Introduction
Influenza A and B viruses cause winter-seasonal epidemics of respiratory illness in the northern hemisphere that have been reported to affect 5–15% of the population each winter [
40], with reports of paediatric attack rates between 20% and 35% depending on season and methodology. Symptoms of the disease vary from mild (e.g. requiring little or no treatment) to severe (e.g. requiring hospitalisation). Though death is more common in the elderly and populations that have a higher risk of developing complications following an influenza virus infection (e.g. persons with chronic heart and lung diseases, diabetes, immunodeficiency, pregnancy etc.), severe disease and some deaths occur each season in healthy young and middle-aged adults and children.
Recommendations to vaccinate high-risk populations and persons over 65 years have been implemented in Europe since the 1980s/1990s (1999/2000 season in the UK) [
7,
24,
33]. With minor exceptions, vaccination recommendations are broadly similar across Europe, with most countries recommending the vaccination of persons over 65 years and high-risk groups. In Hungary, Germany and The Netherlands, the age threshold is 60 years; in Finland (since 2007), vaccination of children aged 6–35 months is recommended; in Austria, vaccination is recommended for persons of all ages [
27]. All countries in Europe aim to meet the WHO Assembly goal of vaccinating 75% of high-risk groups by 2010. Results of a regional (European Union and European Economic Area) survey published in 2008 indicated that influenza vaccination coverage rates in the elderly (i.e. ≥65 years) varied substantially from less than 10% in some countries to over 70% in others [
27].
Several countries, including Argentina, Canada, Finland, Mexico, Singapore and the USA, have recently extended their vaccination recommendations to include younger age groups [
41]. These decisions were based, in part, on evidence demonstrating that influenza has substantial adverse impacts among school-age children and their contacts (e.g. significant school absenteeism, antibiotic use, medical care visits and parental work loss) compared to uninfected or asymptomatic children [
5,
15,
17,
28]. Additionally, studies have suggested that vaccination of children has the potential to reduce influenza among their household contacts and within the community, thereby reducing the risk of influenza even in high-risk groups (herd immunity) [
18,
32,
39]. The US recommendations have recently evolved from 6 to 23 months in 2004 to 6–59 months in 2006 to now include all children up to 18 years of age. The increasing focus on paediatric age groups was in large part fuelled by the heightened awareness of paediatric influenza mortality starting with the severe 2003–2004 Fujian A(H3N2) season [
2,
3].
In 2007, a scientific panel on vaccines and immunisation, in conjunction with the European Centre for Disease Prevention and Control (ECDC), published a technical report on routine influenza vaccination in children [
36]. The report emphasised that the first step towards any decision regarding routine immunisation in children is to determine specific national profiles of the disease burden. Estimates of the burden of influenza in children using sentinel practice data from England and Wales suggested that in a typical winter epidemic between 1987/1988 and 1996/1997, 1.2% of children aged 0–4 and 1.1% of children aged 5–14 years sought medical attention and were diagnosed with ILI; in addition, many more children were diagnosed with other respiratory syndromes such as acute bronchitis and otitis media [
14]. The same study using similar data from The Netherlands estimated that 3.0% of children 0–4 years and 1.9% of children 5–14 years had medically attended ILI in a season. Paradoxically, the Dutch general practitioners, who reported a higher seasonal ILI percentage, worked with a stricter case definition than in the UK.
Because the ECDC report concluded that paediatric disease burden estimates were scarce in most European countries and that this would hamper the ability of countries to make policy decisions about the influenza vaccine, the European Paediatric Influenza Analysis (EPIA) project was created in 2008 to collect, analyse and present paediatric influenza burden data in countries across Europe. The approach taken by EPIA was to base the modelling on the robust virological and epidemiological surveillance networks in European countries to generate country-specific disease burden estimates for mild illness (ILI), severe illness (e.g. pneumonia hospitalisations) and mortality. Here, we present the EPIA project, its methods, planned studies and results so far.
The EPIA project
Background
Table
1 outlines the different types of data that have been (or will be in the future) collected by EPIA. The project was formed around the European Influenza Surveillance Scheme (EISS) [
10], and the first modelling work has centred on the ILI data and virological data collected by this network from 1996 up to 2008. Both the ILI and virological data were collected weekly for the winter periods (i.e. seasons) from week 40 (October) to week 20 (May) of the following year. Data have been collected according to a case definition (in most countries), and the sentinel physicians took nose/throat swabs from a selection of their patients and sent the specimens to their National Influenza Centre to validate the clinical reports made by the sentinel physicians and to determine virus characteristics (i.e. (sub)type) which might impact the severity of disease and extent of virus circulation (e.g. Arkema et al. [
1]). While multiple ILI consultations in the context of a single episode are not reported by physicians, multiple episodes for the same patient are reported on occasion but would likely represent a small effect on the incidence estimates reported in the current study.
Table 1
Data types collected by EPIA for disease and pharmacoeconomic burden estimation
Weekly outpatient visits from sentinel physicians (ILI data) |
Weekly virological data from sentinel and non-sentinel sources (influenza and RSV data) |
Weekly or monthly hospitalisation data: pneumonia, sepsis and more; outcomes may include numbers of visits, hospital days and the cost of the event |
Weekly or monthly emergency department data |
Weekly or monthly antibiotic utilisation data |
Weekly or monthly mortality data: influenza and pneumonia, sepsis and more |
The virological data were obtained from weekly sentinel and non-sentinel reports from National Influenza Centres, with the sentinel data coming from the sentinel surveillance systems and the non-sentinel specimens coming from other sources (e.g. hospital and peripheral diagnostic laboratories). As most sentinel specimens have been tested for influenza and RSVs, with the exception of Spain, the National Influenza Centres provide weekly data on both viruses. Within three of the four country datasets (England, The Netherlands and Spain), the majority of the RSV data were non-sentinel in nature (in The Netherlands and Spain, these data were obtained from separate surveillance systems: the Dutch Working Group on Clinical Virology in The Netherlands and the Microbiological Information System in Spain), but valid inclusion was assumed based on published reports of these isolates being derived from mostly children [
14,
16,
38]. Laboratories within the EISS system regularly participated in quality control assessments reported elsewhere [
25,
26]. RSV is a virus that often represents a confounding variable in influenza research of this type as its resulting infection can produce similar symptoms and the virus often circulates in a seasonal pattern along with influenza viruses [
11]. Whilst the ILI data are age specific (0–4, 5–14, 15–64 and 65+), the virological data were only available for all ages; for the purpose of EPIA modelling, we have assumed that all-age epidemic patterns for influenza virus and RSV detections are representative of epidemic patterns (intensity and duration) in the paediatric age groups, a generally accepted method within this area of research (e.g. [
13,
14,
19,
30]).
To estimate the contribution of moderate and severe outcomes due to influenza virus and RSV infections, EPIA is also collecting weekly or monthly hospital (and, in the case of Denmark, emergency department) discharge data from each country. To this end, EPIA has developed a list of influenza-relevant ICD-9 and ICD-10 code ranges and submitted requests for extraction of data, stratified by up to 24 age groups. These ICD-coded definitions are also being used to obtain mortality data from each country. The current study focuses entirely on the modelled burden of physician-intended ILI in children (in the outpatient setting). Analyses of inpatient and mortality data will be published separately.
Participating countries
All European countries are invited to participate in the EPIA project provided they have several years of virological data (weekly counts of subtyped influenza viruses and RSVs) and data from at least one outcome of interest; for example, ILI or inpatient data. Currently, the following seven countries participate in the EPIA project: Denmark, England, Finland, Italy, The Netherlands, Scotland and Spain. In this paper, we report results from a subset of EPIA member countries for which the ILI data and virology data had been obtained, cleaned, analysed and discussed with the country collaborators.
Management and underlying sponsorship
The private–public EPIA collaborative project is funded by MedImmune, the wholly owned biologics business for AstraZeneca PLC. The project is being implemented by SDI, a US market insight and analytics firm that consolidates electronic healthcare data (e.g. RSV surveillance in the USA [
4]) for clients in the private and public sectors. The partner, NIVEL, is located in The Netherlands and is a not-for-profit research foundation. NIVEL is responsible for coordinating EPIA activities in Europe based on its experience with the coordination of the EISS from November 1999 to September 2008 [
10].
EPIA ensures that the research, analysis and results are clearly independent of its underlying sponsor through the following measures:
1.
SDI, NIVEL and MedImmune have signed a Memorandum of Understanding which ensures that MedImmune is not involved in the study design, analysis, publication (aside from pre-publication review of the final manuscript) or management of the EPIA project (
http://www.nivel.eu/epia/).
2.
An independent Steering Committee (see below) has been established to supervise the EPIA project and ensure, that the Memorandum of Understanding is followed.
3.
Documents detailing the guiding principles enumerated in Box 1 were agreed upon by EPIA members. These principles clearly define the operating procedures with respect to data analyses, authorship, data ownership and conflict resolution.
The EPIA Steering Committee is comprised of five persons from various European Union Member States representing the following fields: influenza researchers, paediatricians, epidemiologists and virologists. In addition, a liaison from ECDC participates in Steering Committee and member meetings.
Box 1 Guiding principles of the European Paediatric Influenza Analysis project
Guiding principles
|
● Data ownership/sharing is decided by members or according to rules of data sources (e.g. private sector data) |
● EPIA is open to all countries in Europe |
● Models are shared with national collaborators |
● Multi-country and national publications are supported |
● EPIA is a publication-driven project |
● EPIA is a research project, not a surveillance project |
● A Memorandum of Understanding between the sponsor and the project managers ensures the sponsor does not influence data analysis or interpretation |
● The sponsor does not have access to the EPIA data |
● The project is guided by an independent Steering Committee |
Discussion
This paper outlines the design of the EPIA project, the modelling approach, and provides initial modelling results of the burden of medically attended influenza illness in four member countries and for two paediatric age groups. Across the four countries and two age groups investigated in this study, the total ILI burden varied widely between countries, with seasonal averages between 0.4% and 18% (mean = 5.2%; median = 2.4%) of the populations studied. Influenza epidemics were responsible for most of these ILI events, with seasonal averages of 0.3–9.8% (mean = 1.6%; median 3.3%) observed across countries and age groups. Calculated ILI consultation incidences for the UK and The Netherlands were slightly lower than those reported previously over the period 1986–1997 [
14], which is in line with other reports of decreasing incidence of ILI in recent years [
9]. With the exception of Spain, data from all countries revealed a higher incidence of influenza-attributed physician consultations in children aged 0–4 years. These findings are consistent with prior reports of younger children (e.g. infants and toddlers) bearing the highest influenza burden [
9].
As seen in Table
3, the results presented from the current study reflect considerable between-country variability in the burden of ILI that is attributed to influenza virus infections, with England having the smallest burden and Italy the highest. These international differences may be influenced by a number of factors. Case definitions, for example, vary between the countries studied (as a function of the fact that many national surveillance networks predate the establishment of the international EISS network). The number of symptoms required to diagnose a patient with ILI as well as specific symptoms themselves are not homogeneous across the countries analysed (i.e. fever is not necessary to diagnose ILI in all countries possibly allowing for a diagnosis in one country that would not otherwise be made in another). Many ILI symptoms are also subjective (e.g. weakness, myalgia, irritability) and diagnosed by self-report or parental reports, which may be sensitive to sociocultural differences between countries (e.g. the outlook of parents on what paediatric symptoms merit a visit to the doctor). Cultural and/or training differences may also play a role on the part of the diagnostician as well as adherence to case definitions. Health systems may also impact health-seeking behaviour through their funding structures, shortages of primary care physicians or other factors that could discourage patients from seeking care such as excessive waiting times, limited physician office hours or appointments.
Provision of primary care in paediatric populations may play a role in health-seeking behaviour as well. Paediatric primary care in Europe can be categorised into three distinct groups: (1) paediatrician-led, (2) GP-led and (3) a combination of the two [
22]. Two of the EPIA countries discussed (England and The Netherlands) represent the GP-led primary care system, where GPs act as ‘gatekeepers’ to more specialised care, while Spain has a paediatrician-led system and Italy a combined system (young children are generally cared for by paediatricians while school-age children have the option to see
either a paediatrician or a GP [
6]). Thus, our reported between-country differences are in agreement with more conservative health-seeking behaviour in GP-led primary care systems and far higher numbers of visits in the paediatrician-led systems. It is also important to note two specific points regarding the situation in Italy, where the highest ILI consultation rates were observed. There are more paediatricians in Italy than any other country in Europe, perhaps creating an environment where consulting a physician is easier for parents in this country compared to others. Additionally, there is a separate, more inclusive, case definition used to diagnose ILI in Italian children. Paediatric-specific ILI case definitions are not employed in the other countries studied.
The finding that an average (across countries and age groups) of 27% (range 13–48%) of the observed ILI incidence in children was not attributed to influenza or RSV by the model is in agreement with laboratory-based studies where, depending on the time point during winter, a varying proportion of ILI cases are determined to be due to respiratory pathogens other than influenza and RSV [
37]. Thus, pathogens including adenoviruses, metapneumovirus, parainfluenza viruses and
Streptococcus pneumoniae may explain some of the residual (unexplained) ILI consultations. However, the importance of influenza driving the ILI signal was evident as the ILI peak always coincided with the peak incidence in influenza virus data. Ideally, it would be useful to expand the model to include additional pathogens.
The low average seasonal attribution to influenza A(H1N1) viruses in England and The Netherlands (≤0.1% compared to the range of 0.4% (5–14 years old in Spain) and 2.6% (0–4 years old in Italy)) may reflect its low circulation during the study period 2002–2008 in those countries. Interestingly, our model attributed a relatively small proportion of ILI visits to RSV—a proportion that dropped further in the Dutch data sensitivity analysis when limiting the model period to seasons with discrete (rather than overlapping) RSV and influenza epidemics. Thus, our modelling approach likely tended to overestimate the RSV contribution to outpatient ILI visits.
A direct comparison between previous reports and the current study is not straightforward as the methods employed, range of study years and the outcomes under study are not identical. For example, the study of Fleming et al. [
13] was based solely on paediatric RSV and influenza during 1994–2000 and studied a more inclusive outcome, acute respiratory infections. The study of Pitman et al. [
30] utilised (among other datasets) national laboratory data for several viruses from 1990 to 2004 and numbers of outpatient consultations for all acute respiratory infections recorded in the General Practice Research Database during the winter of 2002 to 2003. The study of Jansen et al. [
20] utilised data from Dutch outpatients using a broader range of diagnoses that would not be captured in the ILI case definition, and utilised GP data from a single regional network rather than a national sentinel network. These three studies [
13,
20,
30] all found larger incidence rates of RSV, which emphasises that there is a need for data encompassing all acute respiratory infections (in order to capture more of the RSV burden), data which is not available in all but one of the EPIA countries (England) and as such could not be presented in this multi-country paper.
One additional limitation of EPIA between-country comparisons is that no standardised protocol was used in the national influenza surveillance systems in Europe; despite EISS collaborations since the 1990s [
1], the surveillance systems in each country have a different history, meaning that each country uses a different case definition and different types of reporting physicians (see Table
1), providing multiple opportunities for potential bias in estimated incidence rates. Efforts to harmonise the surveillance systems were initiated by the EISS project (e.g. age groups and virological swabbing forms [
1]), but differences remain and these almost certainly affect the incidence estimates. Because of this, we have chosen to present results by country and not for all countries grouped together.
With the modelling approach firmly established, the next steps for EPIA will be to extend the analysis to consider more severe outcomes of paediatric influenza, such as hospitalisations and deaths. Also, EPIA plans a number of special subset studies to investigate the consequence of different ILI case definitions in different countries, and the introduction of more viral respiratory pathogens into the model. Furthermore, an expanded age group analysis will be done to study the influenza versus RSV burden in infants. Finally, the emergence of the pandemic A(H1N1) swine-origin influenza virus in the spring of 2009 may inspire countries to use the EPIA model to estimate, near real time, the burden of this emerging virus in the subsequent winters when co-circulation of seasonal influenza viruses and RSV may occur.
The models developed and applied in the EPIA project will facilitate research to derive country-specific results indicating the national burden of paediatric influenza disease in each of the member countries. The overall objective will be to publish this burden of disease data (including pharmacoeconomic analyses) to inform paediatric vaccination recommendations. These analyses concern a very large population in Europe, with more than 52 million inhabitants in the European Union being children aged 0–14 [
8]. Our results so far demonstrate that there was a substantial outpatient febrile respiratory disease burden in some countries of the European Union in an average season between the years of 2002 (2003 in Italy) and 2008: In Italy, 9% to 10% of all children aged 0–14 visited their physician with influenza; in Spain, 2–3%; and in England and The Netherlands, <1%.
It is important to bear in mind that our results represent an underestimate of the influenza burden for several reasons: (1) the outcome measured excludes cases of influenza that were treated in other settings (i.e. hospitals and emergency departments) or those that were not professionally attended to, and (2) not all influenza infections are diagnosed as ILI.
As national profiles of paediatric influenza disease burden are determined, new issues and knowledge gaps must be considered. The pharmacoeconomic impact (e.g. cost–benefit analyses) of implementing a new recommendation should be investigated in addition to programmatic issues including feasibility and sustainability (from both financial and logistical perspectives). Finally, although safety, tolerability and efficacy of currently licensed influenza vaccines have been established [
21], post-licensure surveillance is crucial to monitor serious adverse events, coverage, effectiveness and the long-term effects on the population [
8,
31]. EPIA aims to provide some of the elements that will help support evidence-based decisions regarding influenza vaccination recommendations for children in Europe.
Acknowledgements
We wish to thank Richard Pitman for his assistance developing the model and Marianne van der Sande for her comments to an earlier draft of the manuscript. We would also like to thank all of the physicians and virologists who collected, tested and reported the data used in the analyses and to all EPIA members and their associates for helping make this research possible.
EPIA members (February 2010):