2002), influenza was confirmed in 51.8% of those who tested negative for respiratory syncytial virus [44]. Among hospitalised children, the prevalence of influenza was highest in the toddler group (2-3 years; 68.9%), followed by infants (≤ 1 year; 42.4%), pre-school children (3-5 years; 41.2%), and school-aged children (6-15 years; 36.8%) [44].

Complications of influenza

A wide range of complications occurred due to laboratory-confirmed paediatric influenza (Figure 2) [35–38, 42–44, 46, 47, 50]. Frequently reported complications included acute otitis media (10 articles), pneumonia (7 articles), bronchitis (7 articles), and wheezing (6 articles) (Figure 2). The most commonly occurring complications were pharyngitis (range: 31% - 58%), acute otitis media (range: 0% - 40.9%), and febrile seizures or convulsions (range: 0% - 45%) (Figure 2).

Figure 2 Incidence of complications in children with laboratory-confirmed influenza. ED = emergency department; GI = gastrointestinal. Notes: Confidence intervals were not presented for any of these values within any of the source articles. We calculated the rate of acute otitis media for the placebo group from the Heinonen et al. [42] article as follows: (6 [the number of patients with acute otitis media at baseline] + 19 [the number of the number of patients with new episodes of acute otitis media during the study]) ÷ 61 [the total number of patients in the placebo group] = 40.9%. Full size image

Febrile seizures [43, 44, 47], respiratory distress [44], and croup [36, 43, 46, 47] were reported only in ED- or hospital-based studies. Wheezing and pneumonia were less prevalent in community- or primary care-based studies than in studies conducted in ED or hospitals (Figure 2). Respiratory distress was more common in children younger than 3 years than in those younger than 15 years [44].

Economic burden

Health care resource use

Studies reported health care use primarily through hospitalisations, medical visits, and medications (antibiotic, antipyretic, or analgesic). Hospitalisation rates of children with laboratory-confirmed influenza ranged from 0% to 20% (Figure 3), and the mean length of stay ranged from 1.8 to 7.9 days (Figure 4). As would be expected, hospitalisation rates reported in physician office-based studies (0.7% [37]) and community studies (0.3% [35]) were lower than in ED-based studies (20% [43], 10% [36], 5.6% [47]) due to more severe influenza illness in children presenting to the ED than in those treated at a physician’s office. Two studies with identical country, influenza season, and health care settings demonstrated that infants (aged 0-11 months) presenting to the ED were more likely to be hospitalised (20%) and stayed in the hospital longer (mean: 7.9 days) [43] than children 0 through 3 years of age (10%; mean: 1.8 days) [36].

Figure 3 Hospitalisations, antibiotic use, and antipyretic or symptomatic treatment use by children with culture-confirmed influenza. ED = emergency department. Notes: Each point represents a percentage value reported in one of the identified studies. Confidence intervals were not presented for any of these values within any of the source articles. Full size image

Figure 4 Length of hospital stay and number of medical visits by children with culture-confirmed influenza. ED = emergency department. * The mean number of medical visits = number of reported additional medical visits + initial 1 primary care or ED visit. † Length of stay in the ED, rather than in the hospital. Notes: Each point represents a mean or median value from one of the identified studies: ♦ = mean value; ▪ = median value. Effect sizes around each point represent standard deviation if value is a mean, range if value is a median. Full size image

Infants and toddlers had a higher number of medical visits than children who were older (Figure 4). For example, in community-based studies, hospitalisation rates were 1.5% (for children < 2 years), 0.7% (2-5 years), and 0.4% (6-13 years) in Italy [37] and 0.8% (< 3 years), 0% (3-6 years), and 0% (7-13 years) in Finland [35]. A similar trend was observed in ED-based studies: children younger than 14 years had, on average, 1.7 medical visits [38]; by comparison, toddlers (< 3 years) had an average of 2.1 visits [36] and infants (< 1 year) had an average of 2.8 visits [43].

Medication use was high in children with influenza and varied by the study setting. Antibiotics were prescribed to 28% of children in community-based studies [35]; to 43% of children in primary care-based studies [37]; to 52% [50], 42% [36, 43], or 55% [38] in the ED studies; and to 34% in hospital-based studies [44] (see Additional file 1: Table S3 in the Online Appendix). Furthermore, antibiotic use varied by age: infants and toddlers were more likely to receive antibiotics than older children. In a community-based study, the age trend of receipt of antibiotics was obvious: 42% (in children < 3 years), 28% (3-6 years), and 8% (7-13 years) [35]. The trend was similar, but less pronounced, in a primary care study (38% [< 2 years], 47% [2-5 years], and 38% [6-13 years] [37]) and in a hospital-based study (43% [< 1 year], 41% [1-3 years], and 7.1% [> 3years] [44]) (Figure 3). Most children with laboratory-confirmed influenza (76% - 99%) received antipyretics and other symptomatic treatment, with no obvious age-related trend (Figure 3).

Family members of children with influenza also consumed health care resources due to subsequent ILI (Additional file 1: Table S3 in the Online Appendix). For 10% to 43% of children with confirmed influenza, a similar illness was observed in a household member [37, 38, 46, 47]. Between 0.3% and 0.4% of family members required hospitalisation [38, 46–48], 5% to 8% received a prescription for antibiotics [38, 46, 47], 13% to 16% received antipyretics [38, 46, 47], and 10% to 14% required medical visits [46, 47] (Additional file 1: Table S3 in the Online Appendix).

Costs

Multiple studies reported medical and societal costs associated with paediatric influenza, but only two reported results based on laboratory-confirmed illness (Table 3) [37, 45]. In the first study, the annual total cost of paediatric community-acquired influenza in Germany was estimated at €7,530,105. This study considered children between 0 and 36 months of age with lower respiratory tract infection and estimated 2,913 influenza cases per year, with a median hospitalisation cost of €2,585 per case. Hospitalised paediatric influenza cases were more expensive than the office-based ones (€2, 597 vs. €223, year 2002 costs [45]).

Table 3 Costs associated with paediatric influenza Full size table

The second study was conducted in Italy and considered both direct (medical) and indirect (absenteeism) costs. The care for children with laboratory-confirmed influenza (averaging €132 per patient) was 32% more expensive than that for children with influenza-negative ILI [37]. An influenza hospitalisation cost approximately €3,000, and associated costs averaged €22.40 among all influenza cases (the total cost of hospitalization divided by the total number of children with influenza, regardless of their hospitalization status). The average indirect cost of working days lost by parents (€70) had the greatest impact on the average total cost of an influenza case. Furthermore, the cost of care for young children was greater than the cost of care for older children: €153 for children younger than 2 years, €148 for children aged 2 to 5 years, and €74 for children aged 5 to 13 years.

Absenteeism

Childhood influenza resulted in absenteeism for sick children, their siblings, and parents (Additional file 1: Table S3 in the Online Appendix and Figure 5). Absenteeism in ill children was assessed through absence from school or day care [35, 38, 42, 46–48] or lost work or school days for the parents or siblings of infected children [35–38, 42, 43, 46–48]. The rates of child absenteeism in the community-based study were 76% (in children < 3 years), 73% (3-6 years), and 77% (7-13 years) [35]; absenteeism was not assessed in other studies. The duration of absenteeism depended on influenza severity (Additional file 1: Table S3 in the Online Appendix). For example, children in ED-based studies were absent from school for a median of 12.0 days [46, 47] and 5.1 days [38], children in physician office-based studies were absent from school for a median of 4.0 days [42], and children in community-based studies were absent from school for a mean of 3.6 days (calculated as weighted mean from Heikkinen et al. [35]). One study reported that some children missed up to 15 school days [46].

Figure 5 Children’s absence from day care or school and parents’ absence from work associated with paediatric influenza. ED = emergency department. * Interquartile range. † This is the number of children with confirmed influenza in this article, so the value is the same for the row showing the whole parent population, the mothers only, and the fathers only. The article does not provide the number of mothers and the number of fathers. Notes: Each point represents a mean or median value from one of the identified studies: ♦ = mean value; ▪ = median value. Effect sizes around each point represent standard deviation if the value is a mean; range represents minimum-maximum range if the value is a median. Full size image

Parental absenteeism was common: between 11.2% and 61% of parents of children with laboratory-confirmed influenza took absence from work for their own influenza illness or to care for their children (Additional file 1: Table S3 in the Online Appendix). In Finland, parents were slightly more likely to take time off if their children were younger (61% [for children < 3 years], 54% [3-6 years], and 26% [7-13 years] [35]). However, the results were mixed in an Italian study (37.9% [for children < 2 years], 51.8% [2-5 years], and 32.5% [6-13 years] among mothers and 5.5% [for children < 2 years], 6.9% [2-5 years], and 2.5% [6-13 years] among fathers [37]) and two French studies (53% [for children 0-11 months] and 54% [for children < 36 months] [36, 43]). The mean duration of work absenteeism for parents ranged from 1.3 to 6.3 days [35–38], and the median work absenteeism for parents ranged from 2 to 4 days [42, 46, 47].

Siblings of children with influenza also missed school days due to subsequent ILI. For example, siblings of children with influenza lost a mean of 1.3 days [38, 48] or a median of 5.0 to 6.0 days [46, 47] of school or work.

Health-related quality of life

A single study reported HRQoL associated with confirmed influenza specifically in children [49]. That study (a prospective, randomised, double-blind, placebo-controlled trial) compared trivalent-inactivated vaccine with no vaccine. It assessed HRQoL in children with asthma through the Paediatric Asthma Quality of Life Questionnaire (range of possible scores: 1-7, with 7 indicating the highest HRQoL) [49]. Both the vaccinated and the placebo groups experienced worsening of asthma-related HRQoL. However, the worsening was less severe in children in the vaccinated group than in children in the placebo group, as measured by the total score (–0.40 vs. –1.0 points; P value = 0.02), the “activities” domain (–0.49 vs. –1.31 points; P value = 0.02), the “emotions” domain (–0.21 vs.–0.41 points; P value = 0.29), and the “symptoms” domain (–0.52 vs. –1.35 points; P value = 0.04). No other studies were identified that reported the quality-of-life impact of confirmed influenza specifically in children.

Data availability by country

Data availability varied by country. Studies reporting burden of laboratory-confirmed influenza were conducted in Italy (5 articles), France (3 articles), Finland (2 articles), the Netherlands (2 articles), and Germany (1 article). No articles that reported burden data relating to confirmed influenza were identified from Austria, Spain, or the UK.

Data on health care resource use were most commonly reported in Italy and France, whereas costs of laboratory-confirmed influenza were reported for Germany and Italy. Absenteeism data were most commonly reported for Italy, whereas HRQoL impact of confirmed influenza was reported only in the Netherlands.