The burden of influenza is unevenly distributed, with more severe outcomes in children aged <5 years than older children and adults. In spite of this, immunisation policies for young children are far from universal. This article provides an overview of the published evidence on the burden of influenza in children worldwide, with a particular interest in the impact of pandemic influenza in 2009–2010 (caused by the H1N1pdm09 virus). In an average season, up to 9.8 % of 0- to 14-year olds present with influenza, but incidence rates can be markedly higher in younger children. Children aged <5 years have greater rates of hospitalisation and complications than their older counterparts, particularly if the children have co-existing illnesses; historically, this age group have had higher mortality rates from the disease than other children, although during the 2009–2010 pandemic the median age of those who died of influenza was higher than in previous seasons. Admissions to hospital and emergency departments appear to have been more frequent in children with H1N1pdm09 infections than during previous seasonal epidemics, with pneumonia continuing to be a common complication in this setting. Outcomes in children hospitalised with severe disease also seem to have been worse for those infected with H1N1pdm09 viruses compared with seasonal viruses. Studies in children confirm that vaccination reduces the incidence of seasonal influenza and the associated burden, underlining the importance of targeting this group in national immunisation policies. Conclusions: Children aged <5 years are especially vulnerable to influenza, particularly that caused by seasonal viruses, and vaccination in this group can be an effective strategy for reducing disease burden.
Influenza is disproportionate in its effect on different age groups. For example, US children aged 0–19 years had a higher risk of being infected with influenza A/H1N1 or A/H3N2 than adults of any age during yearly epidemics between 1977 and 1978 and 1980 and 1981, and in two influenza B epidemics (1976–1977 and 1979–1980), the age group at highest risk of infection was 5- to 14-year olds . In a cohort of 209 US infants monitored weekly from birth until the age of 1 year, 69 (33 %) developed influenza infection . More recent data tell a similar story: in the first 10 months of the 2009–2010 influenza pandemic, the hospitalisation rate in US children under the age of 5 years with laboratory-confirmed influenza was more than double that of any other age group , and among 722 patients admitted to intensive care unit (ICU) with confirmed H1N1pdm09 infection in Australia and New Zealand during 2009, the age-specific incidence of admission was higher in infants <1 year old than in any other age group . In Germany, mortality rates in 2009–2010 were highest in children in their first year of life and middle-aged adults (aged 35–59 years) .
Since the 2008–2009 influenza season, influenza vaccination has been recommended for children aged 6 months to 18 years in the USA . In addition, the Influenza Working Group for the World Health Organisation Strategic Advisory Group of Experts has recommended that children aged 6 months to 5 years be considered as a target group for annual influenza vaccination , and the UK Department of Health recently announced a plan to vaccinate children aged 2–17 years annually from 2014 . However, in many other European countries, routine immunisation of children against influenza is not yet recommended. Cost-effectiveness arguments certainly play a part in this, but it is also possible that doubts remain about the burden that influenza poses in children.
This article provides an overview (non-systematic review) of published evidence on this topic. Most of the papers cited in this article came from a search of the PubMed database on 27 April 2012 for articles published at any time in English or German with ‘influenza’ and any of the following words in the title: child, children, schoolchildren, infant (and words with ‘infant’ as root), pediatric(s) or paediatric(s). The search field was restricted to title only to produce a manageable number of papers (1,686) for further searching. The results were searched for publications relevant to our subject headings, with a focus on recently published papers on the impact of the 2009–2010 influenza pandemic (infections with the H1N1pdm09 virus) in children. No formal screening criteria were used, and additional publications not found by the search that contain data pertinent to influenza burden in children are also cited.
Burden of influenza in children
Incidence and attack rate
The burden of influenza on communities worldwide is uneven, because the annual disease epidemics vary considerably in severity. Distinguishing the morbidity caused by influenza from that due to influenza-like illness (ILI) caused by other respiratory viruses, such as respiratory syncytial virus (RSV) presents a challenge not only to epidemiologists but also to physicians in relation to diagnosis and treatment. Nevertheless, a systematic review and meta-analysis published in the Lancet in 2011 estimated that 90 million cases of influenza occur each year in children aged <5 years around the world; of these, 20 million are associated with acute lower respiratory tract infections (LRTI), one million of which are severe in nature . By modelling surveillance data on all ILI in four countries from 2002 to 2008, the European Paediatric Influenza Analysis project calculated that between 0.3 and 9.8 % of children aged 0–14 years present to a physician with influenza in the average season . These data are in line with the findings of an earlier systematic review, by Bueving et al. , of 26 studies from a variety of countries and settings; although the incidence of laboratory-confirmed influenza from individual studies in that review ranged from 0 to 46 %, two studies that measured incidence over a period at least of 5 years reported estimated incidences of 4.6 % for children and adolescents aged ≤19 years  and 9.6 % for children up to 5 years old . Incidence rates could be even higher in the youngest groups of children: during two seasons considered to be milder influenza epidemics, namely 2000–2001 (primarily A/H1N1) and 2001–2002 (primarily A/H3N2), the average annual rate of influenza in Finnish children <3 years old seen as outpatients was 179/1,000 . Surveillance in the USA over three seasons showed that the cumulative rate of influenza-associated acute respiratory illness was nearly twice as high in children aged 0–18 years (median, 6 years) as in elderly adults (20 and 11 %, respectively) .
The attack rate, i.e., the probability of people at risk of becoming infected during an influenza outbreak, is often reported as an outcome measure in vaccine efficacy trials. For example, placebo group attack rates in a Japanese study of 6- to 24-month-old children ranged from 7.2 to 12.5 % over the three seasons 2000–2002 , and in German and Finnish children aged <6 years, the placebo group attack rates for seasons 2007–2008 and 2008–2009 were 2.4 and 5.2 % . It is also of value for comparing the virulence of infecting viruses from season to season, with clinical attack rates (i.e. infected patients with symptoms) of 12–24 % for seasonal influenza and 20 % for H1N1pdm09 influenza being reported in children up to 14 years old [45, 50] and 3–16 % in infants aged 6–24 months . The statistic should be interpreted with care, however, as attack rates vary by season and geographic location depending on the virulence of the infecting virus. For example, clinical attack rates in a prospective cohort trial in Finnish children were quite similar across the three age groups studied (<3 years; 3–6 years, and 7–13 years) in 2000–2001, when A/H1N1 infections predominated, but in 2001–2002, when A/H3N2 predominated, the attack rate was markedly higher in the youngest children (21.3 %) than the oldest (3.0 %) . In addition, infected individuals do not always develop symptoms ; in recent German surveillance, secondary H1N1pdm09 infections in adults were significantly more likely to be asymptomatic than those in children . It is notable that during the 2009 pandemic, H1N1pdm09 seroprevalence rates in Germany were nearly twice as high in 5- to 17-year olds (48 %) as in 1- to 4-year olds (25 %) , in agreement with patterns of mortality and hospitalisation rates described in later sections of this article.
Transmission and infectiousness
Children appear to be more vulnerable to developing infection when influenza is circulating. A study of household transmission from index cases with laboratory-confirmed influenza found that children aged 0–5 years were significantly more likely to develop clinical influenza than adults (hazard ratio, 1.85; 95 % CI, 1.09–3.26)  and in a prophylaxis study, the incidence of laboratory-confirmed influenza in contacts aged 1–12 years receiving expectant treatment was approximately three times as that in those aged >13 years . In 2008–2009, the risk of secondary infections in German households with an influenza-infected index case increased as the age of the household member decreased, but in 2009–2010 (pandemic season), rates in those aged 0–4 years were lower than any other age group, with the highest risk in those aged 5–34 years .
Children with influenza contribute to the burden on all age groups because of their high infectiousness . In the French transmission study mentioned above, the risk of developing clinical influenza was significantly higher in contacts exposed to infected children (aged 0–15 years) than infected adults (aged >15 years) . Prolonged viral shedding may play a role in disease transmission. A long duration of shedding was recently demonstrated in children aged <15 years infected with H1N1pdm09 virus by Esposito et al. ; at 9 days after influenza onset, 35/74 (47 %) were still shedding virus and 14 (19 %) were still doing so at day 13. Moreover, in households with children shedding virus for at least 9 days, there was significantly more ILI in the 2 weeks after the initial disease compared with children shedding for <9 days .
From real-time surveillance of patient visits in a variety of settings, children aged 3–4 years were consistently the earliest age group to make healthcare visits during pneumonia and influenza epidemics, so contributing to disease spread beyond the household . This idea is supported by results of an influenza transmission model based on children in Taipei, suggesting that children aged 4–6 years have the highest transmission potential , although other studies have found that older children are a more important age group for transmission than younger children [42, 108, 127], probably because the opportunity for onward spread is greater once children are attending school. As discussed in a later section, vaccinating children can reduce the community infection rate [8, 44, 94].
Influenza illness causes children to lose school time, and their parents to lose work time, causing a socioeconomic as well as a clinical burden. In Finland, influenza infections were estimated to cause 216–274 days of absence from school or day care and 54–195 parental work days lost for every 100 children aged 0–13 years . A US group estimated that 247,000 work days/year were lost nationally by caregivers of children who were taken to emergency departments for influenza infections , and an Italian study estimated that, including indirect costs of lost work time, the mean cost of a childhood influenza infection was at least €130 . A study in Hong Kong found that school absenteeism rates associated with influenza A epidemics from 2003to 2004 to 2005to 2006 were much higher in those aged ≤5 years (105–142 days/10,000 population) than in those aged 6–17 years (15–20 days) .
The 2011 meta-analysis by Nair and colleagues estimated that between 28,000 and 111,500 children aged <5 years die each year as a result of acute LRTI associated with influenza, and that 99 % of deaths happen in developing countries . Many other studies emphasise the relative vulnerability of younger children with respect to the risk of dying from influenza. In 2004–2007, the US Centres for Disease Control and Prevention (CDC) were notified of 166 influenza deaths in children aged <18 years, with the median age of these children being 5 years , and in the survey of seasonal influenza deaths in US children published by Bhat et al. , two thirds of deaths occurred in those aged <5 years. In the latter study, the estimated mortality rate associated with influenza was 0.21/100,000 children, but the rates in age groups younger than 2 years old was 0.59 to 0.88/100,000 . In an earlier study by CDC using data from 1990 to 1999, estimated annual rates of underlying respiratory and circulatory deaths associated with influenza per 100,000 were 0.4 in children aged 1–4 years and 0.6 in those aged <1 year . Recent CDC estimates based on a larger time span (1976–2007) suggest that average annual rates for all ages could be 35 % lower than the 2003 estimates, although rates for young children were not calculated . The mortality rate appears to be highest in those aged <1 year for infections caused by either seasonal or pandemic influenza viruses [38, 105]. As would be expected, mortality risk is much higher when the infection follows a more severe course. In H1N1pdm09-infected children with severe illness admitted to ICUs, 81 % of whom underwent mechanical ventilation, death rates were 47 % ; many of these children had pre-existing illnesses such as asthma and congenital heart disease, and co-infection with RSV was found to be significantly associated with mortality.
The influenza pandemic of 2009–2010 saw a spike in the number of influenza-associated deaths in children compared with previous seasons in the USA . However, surveys in the USA suggest a change in the age distribution of child deaths during the pandemic. During the early part of the pandemic (April to August 2009), 19 % of reported deaths from H1N1pdm09 influenza in US children were in those aged <5 years , yet more recent CDC data showed that after the pandemic, nearly half (46 %) of all child influenza deaths were in this age group , similar to the rate calculated for under 5 years who died from seasonal influenza in 2007–2008 (Fig. 1) . This is consistent with a study showing the median age of US children who died from H1N1pdm09 influenza being significantly higher than in those who died in 2007–2009 from seasonal influenza (9.4 and 6.2 years, respectively; p < 0.01) (Fig. 2) . However, some of the findings of a recent Dutch study disagree with the US data described above. Using regression modelling, this group estimated that influenza-related mortality in Dutch children aged 0–4 years was much higher during the 2009–2010 pandemic than the average of ten previous seasons ; in the 5- to 24-year age group, the estimated pandemic mortality was also higher than the seasonal influenza average.
In more severely ill children, i.e. those requiring admission to an ICU, mortality rate was higher in those with H1N1pdm09 infections than those with influenza A infections during previous seasons . In the context of H1N1pdm09 influenza, children with existing illness appear to have had the highest mortality risk: roughly two thirds of children who died after having H1N1pdm09 infections had co-morbidities [17, 29, 105].
Clinical manifestations of disease
The presenting symptoms of influenza in children do not differ greatly between clinical settings. In children aged <14 years who were treated as outpatients, fever was very common (affecting 95 %), as were cough and rhinitis (77 and 78 % affected, respectively) but headache (39 %) and myalgia (13 %) were less common . An earlier prospective study reported a high prevalence of fever, cough and rhinorrhoea (95–96 %) in influenza-infected outpatients <5 years old . These three symptoms were almost as common in hospital inpatients of the same age, with cough slightly but significantly more common in those >6 months old (94 %) than those up to 5 months old (80 %; p = 0.01) . Even in very young hospitalised infants (aged ≤2 months) with confirmed influenza, fever was the main presenting symptom . Similarly, high rates of fever and cough were reported from a more recent study of hospitalised children and adolescents with H1N1pdm09 influenza . Studies of hospitalised influenza patients also report neurological symptoms, such as febrile convulsions [97, 115, 119], although these are often reported as complications of the disease rather than symptoms (see next section). As well as the neurological system, other non-respiratory systems can be commonly affected in influenza: in some epidemics, up to 50 % of children have presented with gastrointestinal symptoms such as vomiting and diarrhoea, particularly those who are admitted to hospital, and affecting children of all age groups [1, 11, 67, 69, 90, 134]. In a study of children and adolescents hospitalised with laboratory-confirmed influenza, sepsis-like illness was the admission diagnosis for 52 % of those aged <6 months and for up to 16 % of older children .
Differentiating influenza from other respiratory infections on the basis of symptoms alone is challenging, and virological testing is necessary to confirm the diagnosis. A Finnish group who used a matched case-control study in children aged ≤13 years to compare confirmed influenza patients with those who had respiratory symptoms but were influenza-negative found fever to be the only reliable predictor of influenza .
Complications of influenza
Influenza-associated complications contribute significantly to the disease burden in children. Complications are more likely to develop in recognised high-risk groups, including those with co-morbidities [26, 71] and younger children .
One of the most common complications of seasonal influenza in children is otitis media, which is associated with excess healthcare visits, antibiotic use and surgical procedures, and can lead to hearing loss. Otitis media affected 28 % of under 5 years presenting as outpatients in the US population-based study by Poehling et al.  and occurred in 24 % of young hospitalised children in both a Finnish and a US study [90, 93]. Infants and young children aged under 2 years old, however, appear to be at higher risk of acute otitis media than older children , which is consistent with the results of the Finnish prospective cohort study that reported a rate of 40 % in children <3 years old in an outpatient setting .
Respiratory tract infections (RTIs) are also frequently encountered as influenza complications. The most important RTI with respect to healthcare burden is pneumonia which is associated with hospitalisation and poorer outcomes. The incidence of pneumonia is high in children admitted to hospital with more severe influenza; in 2,992 hospitalised children and adolescents with seasonal influenza, radiographic evidence of pneumonia was found in 1,072 (36 %) , and recently published studies in European and Asian children suggest a similar rate in hospitalised children with H1N1pdm09 influenza, with estimates ranging from 22 to 43 % [11, 69, 91, 111], although two groups found the rate to be higher for H1N1pdm09 infections during 2009 than for influenza A infections in previous seasons [5, 78]. Pneumonia is less common outside the hospital setting: in the Finnish prospective cohort study in outpatients mentioned above, pneumonia was diagnosed in 9 of 370 (2.4 %) children with confirmed influenza, 8 of whom were aged ≤6 years . In a retrospective study of 936 children aged 0–15 years with confirmed influenza seen as hospital outpatients or inpatients, pneumonia was present in 134 (14 %) children, 66 % of whom were <3 years old . As with otitis media, infants aged under 2 years appeared to have a higher risk of LRTI than those aged 2–4 years in a 25-year cohort study, although absolute rates were quite low (annual rates per 1,000 children of 11 and 10 in the first and second years of life, respectively, and 4 for those aged 2–4 years) .
Neurological events or disorders are frequently reported as complications of influenza, ranging from febrile convulsions, which typically have a good prognosis, to encephalitis and encephalopathy, which may be fatal.
Japanese and Taiwanese children appear to have a higher vulnerability to CNS complications, although these findings may be the result of more intense surveillance. In 1,000 Japanese patients aged 0–20 years with H1N1pdm09, neurological complications resulted in hospital admission in 255 (25.5 %) patients; the most common events were febrile convulsions (135 children) whereas encephalopathy, mostly mild, was only seen in 12 . CNS dysfunction occurred in 26 of 84 (31 %) Taiwanese children with seasonal influenza, 60 of whom were aged <5 years; one of the patients had febrile convulsions, but 21 had encephalitis or encephalopathy . In a recent Israeli study, 14 of 74 (19 %) children aged 0–16 years hospitalised with H1N1pdm09 had CNS complications, but these were mainly mild seizures .
CNS complications were less common in US studies of seasonal and pandemic influenza. In the earlier survey, 72/842 children hospitalised with seasonal influenza (8.6 %) had CNS complications; 56 had seizures (median age, 1.4 years) and 10 (median age, 3.5 years) had mild encephalopathy . In 307 children aged 1–19 yrs who were hospitalised with H1N1pdm09 infection, 23 (7.5 %) had CNS complications (17 with seizures and 7 with encephalopathy), but 15 patients required monitoring in ICU and three died .
Neurological complications appear to be more common in severely ill children. In a French study of 181 children admitted to hospital with H1N1pdm09, 14 (7.7 %) had CNS dysfunction; of the 14 children (median age, 5.1 years), eight had febrile seizures and three had encephalitis or encephalopathy . Twenty-four of the 181 children needed admission to ICU, however, including nine of those with CNS complications (38 % of the ICU cohort). In a study of 20 German children aged 0–15 years (median 7.5 years) who were admitted to ICU with severe seasonal influenza infections, encephalitis or encephalopathy occurred in five cases .
Hospitalisation rates in influenza patients
Several studies demonstrate that the burden of hospital admission and emergency department visits in younger children who are infected with influenza is considerable [12, 13, 81, 84, 86]. Younger children are much more likely to be hospitalised as a result of influenza and its complications than their older counterparts. As shown in Table 1, a number of surveys have reported that influenza-associated hospitalisation rates were higher in those aged <5 years than aged ≥5 years. Furthermore, studies consistently report that the highest rates of all are in infants in their first year of life [4, 59, 81, 96, 107, 109, 116].
A 5-year survey of admissions to two children’s hospitals in Kiel, Germany, compared incidence rates for types A and B influenza; the cumulative population-based rates per 100,000 children aged 0–5 years were 123 and 30 for influenza A and B, respectively, whereas rates in those aged 6–16 years were 22 and 9, respectively . The authors also noted that co-existing cardiac disorders and asthma increased the risk of hospital admission in influenza A patients, in agreement with earlier data from US studies showing that high-risk children, e.g., those with asthma, are more likely to be hospitalised or to have prolonged hospital stays compared with otherwise healthy children [26, 82]. The higher-risk group also have poorer outcomes than low-risk patients after hospitalisation , and more than 50 % of the hospital costs of US children aged ≤18 years with an influenza diagnosis was in higher-risk children alone .
Recent papers on epidemiology and outcomes in hospitalised children have compared H1N1pdm09 influenza with historical data on seasonal influenza. Some of these studies report a worsening of the disease burden with H1N1pdm09 influenza, either as higher hospitalisation or mortality rates or more severe disease [31, 55, 68, 135] and others report large increases in the hospitalisation rate for ILI during the first months of the pandemic compared with previous seasons [75, 118]. Consistent with the experience from previous pandemics, hospitalised children with H1N1pdm09 infections were significantly older than those hospitalised with seasonal influenza (range of median ages, 2–5 and 0–2 years, respectively) [31, 55, 118, 135]. A study on the impact of H1N1pdm09 influenza in Japan suggested that although infants <1 year old were hospitalised at a higher rate than those aged 12–23 months, agreeing with the historical data for seasonal influenza described above, those in their second year of life had three times the rate of influenza-related complications .
Managing the influenza burden
A large systematic review of vaccine studies, published in 2012, concluded that live attenuated influenza vaccines (LAIVs) and inactivated vaccines have similar effectiveness in preventing influenza in children >2 years old (33 and 36 % respectively), but that in children aged ≤2 years, inactivated vaccines (the only type licensed for use in this age group) were no more effective than placebo . Authors of another systematic review and meta-analysis found that vaccine effectiveness in children aged 6–59 months was only significant in three of eight seasons, and concluded that there is a need to improve the effectiveness of current influenza vaccines . A prospective, non-randomised cohort study on trivalent inactivated influenza vaccine (TIV) not included in the Cochrane review showed 66 % effectiveness in preventing infection both in children aged 9 months to 3 years and, notably, in the subgroup of infants aged under 2 years . Adding the oil-in-water adjuvant MF59 to TIV appears to boost vaccine efficacy further, as shown in children aged 6 months to 6 years in a randomised study . Most recently of all, a meta-analysis of eight trials (two-season and single-season) in children 2–17 years old found that intranasal LAIV reduced influenza illness caused by all strains by 79 % compared with placebo and by 48 % compared with TIV .
Evidence from several countries suggests that vaccination against seasonal influenza can reduce disease burden. In a randomised placebo-controlled study in Italian children aged 6 months to 14 years, intranasal TIV reduced the mean number of missed school days (5.4 and 13.8 days, respectively) and the mean number of lost work days in household contacts (0.42 and 2.50), although no 95 % CI were reported . A similar single-season study in Sardinia, in younger children (1–6 years old) showed that TIV significantly reduced the rate of ILI compared with no treatment (12.4 and 37.7 %, respectively (risk reduction of 67 %; 95 % CI, 59–74 %)) and the mean duration of absenteeism from day care centres (0.5 and 2.3 days; no 95 % CI given) . Over six consecutive seasons in Japan, a non-randomised community-based study showed a small but significant difference in the aggregate rate of hospitalisation associated with influenza A infections in children aged 6–59 months who were given two doses of TIV; rates were 0.6 % and 2.0 % in the vaccinated and unvaccinated groups, respectively (71 % risk reduction [95 % CI, 59–80 %]) . In a US study of the 2003–2004 season, two doses of inactivated vaccine reduced the risk of an ILI office visit in infants aged 6–21 months by 69 % (hazard ratio 0.31; 95 % CI, 0.26–0.36 %), although one dose was not effective . In a cost-effectiveness analysis of a 2-year randomised placebo-controlled trial, intranasal LAIV reduced the mean number of ILI fever days per child by 1.2 days in US children aged 15–71 months, although the statistical significance was not reported .
As reducing the number of cases in children makes onward transmission in households less likely , societal benefits of childhood vaccination are not only predicted by modelling studies [8, 41, 95] but also borne out in practice. Analysis of deaths attributable to pneumonia and influenza in Japan from 1950 to 2000 suggested that the lower rate of excess deaths during the middle three decades was probably due to vaccine-induced herd immunity resulting from the child immunisation programmes that operated from 1962 to 1994 , and later statistical analysis of these data, comparing the 1978–1994 and 1995–2006 periods, estimated that the programmes had reduced mortality risk in adults ≥65 years by 36 % (95 % CI, 17–51 %) after adjusting for virus subtype, population demographics and baseline mortality risk . Lower rates of ILI in other age groups followed vaccination of children in Russia and the USA [40, 94]. Complication rates are also lower in vaccinated children, notably the incidence of otitis media [10, 32, 49, 74, 88] and the rate of respiratory illness in children with asthma .
Influenza vaccines cause fever and myalgia, and administration-site-related reactions such as pain and swelling (and nasal congestion for the intranasal vaccine), which are usually mild and temporary. A more serious but rare side-effect is allergic reactions, and adverse reactions such as febrile convulsions [7, 22] and narcolepsy  have been reported to be associated with specific vaccine brands.
The neuraminidase inhibitors oseltamivir and zanamivir are preferred to amantadine and rimantadine as influenza antiviral therapy because of lower rates of drug resistance. Systematic reviews of studies in children showed evidence of their usefulness in shortening influenza duration and reducing the incidence of acute otitis media in paediatric seasonal influenza, although reduction in the incidence of symptomatic influenza after prophylactic use was only modest, and their ability to reduce the incidence of serious influenza complications has yet to be proved in large trials [113, 129]. A recent Cochrane review that examined regulatory information on neuraminidase inhibitors, principally from trials in adults but including some in children, was unable to reach conclusions about the effect of oseltamivir on complications and transmission . Recent studies report that prompt initiation of oseltamivir treatment can shorten hospital stay in children with severe influenza, whether caused by seasonal virus strains or H1N1pdm09 virus [27, 36]. Seasonal H1N1 viruses developed naturally occurring resistance to oseltamivir, particularly in the 2007–2009 period [33, 106], but H1N1pdm09 viruses that emerged during the 2009 pandemic appear to be mostly sensitive to inhibition . Oseltamivir appears to be very effective for reducing otitis media incidence in children aged 1–3 years, if treatment is started quickly (within 12 h of symptom onset) . WHO guidelines recommend the use of neuraminidase inhibitors in children in high-risk groups and in all children with severe influenza , although there are still challenges, e.g. timely diagnosis, when selecting patients who could benefit from therapy.
Children treated with oseltamivir have a significantly higher rate of vomiting compared with placebo, but the adverse event profile of neuraminidase inhibitors is otherwise similar to that of placebo . Neuropsychiatric side-effects have been reported in association with oseltamivir administration, although the significance of this is uncertain given that CNS complications are often reported in untreated influenza patients, as already described.
Many of the additional data on influenza in children that have been published in 2009–2012 relate to infections caused by the H1N1pdm09 virus. Some studies report that hospitalisation rates for H1N1pdm09 infections were higher than for seasonal influenza infections, and pneumonia continues to be at least as significant a complication as it was before the arrival of the 2009–2010 pandemic. In contrast, death rates in children under 5 years of age seem to have been lower during the pandemic than they were before and after it and in line with this, there was a difference in the median age of those hospitalised, with pandemic influenza typically affecting children 2–3 years older than those with seasonal influenza. A common theme that does emerge, however, is that young children remain particularly vulnerable to influenza, with greater rates of hospitalisation and complications than their older counterparts, and the burden is worse still in children with co-existing illnesses. The recent data on the effectiveness of vaccines against seasonal influenza supports previous experience, showing that this is a productive strategy for reducing disease burden in children, although more effective vaccines need to be developed.
Al Subaie SS, Al Saadi MA (2012) Features associated with severe disease in hospitalized children with 2009 influenza A (H1N1) infection at a university hospital in Riyadh, Saudi Arabia. Ann Saudi Med 32(1):53–58
Allison MA, Daley MF, Crane LA, Barrow J, Beaty BL, Allred N, Berman S, Kempe A (2006) Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003–2004 season. J Pediatr 149(6):755–762
Ambrose CS, Wu X, Knuf M, Wutzler P (2012) The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: a meta-analysis of 8 randomized controlled studies. Vaccine 30(5):886–892
Ampofo K, Gesteland PH, Bender J, Mills M, Daly J, Samore M, Byington C, Pavia AT, Srivastava R (2006) Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics 118(6):2409–2417
Ampofo K, Herbener A, Blaschke AJ, Heyrend C, Poritz M, Korgenski K, Rolfs R, Jain S, Carvalho Mda G, Pimenta FC, Daly J, Mason EO, Byington CL, Pavia AT (2010) Association of 2009 pandemic influenza A (H1N1) infection and increased hospitalization with parapneumonic empyema in children in Utah. Pediatr Infect Dis J 29(10):905–909
ANZIC Influenza Investigators, Webb SA, Pettilä V, Seppelt I, Bellomo R, Bailey M, Cooper DJ, Cretikos M, Davies AR, Finfer S, Harrigan PW, Hart GK, Howe B, Iredell JR, McArthur C, Mitchell I, Morrison S, Nichol AD, Paterson DL, Peake S, Richards B, Stephens D, Turner A, Yung M (2009) Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 361(20):1925–1934
Armstrong PK, Dowse GK, Effler PV, Carcione D, Blyth CC, Richmond PC, Geelhoed GC, Mascaro F, Scully M, Weeramanthri TS (2011) Epidemiological study of severe febrile reactions in young children in Western Australia caused by a 2010 trivalent inactivated influenza vaccine. Br Med J Open 1(1):e000016
Basta NE, Chao DL, Halloran ME, Matrajt L, Longini IM Jr (2009) Strategies for pandemic and seasonal influenza vaccination of schoolchildren in the United States. Am J Epidemiol 170(6):679–686
Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE, Balish A, Medina MJ, Wallis TR, Guarner J, Paddock CD, Shieh WJ, Zaki SR, Sejvar JJ, Shay DK, Harper SA, Cox NJ, Fukuda K, Uyeki TM, Team ISI (2005) Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med 353(24):2559–2567
Block SL, Heikkinen T, Toback SL, Zheng W, Ambrose CS (2011) The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children. Pediatr Infect Dis J 30(3):203–207
Blumental S, Huisman E, Cornet MC, Ferreiro C, De Schutter I, Reynders M, Wybo I, Kabamba-Mukadi B, Armano R, Hermans D, Nassogne MC, Mahadeb B, Fonteyne C, Van Berlaer G, Levy J, Moulin D, Vergison A, Malfroot A, Lepage P (2011) Pandemic A/H1N1v influenza 2009 in hospitalized children: a multicenter Belgian survey. BMC Infect Dis 11(1):313
Bourgeois FT, Valim C, Wei JC, McAdam AJ, Mandl KD (2006) Influenza and other respiratory virus-related emergency department visits among young children. Pediatrics 118(1):e1–e8
Bourgeois FT, Valim C, McAdam AJ, Mandl KD (2009) Relative impact of influenza and respiratory syncytial virus in young children. Pediatrics 124(6):e1072–e1080
Brownstein JS, Kleinman KP, Mandl KD (2005) Identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system. Am J Epidemiol 162(7):686–693
Bueving HJ, van der Wouden JC, Berger MY, Thomas S (2005) Incidence of influenza and associated illness in children aged 0–19 years: a systematic review. Rev Med Virol 15(6):383–391
Buss BF, Shinde VM, Safranek TJ, Uyeki TM (2009) Pediatric influenza-associated myositis—Nebraska, 2001–2007. Influenza Other Respi Viruses 3(6):277–285
Centers for Disease Control and Prevention (2009) Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection— United States, April–August 2009. MMWR Morb Mortal Wkly Rep 58(34):941–947
Centers for Disease Control and Prevention (2010) Estimates of deaths associated with seasonal influenza – United States, 1976–2007. MMWR Morb Mortal Wkly Rep 59(33):1057–1062
Centers for Disease Control and Prevention (2010) Flu-related hospitalizations and deaths in the United States from April 2009–January 30, 2010. http://www.cdc.gov/h1n1flu/hosp_deaths_ahdra.htm. Accessed 26 Aug 2012
Centers for Disease Control and Prevention (2011) Influenza-associated pediatric deaths–United States, September 2010-August 2011. MMWR Morb Mortal Wkly Rep 60(36):1233–1238
Centers for Disease Control and Prevention (2011) Who should get vaccinated against influenza. http://www.cdc.gov/flu/protect/whoshouldvax.htm. Accessed 26 Aug 2012
Centers for Disease Control and Prevention (2012) Prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices (ACIP)—United States, 2012–13 Influenza Season. Morb Mortal Wkly Rep 61(32):613–618
Charu V, Viboud C, Simonsen L, Sturm-Ramirez K, Shinjoh M, Chowell G, Miller M, Sugaya N (2011) Influenza-related mortality trends in Japanese and American seniors: evidence for the indirect mortality benefits of vaccinating schoolchildren. PLoS One 6(11):e26282
Chen SC, Liao CM (2008) Modelling control measures to reduce the impact of pandemic influenza among schoolchildren. Epidemiol Infect 136(8):1035–1045
Chiu SS, Chan K-H, So LY, Chen R, Chan EL, Peiris JS (2012) The population based socioeconomic burden of pediatric influenza-associated hospitalization in Hong Kong. Vaccine 30(10):1895–1900
Coffin SE, Zaoutis TE, Rosenquist AB, Heydon K, Herrera G, Bridges CB, Watson B, Localio R, Hodinka RL, Keren R (2007) Incidence, complications, and risk factors for prolonged stay in children hospitalized with community-acquired influenza. Pediatrics 119(4):740–748
Coffin SE, Leckerman K, Keren R, Hall M, Localio R, Zaoutis TE (2011) Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. Pediatr Infect Dis J 30(11):962–966
Colombo C, Argiolas L, La Vecchia C, Negri E, Meloni G, Meloni T (2001) Influenza vaccine in healthy preschool children. Rev Epidemiol Sante Publique 49(2):157–162
Cox CM, Blanton L, Dhara R, Brammer L, Finelli L (2011) 2009 pandemic influenza A (H1N1) deaths among children–United States, 2009–2010. Clin Infect Dis 52(Suppl 1):S69–S74
Dawood FS, Fiore A, Kamimoto L, Nowell M, Reingold A, Gershman K, Meek J, Hadler J, Arnold KE, Ryan P, Lynfield R, Morin C, Baumbach J, Zansky S, Bennett NM, Thomas A, Schaffner W, Kirschke D, Finelli L, Emerging Infections Program (EIP) Network (2010) Influenza-associated pneumonia in children hospitalized with laboratory-confirmed influenza, 2003–2008. Pediatr Infect Dis J 29(7):585–590
Engelhard D, Bromberg M, Averbuch D, Tenenbaum A, Goldmann D, Kunin M, Shmueli E, Yatsiv I, Weintraub M, Mandelboim M, Strauss-Liviatan N, Anis E, Mendelson E, Shohat T, Wolf DG, Shapiro M, Grotto I (2011) Increased extent of and risk factors for pandemic (H1N1) 2009 and seasonal influenza among children, Israel. Emerg Infect Dis 17(9):1740–1743
Esposito S, Marchisio P, Cavagna R, Gironi S, Bosis S, Lambertini L, Droghetti R, Principi N (2003) Effectiveness of influenza vaccination of children with recurrent respiratory tract infections in reducing respiratory-related morbidity within the households. Vaccine 21:3162–3168
Esposito S, Molteni CG, Daleno C, Valzano A, Fossali E, Da Dalt L, Cecinati V, Bruzzese E, Giacchino R, Giaquinto C, Galeone C, Lackenby A, Principi N (2010) Clinical importance and impact on the households of oseltamivir-resistant seasonal A/H1N1 influenza virus in healthy children in Italy. Virol J 7:202
Esposito S, Cantarutti L, Molteni CG, Daleno C, Scala A, Tagliabue C, Pelucchi C, Giaquinto C, Principi N (2011) Clinical manifestations and socio-economic impact of influenza among healthy children in the community. J Infect 62(5):379–387
Esposito S, Daleno C, Baldanti F, Scala A, Campanini G, Taroni F, Fossali E, Pelucchi C, Principi N (2011) Viral shedding in children infected by pandemic A/H1N1/2009 influenza virus. Virol J 8:349
Fanella ST, Pinto MA, Bridger NA, Bullard JM, Coombs JM, Crockett ME, Olekson KL, Poliquin PG, Van Caeseele PG, Embree JE (2011) Pandemic (H1N1) 2009 influenza in hospitalized children in Manitoba: nosocomial transmission and lessons learned from the first wave. Infect Control Hosp Epidemiol 32(5):435–443
Finelli L, Fiore A, Dhara R, Brammer L, Shay DK, Kamimoto L, Fry A, Hageman J, Gorwitz R, Bresee J, Uyeki T (2008) Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection. Pediatrics 122(4):805–811
Fleming DM, Pannell RS, Cross KW (2005) Mortality in children from influenza and respiratory syncytial virus. J Epidemiol Community Health 59(7):586–590
Frobert E, Sarret C, Billaud G, Gillet Y, Escuret V, Floret D, Casalegno JS, Bouscambert M, Morfin F, Javouhey E, Lina B (2011) Pediatric neurological complications associated with the A(H1N1)pdm09 influenza infection. J Clin Virol 52(4):307–313
Ghendon YZ, Kaira AN, Elshina GA (2006) The effect of mass influenza immunization in children on the morbidity of the unvaccinated elderly. Epidemiol Infect 134(1):71–78
Giglio N, Gentile A, Lees L, Micone P, Armoni J, Reygrobellet C, Crepey P (2012) Public health and economic benefits of new pediatric influenza vaccination programs in Argentina. Hum Vaccin Immunother 8(3):312–322
Glass LM, Glass RJ (2008) Social contact networks for the spread of pandemic influenza in children and teenagers. BMC Publ Health 8:61
Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA (1997) Influenza virus infections in infants. Pediatr Infect Dis J 16(11):1065–1068
Glezen WP, Gaglani MJ, Kozinetz CA, Piedra PA (2010) Direct and indirect effectiveness of influenza vaccination delivered to children at school preceding an epidemic caused by 3 new influenza virus variants. J Infect Dis 202(11):1626–1633
Gordon A, Saborío S, Videa E, López R, Kuan G, Balmaseda A, Harris E (2010) Clinical attack rate and presentation of pandemic H1N1 influenza versus seasonal influenza A and B in a pediatric cohort in Nicaragua. Clin Infect Dis 50(11):1462–1467
Halasa NB (2010) Update on the 2009 pandemic influenza A H1N1 in children. Curr Opin Pediatr 22(1):83–87
Hassan F, Lewis TC, Davis MM, Gebremariam A, Dombkowski K (2009) Hospital utilization and costs among children with influenza, 2003. Am J Prev Med 36(4):292–296
Hayden FG, Belshe R, Villanueva C, Lanno R, Hughes C, Small I, Dutkowski R, Ward P, Carr J (2004) Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 189(3):440–449
Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P (1991) Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 145(4):445–448
Heikkinen T, Ziegler T, Peltola V, Lehtinen P, Toikka P, Lintu M, Jartti T, Juvén T, Kataja J, Pulkkinen J, Kainulainen L, Puhakka T, Routi T (2003) Incidence of influenza in Finnish children. Pediatr Infect Dis J 22(10 Suppl):S204–S206
Heikkinen T, Silvennoinen H, Peltola V, Ziegler T, Vainionpaa R, Vuorinen T, Kainulainen L, Puhakka T, Jartti T, Toikka P, Lehtinen P, Routi T, Juven T (2004) Burden of influenza in children in the community. J Infect Dis 190(8):1369–1373
Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Vahlberg T, Ziegler T, Ikonen N, Puhakka T, Heikkinen T (2010) Early oseltamivir treatment of influenza in children 1–3 years of age: a randomized controlled trial. Clin Infect Dis 51(8):887–894
Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Ziegler T, Heikkinen T (2011) Effectiveness of inactivated influenza vaccine in children aged 9 months to 3 years: an observational cohort study. Lancet Infect Dis 11(1):23–29
Heinonen S, Peltola V, Silvennoinen H, Vahlberg T, Heikkinen T (2012) Signs and symptoms predicting influenza in children: a matched case–control analysis of prospectively collected clinical data. Eur J Clin Mic Infect Dis 31(7):1569–1574
Herberg JA, Jones KD, Paulus S, Gormley S, Muir D, Cooper M, Levin M (2011) Comparison of pandemic and seasonal influenza reveals higher mortality and increased prevalence of shock in children with severe H1N1/09 infection. Pediatr Infect Dis J 30(5):438–440
Hoberman A, Greenberg DP, Paradise JL, Rockette HE, Lave JR, Kearney DH, Colborn DK, Kurs-Lasky M, Haralam MA, Byers CJ, Zoffel LM, Fabian IA, Bernard BS, Kerr JD (2003) Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA 290(12):1608–1616
Hu JJ, Kao CL, Lee PI, Chen CM, Lee CY, Lu CY, Huang LM (2004) Clinical features of influenza A and B in children and association with myositis. J Microbiol Immunol Infect 37(2):95–98
Hurwitz ES, Haber M, Chang A, Shope T, Teo S, Ginsberg M, Waecker N, Cox NJ (2000) Effectiveness of influenza vaccination of day care children in reducing influenza-related morbidity among household contacts. JAMA 284(13):1677–1682
Izurieta HS, Thompson WW, Kramarz P, Shay DK, Davis RL, DeStefano F, Black S, Shinefield H, Fukuda K (2000) Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 342(4):232–239
Jefferson T, Jones MA, Doshi P et al (2012) Neuraminidase inhibitors for preventing influenza in healthy adults and children (Review). Cochrane Database Syst Rev 1, CD008965
Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Ferroni E (2012) Vaccines for preventing influenza in healthy children (Review). Cochrane Database Syst Rev 8, CD004879
Joint Committee on Vaccination and Immunisation (2012) JCVI statement on the annual influenza vaccination programme—extension of the programme to children. https://www.wp.dh.gov.uk/transparency/files/2012/07/JCVI-statement-on-the-annual-influenza-vaccination-programme-25-July-2012.pdf. Accessed 12 Sep 2012
Katayose M, Hosoya M, Haneda T, Yamaguchi H, Kawasaki Y, Sato M, Wright PF (2011) The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons. Vaccine 29(9):1844–1849
Kedia S, Stroud B, Parsons J, Schreiner T, Curtis DJ, Bagdure D, Brooks-Kayal AR, Glode MP, Dominguez SR (2011) Pediatric neurological complications of 2009 pandemic influenza A (H1N1). Arch Neurol 68(4):455–462
Lahti E, Peltola V, Virkki R, Ruuskanen O (2006) Influenza pneumonia. Pediatr Infect Dis J 25(2):160–164
Landau YE, Grisaru-Soen G, Reif S, Fattal-Valevski A (2011) Pediatric neurologic complications associated with influenza A H1N1. Pediatr Neurol 44(1):47–51
Launay E, Ovetchkine P, Saint-Jean M, Coïc L, Ducruet T, Charest H, Desmarais N, Lamarre V, Tapiéro B (2011) Novel influenza A (H1N1): clinical features of pediatric hospitalizations in two successive waves. Int J Infect Dis 15(2):e122–e130
Libster R, Bugna J, Coviello S, Hijano DR, Dunaiewsky M, Reynoso N, Cavalieri ML, Guglielmo MC, Areso MS, Gilligan T, Santucho F, Cabral G, Gregorio GL, Moreno R, Lutz MI, Panigasi AL, Saligari L, Caballero MT, Egües Almeida RM, Gutierrez Meyer ME, Neder MD, Davenport MC, Del Valle MP, Santidrian VS, Mosca G, Garcia Domínguez M, Alvarez L, Landa P, Pota A, Boloñati N, Dalamon R, Sanchez Mercol VI, Espinoza M, Peuchot JC, Karolinski A, Bruno M, Borsa A, Ferrero F, Bonina A, Ramonet M, Albano LC, Luedicke N, Alterman E, Savy V, Baumeister E, Chappell JD, Edwards KM, Melendi GA, Polack FP (2010) Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med 362(1):45–55
Lochindarat S, Bunnag T (2011) Clinical presentations of pandemic 2009 influenza A (H1N1) virus infection in hospitalized Thai children. J Med Assoc Thai 94(Suppl 3):S107–S112
Long CE, Hall CB, Cunningham CK, Weiner LB, Alger KP, Gouveia M, Colella CB, Schnabel KC, Barker WH (1997) Influenza surveillance in community-dwelling elderly compared with children. Arch Fam Med 6(5):459–465
Loughlin J, Poulios N, Napalkov P, Wegmüller Y, Monto AS (2003) A study of influenza and influenza-related complications among children in a large US health insurance plan database. PharmacoEconomics 21(4):273–283
Luce BR, Zangwill KM, Palmer CS, Mendelman PM, Yan L, Wolff MC, Cho I, Marcy SM, Iacuzio D, Belshe RB (2001) Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children. Pediatrics 108(2):E24
Maeda T, Shintani Y, Nakano K, Terashima K, Yamada Y (2004) Failure of inactivated influenza A vaccine to protect healthy children aged 6-24 months. Pediatr Int 46(2):122–125
Marchisio P, Esposito S, Bianchini S, Dusi E, Fusi M, Nazzari E, Picchi R, Galeone C, Principi N (2009) Efficacy of injectable trivalent virosomal-adjuvanted inactivated influenza vaccine in preventing acute otitis media in children with recurrent complicated or noncomplicated acute otitis media. Pediatr Infect Dis J 28(10):855–859
Miroballi Y, Baird JS, Zackai S, Cannon JM, Messina M, Ravindranath T, Green R, Della-Latta P, Jenkins S, Greenwald BM, Furuya EY, Graham PL 3rd, Sonnett FM, Platt S, Delamora P, Saiman L (2010) Novel influenza A(H1N1) in a pediatric health care facility in New York City during the first wave of the 2009 pandemic. Arch Pediatr Adolesc Med 164(1):24–30
Monto AS, Koopman JS, Longini IM Jr (1985) Tecumseh study of illness. XIII. Influenza infection and disease, 1976–1981. Am J Epidemiol 121(6):811–822
Monto AS, Sullivan KM (1993) Acute respiratory illness in the community. Frequency of illness and the agents involved. Epidemiol Infect 110(1):145–160
Mori T, Morii M, Terada K, Wada Y, Kuroiwa Y, Hotsubo T, Fuse S, Nishioka S, Nishioka T, Tsutsumi H (2011) Clinical characteristics and computed tomography findings in children with 2009 pandemic influenza A (H1N1) viral pneumonia. Scand J Infect Dis 43(1):47–54
Mullooly JP, Barker WH (1982) Impact of type A influenza on children: a retrospective study. Am J Public Health 72(9):1008–1016
Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi SA, Simmerman JM, Gordon A, Sato M, Howie S, Krishnan A, Ope M, Lindblade KA, Carosone-Link P, Lucero M, Ochieng W, Kamimoto L, Dueger E, Bhat N, Vong S, Theodoratou E, Chittaganpitch M, Chimah O, Balmaseda A, Buchy P, Harris E, Evans V, Katayose M, Gaur B, O'Callaghan-Gordo C, Goswami D, Arvelo W, Venter M, Briese T, Tokarz R, Widdowson MA, Mounts AW, Breiman RF, Feikin DR, Klugman KP, Olsen SJ, Gessner BD, Wright PF, Rudan I, Broor S, Simões EA, Campbell H (2011) Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 378(9807):1917–1930
Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR (2000) The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 342(4):225–231
Neuzil KM, Wright PF, Mitchel EF Jr, Griffin MR (2000) The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 137(6):856–864
Neuzil KM, Hohlbein C, Zhu Y (2002) Illness among schoolchildren during influenza season: effect on school absenteeism, parental absenteeism from work, and secondary illness in families. Arch Pediatr Adolesc Med 156(10):986–991
Neuzil KM, Zhu Y, Griffin MR, Edwards KM, Thompson JM, Tollefson SJ, Wright PF (2002) Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis 185(2):147–152
Newland JG, Laurich VM, Rosenquist AW, Heydon K, Licht DJ, Keren R, Zaoutis TE, Watson B, Hodinka RL, Coffin SE (2007) Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors. J Pediatr 150(3):306–310
O'Brien MA, Uyeki TM, Shay DK, Thompson WW, Kleinman K, McAdam A, Yu XJ, Platt R, Lieu TA (2004) Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics 113(3 Pt 1):585–593
Osterholm MT, Kelley NS, Sommer A, Belongia EA (2012) Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 12(1):36–44
Ozgur SK, Beyazova U, Kemaloglu YK, Maral I, Sahin F, Camurdan AD, Kizil Y, Dinc E, Tuzun H (2006) Effectiveness of inactivated influenza vaccine for prevention of otitis media in children. Pediatr Infect Dis J 25(5):401–404
Paget WJ, Balderston C, Casas I, Donker G, Edelman L, Fleming D, Larrauri A, Meijer A, Puzelli S, Rizzo C, Simonsen L, EPIA collaborators (2010) Assessing the burden of paediatric influenza in Europe: the European Paediatric Influenza Analysis (EPIA) project. Eur J Pediatr 169(8):997–1008
Paisley JW, Bruhn FW, Lauer BA, McIntosh K (1978) Type A2 influenza viral infections in children. Am J Dis Child 132(1):34–36
Park SI, Kim MJ, Hwang HY, Oh CE, Lee JH, Park JS (2010) Clinical characteristics of children with 2009 pandemic influenza A (H1N1) admitted in a single institution. Korean J Pediatr 53(10):886–891
Peebles PJ, Dhara R, Brammer L, Fry AM, Finelli L (2011) Influenza-associated mortality among children—United States: 2007–2008. Influenza Other Respi Viruses 5(1):25–31. doi:10.1111/j.1750-2659.2010.00166.x
Peltola V, Ziegler T, Ruuskanen O (2003) Influenza A and B virus infections in children. Clin Infect Dis 36(3):299–305
Piedra PA, Gaglani MJ, Kozinetz CA, Herschler G, Riggs M, Griffith M, Fewlass C, Watts M, Hessel C, Cordova J, Glezen WP (2005) Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 23(13):1540–1548
Pitman RJ, White LJ, Sculpher M (2012) Estimating the clinical impact of introducing paediatric influenza vaccination in England and Wales. Vaccine 30(6):1208–1224
Poehling KA, Edwards KM, Weinberg GA, Szilagyi P, Staat MA, Iwane MK, Bridges CB, Grijalva CG, Zhu Y, Bernstein DI, Herrera G, Erdman D, Hall CB, Seither R, Griffin MR, Network NVS (2006) The underrecognized burden of influenza in young children. N Engl J Med 355(1):31–40
Polkinghorne BG, Muscatello DJ, Macintyre CR, Lawrence GL, Middleton PM, Torvaldsen S (2011) Relationship between the population incidence of febrile convulsions in young children in Sydney, Australia and seasonal epidemics of influenza and respiratory syncytial virus, 2003–2010: a time series analysis. BMC Infect Dis 11(1):291
Randolph AG, Vaughn F, Sullivan R, Rubinson L, Thompson BT, Yoon G, Smoot E, Rice TW, Loftis LL, Helfaer M, Doctor A, Paden M, Flori H, Babbitt C, Graciano AL, Gedeit R, Sanders RC, Giuliano JS, Zimmerman J, Uyeki TM, the Pediatric Acute Lung Injury and Sepsis Investigator's Network and the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (2011) Critically ill children during the 2009-2010 influenza pandemic in the United States. Pediatrics 128(6):e1450–e1458
Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M (2001) The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med 344(12):889–896
Reingold AL, on behalf of Miller L and the SAGE Influenza Working Group (2012) Proposed revisions to the 2005 WHO position paper on influenza vaccines, 2012. http://www.who.int/immunization/sage/meetings/2012/april/4_A.Reingold_WHO-InflWorkGrpPosPaper.pdf. Accessed 12 Sep 2012
Rekhtman D, Wolf DG, Levy-Khademi F, Averbuch D, Kerem E, Wexler ID (2011) Influenza A infection in young infants. Arch Dis Child 96(11):1085–1087
Robert Koch Institute (2010) Review: epidemiology and infection protection during the H1N1(2009) influenza pandemic [in German]. Epidemiologisches Bulletin 21:191–197
Robert Koch Institute (2011) Influenza infection: comparison of risk factors in households during the seasons 2008/09 and 2009/10 in Germany [in German]. Epidemiologisches Bulletin 49:443–450
Robert Koch Institute (2012) Elimination and transmission characteristics of influenza in households. Comparison of four seasons between 2007-08 and 2010-11 [in German]. Epidemiologisches Bulletin 18:151–161
Sachedina N, Donaldson LJ (2010) Paediatric mortality related to pandemic influenza A H1N1 infection in England: an observational population-based study. Lancet 376(9755):1846–1852
Saito R, Sato I, Suzuki Y, Baranovich T, Matsuda R, Ishitani N, Dapat C, Dapat IC, Zaraket H, Oguma T, Suzuki H (2010) Reduced effectiveness of oseltamivir in children infected with oseltamivir-resistant influenza A (H1N1) viruses with His275Tyr mutation. Pediatr Infect Dis J 29(10):898–904
Schanzer DL, Langley JM, Tam TW (2006) Hospitalization attributable to influenza and other viral respiratory illnesses in Canadian children. Pediatr Infect Dis J 25(9):795–800
Schanzer D, Vachon J, Pelletier L (2011) Age-specific differences in influenza A epidemic curves: do children drive the spread of influenza epidemics? Am J Epidemiol 174(1):109–117
Schrag SJ, Shay DK, Gershman K, Thomas A, Craig AS, Schaffner W, Harrison LH, Vugia D, Clogher P, Lynfield R, Farley M, Zansky S, Uyeki T, Emerging Infections Program Respiratory Diseases Activity (2006) Multistate surveillance for laboratory-confirmed, influenza-associated hospitalizations in children: 2003–2004. Pediatr Infect Dis J 25(5):395–400
Serwint JR, Miller RM, Korsch BM (1991) Influenza type A and B infections in hospitalized pediatric patients. Who should be immunized? Am J Dis Child 145(6):623–626
Sharon N, Talnir R, Lavid O, Rubinstein U, Niven M, First Y, Tsivion AJ, Schachter Y (2011) Transient lymphopenia and neutropenia: pediatric influenza A/H1N1 infection in a primary hospital in Israel. Isr Med Assoc J 13(7):408–412
Shin SY, Kim JH, Kim HS, Kang YA, Lee HG, Kim JS, Lee JK, Kim WK (2010) Clinical characteristics of Korean pediatric patients critically ill with influenza A (H1N1) virus. Pediatr Pulmonol 45(10):1014–1020
Shun-Shin M, Thompson M, Heneghan C, Perera R, Harnden A, Mant D (2009) Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. BMJ 339:b3172. doi:10.1136/bmj.b3172
Silvennoinen H, Peltola V, Lehtinen P, Vainionpää R, Heikkinen T (2009) Clinical presentation of influenza in unselected children treated as outpatients. Pediatr Infect Dis J 28(5):372–375
Silvennoinen H, Peltola V, Vainionpää R, Ruuskanen O, Heikkinen T (2011) Admission diagnoses of children 0–16 years of age hospitalized with influenza. Eur J Clin Microbiol Infect Dis 31(3):225–231
Silvennoinen H, Peltola V, Vainionpää R, Ruuskanen O, Heikkinen T (2011) Incidence of influenza-related hospitalizations in different age groups of children in Finland: a 16-year study. Pediatr Infect Dis J 30(2):e24–e28
Smits AJ, Hak E, Stalman WA, van Essen GA, Hoes AW, Verheij TJ (2002) Clinical effectiveness of conventional influenza vaccination in asthmatic children. Epidemiol Infect 128(2):205–211
Song X, DeBiasi RL, Campos JM, Fagbuyi DB, Jacobs BR, Singh N (2012) Comparison of pandemic and seasonal influenza A infections in pediatric patients: were they different? Influenza Other Respi Viruses 6(1):25–27. doi:10.1111/j.1750-2659.2011.00258.x
Stein M, Tasher D, Glikman D, Shachor-Meyouhas Y, Barkai G, Yochai AB, Leibovitz E, Hausman-Kedem M, Hess A, Megged O, Kassis I, Gresario G, Somekh E (2010) Hospitalization of children with influenza A(H1N1) virus in Israel during the 2009 outbreak in Israel: a multicenter survey. Arch Pediatr Adolesc Med 164(11):1015–1022
Streng A, Grote V, Liese JG (2011) Severe influenza cases in paediatric intensive care units in Germany during the pre-pandemic seasons 2005 to 2008. BMC Infect Dis 11:233
Sugaya N, Shinjoh M, Mitamura K, Takahashi T (2011) Very low pandemic influenza A (H1N1) 2009 mortality associated with early neuraminidase inhibitor treatment in Japan: analysis of 1000 hospitalized children. J Infect 63(4):288–294
Takeuchi M, Yasunaga H, Horiguchi H, Matsuda S (2012) Clinical features of infants hospitalized for 2009 pandemic influenza A (H1N1) in Japan: analysis using a national hospital discharge database. Pediatr Infect Dis J 31(4):368–372
Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289(2):179–186
Torres SF, Iolster T, Schnitzler EJ, Farias JA, Bordogna AC, Rufach D, Montes MJ, Siaba AJ, Rodríguez MG, Jabornisky R, Colman C, Fernández A, Caprotta G, Diaz S, Poterala R, De Meyer M, Penazzi ME, González G, Saenz S, Recupero O, Zapico L, Alarcon B, Ariel E, Minces P, Mari E, Carnie A, Garea M, Jaen R (2012) High mortality in patients with influenza A pH1N1 2009 admitted to a pediatric intensive care unit: a predictive model of mortality. Pediatr Crit Care Med 13(2):e78–e83
Vesikari T, Knuf M, Wutzler P, Karvonen A, Kieninger-Baum D, Schmitt HJ, Baehner F, Borkowski A, Tsai TF, Clemens R (2011) Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 365(15):1406–1416
Viboud C, Boelle P-Y, Cauchemez S, Lavenu A, Valleron AJ, Flahault A, Carrat F (2004) Risk factors of influenza transmission in households. Br J Gen Pract 54(506):684–689
von Kries R, Weiss S, Falkenhorst G, Wirth S, Kaiser P, Huppertz HI, Tenenbaum Schroten H, Streng A, Liese J, Shai S, Niehues T, Girschick H, Kuscher E, Sauerbrey A, Peters J, Wirsing von König CH, Rückinger S, Hampl W, Michel D, Mertens T (2011) Post-pandemic seroprevalence of pandemic influenza A (H1N1) 2009 infection (swine flu) among children <18 years in Germany. PLoS One 6(9):e23955
Wang YH, Huang YC, Chang LY, Kao HT, Lin PY, Huang CG, Lin TY (2003) Clinical characteristics of children with influenza A virus infection requiring hospitalization. J Microbiol Immunol Infect 36(2):111–116
Wang K, Shun-Shin M, Gill P, Perera R, Harnden A (2012) Neuraminidase inhibitors for preventing and treating influenza in children (published trials only). Cochrane Database Syst Rev 4, CD002744
Weigl JA, Puppe W, Schmitt HJ (2002) The incidence of influenza-associated hospitalizations in children in Germany. Epidemiol Infect 129(3):525–533
Wijngaard CC, Asten L, Koopmans MP, Pelt W, Nagelkerke NJ, Wielders CC, Lier A, Hoek W, Meijer A, Donker GA, Dijkstra F, Harmsen C, Sande MA, Kretzschmar M (2012) Comparing pandemic to seasonal influenza mortality: moderate impact overall but high mortality in young children. PLoS One 7(2):e31197
World Health Organisation (WHO) (2010) WHO guidelines for pharmacological management of pandemic influenza A(H1N1) 2009 and other influenza viruses. Available at: http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf
Wright PF, Ross KB, Thompson J, Karzon DT (1977) Influenza A infections in young children. Primary natural infection and protective efficacy of live-vaccine-induced or naturally acquired immunity. N Engl J Med 296(15):829–834
Wright PF, Bryant JD, Karzon DT (1980) Comparison of influenza B/Hong Kong virus infections among infants, children, and young adults. J Infect Dis 141(4):430–435
Zuccotti G, Dilillo D, Zappa A, Galli E, Amendola A, Martinelli M, Pariani E, Salvini F, Tanzi E, Riva E, Giovannini M (2011) Epidemiological and clinical features of respiratory viral infections in hospitalized children during the circulation of influenza virus A(H1N1) 2009. Influenza Other Respi Viruses 5(6):e528–e534. doi:10.1111/j.1750-2659.2011.00264.x
Medical writing support for the development of this article was provided by Roger Nutter and Scott Malkin at Gardiner-Caldwell Communications, Macclesfield, UK. Funding for this support was provided by AstraZeneca. The article was the concept of the authors, who directed all aspects of the searching and drafting as well as reviewing and commenting on all drafts. The medical writers supported the authors by identifying articles for potential inclusion, developing outline content, and developing and revising drafts with authors’ input. Comments from Christopher S Ambrose, MD (Vice President Medical and Scientific Affairs, MedImmune, LLC, Gaithersburg, USA) on the final draft were considered by the authors and taken in where considered helpful.
Conflict of interest
MK has received honoraria for presentations and advisory activities and compensation for travel expenses from AstraZeneca, GSK and Novartis. BRR has received honoraria for presentations and advisory activities and compensation for travel expenses from AstraZeneca, GSK, Pfizer, Roche and Sanofi Pasteur MSD.
About this article
Cite this article
Ruf, B.R., Knuf, M. The burden of seasonal and pandemic influenza in infants and children. Eur J Pediatr 173, 265–276 (2014). https://doi.org/10.1007/s00431-013-2023-6