Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children
Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children
published online 0
. Presented in part: XVIIIth International Symposium on Respiratory Viral Infections 0
March- 0 1
. Correspondence: T. Heikkinen 0
Department of Pediatrics 0
University of Turku 0
Finland (). The Journal of Infectious Diseases® 0
0 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions , e-mail
1 Department of Virology, University of Turku , Finland
2 Department of Pediatrics, University of Turku and Turku University Hospital
Background. Vaccines and antivirals against respiratory syncytial virus (RSV) are being developed, but there are scarce data on the full impact of RSV infection on outpatient children. Methods. We analyzed the burden of RSV illness in a prospective cohort study of children aged ≤13 years during 2 consecutive respiratory seasons in Turku, Finland (2231 child-seasons of follow-up). We examined the children and obtained nasal swabs for the detection of RSV during each respiratory illness. The parents filled out daily symptom diaries throughout the study. Results. Of 6001 medically attended respiratory infections, 302 (5%) were caused by RSV. Per 1000 children, the average annual RSV infection incidence rates among children aged <3, 3-6, and 7-13 years were 275, 117, and 46 cases, respectively. In children aged <3 years, acute otitis media developed in 58%, and 66% of children in this age group received antibiotics. The mean duration of RSV illness was longest (13.0 days) and the rate of parental work absenteeism was highest (136 days per 100 children with RSV illness) in children aged <3 years. Conclusions. The burden of RSV is particularly great among outpatient children aged <3 years. Young children are an important target group for the development of RSV vaccines and antivirals.
Respiratory syncytial virus (RSV) is the leading cause of
hospitalization for acute respiratory tract infection in infants and a
major cause of acute lower respiratory tract infection in children
[1–6]. Although RSV infections occur in all age groups, the
burden of this virus is clearly greatest in children [3, 7]. According
to a global analysis, 66 000–199 000 children <5 years of age die
annually because of RSV infection, and >3 million children in
this age group are hospitalized .
Because of the great clinical burden of RSV infection, safe and
effective vaccines and antivirals are needed to combat the disease.
In recent years, after decades of virtual silence in the field, several
candidate RSV vaccines have been developed and are at various
stages of testing [9–11]. Furthermore, a few antiviral drugs against
RSV have already entered clinical trials and have shown both
antiviral and clinical efficacy in virus challenge studies [11–13].
Although the primary role of RSV in bronchiolitis-associated
hospitalization of young infants is well established , there is
surprisingly little information available about the burden of
RSV infection in children in the outpatient setting [7, 15].
Clinical and socioeconomic data on the full burden of RSV
illness and its consequences in different age groups of children are
needed to inform the development and optimal use of emerging
RSV vaccines and antivirals and to provide essential data for the
evaluation of their cost-effectiveness . The purpose of our
study was to determine the burden of virologically confirmed
RSV infections in prospectively followed cohorts of outpatient
children and their families.
This analysis was based on clinical and virologic data from a
prospective cohort study among outpatient children that was
conducted during 2 consecutive respiratory seasons (October–May
2000–2001 and 2001–2002) in Turku, Finland . The
participants were recruited through day care centers, family day care,
and schools. All children ≤13 years of age were eligible for
participation, regardless of any underlying medical conditions. Any
child who was examined at the study clinic at least once and/or
who returned completed symptom diaries for an entire
respiratory season was considered an active participant and constituted 1
child-season; only active participants were included in this
analysis. Of 1458 children recruited in the autumn of 2000, 1338 were
active participants during the season of 2000–2001. For the
2001–2002 season, the recruited group consisted of 907 children,
of whom 893 were active participants. Overall, the study
comprised 2231 child-seasons of follow-up. The baseline
characteristics of the children are presented in Table 1.
Table 1. Characteristics of the Children at the Start of Follow-up During
No. (%) (n = 1338)
No. (%) (n = 893)
The study protocol was approved by the Ethics Committee of
the Hospital District of Southwest Finland, and it was
conducted in accordance with the Declaration of Helsinki. The parents
or guardians of all participating children provided their written
informed consent prior to commencement of the study.
The parents were asked to bring their child to the study clinic
every time the child had fever or signs or symptoms of a
respiratory tract infection. The study clinic was open every day, and
all visits were free of charge to the families. At each visit, the
children were examined by a study physician who filled out a
structured medical record containing the history, signs and
symptoms, clinical findings, diagnosis, and treatment. Chest
or sinus radiographs were routinely obtained for all children
who were clinically suspected of having pneumonia or sinusitis.
Pneumatic otoscopy, tympanometry, and spectral-gradient
acoustic reflectometry were used for diagnosing acute otitis
media . Children without any complications at the first
visit were routinely reexamined after 5–7 days and whenever
the parents deemed it necessary.
During each season, the parents were provided with daily
symptom diaries inquiring about the symptoms of the child,
the child’s absence from day care or school because of
respiratory illness, and parental absence from work because
of the child’s illness. The days of absenteeism included only
actual days lost; days of illness occurring during free
weekends or other days off were not recorded as causing
Sources of Data
The data for this analysis were derived from the structured
medical records filled out by the study physicians and from the daily
symptom diaries filled out by the parents.
Viral Diagnostic Assays
During each episode of respiratory infection, regardless of the
severity of symptoms, a nasal swab was obtained from a depth
of 2–3 cm in the nostril by use of a sterile cotton swab that was
then inserted into a vial that contained viral transport medium
[19, 20]. The specimens were kept in a refrigerator and
transported daily to the Department of Virology, University of
Turku, where all virologic analyses were performed. The
detection of RSV in the specimens was based on both viral culture
and reverse-transcription polymerase chain reaction
(RTPCR). Nucleic acids were extracted from the specimens by
using the High Pure Viral Nucleic Acid Kit or the MagNA
Pure LC extractor (Roche Diagnostics, Espoo, Finland)
according to the manufacturer’s protocols. The extracts were
then stored at −70°C and later analyzed for RSV N gene
RNA by RT-PCR differentiating between group A and B
The diagnoses of pneumonia and sinusitis were only made in
children with radiological confirmation of the illness. The
diagnosis of acute otitis media required the presence of middle-ear
effusion as detected by pneumatic otoscopy, signs of
inflammation of the tympanic membrane, and at least 1 sign of acute
infection. Any complications were considered to be associated
with RSV if they were diagnosed within 14 days after the visit
at which the RSV-positive specimen was obtained, if the child
had remained symptomatic, and if no other virus was detected
in the meantime.
For determination of the seasonal incidence of RSV
infections, children were divided into different age groups according
to their age at the start of the follow-up during each season. For
assessment of the clinical and socioeconomic features of RSV
infection, classification into different age groups was based on
the age of the children on the day when they made their first
visit to the study clinic because of RSV illness. For the purposes
of this study, children who had 2 episodes of RSV infection were
considered separate children in the analyses, and they were
analyzed in the age group that they belonged to at the time of the
illness. When calculating the total duration of RSV illness, we
included all consecutive days on which the child had fever,
rhinitis, or cough.
Because it is well established that RSV infection epidemics in
Finland follow a distinct 2-year pattern (with minor and
major outbreaks alternating during consecutive seasons) [21,
22] and because the relative proportions of children in different
age groups varied between the seasons of follow-up, the
agebased RSV infection incidence rates were calculated separately
for each season. The incidence rates of RSV infections were
calculated by dividing the numbers of RSV infection episodes by
the follow-up time. Considering the well-known virtual absence
of RSV circulation outside of the epidemic periods and the need
to provide conservative estimates of annual incidence rates, the
follow-up time for each season of the study was determined as 1
year, although the actual follow-up times were shorter.
Calculation of confidence intervals (CIs) for incidence rates and their
ratios and testing of the differences in incidence rates between
the age groups were based on the Poisson distribution.
Normally distributed continuous data between the age groups were
compared using 1-way analysis of variance and unpaired
t tests, and nonnormally distributed continuous data were
compared using the Kruskal–Wallis test and the Mann–Whitney
U test. Comparison of proportions between the groups was
performed by the χ2 test. All analyses between the age groups were
primarily based on comparisons between 3 independent
groups, and comparisons between 2 groups were only
performed in case of a statistically significant difference
between the 3 groups. Two-sided P values of <.05 were
considered to indicate statistical significance. All statistical analyses
were performed with StatsDirect, version 2.8.0 (StatsDirect,
Altrincham, United Kingdom).
Incidence of RSV Illnesses
Of 6001 respiratory infections diagnosed in the children at
the study clinic, 302 (5%) in 287 children were caused by
RSV (115 episodes in the first season and 187 in the second
season; Figure 1). In 15 children who had 2 separate RSV
infections, the mean interval between the episodes was 191 days
(range, 32–320 days). RSV group A strains were detected in
258 (85%) and group B strains in 14 (5%) of the 302 cases; 1
child had RSV A and B detected simultaneously, and the
virus group was not determined in 31 cases. In 30 of 302
cases (10%), the diagnosis of RSV infection was based on
viral culture only; PCR yielded negative results (13 cases) or
was not performed (17 cases). Of all RSV illnesses, 158 (52%)
occurred in boys and 144 (48%) in girls.
During each season, the rates of RSV illnesses were clearly
highest among children <3 years of age (Table 2). In the first
season, the RSV illness incidence rate in children <3 years
of age was 2.9 times (95% CI, 1.9–4.6 times) that in children
Abbreviation: CI, confidence interval.
3–6 years of age, and in the second season the corresponding
incidence rate ratio was 2.2 (95% CI, 1.6–3.0; P < .001 for
both comparisons). The average annual RSV illness incidence
rates per 1000 children were 275 in children <3 years of age,
117 in those 3–6 years of age, and 46 in those aged 7–13
years. In the entire group of children ≤13 years of age, the
average annual incidence rate of RSV infection was 148 cases per
Complications and Management
Two children with RSV infection were excluded from all further
analyses because of confirmed double viral infection (1 with
adenovirus and 1 with parainfluenza virus). Acute otitis media was
the most frequent complication of RSV infection, occurring in
148 children in the study population (50%) and in 87 children
<3 years of age (58%; Table 3). Pneumonia and sinusitis were
each diagnosed in 9 children (3%), and exacerbation of asthma
or expiratory wheezing were diagnosed in 31 children (10%).
Overall, 162 of children in the study population (54%) and 98
aged <3 years (66%) received antibiotic treatment. Nine
children (3%) were referred to the emergency department, and 3
(1%) were hospitalized.
Duration of Illness
The duration of RSV illness could be determined in 278 of
300 children (93%) on the basis of the daily symptom diaries
(Table 3). The mean duration of illness (±SD) was
significantly longer (13.0 ± 7.8 days) in children <3 years of age
than in children aged 3–6 years (10.5 ± 6.5 days; P = .005)
or 7–13 years (7.3 ± 3.8 days; P < .001). The median
durations of illness in these age groups were 11.0 days
(interquartile range [IQR], 8.0–15.0 days), 9.0 days (IQR, 6.0–13.0
days), and 6.0 days (IQR, 4.0–10.0 days), respectively; all
differences between the age groups were statistically significant
Parental Work Absenteeism
Detailed data on parental work absenteeism were available for
288 of 300 children (96%) with RSV infection; 40 children who
were cared for at home were excluded from the analyses of
absenteeism (Table 4). In the age group <3 years of age, a parent
had to miss ≥1 day of work in 57 of 110 cases (52%), with a
mean duration of absenteeism of 2.6 days. The rate of parental
work absenteeism per 100 children with RSV illness was
significantly higher (136 days) for children <3 years of age than for
Children Followed Up, No. RSV Episodes, No.
Incidence Rate, Cases/1000
Person-Years (95% CI)
Children Followed Up, No. RSV Episodes, No.
Incidence Rate, Cases/1000
Person-Years (95% CI)
Data on clinical features and management were available for 298 children.
Age Group, No. (%)
<1 y (n = 11)
1 y (n = 48)
2 y (n = 90)
3–6 y (n = 124)
7–13 y (n = 25)
All Children (n = 298)
Table 4. Parental Work Absenteeism Because of Child’s Respiratory
Syncytial Virus (RSV) Illness and Children’s Absenteeism From Day Care
Total Days of
Forty children who were cared for at home were excluded from this analysis.
Abbreviation: CI, confidence interval.
a Calculated for parents and children who were absent for at least 1 day.
b Includes all parents and children with or without absenteeism.
children aged 3–6 years (92 days; P = .03) or 7–13 years (29
days; P < .001).
Among 110 children <3 years of age, 71 (65%) missed ≥1 day of
day care, with a mean duration of absenteeism of 3.0 days
(Table 4). Per 100 children with RSV illness, the rates of
children’s absenteeism from day care or school were significantly
higher in children aged <3 years (195 days) and 3–6 years
(162 days) than in children 7–13 years of age (58 days;
P < .001 for both comparisons).
Our prospective follow-up of large cohorts of children during 2
consecutive respiratory illness seasons provides direct and
comprehensive evidence for a substantial burden of RSV infections
among children treated as outpatients. The burden of RSV
illness was particularly great among children <3 years of age, who
had the highest rates of infection, the longest duration of illness,
and the highest frequency of complications requiring antibiotic
The incidence of RSV infection in our population was much
higher than that observed in a previous study in the United
States . In that study, the estimated annual rate of RSV
infection, based on 171 outpatient children <5 years of age treated in
pediatric offices, was 80 cases per 1000 children, whereas the
corresponding rate in our study was 209 cases per 1000
children. The most likely explanation for the observed difference
is dissimilarities in the design of the studies, but other potential
reasons include differences in the relative severity of RSV
seasons, populations studied, healthcare systems, and
healthcareseeking behavior. In our study, free access to the study clinic
for the families probably lowered the threshold of bringing
the children to the clinic for examination and providing samples
for laboratory analysis during respiratory illnesses. However,
this should not be seen as a limitation but rather a strength of
the study because it allowed us to diagnose all symptomatic RSV
illnesses in the study cohorts, without a potential bias caused by
variation in access to health care.
Acute otitis media developed as a complication of RSV
infection in 58% of children <3 years of age, which is higher than the
diagnosis frequency of 40% in the same age group of children
with influenza . This finding is in agreement with previous
studies demonstrating that RSV is the principal virus invading
the middle ear and predisposing children to acute otitis media
[23–26]. Because the children in our study were routinely
reexamined after the initial visit, we could also diagnose cases of
acute otitis media that developed later during the course of
the illness [27, 28]. The costs of otitis media are high, and a
study assessing the economic impact of RSV illness showed
that otitis media was a major cost driver for physician visits
[29, 30]. Even more importantly, increasing antimicrobial
resistance of bacteria calls for reduced use of antibiotics, and acute
otitis media is the primary cause of antibiotic treatment in
children . Because of the proven efficacy of influenza vaccines to
prevent acute otitis media [32, 33], an effective RSV vaccine for
young children could be expected to have a major impact on
acute otitis media. Similarly, it is possible that early treatment
with effective RSV antivirals could substantially modify the
illness and decrease the incidence of acute otitis media developing
as a complication of RSV infection .
In our study, only 2% of children <3 years of age with a
diagnosis of RSV infection were hospitalized. Although this rate
may sound low, it corresponds to a population-based rate of
admission of 4 cases per 1000, which is in accordance with
previous studies . This finding does not challenge previous studies
that have demonstrated much higher rates of RSV-associated
hospitalization among very young infants and those with severe
comorbidities , but it serves to confirm that the greatest part
of the RSV-associated disease burden, including its
complications, occurs and is managed in the outpatient setting.
The rate and duration of parental work absenteeism were
highest for children <3 years of age. Because children cared
for at home were excluded from those analyses, the results are
generally applicable to circumstances in which children attend
day care. However, it is obvious that the exact rates of
absenteeism observed in our study cannot be directly applied to other
environments because a multitude of factors related to patterns
of child care and social security systems affect parental absence
from work because of the child’s illness.
We believe that our findings provide accurate estimates of the
burden of RSV illness in the outpatient setting because of some
important features of our study: careful follow-up for 2 RSV
illness seasons (including both minor and major outbreaks) of
hospitalization in children in our area, we may have missed
aplarge cohorts of children enrolled without any exclusion criteria;
unlimited, free daily access to the study clinic for clinical
examination; and sampling for the detection of RSV during each
respiratory illness, regardless of the presence of fever or the
severity of symptoms. There are also some limitations. First,
because of small numbers of children <6 months of age in the
follow-up cohorts, we were unable to determine the incidence of
RSV-associated hospitalization due to bronchiolitis. Second,
due to the summer break in our study and the extension of
the RSV infection outbreak to June in the first season, we
probably missed several cases of RSV illness occurring in the
children. Estimating from the weekly rates of RSV-associated
proximately 14% of actual RSV illnesses during the entire study
period, and therefore the true RSV illness incidence rates are
most likely even higher than those recorded in this study.
Third, we could only obtain specimens from children who
visited the study clinic, whereby some children with RSV infection
may have remained unidentified; however, such cases were
probably mild with limited clinical significance . Fourth,
although our study was so far the largest follow-up of RSV
infections among outpatient children, inclusion of additional RSV
illness seasons and increasing the sample size would obviously
have increased the accuracy of the estimates of the illness
burden. Finally, our study was performed in Finland, and therefore
our detailed findings on children’s and their parents’
absenteeism are not directly applicable to countries with different
patterns of child care. By contrast, however, it is generally
accepted that medical issues such as clinical presentation and
complications of an illness are largely generalizable to all
Owing to high rates of bronchiolitis-associated
hospitalization in infants during their first months of life, young infants
are generally considered the primary target population for an
RSV vaccine; however, innovative strategies such as vaccination
of pregnant women may be needed to overcome the challenges
of effectively immunizing young infants [9, 10]. Our findings
demonstrate that young children, especially those <3 years of
age, are another important target group for vaccine
development. Besides providing direct benefits to children themselves,
vaccination of children might substantially help protect young
infants against RSV because siblings are among the main
introducers of RSV into the family [35–37]. Furthermore,
analogously to influenza antivirals, the availability of effective RSV
antivirals for use in children could provide substantial benefits
by potentially shortening the duration of illness and decreasing
the incidence of bacterial complications requiring antibiotic
Acknowledgments. We thank all participating children and their
families and the study physicians, nurses, and laboratory personnel involved in
the performance of the study for their invaluable contributions.
Disclaimer. None of the sponsors had any role in the design or conduct
of the study; in the collection, management, analysis, or interpretation of the
data; or in the preparation of the manuscript. The decision to publish the
data was made solely by the authors, who are fully responsible for all
contents of the manuscript.
Financial support. This work was supported by Novavax, Wyeth,
GlaxoSmithKline, the Academy of Finland, the European Scientific
Working Group on Influenza, the Foundation for Pediatric Research in Finland,
and the Jenny and Antti Wihuri Foundation, Finland.
Potential conflicts of interest. T. H. has been a consultant to
GlaxoSmithKline, Alios BioPharma, and Novavax. All other authors report
no potential conflicts. All authors have submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider
relevant to the content of the manuscript have been disclosed.
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