Heterogeneous influenza activity across Europe during the winter of 2002-2003

WJ Paget 1, TJ Meerhoff 1, H Rebelo de Andrade 2 on behalf of EISS*

1 European Influenza Surveillance Scheme co-ordination centre, Netherlands Institute for Health Services Research (NIVEL), Utrecht, the Netherlands.
2 Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal

 

Influenza activity varied across Europe during the 2002-2003 season both in terms of the intensity of clinical activity and the circulating virus types/subtypes. Influenza B was generally predominant in the ´western´ parts of Europe (Portugal, Spain, the United Kingdom and Ireland) and influenza A (H3N2) in the ´central´ and ´eastern´ areas (Germany, Italy, Denmark, Switzerland, Poland, Slovenia, the Slovak Republic, the Netherlands). A number of countries experienced mixed seasons, first experiencing activity associated with influenza B and then with influenza A (Belgium, France and Spain). Generally, countries where influenza B was predominant had low (compared to historical data) levels of intensity (a mild season) and longer periods of influenza activity compared to countries where influenza A (H3N2) was predominant. A number of countries, all where influenza A (H3N2) was predominant, reported high levels of intensity compared to historical data: the Czech Republic, Denmark, Germany and Poland. In the six countries where age-specific incidence rates were available, the highest rates were observed among those aged 0-14 years. The influenza virus strains circulating in Europe had a good match with the virus strains in the influenza vaccine. A small number of isolates (A/Fujian/411/2002 (H3N2)-like) were reported at the end of the season that had a reduced reactivity to anti-sera of the vaccine strain. The composition of the 2003-2004 influenza vaccine is the same as during the 2002-2003 season.

Influenza is an important public health problem in Europe. It is associated with higher general practice consultation rates (1), increased hospital admissions (2) and excess deaths (2,3). Other aspects to be considered are the number of increased days lost due to absence from work, its seasonal impact on health care systems and the possibility of an influenza pandemic (4). In England and Wales, the average number of excess deaths during influenza epidemic periods (1989-1998) was estimated to be 12 554 per season (range 0-27, 587) (2). Extrapolating these figures to the European Union (15 countries), the average number of excess deaths during influenza epidemic periods between 1989 and 1998 was about 90 000, the total number in each country ranged from roughly 100 in Luxembourg to 19 500 in Germany.
The European Influenza Surveillance Scheme (EISS) is a collaborative project (5-7) that aims to contribute to a reduction in morbidity and mortality due to influenza in Europe. The project has received funding from the European Commission since November 1999 and adopted new objectives at the beginning of the 2002-2003 season:
o To collect and exchange timely information on influenza activity in Europe;
o To aggregate, interpret and make publicly available clinical and virological data concerning influenza activity in Europe;
o To strengthen, and harmonise where appropriate, epidemiological and virological methods, primarily based on the integrated sentinel surveillance model, for assessing influenza activity in Europe;
o To contribute to the annual determination of the influenza vaccine content;
o To monitor influenza prevention and control policies in Europe, including influenza vaccine uptake;
o To contribute to European planning and response to pandemic influenza through surveillance, investigation and provision of information;
o To promote research in support of these objectives.

During the 2002-2003 season, 22 surveillance networks (from 19 European countries) were active members of EISS. The scheme aims to include all member states of the European Union: the current 15 members and the 10 candidate countries (8). For full membership, networks must meet the following criteria: 1) the surveillance network (consisting of sentinel physicians providing clinical information and national reference laboratories providing virological data) is nationally or regionally representative; 2) the authority of the network is recognised by the national or regional health authority in the country or region; 3) clinical surveillance and virological surveillance are integrated in the same population (community); 4) the network has functioned successfully for at least two years; and 5) the network can deliver data on a weekly basis.
Sixteen networks were full members of EISS and six were ´associate´ members (Lithuania, Northern Ireland, Poland, Romania, the Slovak Republic and Sweden) during the 2002-2003 season, as they did not completely fit the membership criteria. Poland, Romania, the Slovak Republic and Sweden were ´associate´ members because they did not combine clinical and virological data in the same population; Northern Ireland and Lithuania because they were new members to the scheme. Including all members, the EISS project comprised 28 national influenza reference laboratories, at least 10 600 sentinel physicians and presented surveillance data during the 2002-2003 season for a total population of 441 million inhabitants.

Methods
EISS members actively monitored influenza activity from week 40/2002 (30/9/2002 - 6/10/2002) to week 20/2003 (12/5/2003 - 18/5/2003) during the 2002-2003 season. In each of the countries, one or several networks of sentinel physicians collected weekly (consultation) incidences of cases of influenza-like illness (ILI) and/or acute respiratory infection (ARI) (9). Sentinel physicians also obtained nasal, pharyngeal, or nasopharyngeal specimens from a sample/subset of patients and these were sent to the national reference laboratory-ies) for virological monitoring. Combining clinical and virological data in the same population allows the validation of clinical reports made by the sentinel physicians and provides virological data in a clearly defined population (the general population that visits their physician with an influenza-like illness or an acute respiratory infection) (9).
The virological data included results from rapid diagnostic (immuno-enzymological or immunofluorescence) tests and from cell cultures with specific identification. Many laboratories also use reverse transcription polymerase chain reaction (RT-PCR) routinely (10). In addition to specimens obtained from physicians in the sentinel surveillance systems, the laboratories also collect and report results on specimens obtained from other sources (e.g. from hospitals or non-sentinel physicians). These data are collected as a range of indices and used to monitor influenza activity and it allows the validation of virological data obtained from the sentinel sources.

During the influenza season, the weekly clinical and virological data are processed and analysed by the national centres and then entered into the EISS database the following week via the internet (11). This allows members to view data in neighbouring countries and the publication of a weekly bulletin on influenza activity in Europe on the EISS website each Friday.
This paper presents epidemiological and virological data collected between week 40/2002 and week 16/2003.

Results
Figure 1 presents a graphic display of the two predominant influenza viruses that circulated in Europe during the 2002-2003 season (influenza B and A (H3N2)). The countries are ranked according to the week when there was a steady circulation of each virus in the population (defined as the isolation/detection of the virus in sentinel and/or non-sentinel specimens with no more than one week interruption). Overall, influenza B was reported earlier in the season and the period of influenza activity was longer. Belgium, France and Spain had a mixed season, with influenza B reported at the beginning of the season and influenza A (H3N2 in Belgium and France and H1N1 in Spain) at the end of it.


The spread of influenza B first affected Portugal in week 43/2002 and then moved to Spain, France and Belgium. The virus was detected in the United Kingdom in weeks 50/2002 (Scotland) and 01/2003 (England), and there was then a steady circulation in most of the rest of Europe. The circulation of influenza A (H3N2) occurred later in the season, with a steady circulation first reported in Germany in week 51/2002. It then spread rapidly to England, France, Italy, Ireland, Denmark and most of the rest of Europe. Some countries e.g. Northern Ireland, Slovenia and Wales only reported sporadic cases of influenza B and A (H3N2). On average, there was a better overlap of the peaks of clinical (sentinel incidence data) and virological activity (sentinel and non-sentinel laboratory reports) for influenza A (H3N2) than for influenza B.

The geographical spread and intensity of influenza activity in the member countries varied during the 2002-2003 season (Table). The influenza activity was sporadic in Ireland, Norway, Portugal, Sweden and the United Kingdom. In the Netherlands, Lithuania, Poland, Romania and Spain it was local or regional and in Belgium, the Czech Republic, Denmark, France, Germany, Italy, Slovak Republic, Slovenia and Switzerland it was widespread. The intensity of influenza activity (compared to historical data) ranged from low in the Netherlands, Norway, Portugal and the United Kingdom to high in the Czech Republic, Denmark, Germany and Poland.
The peak levels of clinical morbidity in Europe were reached between week 02/2003 and 12/2003 (Figure 1 and Table), with the majority of countries reporting peak levels from mid-February to mid-March (weeks 07/2003 to 11/2003). Overall, influenza B was predominant in the west of Europe (Portugal, the United Kingdom and Ireland) and in Romania, and influenza A (H3N2) was predominant in central and eastern Europe (the Czech Republic, Denmark, Germany, Italy, Lithuania, the Netherlands, Norway, Poland, the Slovak Republic, Slovenia and Switzerland). Belgium, France and Spain had mixed seasons, with influenza B being predominant at the beginning of the season and influenza A (H3N2 in Belgium and France and H1N1 in Spain) at the end of the season.

During the 2002-2003 influenza season, a total of 17 302 respiratory specimens were collected by the sentinel physicians and tested for influenza; 4613 (26.7%) were positive for influenza (17.0% for influenza A and 9.7% for influenza B). Figure 2 presents a pie chart of positive sentinel specimens during the 2002-2003 season, broken down by type (the large pie chart) and subtype (the smaller pie chart). Germany reported 46.5% (2145/4613) of the positive specimens. In order to obtain a less skewed distribution of types and subtypes in Europe, the data have been averaged for all reporting countries (this means that each country has an equal weight in the overall calculation of percentages). On average, 56% of specimens were positive for influenza A and 44% for influenza B. Among the influenza A subtyped specimens, on average, influenza A (H3N2) was found among 78% of specimens, influenza A (H1N1) among 15% and influenza A (H1N2) among 7%. The crude distributions, with no weighting, were: 64% influenza A and 36% influenza B [among the subtyped cases of influenza A, 91% were A (H3N2), 8% influenza A (H1N1) and 1% influenza A (H1N2)]. EISS received no sentinel reports of influenza A (H7N7).


Figure 3 presents the results of the strain characterisations of influenza virus isolates reported by the national reference laboratories in EISS. These data were collected for the first time during the 2002-2003 season and combine sentinel and non-sentinel data. The pie chart percentages have not been weighted and this means that the data from Germany (a network that reported 69% of the isolates) makes a disproportionate contribution to the pie chart. Over 99% of the isolates characterised by the reporting networks were covered by the 2002-2003 vaccine. There were 26 reports of non-vaccine strain A/Fujian/411/02(H3N2)-like viruses (13 in Norway and 13 in Switzerland; reported at the end of the season) and these isolates represented less than 0.75% of all characterised isolates. In Norway, where A/Fujian/411/02-like viruses were the most numerous (more than 70 per cent of characterised H3N2 strains), the circulation of these viruses failed to cause significant outbreaks (Olav Hungnes, personal communication).



Figure 4 presents age-specific weekly incidence rates for four countries that reported cases of ILI and two countries that reported cases of ARI during the 2002-2003 season. These countries were chosen as they reported age-specific data (some EISS networks do not report these data) and because there were sufficient data to present the rates (England, the Netherlands and Portugal did not have sufficient cases of ILI each week to present meaningful graphs). The virological results for influenza positive sentinel specimens are also presented to demonstrate the temporal relationship between clinical and virological activity.
The incidence rates were highest, in all countries, among those aged 0-4 and 5-14 years. The lowest rates, in all six countries, were reported in the 65+ age group. The age-specific incidence rates in each country varied considerably. In Denmark, the Slovak Republic and Switzerland, the peak incidence rates in the age groups 0-4 and/or 5-14 were 3-5 times higher than in those aged 65+. In the other countries, the differences were larger and even rose to 16 times higher in Spain (38 ILI consultations per 100 000 in persons aged 65+ compared to 611 ILI consultations per 100 000 in persons aged 5-14).



Discussion
The 2002-2003 influenza season in Europe was a heterogeneous one in terms of intensity and type/subtype diversity. Some countries reported high levels of influenza activity (the Czech Republic, Denmark, Germany and Poland) whilst others had very quiet seasons (Ireland, the Netherlands, Norway, Sweden and the United Kingdom). Some countries had activity that was driven by the influenza B virus (mainly in the western part of Europe), whilst in other countries it was influenza A (usually influenza A (H3N2)). Influenza B activity was generally earlier in the season (weeks 49/2002-08/2003), it lasted a longer time period, and was associated with lower weekly incidence rates.
The weekly incidence rates of ILI and ARI collected and presented by EISS provide valuable information on the dynamic spread of influenza in the population and are an important indicator for the evaluation of national influenza vaccination campaigns (other indicators include the availability of vaccines before the start of the season and vaccination uptake rates). The results (see Figure 4) indicate that the lowest incidence rates were observed in persons aged 65+, a population group that the vaccination campaigns target (12) - in all six countries.
Comparisons of age-specific incidence rates across Europe (e.g. the rates in Denmark compared to those in Spain) must be made with care. The differences in incidence rates observed among the four countries reporting ILI incidences (see Figure 4) can probably be explained by a number of different factors, including: different case definitions (13), changes in the surveillance systems over time (the sentinel physicians in the Slovak Republic began reporting cases of ILI (instead of ARI) during the 2001-2002 season, and some of the physicians may have still been reporting cases of ARI during the 2002-2003 season) and different consultation behaviours e.g. due to cultural differences and the need to have a medical certificate to be absent from work (14).

At the end of the 2002-2003 season (late February 2003), the Netherlands experienced an epidemic of highly pathogenic avian influenza A (H7N7) in poultry that also went on to affect Belgium and Germany (the regions bordering the Netherlands). As of 30 August 2003, there were 89 cases (15) of H7N7 influenza among poultry workers and their families, causing mainly mild conjunctivitis, sporadically ILI, but also one case (a veterinarian who had visited one of the affected farms) of severe fatal pneumonitis. Epidemiological and virological studies indicated that there were three cases of human to human transmission: from two poultry workers to three of their family members. Fortunately, the epidemic in poultry in the Netherlands and the outbreaks in Belgium and Germany were contained. The last human case of H7N7 influenza (laboratory confirmed) in the Netherlands occurred on 19 April 2003 (15), indicating that the outbreak among humans was also over.
The identification of circulating viruses within the population and the recognition of virological changes are important tasks for EISS. There is a particular need to detect and monitor the emergence or re-emergence of viruses with pandemic potential and viruses that have a ´mismatch´ with the vaccine strain components. The emergence of two ´novel´ viruses during the 2001-2002 season (influenza A (H1N2) and B/Victoria/2/87 lineage) were carefully documented by EISS and have exemplified the benefit of having a surveillance system to facilitate the rapid exchange of information across Europe (6). During the 2002-2003 season, another ´novel´ virus was detected: the influenza A/Fujian/H3N2-like virus. Fortunately, only sporadic cases were detected and patients had normal/typical clinical symptoms.

The composition of the influenza vaccine for the 2003-2004 season (northern hemisphere winter) was announced by the World Health Organization (WHO) in March 2003 (16). The strains are unchanged compared to the 2002-2003 season. The WHO delayed the announcement of the strains due to the detection of some cases at the end of the season that had a reduced reactivity to the A/Panama/2007/99 antiserum (and appeared to be similar to A/Fujian/411/2002) (16). Considering there was no A/Fujian/411/2002-like virus suitable as a vaccine strain candidate isolated in embryonated eggs, the composition of the 2003-2004 influenza vaccine in the northern hemisphere will remain the same as the current season.
The European influenza vaccine (17) for the 2003-2004 season contains:
o an A/New Caledonia/20/99 (H1N1)-like virus
o an A/Moscow/10/99 (H3N2)-like virus (the widely used vaccine strain is A/Panama/2007/99)
o a B/HongKong/330/2001-like virus (currently used vaccine strains include B/Shandong/7/97, B/Hong Kong/330/2001, B/Hong Kong/1434/2002)

The emergence of the influenza A (H3N2) Fujian-like virus at the end of the 2002-2003 season in Norway and Switzerland and its wide circulation in Australia and New Zealand during the southern hemisphere winter (2003) (18), mean that there is the possibility of a ´mismatch´ occurring between the H3N2-vaccine strain component and the circulating H3N2 virus strains during the 2003-2004 season (15). The current data from Australia indicate that only sporadic cases of influenza-like illness were observed in immunised (i.e. vaccinated) individuals and there does not appear to have been a major reduction in vaccine protection (18). It is very difficult to predict which virus(es) will circulate in Europe during the 2003-2004 season (e.g. there could be a co-circulation of influenza A (H3N2) viruses) and which age groups will be affected. Influenza vaccination is therefore extremely important; even if the Fujian-like virus circulates in Europe during the 2003-2004 season, vaccination will offer some cross protective immunity. The spread of virus strains in Europe during the 2003-2004 season will be carefully monitored by the virological, epidemiological and clinical experts within EISS. Assessments of the influenza activity will be made in collaboration with the WHO Collaborating Centre in London and will be reported on the EISS website on a weekly basis.

This article was written on behalf of all EISS members: Alexandrescu V (RO), Aymard M (FR), Bartelds AIM (NL), Buchholz U (DE), Burguiere A-M (FR), Brydak L (PL), Cohen JM (FR), Domegan L (IE), Dooley S (IE), Falcao I (PT), Fleming DM (UK), Grauballe P (DK), Haas, W (DE), Hagmann R (CH), Havlickova M (CZ), Heckler R (DE), Heijnen M-L (NL), Hungnes O (NO), Iversen B (NO), de Jong JC (NL), Kennedy H (UK), Kristufkova Z (SK), Libotte M-L (BE), Lina B (FR), Linde A (SE), Lupulescu E (RO), Machala M (PL), Manuguerra J-C (FR), de Mateo S (ES), Meijer A (NL), McMenamin J (UK), Meerhoff T (NL), Mosnier A (FR), Meijer A (NL), Nolan D (IE), O´Flanagan D (IE), O´Neill H (UK), Opp M (LU), Paget WJ (NL), Penttinen P (SE), Perez-Brena P (ES), Pierquin F (BE), Pregliasco F (IT), Prosenc K (SI), Rebelo de Andrade H (PT), Rokaite D (LT), Samuelsson S (DK), Schweiger B (DE), Socan M (SI), Thomas D (UK), Thomas Y (CH), Tumova B (CZ), Uphoff H (DE), Valette M (FR), Vega T (ES), van der Velden K (NL), van der Werf S (FR), Watson J (UK), Wilbrink B (NL), Yane F (BE) and Zambon M (UK).

Acknowledgements
EISS would not exist without the regular participation of sentinel physicians across Europe. We would like to thank them for making this surveillance scheme possible.

*Participants
Belgique / Belgium
Scientific Institute of Public Health, Bruxelles
République Tchèque / Czech Republic
National Institute of Public Health, Praha; National Influenza Centre, Praha
Danemark / Denmark
Statens Serum Institut, Copenhagen
France
Groupes Régionaux d´Observation de la Grippe, Open Rome, Paris; Institut Pasteur, Paris; Centre Hospitalo-Universitaire, Lyon
Allemagne / Germany
ArbeitsGemeinschaft Influenza, Marburg; Robert Koch Institute, Berlin; Niedersächsisches Landesgesundheitsamt, Hannover
Irlande / Ireland
Irish College of General Practitioners, Dublin; National Disease Surveillance Centre, Dublin; National Virus Reference Laboratory, University College Dublin
Italie / Italy
Istituto di Virologia, Milano; Dipartimento di Scienze della Salute, Genova; Istituto Superiore di Sanita, Roma
Lituanie / Lithuania
Centre for Communicable Disease Prevention and Control, Vilnius
Pays-Bas / Netherlands
Netherlands Institute for Health Services Research, Utrecht; National Institute for Public Health and the Environment, Bilthoven; Erasmus University, Rotterdam
Norvège / Norway
National Institute of Public Health, Oslo
Pologne / Poland
National Institute of Hygiene, Warsaw
Portugal
Instituto Nacional de Saude, Lisboa
Roumanie / Romania
Cantacuzino Institute, Bucharest
Slovaquie / Slovak Republic
State Health Institute of the Slovak Republic, Bratislava
Slovénie / Slovenia
Institute of Public Health, Ljubljana
Espagne / Spain
Instituto de Salud Carlos III, Madrid; Sentinel Networks of Madrid, Castilla y Leon, C. Valenciana, Pais Vasco, Guadalajara, Andalucia, Aragon y Baleares.
Suède / Sweden
Swedish Institute for Infectious Disease Control, Solna
Suisse / Switzerland
Swiss Federal Office of Public Health, Bern; National Centre for Influenza, Hôpital Cantonal Universitaire, Geneva
Royaume-Uni / United Kingdom
Royal College of General Practitioners, Birmingham; HPA Communicable Disease Surveillance Centre, London; HPA Central Public Health Laboratory, London; Scottish Centre for Infection and Environmental Health, Glasgow, Scotland; HPA Communicable Disease Surveillance Centre, Cardiff, Wales; HPA Communicable Disease Surveillance Centre, Belfast, Northern Ireland

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