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Influenza Burden of Illness
Estimates From a National Prospective Survey of Household Contacts in France
Fabrice Carrat, MD, PhD;
Camille Sahler, MPH;
Sylvie Rogez, PharmD, PhD;
Marianne Leruez-Ville, MD, PhD;
François Freymuth, MD, PhD;
Catherine Le Gales, PhD;
Martine Bungener, PhD;
Bruno Housset, MD;
Marlène Nicolas, MPH;
Christine Rouzioux, PhD
Arch Intern Med. 2002;162:1842-1848.
ABSTRACT
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Background The burden of influenza among ambulatory patients is still relatively
unknown, although this knowledge is crucial for evaluating strategies against
influenza. We estimated the impact of influenza in terms of uncomplicated
morbidity and its consequences on health care utilization and lost workdays.
Methods A national prospective household contact study between January 4, 2000,
and March 15, 2000, in France recruited the households of 946 persons who
visited a physician (index cases); 395 households with influenza-positive
index cases completed the follow-up, which assessed the clinical impact of
influenza, medical visits, treatment, and lost workdays in these index cases
and their contacts.
Results Of 817 assessable household contacts, 313 developed clinical influenza
(secondary cases); 178 (57%) of them visited a physician at least once (consulting
secondary cases). The median duration of illness was 8 days (95% confidence
interval [CI], 7-8 days) in index cases, 7 days (95% CI, 7-8 days) in consulting
secondary cases, and 4 days (95% CI, 3-5 days) in nonconsulting secondary
cases (P<.001); the median duration of treatment
in these groups was 8 days (95% CI, 8-9 days), 8 days (95% CI, 7-10 days),
and 5 days (95% CI, 4-6 days), respectively (P<.001);
and their mean ± SD number of lost workdays was 4.0 ± 2.8, 2.9
± 2.5, and 0.3 ± 0.6, respectively, in working adults (P<.001).
Conclusions These results confirm the substantial burden of illness of influenza.
The results should be useful for evaluating the cost-effectiveness of strategies
against influenza.
INTRODUCTION
INFLUENZA EPIDEMICS have an important and well-documented impact on
mortality, particularly in at-risk individuals, including elderly persons.1-4 Recent
work5 suggests that influenza epidemics are
also associated with an elevated number of hospitalizations. On the other
hand, their impact on uncomplicated morbidity and their consequences on health
care utilization and lost productivity are still relatively unclear, despite
the development of influenza surveillance systems in many countries. These
systems are based on data collected from physicians who report cases of syndromes
meeting a clinical case definition of influenza, sometimes but not always
combined with virologic testing; they make it possible to detect epidemics
early, to identify the circulating viral strains, and to supply quantitative
information, for example, about the number of "excess" physician visits associated
with an epidemic.6-7 For several
reasons, however, the results of this surveillance yield an incomplete picture
of the true impact of epidemics. The clinical expression of the infection
caused by influenza viruses is variable, and some physician visits for influenza
infection will not be counted (and no sample will be taken) because the patient's
clinical presentation does not meet the case definition. Carrat et al8 previously showed that nearly half of the patients
visiting a physician for influenza had an attenuated form of the disease.
Moreover, some individuals with influenza do not visit physicians; this fraction
may represent 30% to 65% of patients whose clinical picture suggests influenza.9-10 These individuals cannot be captured
by a medically based surveillance system. At the other end of the spectrum,
some patients may visit a physician several times for the same influenza episode,11 and these new visits are rarely counted. Failure
of the surveillance systems to take into account these categories of patients
leads to a potentially important underestimation of the epidemic's impact
on uncomplicated morbidity. This knowledge is nonetheless essential, especially
for an accurate evalua tion of the clinical and economic benefits of preventive
and treatment strategies against influenza.12-13
A prospective household contact study was performed between January
4, 2000, and March 15, 2000, to describe the different syndromes associated
with influenza virus entry into a household and their consequences on health
care utilization and lost workdays among patients who did and did not visit
physicians.
MATERIALS AND METHODS
The study took place during an influenza epidemic associated with the
circulation of 2 viruses: A/Sydney/5/97 (H3N2) (the variant responsible for
epidemics in Europe since the winter of 1997-1998) and A/Moscow/10/99 (H3N2)
(a variant antigenically closely related to the previous one). Households
were included in this study by 161 general practitioners across France who
were members of the "Sentinelles" network.14
These physicians received training in taking virologic samples and about this
study during a pilot phase in October 1999.
INCLUSION CRITERIA
A household was recruited when 1 member (the index case) made an office
visit to or received a house call from a physician, and a household was included
in the study if the following criteria were met: the index case visited a
participating physician because of the onset within 48 hours of a fever (temperature
>38°C) or feverishness, with respiratory signs, and the index case lived
with at least 1 other person (the contact subject), was the first case in
the household, was not hospitalized as a result of this first visit, and consented
to virologic sampling and study participation.
DESIGN
During the visit, the physician explained the principle of the study
to an adult household member (the index case or the adult accompanying a minor
index case), took a nasal swab sample from the index case and mailed it to
1 of the 3 participating virology centers, and mailed an inclusion form to
the study administrative center. The physician also gave the adult a 2-part
questionnaire to be completed at home for all members of the household: the
first part collected the general characteristics, the influenza and vaccination
history, and the social and demographic characteristics of each household
member, and the second part, presented as a diary checklist, described for
each person on each of the following 15 days the following items: symptoms
(13 symptoms and "none of the above"), work, medications, and physician visits.
If any family member visited a physician, information about any prescriptions
and tests ordered were noted on a separate sheet. The questionnaire was to
be mailed to the study center after 15 days of follow-up.
SECONDARY CASES
To include the broadest possible spectrum of clinical syndromes occurring
among the contact subjects, we defined clinical influenza by the presence
within 5 days of inclusion of fever (temperature >38°C) or feverishness
(patient's subjective sensation of fever or chills) or at least 2 of the following
signs: sore throat, headache, stiffness or myalgias, fatigue, cough, and nasal
congestion, rhinorrhea, or sneezing. To avoid modifying the contact subjects'
behavior as to health care utilization, no samples were obtained from them.
MONITORING
In the 3 days after inclusion, the study administration center telephoned
92% of the households to offer help in completing the questionnaire. The first
528 households were also enrolled in a study that measured their willingness
to pay for faster amelioration of the principal influenza symptoms.
VIROLOGIC METHODS
Specimens
Nasal swab samples were collected and stored in 3 mL of viral transportation
medium. Samples were sent through the mail without any refrigeration. Mean
± SD transportation time was 1.7 ± 1.4 days. One milliliter
of sample was used immediately for direct immunofluorescence staining. The
remaining 2 mL was stored at -70°C until use for culture and polymerase
chain reaction (PCR).
Methods
One milliliter of sample was used to perform direct immunofluorescence
staining on the cell pellets with specific monoclonal antibodies for influenza
A and B viruses, parainfluenzae viruses, adenoviruses, and respiratory syncytial
viruses (DAKO Imagen, Trappes, France). Viral cultures were performed on Madin-Darby
canine kidney cell monolayers.
Two types of PCR were used to test for influenza viruses. Reverse transcription
PCR with hybridization was used by 2 of the 3 virology centers; it has been
validated and described elsewhere.15 In the
third virology center, a real-time PCR (TaqMan; Applied Biosystems, Foster
City, Calif) followed the method recently reported16
but used other specific primers. A cross-validation study of these different
PCR tests is under way. Influenza was diagnosed if the results of any 1 of
these 3 tests were positive.
STATISTICAL ANALYSIS
The impact of influenza was estimated by identifying 3 groups: index
cases, secondary cases who visited a physician at least once (consulting),
and secondary cases who did not visit a physician (nonconsulting). Each participant
checked off his or her symptoms daily from the following list: fever (temperature
>38°C); feverishness; cough; sore throat; nasal congestion, rhinorrhea,
or sneezing; dysphonia; fatigue; headache; stiffness or myalgias; otalgias;
ocular symptoms; loss of appetite; and sleep disturbances. A symptom score
was calculated by dividing the total number of symptoms by 13: a score of
1 indicated the presence of all 13 symptoms, and a score of 0 indicated the
absence of any symptoms. To estimate the time lost from work by working participants,
a daily index was calculated: a normal workday was coded 0, a complete workday
in which work was disturbed because of illness was coded 0.25, absence of
less than 1 full workday was coded 0.5, and a complete day of absence was
coded 1. Weekends and holidays were coded 0. This index gives us an idea of
the real time lost from work associated with influenza-related sick leave.
Quantitative variables were compared between groups by using analysis
of variance. Qualitative variables were compared using the  2
test or, for small groups, an exact test. Correlation coefficients were estimated
using the Spearman method. Median durations were estimated using the Kaplan-Meier
method, and comparisons of duration were made using a log-rank test. Repeated-measures
analyses of variance were used to compare quantitative variables measured
over time, and the time-variable interactions were tested. All comparisons
used bilateral tests and a 5% cutoff point. Data are given as mean ±
SD.
RESULTS
Between January 4, 2000, and March 15, 2000, 946 households throughout
France were included in the study; in 510 households (54%), the index case
had positive test results for influenza A (Figure 1). Two index cases were infected by influenza B (1 of whom
was also positive for type A) and 25 by respiratory syncytial virus (2 of
whom were also positive for influenza A). There were no positive diagnoses
of adenovirus or of any parainfluenza virus. One sample, which arrived at
the laboratory 29 days after mailing, was not analyzed. The virologic examination
results of 411 index cases (43%) were negative for all of the viruses tested.
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Figure 1. Study participant flow diagram.
Asterisk indicates 1 household with missing virologic test results.
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Of the 510 households with an index case diagnosed as having influenza
A, 395 (77%) returned the questionnaire and 115 (23%) were lost to follow-up.
The percentage of households lost to follow-up varied according to the sex
of the index case (19% for women and 26% for men; P
= .04). At inclusion, households that completed the study and those lost to
follow-up did not differ significantly for the other variables, in particular,
for age of the index case, severity of the disease as reported by the physician,
temperature measured by the physician or reported by the patient, inclusion
date, drugs prescribed during the visit, or proportion of working adults among
the index cases.
The 395 households we followed had a mean size (including the index
case) of 3.25 ± 1.26 individuals. Insufficient information about the
clinical follow-up meant that 74 of 891 contact subjects could not be categorized.
Of the others, 313 (38%) developed symptoms in the 5 days after inclusion
and were classified as secondary cases. At least 1 secondary case was reported
in 56% of the households in which the index case was positive for influenza
A.
CHARACTERISTICS AT INCLUSION
The mean age of the individuals followed was 32.8 ± 19.7 years
(range, 0.2-89.9 years), 49% were men, 10% had had an influenzalike illness
during the preceding winter, 8% had been vaccinated against influenza, 19%
were current smokers, 46% were working adults, and 16% had 1 or more chronic
diseases (36% cardiovascular, 27% pulmonary, 3% diabetes mellitus, and 40%
others). Table 1 gives the principal
characteristics of the individuals we followed as a function of their status.
Index cases were, on average, older and more frequently affected by chronic
diseases than contacts. Contacts who became secondary cases did not differ
significantly from those who remained healthy.
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Table 1. Baseline Characteristics of Influenza-Positive Households
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Of the 313 secondary cases, 178 (57%) visited a physician at least once
for their symptoms (consulting) and 135 (43%) did not (nonconsulting).
CLINICAL IMPACT
Table 2 describes the clinical
presentation of the syndromes observed, according to group. The mean time
elapsed between inclusion and appearance of the first symptoms was 1.35 ±
1.50 days, with no difference between consulting and nonconsulting cases.
On the first day of illness, the signs most frequently found in secondary
cases were coughing and fatigue, but only 44% of the consulting and 30% of
the nonconsulting secondary cases reported a fever or feverishness that day
(P = .02). The median duration until alleviation
of major symptoms in index cases was 8 days (95% confidence interval [CI],
7-8 days), which did not differ significantly from that in consulting secondary
cases (7 days; 95% CI, 7-8 days) but was greater than in nonconsulting secondary
cases (4 days; 95% CI, 3-5 days; P<.001) (Figure 2).
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Table 2. Clinical Impact of the Influenza Syndromes Observed
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Figure 2. Time to alleviation of major influenza
symptoms (Kaplan-Meier estimate).
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HEALTH CARE UTILIZATION
Table 3 describes the utilization
of health care by group. The mean number of visits related to clinical influenza
was 1.35 ± 0.63 in index cases and 1.35 ± 0.66 in consulting
secondary cases (P = .91). Secondary cases first
visited a physician a mean of 1.1 ± 2.0 days after symptoms began.
Second visits, if any, took place 4.8 ± 3.2 days after the first. The
mean number of prescription and over-the-counter drugs taken on the first
day of illness differed among groups; this number was correlated with the
clinical severity of the patient's disease (r = 0.41; P<.001). The proportion of patients treated with antibiotics
varied with the number of visits: 17% for nonconsulting secondary cases, 48%
for those who visited a physician only once, 70% for those consulting twice,
and 85% for those who visited a physician more than twice (P<.001, Cochran-Armitage trend 2). The median duration
of antibiotic treatment was 6 days (95% CI, 6-7 days) in index cases, 7 days
(95% CI, 6-8 days) in consulting secondary cases, and 4.5 days (95% CI, 3-6
days) in nonconsulting secondary cases (P = .02).
In all, the median duration of actual treatment, whatever the drug, was higher
in consulting (8 days) than in nonconsulting (5 days) secondary cases (P<.001) and was correlated with the symptom score on
the first day of the disease (hazard ratio, 0.54 [95% CI, 0.38-0.77]; P<.001). The percentage of medicine prescribed for the
patient among all the medicine taken was 90% for index cases, 85% for consulting
secondary cases, and 28% for nonconsulting secondary cases (P<.001). In the latter, this result is explained by the use of treatments
prescribed for them during the visit of another member of the household or
of medication prescribed for them before study entry. The following additional
tests were ordered: 15 lung radiographs, 5 sinus radiographs, and 1 complete
blood cell count.
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Table 3. Health Care Utilization in Individuals With Influenza*
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LOST WORKDAYS
Working adults accounted for 199 of the index cases (50%), 66 of the
consulting secondary cases (37%), and 65 of the nonconsulting secondary cases
(48%). Figure 3 shows the daily
index of sick leave from work for the 15 days after the disease began. The
3 groups differ in the mean number of lost workdays (sum of the daily index
for the 15 days for each group), the percentage of individuals who did not
stop working, and the median duration until return to usual work activity
in those who had stopped working (Table
4). The difference is greatest between individuals who visited physicians
and those who did not. The number of lost workdays was correlated with the
symptom score on the first day of illness (r = 0.45; P<.001). Of working contacts who did not become secondary
cases, the number of lost workdays was estimated to be 0.03 ± 0.18
days per sick adult in the household and 0.11 ± 0.41 days per sick
child.
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Figure 3. Daily index of sick leave from
work among working adults with influenza.
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Table 4. Occupation Activity in Working Adults With Influenza*
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COMMENT
The results of this study confirm that the impact of the uncomplicated
morbidity associated with influenza epidemics is substantial and cannot be
deduced directly from surveillance data. We showed that 43% of the contact
subjects who experienced an episode of respiratory tract infection, presumably
caused by influenza, did not visit a physician for these episodes; that the
mean number of visits for those who did go to a physician was 1.35; and that
the duration of treatment, like the number of drugs taken and the translation
of the episodes into lost workdays, varied as a function of recourse to consultation,
which in turn was associated with the seriousness of the patient's illness.
Of the principal choices and assumptions that might have affected the
validity of our results, we must discuss the potential bias induced by the
choices of our experimental design, especially in terms of the representativeness
of the population studied and of the case definition retained for classifying
contact subjects.
We used a quantitative approach to assess uncomplicated morbidity by
performing a prospective study of household contacts. The advantage of this
type of design over a standard cohort design is that it increases the study
power at the same time as it reduces the duration of follow-up for each case
and increases the likelihood that the study cases will develop the disease.
On the other hand, it has the disadvantage of preventing observation of individuals
who live alone. Nonetheless, we do not believe that exclusion of these individuals
biased our results substantially. The principal factor correlated in this
study with utilization of health care resources and lost workdays was the
clinical seriousness of the patient's illness, and there is no reason to think
that this might be correlated with living alone: no correlation was observed
between household size and the secondary cases' symptom score on the first
day of illness (r = -0.04; P = .44).
We compared participants with the last census for several variables
to assess national representativeness. The mean size of the households we
studied was 3.25 persons, and the mean age of household members was 33 years;
the corresponding national figures for households with more than 1 person
are similar (3.10 persons and 34 years). The proportion of working adults
(among all study participants) was 46%, whereas the national proportion is
45%. The social and demographic structure of the households in this study
do not differ in any important way from the national means for occupational
category or mean net household income. Moreover, all French regions were represented.
Thus, it seems reasonable to consider that the households observed were representative
of the French population.
The other possible source of bias is that the participants' inclusion
in the study might have induced a change in their behavior as to health care
utilization (drugs and physician visits). This bias is inherent in all prospective
studies, but its extent is less herein than that observed in therapeutic trials.
We intentionally provided no instructions to either the physician or the family
about recommended treatments, physician visits, and so on. For the same reason,
virologic samples were not taken from contact subjects who developed symptoms,
and follow-up information was collected by a self-administered questionnaire.
Our results for the prescription of antibiotic treatment are consistent with
the values reported in France (61% of antibiotic use, data from a national
retrospective survey of a representative population sample in 1999/200017). The rate of neuraminidase inhibitor prescriptions
was also consistent with data for their sales in France during the 1999/2000
epidemic (A. El-Hasnaoui, MD, PhD, Health Economic Department, GlaxoSmithKline,
oral communication, December 2000). For these reasons, we do not think that
the results were biased by the participants' participation in the follow-up.
Households enrolled in the willingness-to-pay nested study did not differ
from the others in terms of rate of secondary cases, self-evaluation of symptoms,
and rate of physician visits; these data indicate that the results were not
affected by participation in the willingness-to-pay study.
We deliberately used a "broad" definition of secondary cases that allowed
inclusion of patients with minor clinical forms so that we could accurately
quantify the impact of influenza, and we did not collect virologic samples
from contacts for the reasons stated previously. It is accordingly possible
that some contacts classified as secondary cases were infected by a respiratory
pathogen other than an influenza virus. It also explains why we observed a
substantially higher proportion of secondary cases among contact subjects
of positive index cases (38%) than the corresponding proportions of laboratory-confirmed
clinical influenza recently reported in the placebo groups of randomized studies
of prophylaxis for contact subjects (13%-15%).18-19
In these studies, the case definitions used for clinical influenza relied
on a combination of symptoms sufficiently severe that 35% and 39% of laboratory-confirmed
influenza infections among contacts did not have clinical influenza. In one
of these studies,18 low-grade illnesses that
did not meet the case definition represented 28% of all symptomatic influenza
infections. Applying the case definitions used in those studies to our patients
showed that they would not have classified 74 of our secondary cases (24%)
as clinical influenza, mainly because of lack of fever. In other words, we
found a similar rate of low-grade illnesses in our study. Moreover, our 38%
rate of secondary cases is lower than that observed in the control group of
another trial20 in which the onset of a respiratory
tract illness in contacts of nonvaccinated children was 56%; it fell to 20%
when fever was included in the disease definition criteria. A temperature
higher than 37.8°C is a relatively erratic sign among patients with positive
test results for influenza: 30% of the positive individuals in the zanamivir
trial21 did not meet this inclusion criterion.
Two other studies9, 22 found that
35% and 40% of influenza A/H3N2–positive patients were afebrile. Thus,
we believe that the spectrum of syndromes classified as secondary cases in
our study corresponded to the spectrum of syndromes associated with influenza
infections.
Although contact cases did not undergo virologic testing, we think that
we minimized the risk that the syndromes observed in secondary cases had a
noninfluenza origin by choosing a window of 5 days from the inclusion of the
index case positive for influenza A for the onset of symptoms among secondary
cases. This conclusion is also supported by the actual mean delay to onset
of symptoms of 1.3 days. Finally, the combination of symptoms that we used
to determine secondary cases was different from the inclusion criteria that
justified virologic samples from the index cases; this difference is seen
in the higher symptom scores in index cases vs secondary cases.
To our knowledge, there are no recent observational studies in general
populations that would allow us to compare these results with other data.
The median duration of disease observed in this study in individuals who visited
a physician was similar to that reported for placebo groups in neuraminidase
inhibitor trials,23 although lower values have
been observed.24-25 The rate of
physician visits by individuals with documented influenza varied between 38%
and 49% in observational studies conducted in the United States between 1976
and 1980.26 Our results are close to those
observed in these studies.
The impact on productivity, that is, workdays lost or wasted because
of influenza, is the key indicator in an assessment of the economic benefits
of influenza control strategies—either treatment or vaccination. The
mean number of days lost per working adult has been assessed to be 2.8 to
10.0 principally on the basis of studies in occupational settings11, 27 and 2.0 to 5.0 in pandemic contexts,28 although lower values have also been observed in
the placebo groups in prevention studies.29-31
Our results are, on the whole, consistent with these values.
In conclusion, this study is, to our knowledge, the first to describe
the repercussions on health care utilization and work that follow influenza
virus entry into households. It shows that a substantial fraction of the population
of patients with influenza "escapes" standard surveillance. We believe that
these results provide important data for evaluating the cost-effectiveness
of strategies against influenza.
AUTHOR INFORMATION
Accepted for publication January 3, 2002.
This study was funded by GlaxoSmithKline, Marly-le Roi, France.
Preliminary analyses of these data were presented as abstract W21-4
at the Congress Options for the Control of Influenza IV, Hersonissos, Greece,
September 24, 2000.
We thank the patients, their families, and the 161 general practitioners
of the French "Sentinelles" system who participated in the study; Isabelle
Goderel, BS, Gregory Pannetier, BS, Audrey Lavenu, MSc, Michael Schwarzinger,
MD, MSc, and Astrid Vabret, MD, for technical assistance in data collection
and analysis; Bertrand Basset, BS, Hélène Chabernaud, BS, and
Anna Garafano, BS, for technical assistance in data processing; and Abdelkader
El-Hasnaoui, MD, PhD (GlaxoSmithKline) for helpful comments.
Corresponding author and reprints: Fabrice Carrat, MD, PhD, INSERM
U444, Faculté de Médecine Saint-Antoine, 27 rue Chaligny, 75571
Paris CEDEX 12, France (e-mail: carrat{at}u444.jussieu.fr).
From Institut National de la Santé et de la Recherche Médicale
(INSERM), Unit 444, Faculté de Médecine Saint-Antoine, Paris
(Dr Carrat and Ms Sahler); Laboratoire de Bactériologie, Virologie
et Hygiène, Centre Hospitalier Universitaire (CHU) Dupuytren, Limoges
(Dr Rogez); Laboratoire de Virologie, CHU Necker Enfants-Malades, Paris (Drs
Leruez-Ville and Rouzioux); Laboratoire de Virologie Humaine et Moléculaire,
CHU Côte de Nâcre, Caen (Dr Freymuth); INSERM Unit 537, Le Kremlin
Bicêtre (Dr Le Gales); INSERM Unit 502, Centre National de la Recherche
Scientifique (CNRS) Unit 8559, Paris (Dr Bungener); Service de Pneumologie,
Centre Hospitalier Inter-Communal, Créteil (Dr Housset); and Université
Paris II Panthéon–Assas, Paris (Ms Nicolas), France.
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