Introduction
Influenza has an important public health impact each winter in Europe.
It is associated with higher general practice consultation rates [1],
increased hospital admissions [2] and excess deaths [2,3]. 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 (25 countries),
the average number of excess deaths during influenza epidemic periods
between 1989 and 1998 was about 107 000 per winter, with the total number
in each country ranging from roughly 100 in Luxembourg and Malta to 19
500 in Germany. In recent winters, influenza activity in Europe has generally
not been as intense as during the 1989-1998 period [4,5] and the average
number of excess deaths has probably therefore been lower.
The European Influenza Surveillance Scheme (EISS) is a collaborative
project [6-8] that aims to contribute to a reduction in morbidity and
mortality due to influenza in Europe. During the 2003-2004 season,
25 surveillance networks from 22 European countries were active members
of EISS. The scheme aims to include all member states of the European
Union [9] and networks must meet the following criteria for full membership:
1) the surveillance network (consisting of sentinel physicians providing
clinical data 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) the 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 during the 2003-2004 season
and nine were associate members (Latvia, Luxembourg, Lithuania, Malta,
Northern Ireland, Poland, Romania, the Slovak Republic and Sweden).
Poland, Romania, the Slovak Republic and Sweden were associate members,
as they did not combine clinical and virological data in the same population.
Luxembourg, Malta, Northern Ireland, Latvia and Lithuania had this
status as they did not fulfil the EISS criteria of two years of successful
functioning prior to the 2003-2004 season, or were recent members of
EISS. Including all members, the EISS project comprised 30 national
influenza reference laboratories, at least 11 000 sentinel physicians,
and presented surveillance data for a total population of 445 million
inhabitants.
Methods
EISS members actively monitored influenza activity from week 40/2003
(29/9/2003 - 5/10/2003) to week 20/2004 (10/5/2004 - 16/5/2004) during
the 2003-2004 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). Sentinel physicians also obtained nasal, pharyngeal, or nasopharyngeal
specimens from a subset of patients and these were sent to the national
reference laborator(y)(ies) for virological analysis. 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 ILI or ARI) [10]. In addition to specimens
obtained from physicians in the sentinel surveillance systems, the
laboratories also collected and reported results on specimens obtained
from other sources (e.g. from hospitals or non-sentinel physicians).
These data are called ‘non-sentinel’ in this paper and
are collected to validate the virological data obtained from the sentinel
physicians and to have a second measure of influenza activity.
The virological data included results mainly from typing and subtyping
of viruses isolated using cell culture and additionally from rapid
diagnostic enzyme-immunological or immunofluorescence tests identifying
the virus type only. Many laboratories also used reverse transcription
polymerase chain reaction (RT-PCR) routinely for detection and (sub)typing
[11]. About 55% of the laboratories also reported antigenic characterisation
data and about 30% of the laboratories reported genetic characterisation
data of the virus isolates [12].
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 (www.eiss.org)
[13]. The indicators of influenza activity are established on a weekly
basis by the national coordinators: the intensity of clinical activity
(compared with historical data), the geographical spread of influenza
(a World Health Organization indicator) and the dominant type/subtype
circulating in the population. This allows members to view data in
neighbouring countries and is the basis for the publication of a Weekly
Electronic Bulletin that appears on the EISS website each Friday.
This paper presents epidemiological and virological data collected
between week 40/2003 (29/9/2003 - 5/10/2003) and week 16/2004 (12/4/2004
- 18/4/2004). Week 16/2004 was chosen as some networks stopped collecting
clinical data at the end of the season and data was therefore incomplete
for weeks 17-20/2004.
Results
The influenza activity started in the west of Europe (Ireland, the United
Kingdom (UK) and the Iberian Peninsula) in October/November and gradually
moved east, affecting Lithuania, Slovenia, Latvia, Poland, Italy and
Germany during the months of January/February 2004 (Table 1). The peak
weekly level of intensity and geographical spread of influenza activity
varied between the member countries during the 2003-2004 season (Table
1). The peak intensity of clinical influenza activity (compared with
historical data) ranged from low in Germany, Luxembourg and Wales,
to high in nine networks. Most networks reported widespread influenza
activity during the 2003-2004 season (16 out of 25). The peak levels
of weekly ILI/ARI incidences in Europe were reached between week 46/2003
and 6/2004 (Table 1), with the majority of networks reporting peak
levels before the end of the year (16 out of 24). A more detailed breakdown
of the epidemiological data by country is available on the EISS website
[Supplement, click here (http://www.eiss.org/documents/eurosurveillance_supplement_2003-2004_season.pdf)]. In
countries reporting age specific data, the highest consultation incidences
were observed among children aged 0-14 (data not shown).
Figure 1 presents the total number of specimens positive for influenza
viruses by week during the 2003-2004 season. The largest number of
positive specimens was detected before the new year, between week 48/2003
and 51/2003. Detections continued during the first three months of
2004, but at a lower level. The peak weekly level of influenza virus
detections varied among the member countries, and coincided roughly
with the week of peak clinical morbidity [TABLE 1].
A total of 13 652 sentinel and non-sentinel specimens were positive
for influenza virus during the 2003-2004 influenza season. The largest
number of positive specimens were reported by France (3607), England
(1704), Belgium (1260), Scotland (1139) and Norway (1000). Less than
one per cent of the specimens (0.86%) were positive for the influenza
B virus. The predominant viruses by country are shown in Table 1. A
more detailed breakdown of the virological data by country is available
as a Supplement on the EISS website [click
here]. Influenza A virus
was predominant in all countries that reported virological data (>91%
of all influenza virus isolates per country; total N=13 535). In most
countries, the haemagglutinin of the influenza A isolates was subtyped
(range: 0% - 100% of total influenza A isolates, average 50%, median
44% per country; total N=5841), and the predominant subtype was H3
(excluding the one country that reported no subtyping, >90% of H-subtyped
isolates per country; total N=5781). Among the 5841 subtyped influenza
A virus isolates, only 60 (1.0%) were A(H1) and of the 36 neuraminidase
subtyped A(H1) isolates, 22 had the N1 and 14 had the N2 subtype. EISS
received no reports of influenza A(H5N1), A(H7N2) or A(H7N3) viruses
that caused outbreaks among poultry in Asia, Canada and the United
States (US), and also infected humans [14-17].
Of a total of 3457 virus isolates, the haemagglutinin was antigenically
characterised. The largest number of characterisations was reported
by Latvia (796), Germany (491), France (392), the Netherlands (390),
and England (348). Over 97% of the characterised isolates had an A/Fujian/411/02
A(H3N2)-like H3 haemagglutinin. There were 46 isolates with an H3 haemagglutinin
similar to the vaccine strain A/Moscow/10/99 (H3N2), 34 with an H1
haemagglutinin similar to the vaccine strain A/New Caledonia/20/99
(H1N1) and seven with a haemagglutinin similar to the vaccine strain
B/Hong Kong/330/2001. There were 11 non-vaccine strain reports of influenza
B isolates: seven with a haemagglutinin similar to the B/Sichuan/379/99-like
virus (in the Netherlands (3), Switzerland (2), France and Germany)
and four with a haemagglutinin similar to the B/Shanghai/361/2002-like
virus (in England (2), Italy and Norway). Of the antigenically characterised
isolates, 166 were also genetically characterised and all haemagglutinins
were antigenically and genetically similar to the same vaccine strain.
In addition, 138 isolates were characterised genetically only, which
added 132 more viruses with an A/Fujian/411/2002 (H3N2)-like haemagglutinin,
four more with an A/New Caledonia/20/99 (H1N1)-like haemagglutinin
and two more with a B/Shanghai/361/2002-like haemagglutinin (from Norway).
The B/Shanghai/361/2002-like viruses were detected at the end of the
2003-2004 season.
Discussion
The 2003-2004 influenza season in Europe was dominated by the emergence
and spread of the new drift variant A/Fujian/411/2002 (H3N2)-like virus.
Sporadic cases of this virus were detected at the end of the 2002-2003
season in Switzerland and Norway [6] and activity related to this virus
started relatively early during the 2003-2004 winter compared with
previous seasons. The intensity of clinical activity was higher than
during the 2002-2003 season in 13 out of 20 networks [6], but did not
reach particularly high levels compared with historical data [4,5,18].
The general west-east spread of influenza activity across Europe during
the 2003-2004 season has also been observed during previous winter
seasons. Plotting the peak weeks of clinical sentinel activity against
the longitude and latitude of each network in EISS during five winter
seasons (1999-2000 to 2003-2004) indicated that there was a west-east
spread of influenza activity in three of five seasons (2003-2004, 2002-2003
and 2001-2002) and that in one of the seasons (2001-2002), there was
also a south-north spread [19]. Another finding of this analysis was
that influenza activity during the 2003-2004 season, for Europe as
a whole, was longer (18 to 22 weeks) than in recent winters (e.g. 14
to 18 weeks during the 2001-2002 season) [19].
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 virological database was therefore
upgraded at the beginning of the 2003-2004 season so that more detailed
information could be collected (e.g. separate recording of H and N
subtyping and antigenic and genetic strain characterisation results)
and the database could be quickly and easily modified to collect information
on emerging influenza viruses (e.g. a new avian influenza virus). These
developments proved particularly relevant in the light of the emergence
of avian influenza outbreaks and transmission to humans in South East
Asia (H5N1), Canada (H7N3) and the US (H7N2) in 2004 [14-17].
Objective determination of the predominant virus by type and H- and
N-subtype in a country was difficult as in many countries only a minority
of influenza A virus isolates was haemagglutinin subtyped and the neuraminidase
even to a lesser extent. More importantly, determining the H- and N-subtype
of influenza A viruses is necessary to detect the emergence of new
(avian) subtypes or reassortant viruses, illustrated by the emergence
of the A(H1N2) reassortant virus in 2001 [20]. EISS is aiming at H-
and N-subtyping of at least a representative sample of isolates throughout
the season in each country in order to fulfil its early warning function
[12].
The predominant virus circulating in Europe during the 2003-2004 season
was the new drift variant A/Fujian/411/2002 (H3N2)-like virus. The
A(H3N2) Fujian-like virus is antigenically different from the influenza
A/Moscow/10/99 (H3N2) virus strain included in the 2003-2004 vaccine
and there were concerns about the effectiveness of the vaccine in preventing
influenza illness [6]. Studies have shown that estimates of influenza
vaccine effectiveness ranged from 25% to 49% in children and 38% to
52% in adults in preventing illness during the 2003-2004 influenza
season in the US [21]. Although estimated protection rates are higher
when the match between the vaccine and circulating virus is good (70-90%
in adults <65 years) [21], our epidemiological data for the 2003-2004
season indicate that the season was not particularly intense compared
with historical data [18]. At the beginning of the 2003-2004 season,
there were reports of deaths in children in the UK [22] which received
considerable media attention and initially seemed to confirm the concerns
about the escape of the A(H3N2) Fujian-like virus from pre-existing
or vaccine induced anti-A(H3N2) immunity. Although we observed the
highest clinical incidences among children aged 0-14 in countries reporting
age specific data, these were not especially high compared with historical
data (data not shown). From these observations, we may conclude that,
despite the A(H3N2) Fujian-like virus being antigenically different
from the previously circulating A(H3N2) virus and the A(H3N2) virus
used in the vaccine, illness was not particularly severe.
The composition of the influenza vaccine for the 2004-2005 season
(northern hemisphere winter) was announced by the World Health Organization
in March 2004 [23]. Based on the analysis of influenza viruses from
all over the world till February 2004, the A/Moscow/10/99 (H3N2)-like
and B/Hong Kong/330/2001-like vaccine strains in the influenza vaccine
of 2003-2204 have been exchanged for more current viruses. The European
influenza vaccine [24] for the 2004-2005 season contains:
- A/NewCaledonia/20/99(H1N1)-like virus (the currently used vaccine virus
is reassortant virus IVR-116 which is derived from A/NewCaledonia/20/99)
- A/Fuijan/411/2002 (H3N2)-like virus (the currently used vaccine virus
is reassortant virus X-147 which is derived from A/Wyoming/3/2003)
- B/Shanghai/361/2002-like virus (the currently used vaccine virus is
B/Jiangsu/10/2003 )
The spread of virus strains in Europe during the 2004-2005 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.
Members of EISS:
Alexandrescu V (Romania), Aymard M (France), Barbara C (Malta), Bartelds
AIM (Netherlands), Blaskovicova H (Slovak Republic), Brydak L (Poland),
Buchholz U (Germany), Burguiere A-M (France), Carman W (Scotland),
Cohen J-M (France), Coughlan S (Ireland), Coyle P (Northern Ireland),
Crovari P (Italy), Domegan L (Ireland), Donatelli I (Italy), Dooley
S (Ireland), Falcao IM (Portugal), Falcao JM (Portugal), Fleming DM
(England), Grauballe P (Denmark), Griskevicius A (Lithuania), Grueber
A (Germany), Hagmann R (Switzerland), Havlickova M (Czech Republic),
Heckler R (Germany), Hungnes O (Norway), Iversen B (Norway), Joyce
M (Ireland), de Jong JC (Netherlands), Kalnina VI (Latvia), Kazanova
L (Latvia), Kennedy H (Northern Ireland), Kristufkova Z (Slovak Republic),
Kyncl J (Czech Republic), Libotte Chasseur M-L (Belgium), Lina B (France),
Linde A (Sweden), Lupulescu E (Romania), Machala M (Poland), Manuguerra
J-C (France), de Mateo S (Spain), Melillo T (Malta), McMenamin J (Scotland),
Mosnier A (France), Nolan D (Ireland), O`Donnell J (Ireland), O'Flanagan
D (Ireland), O’Neill H (Northern Ireland), Opp M (Luxembourg),
Penttinen P (Sweden), Pérez-Brena P (Spain), van der Plas S
(Netherlands), Pierquin F (Belgium), Pregliasco F (Italy), Prosenc
K (Slovenia), Quinn P (Ireland), Rokaite D (Lithuania), Rebelo de Andrade
H (Portugal), Victoria Romanus (Sweden), Rokaite D (Lithuania), Samuelsson
S (Denmark), Schweiger B (Germany), Socan M (Slovenia), Thomas D (Wales),
Thomas Y (Switzerland), Tumova B (the Czech Republic), Uphoff H (Germany),
Valette M (France), Velicko I (Latvia), Vega TA (Spain), Watson J (England),
van der Werf S (France), Westmoreland D (Wales), Wilbrink B (Netherlands),
Wunderli W (Switzerland), Yane F (Belgium) and Zambon M (England).
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
Belgium
Scientific Institute of Public Health, Brussels
Czech Republic
National Institute of Public Health, Prague
Denmark
Statens Serum Institut, Copenhagen
France
Open Rome, Paris; Institut Pasteur, Paris; Hospices Civils de Lyon
Germany
Robert Koch Institute, Berlin; ArbeitsGemeinschaft Influenza, Marburg;
Niedersächsisches Landesgesundheitsamt, Hannover
Ireland
National Disease Surveillance Centre, Dublin; Irish College of General
Practitioners, Dublin; National Virus Reference Laboratory, University
College, Dublin
Italy
Università degli Studi di Milano, Milan; Dipartimento di Scienze
della Salute, Genoa; Istituto Superiore di Sanita, Rome
Latvia
State Public Health Agency Laboratory of Virology, Riga
Lithuania
Centre for Communicable Diseases Prevention and Control, Vilnius ; Lithuanian
AIS Centre Laboratory, Vilnius
Luxembourg
Laboratoire National de Sante, Luxembourg
Malta
Disease Surveillance Unit, Msida; St. Luke’s Hospital, G’Mangia
Netherlands
Erasmus University, Rotterdam; Netherlands Institute for Health Services
Research, Utrecht; National Institute for Public Health and the Environment,
Bilthoven
Norway
National Institute of Public Health, Oslo
Poland
National Institute of Hygiene, Warsaw
Portugal
Instituto Nacional de Saude, Lisbon
Romania
Cantacuzino Institute, Bucharest
Slovak Republic
State Health Institute of the Slovak Republic, Bratislava
Slovenia
Institute of Public Health, Ljubljana
Spain
Instituto de Salud Carlos III, Madrid; Sentinel Networks of Madrid, Castilla
y Leon, C. Valenciana, Pais Vasco, Guadalajara, Andalucia, Aragon y Baleares.
Sweden
Swedish Institute for Infectious Disease Control, Solna
Switzerland
Swiss Federal Office of Public Health, Bern; University Hospital of Geneva,
Geneva
United Kingdom
Royal College of General Practitioners, Birmingham; Health Protection
Agency, Centre for Infections, London; Health Protection Scotland, Glasgow;
NPHS Communicable Disease Surveillance Centre; NPHS Microbiology, University
Hospital of Wales, Cardiff; HPA Communicable Disease Surveillance Centre,
Belfast, Northern Ireland
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