Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children

Journal of Infectious Diseases, Jan 2017

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.

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Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children

JID Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children Received 0 May 0 accepted 0 August 0 published online 0 October 0 . Presented in part: XVIIIth International Symposium on Respiratory Viral Infections 0 Lisbon 0 Portugal 0 March- 0 1 April 0 . Correspondence: T. Heikkinen 0 Department of Pediatrics 0 University of Turku 0 FI- 0 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 [8]. 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 [14], 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 [16]. 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. Subjects 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 [17]. 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 Each Season 2000–2001 Season, No. (%) (n = 1338) 2001–2002 Season, No. (%) (n = 893) 646 (48.3) 692 (51.7) 433 (48.5) 460 (51.5) Ethics 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. Study Conduct 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 [18]. 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 absenteeism. 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 strains [21]. Definitions 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. Statistical Analysis 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 84 5 35 44 28 14 7 5 2 3 115 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 1000 children. 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 (P ≤.02). 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 2000–2001 Season 2001–2002 Season 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 or School Total Days of Absence per 100 Children With RSV Illness, No. (95% CI)b 195 (159–232) 162 (128–196) 58 (15–101) 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). Children’s Absenteeism 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). DISCUSSION 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 treatment. The incidence of RSV infection in our population was much higher than that observed in a previous study in the United States [7]. 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 [17]. 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 [31]. 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 [34]. 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 [4]. 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 [15], 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 [21]. 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 treatment [34]. 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. 1. Shay DK , Holman RC , Newman RD , Liu LL , Stout JW , Anderson LJ . Bronchiolitisassociated hospitalizations among US children , 1980 - 1996 . JAMA 1999 ; 282 : 1440 - 6 . 2. Bourgeois FT , Valim C , McAdam AJ , Mandl KD . Relative impact of influenza and respiratory syncytial virus in young children . Pediatrics 2009 ; 124 : e1072 - 80 . 3. Zhou H , Thompson WW , Viboud CG , et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States , 1993 - 2008 . Clin Infect Dis 2012 ; 54 : 1427 - 36 . 4. Hall CB , Weinberg GA , Blumkin AK , et al. Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age . Pediatrics 2013 ; 132 : e341 - 8 . 5. Garcia-Garcia ML , Calvo C , Pozo F , Villadangos PA , Pérez-Breña P , Casas I. Spectrum of respiratory viruses in children with community-acquired pneumonia . Pediatr Infect Dis J 2012 ; 31 : 808 - 13 . 6. Jain S , Williams DJ , Arnold SR , et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015 ; 372 : 835 - 45 . 7. Hall CB , Weinberg GA , Iwane MK , et al. The burden of respiratory syncytial virus infection in young children . N Engl J Med 2009 ; 360 : 588 - 98 . 8. Nair H , Nokes DJ , Gessner BD , et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis . Lancet 2010 ; 375 : 1545 - 55 . 9. Anderson LJ , Dormitzer PR , Nokes DJ , Rappuoli R , Roca A , Graham BS . Strategic priorities for respiratory syncytial virus (RSV) vaccine development . Vaccine 2013 ; 31S: B209 - 15 . 10. Graham BS . Protecting the family to protect the child: vaccination strategy guided by RSV transmission dynamics . J Infect Dis 2014 ; 209 : 1679 - 81 . 11. Mazur NI , Martinón-Torres F , Baraldi E , et al. Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics . Lancet Respir Med 2015 ; 3 : 888 - 900 . 12. DeVincenzo JP , Whitley RJ , Mackman RL , et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study . N Engl J Med 2014 ; 371 : 711 - 22 . 13. DeVincenzo JP , McClure MW , Symons JA , et al. Activity of oral ALS-008176 in a respiratory syncytial virus challenge study . N Engl J Med 2015 ; 373 : 2048 - 58 . 14. Meissner HC . Viral bronchiolitis in children . N Engl J Med 2016 ; 374 : 62 - 72 . 15. Diez-Domingo J , Pérez-Yarza EG , Melero JA , et al. Social , economic, and health impact of the respiratory syncytial virus: a systematic search . BMC Infect Dis 2014 ; 14 : 544 . 16. Bont L , Baraldi E , Fauroux B , et al. RSV-still more questions than answers . Pediatr Infect Dis J 2014 ; 33 : 1177 - 9 . 17. Heikkinen T , Silvennoinen H , Peltola V , et al. Burden of influenza in children in the community . J Infect Dis 2004 ; 190 : 1369 - 73 . 18. Puhakka T , Pulkkinen J , Silvennoinen H , Heikkinen T. Comparison of spectral gradient acoustic reflectometry and tympanometry for detection of middle ear effusion in children . Pediatr Infect Dis J 2014 ; 33 : e183 - 6 . 19. Heikkinen T , Marttila J , Salmi AA , Ruuskanen O. Nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses . J Clin Microbiol 2002 ; 40 : 4337 - 9 . 20. Waris ME , Heikkinen T , Österback R , Jartti T , Ruuskanen O. Nasal swabs for detection of respiratory syncytial virus RNA . Arch Dis Child 2007 ; 92 : 1046 - 7 . 21. Kutsaya A , Teros-Jaakkola T , Kakkola L , et al. Prospective clinical and serological follow-up in early childhood reveals a high rate of subclinical RSV infection and a relatively high reinfection rate within the first 3 years of life . Epidemiol Infect 2016 ; 144 : 1622 - 33 . 22. Waris M. Pattern of respiratory syncytial virus epidemics in Finland: two-year cycles with alternating prevalence of groups A and B . J Infect Dis 1991 ; 163 : 464 - 9 . 23. Heikkinen T , Thint M , Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media . N Engl J Med 1999 ; 340 : 260 - 4 . 24. Chonmaitree T , Revai K , Grady JJ , et al. Viral upper respiratory tract infection and otitis media complication in young children . Clin Infect Dis 2008 ; 46 : 815 - 23 . 25. Stockmann C , Ampofo K , Hersh AL , et al. Seasonality of acute otitis media and the role of respiratory viral activity in children . Pediatr Infect Dis J 2013 ; 32 : 314 - 9 . 26. Vesa S , Kleemola M , Blomqvist S , Takala A , Kilpi T , Hovi T. Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age . Pediatr Infect Dis J 2001 ; 20 : 574 - 81 . 27. Heikkinen T , Ruuskanen O. Temporal development of acute otitis media during upper respiratory tract infection . Pediatr Infect Dis J 1994 ; 13 : 659 - 61 . 28. Koivunen P , Kontiokari T , Niemelä M , Pokka T , Uhari M. Time to development of acute otitis media during an upper respiratory tract infection in children . Pediatr Infect Dis J 1999 ; 18 : 303 - 5 . 29. Capra AM , Lieu TA , Black SB , Shinefield HR , Martin KE , Klein JO . Costs of otitis media in a managed care population . Pediatr Infect Dis J 2000 ; 19 : 354 - 5 . 30. Paramore LC , Ciuryla V , Ciesla G , Liu L. Economic impact of respiratory syncytial virus-related illness in the US: an analysis of national databases . Pharmacoeconomics 2004 ; 22 : 275 - 84 . 31. Grijalva CG , Nuorti JP , Griffin MR . Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings . JAMA 2009 ; 302 : 758 - 66 . 32. Heikkinen T , Ruuskanen O , Waris M , Ziegler T , Arola M , Halonen P. Influenza vaccination in the prevention of acute otitis media in children . Am J Dis Child 1991 ; 145 : 445 - 8 . 33. Block SL , Heikkinen T , Toback SL , Zheng W , Ambrose CS . The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children . Pediatr Infect Dis J 2011 ; 30 : 203 - 7 . 34. Heinonen S , Silvennoinen H , Lehtinen P , et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial . Clin Infect Dis 2010 ; 51 : 887 - 94 . 35. Hall CB , Geiman JM , Biggar R , et al. Respiratory syncytial virus infections within families . N Engl J Med 1976 ; 294 : 414 - 9 . 36. Munywoki PK , Koech DC , Agoti CN , et al. The source of respiratory syncytial virus infection in infants: a household cohort study in rural Kenya . J Infect Dis 2014 ; 209 : 1685 - 92 . 37. Heikkinen T , Valkonen H , Waris M , Ruuskanen O. Transmission of respiratory syncytial virus infection within families . Open Forum Infect Dis 2015 ; 2 : ofu118 .


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Terho Heikkinen, Emilia Ojala, Matti Waris. Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children, Journal of Infectious Diseases, 2017, 17-23, DOI: 10.1093/infdis/jiw475