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The impact of influenza epidemics on public health is important, and
in general, underestimated (1). Surveillance of this illness is essential
and is usually composed of two different approaches. First, clinical
surveillance is based on weekly reports of consultations for influenza-like
illness (ILI) by sentinel practitioners. These data provide information
on the intensity of the epidemics. Second, virological surveillance
is based on a selection of practitioners who take nasopharyngal swabs
from patients presenting with ILI for virus isolation. The presence
of influenza virus is detected by cell culture combined with immunofluorescence
reaction or polymerase chain reaction (PCR). Virus detection reveals
the antigenic characteristics of the circulating strains. This information
contributes to the choice of influenza vaccine composition, and allows
early detection of new variants. To stress the importance of such surveillance,
WHO has urged member states to contribute to Europe-wide heightened
preparedness for epidemics and pandemics by strengthening national surveillance
and laboratory capacity (2). In response to this, the European Influenza
Surveillance Scheme (EISS, http://www.eiss.org/)
was set up to increase the sensitivity of existing early warning systems
and facilitate communication between European Networks, by sharing and
exchanging epidemiological, virological, and clinical information on
influenza (3-6).
Another aspect of the surveillance is to provide general practitioners
with information on epidemics and thus assist their diagnostic and therapeutic
decisions. Clinical diagnosis of influenza is correct in 65-85% of the
cases when the epidemic is confirmed in the community (7).
Surveillance requires time for data analysis and communication to physicians.
It can take several days from the detection of a significant increase
of influenza activity to the day the information is communicated.. In
order to reduce this delay, a new approach has been tested in the past
four years. This new system is based on the use of a near patient test
(NPT), together with the declaration of medical consultation for ILI.
Several commercial products are available for the detection of influenza
virus antigen in less than 30 minutes and do not require any sophisticated
materials. The highest sensitivity of these tests was evaluated around
80-85% (8-12) of the cell culture sensitivity and so their use for individual
diagnosis should be considered with caution. In contrast, the highest
specificity of these tests was quite high (around 95%) (8-12). This
specificity, together with the speed with which the result is obtained,
make NPT an attractive tool for the surveillance of influenza epidemic
in community practice. Such techniques have been used in several countries
as in France, Germany, Italy, Poland, the United States (Hawaii) and
Switzerland (13-15).
Results of this type of surveillance in Switzerland obtained over four
years are reported here. An enhancement of the surveillance was obtained
through training which is explained in this article too. Because of
this, on behalf of EISS, Switzerland was put in charge of organising
an expert task group made up of members from other European countries.
The objective of the group was an evaluation of this new surveillance
network as an early warning system. A statement on the use of NPTs for
influenza surveillance was produced and is communicated in the present
article.
Material and methods
Clinical surveillance
On a weekly basis between 1999 and 2003, 150 to 250 physicians notified
the Federal Office of Public Health of morbidity due to influenza-like
illness (ILI). Based on these reports, the rate of consultations for
ILI was calculated.
NPTs surveillance
The influenza A/B Rapid Test NPT (Roche Diagnostics) was used, which
is not a commercial test. It enables rapid detection of the influenza
virus. The test consists of an immunochromatographic assay that will
detect the presence of both Influenza A and influenza B viruses without
distinguishing between them. This test has 77.4% sensitivity and 93%
specificity of cell culture (16).
Between 150 and 200 sentinel participants per season were provided with
an influenza A/B Rapid Test kit. Most participants were general practitioners,
and some were paediatricians. Patients with ILI were screened for influenza
antigens by obtaining a throat swab. Although selection criteria were
the same for both methods, no patient simultaneously underwent NPT and
cell culture for the detection of influenza virus. Practitioners communicated
numbers and test results daily by fax to our laboratory, the National
Influenza Centre. This information was collected and communicated twice
a week to sentinel participants via a webpage (http://www.influenza.ch).
Virological surveillance
A restricted number of sentinel participants (range 55-65) took nasopharyngal
swabs. Samples were sent in transport medium to our laboratory where
influenza viruses were detected by cell culture combined with immunofluorescence.
Subtyping was done by a haemagglutination inhibition test using standard
antisera.
Results were published on our webpage (http://www.influenza.ch)
once a week from the clinical and virological surveillance and twice
per week from the NPTs surveillance. Criteria used by the sentinel practitioners
to detect patients with influenza-like illness were the same for the
three different surveillance systems.
Results
Surveillance with near patient test
Surveillance using the near patient test was conducted during four seasons
between 1999 and 2003. Characteristics of the epidemics observed during
that period are summarised in Table 1. Seasons between 2001 and 2003
were comparable. The percentage of medical consultations for ILI and
the number of influenza viruses detected were found to be related. The
nature of viral strains that circulated were the same and were covered
by influenza vaccine. However, the 1999-2000 and 2000-2001 seasons were
rather different as concerns the intensity and types of strains detected.
The heterogeneity of the different epidemics (four seasons) allows an
efficient evaluation of the system.
Results of the surveillance between 1999 and 2003 are summarised in
Table 2. As shown, the number of participants has decreased over the
four years. The number of positive results also varied considerably
during the different seasons, as did the percentage of positive results
which will be discussed later. Clinical, laboratory, and NPT data are
shown in the figure. The two seasons from 1999 to 2001 showed similar
patterns for the two virus detection systems and the clinical incidence
(14). The significant increase of the virus circulation, the maximal
rate of detection, and the decrease in the quantity of viruses detected
by the two systems were systematically observed in the same week, or
with a difference of one week.
The time when test results were made available was analysed. For cell
culture, results were available after 11 days (± 3 days). This
includes seven days needed for cell culture and four additional days
needed for immunofluorescence and for the weekly communication (14).
Results of the ratio of consultations for ILI from the previous week
were in general available on Tuesdays (4-5 days delay). Using the NPT,
95% of the results arrived within two days. With two weekly updates
of our website, results using the NPT were obtained an average of nine
days faster than those obtained by cell culture.
Training
To enhance the quality of results obtained with the NPT by the general
practitioners, training was organised in two consecutive years at the
beginning of the season. This training consisted of sending three anonymised
control samples to the participants: one negative, one weak and one
strongly positive. A viral protein was used as the positive control.
Results are presented in Table 3. In 2001-2002, only 45% of physicians
found the correct combination of results with the three controls. Thirty
seven per cent detected only the strong positive control and 18% did
not detect any of the positive samples. Every participant who did not
find the correct combination received new samples to repeat the test.
In 2002-03, the rate of participants who found the correct combination
increased to 92%. Six per cent did not detect the low positive and 2%
did not detect any positive control. The NPT was therefore used much
more correctly the second year. This training is obviously essential
and is highly recommended for every new participant in order to assure
the quality of the surveillance system.
Statement elaborated and approved by EISS
One major objective of EISS is to increase the sensitivity and efficiency
of early warning system for the surveillance of influenza epidemic.
To achieve this, the EISS coordination centre selected seven members*
based on their virological, clinical, and epidemiological expertise
to form a task group under the leadership of Yves Thomas. They were
in charge of the evaluation of use of the NPTs in influenza surveillance
and the subsequent integration into the EISS network. Additionally,
one member of the EISS Steering Committee was represented in the Task
Group (John Watson). A statement was produced by the task group after
a meeting that occurred 29 November 2002 in Geneva. The final text has
been submitted and endorsed by all the EISS members during a plenary
lecture in Upsala on 25 April 2003 (Table 4).
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Table 4 /
Tableau 4
Déclaration
de EISS sur l'utilisation des tests rapides dans la surveillance
de la grippe
EISS statement on the use of Near Patient Tests (NPTs) for influenza
surveillance
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Remarques générales / General
Remarks
Les tests rapides ne doivent pas affecter les systèmes de
surveillance existants / NPTs should not negatively affect the existing
surveillance systems
Les tests rapides ne doivent pas remplacer la surveillance virologique
par l'isolement du virus / NPTs should not replace virological surveillance
by virus isolation
1. Les tests rapides sont-ils un outil précieux pour
la surveillance de la grippe ?
Are NPTs a valuable tool for influenza surveillance?
Oui / Yes
Malgré leur sensibilité limitée / Despite
its limited sensitivity
En dépit du fait qu'ils prennent plus de temps aux médecins
généralistes / Despite the fact that it is more
time-consuming for the general practitioners (GPs)
En dépit du fait qu'ils peuvent être sources de désagréments
et de temps pour le patient / Despite the fact that it means additional
discomfort and time for the patient
Les expériences précédentes ont montré
la faisabilité d'une surveillance avec les tests rapides
en médecine générale / Previous experience
has demonstrated the feasibility of the NPTs for surveillance
in general practice
La spécificité relativement élevée
rend cet outil précieux dans la surveillance de la grippe
/ Relatively high specificity makes this tool valuable for influenza
surveillance
Aucune infrastructure de laboratoire supplémentaire n'est
nécessaire / No additional laboratory infrastructure is
needed
Les résultats sont disponibles rapidement / The result
is rapidly available
2. Valeur ajoutée potentielle des tests rapides dans
la surveillance ? / Potential added value of the NPTs to surveillance?
'Alerte rapide' plus précoce lors d'un changement de l'activité
grippale / Improved timeliness in the "early warning"
of a change in influenza activity
Augmentation potentielle de la représentativité
du réseau de surveillance / Potential increase of the representativeness
of the surveillance network
Augmentation potentielle des informations virologiques sans surcharger
le laboratoire de virologie/ Potential increase in virological
information without overloading the virological laboratory
En ciblant l'échantillonnage classique, les tests rapides
peuvent améliorer l'efficacité de la surveillance
virologique et le délai de détection de nouveaux
variants /
By targeting classical sampling, it has the potential to enhance
the efficiency of the virological surveillance and improve the
timeliness of the detection of new variants
3. Comment recommander aux pays d'adopter les tests rapides
comme partie intégrante d'un système national de
surveillance / How do we recommend that countries consider the
adoption of NPTs as part of a national surveillance system?
L'utilisation des test rapides dans la surveillance de la grippe
est facultative et les coûts d'intégration au système
de surveillance doivent être soigneusement évalués
/ The use of NPTs for influenza surveillance is optional and the
cost of integrating these tests into the surveillance system must
be carefully assessed
Ils ne doivent pas affecter le système de surveillance
classique en réduisant le nombre de prélèvements
recueillis pour détecter et isoler les virus respiratoires
/ It should not negatively affect the classical surveillance system
by reducing the number of swabs collected for the detection or
isolation of respiratory viruses
Ils ne doivent pas être les seuls outils de surveillance
virologique / It should not be the only virological surveillance
tool
Le médecin qui réalise les tests rapides doit également
fournir les données cliniques / The practitioner carrying
out the NPTs should also supply the clinical data
En début et en fin de saison, le médecin doit prélever
des échantillons chez les patients positifs aux tests rapides
pour culture cellulaire et/ou PCR / At the beginning and end of
the season, the practitioner should take swabs from patients who
are positive by NPTs for cell culture and/or PCR testing
Les résultats des tests rapides ne doivent être interprétés
qu'en combinaison avec les données virologiques cliniques
et conventionnelles (culture et/ou PCR) / The results of NPTs
should only be interpreted in combination with clinical and conventional
(culture and/or PCR) virological data
L'expérience montre que des informations appropriées
(informations générales sur la surveillance, critères
pour les prélèvements, délais entre le début
des symptômes et le prélèvement…) et
une formation pratique (échantillonnage et maniement des
tests) des médecins sont essentielles / Previous experience
shows that appropriate information (general information on surveillance,
swabbing criteria, delay between onset of symptoms and swabbing…)
and practical training (swabbing and test handling) of the GPs
are essential
Le contrôle qualité est un outil pour améliorer
les performances des médecins généralistes
/ Quality control is a tool for improving the performance of the
GPs
Un système distinct de surveillance par tests rapides doit
être évité et les données de ces tests
doivent être intégrées au système national
de surveillance / A separate NPT surveillance system should be
avoided and the NPT data should be integrated into the national
surveillance system
4. Recommandations destinées à EISS sur l'utilisation
des données des tests rapides comme système 'd'alerte
précoce' lors d'un changement d'activité grippale
/ Recommendations on how EISS should use the NPTs data as an "early
warning" system for a change in influenza activity
Les résultats des tests rapides ne doivent être interprétés
qu'en combinaison avec les données virologiques cliniques
et conventionnelles (culture et/ou PCR) The results of NPTs should
only be interpreted in combination with clinical and conventional
(culture and/or PCR) virological data
Les résultats des tests rapides disponibles actuellement
doivent être étudiés par les experts en charge
du Bulletin électronique hebdomadaire / The currently available
results from NPTs should be considered by the experts in charge
of the Weekly Electronic Bulletin
Le site internet de EISS doit être modifié pour recueillir
les données des tests rapides / The EISS website should
be modified in order to collect NPTs data
A l'heure actuelle, les données des tests ne doivent pas
être mises à la disposition du public / For the moment,
NPTs data should not be available in the public domain
Des études complémentaires sont nécessaires
pour compléter l'évaluation de l'interprétation
des données des tests rapides dans la surveillance / Additional
studies are needed to complete the evaluation of the interpretation
of data from NPTs in surveillance:
- Etudes comparatives des tests rapides en médecine générale
/ Comparative studies of NPTs in general practice
- Comparaison de la sensibilité et de la spécificité
des divers tests rapides / Comparison of the sensitivity and specificity
of different NPTs
- Plus de résultats sur l'utilisation des tests rapides
dans la surveillance de la grippe doivent être publiés
/ More results about the use of NPTs for influenza surveillance
should be published
Geneva, 29 November 2002
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Discussion
Sensitivity of the near patient test is lower than that of cell culture
and PCR. So, the use of NPT for individual diagnosis is of limited benefit
because in case of a negative result, interpretation is difficult. However,
the high specificity of some of these tests (8,12,17) make them a valuable
tool for the surveillance of influenza. The major point of interest
of this surveillance is the speed with which information about circulation
of influenza viruses can be obtained, information which is usually confirmed
an average of nine days later using the classical surveillance systems
(14). This time gain was observed in Switzerland during all four seasons,
in France (13) and in Hawaii (15). This rapid detection and reporting
of influenza viruses allows the public health services to take the necessary
precautions for an epidemic and helps physicians to confirm their diagnoses
of influenza (7). As a consequence, this information allows appropriate
use of antiviral drugs against influenza only during the epidemic phase.
The use of PCR would also reduce time in the surveillance of influenza.
Two days for transport and several hours for the PCR analysis are necessary
to obtain results about the presence of viral agent in a sample.
On behalf of EISS, a task group of experts was in charge of the evaluation
of this new surveillance system. Their conclusions were that surveillance
using the NPTs is a valuable tool for an early warning of a change in
influenza activity. The statement produced should be helpful to countries
that would like to use such a system for surveillance of influenza epidemics.
A crucial point is that an existing surveillance system using classical
detection methods should not be negatively affected by the surveillance
with the NPTs. Clinical and virological surveillance based on cell culture
are essential for the reasons already mentioned. Surveillance with the
NPTs provides additional information. However, interpretation of the
results of such surveillance should be made in combination with the
results obtained with the classical systems.
One advantage is that surveillance with NPT requires neither expensive
equipment nor the complicated infrastructure of a laboratory. Because
these tests are easy to use, they can be performed in any physician's
office. In addition, participants in this new surveillance network reported
that they were very pleased to have the NPTs available in their offices,
offering them the possibility of a rapid confirmation of the presence
of influenza virus in their community practice. The use of the NPT could
also enhance the accuracy of their diagnosis. Such a surveillance scheme
is easy to organise. However, organising a surveillance scheme with
the NPTs on parallel with existing surveillance system requires additional
expense of money and effort. This aspect should not be ignored and cost-benefit
must be evaluated. In any case, the introduction of this new surveillance
system should remain optional for the surveillance of influenza epidemic.
Training the sentinel practitioners to use the NPTs improved their use
of these tests. This training is highly recommended for the installation
of such surveillance.
Another potential added value of this system is that it increases virological
information. Indeed, a double swab could be planned for patients with
a positive result detected with NPT. The second sample could then be
sent to the laboratory for cell culture. Further studies on the virus
would give information on the evolution of the strains circulating.
The periods before and after the season could give predictive indications
about the strain that might circulate during the following season.
During the different seasons, the number of positive samples detected
with cell culture and with NPTs per week could be compared. However,
the percentage of positive samples detected with the NPTs are considerably
lower than the one observed with cell culture. This indicates that some
positive samples will be missed because of the general lower sensitivity
of such NPTs. The heterogeneity of the network and of the participation
of physicians could contribute to such differences. These results show
that additional studies are needed to complete the evaluation of the
usefulness of surveillance with the NPTs.
This paper was written on behalf of the EISS Task Group* on 'The use
of NPTs for influenza surveillance'.
* Members of the Task group: Aad Bartelds, Isabel Burckhardt 1, Anne
Mosnier, Yves Thomas, John Watson, Sylvie van der Werf, Werner Wunderli
(National Centre of Influenza, Switzerland).
1 Participated in the Task Group meeting but not in the writing of the
EISS Statement
Acknowledgements
This work was a collaboration between the Swiss Sentinel Surveillance
Network, the National Centre of Influenza and Roche-Pharma AG. We would
like to thank all the sentinel practitioners.
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