The Outpatient Burden of Respiratory Syncytial Virus Infections in Older Children

Journal of Infectious Diseases, Jan 2017

Eric A. F. Simões

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The Outpatient Burden of Respiratory Syncytial Virus Infections in Older Children

JID The Outpatient Burden of Respiratory Syncytial Virus Infections in Older Children Received 1 accepted 0 1 October 1 published online 1 October 1 . Correspondence: E. A. F. Simões 1 Section of Infectious Dis- eases 1 Department of Pediatrics 1 University of Colorado School of Medicine 1 Aurora 1 CO 1 E 1 th Ave 1 Aurora 1 CO 1 (). The Journal of Infectious Diseases® 1 0 Center for Global Health, Colorado School of Public Health , Aurora 1 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions , e-mail 2 Department of Epidemiology 3 Section of Infectious Diseases, Department of Pediatrics, University of Colorado School of Medicine EDITORIAL COMMENTARY hospitalization; emergency room; epidemiology; vaccine; maternal immunization - Although the burden of severe lower respiratory tract infection with respiratory syncytial virus (RSV) in children aged <5 years is well known [1, 2], and although there are reasonable estimates for RSV-associated hospitalization in such children, in most parts of the world [3] the burden of outpatient visits due to RSV in younger and older children is relatively poorly studied. In the United States, it has been estimated that, in children aged <5 years, the annual burden of outpatient visits is 1 660 000–1 720 000 [4, 5], compared with 132 000–172 000 hospitalizations in the same age group [6]. The Centers for Disease Control and Prevention, in conjunction with local partners, has been conducting influenza etiology studies among children and adults with severe acute respiratory illness and influenza-like illness (ILI) in many countries. With the advent of cheaper, specific, polymerase chain reaction (PCR)– based diagnostic tests, there are numerous estimates of the burden of outpatient RSV infection in children and adults with ILI. One such example, from Kenya, estimated the outpatient burden of medically attended ILI to be 24.6 cases per 1000 children <5 years of age and 0.8 cases per 1000 people >5 years of age [7]. In contrast, the burden of RSV-associated hospitalization and outpatient visits among premature infants in the United States [8] was recently estimated to be 223 cases of medically attended outpatient upper respiratory tract infections per 1000 child-years, 330 lower respiratory tract infections per 1000 child-years, 141 emergency department visits per 1000 child-years, and 118 hospitalizations per 1000 child-years during the peak respiratory season months. In another study from the United States, the overall incidence of RSV medically attended acute respiratory infections per 1000 children per season was 171 cases, with the highest rate (293 cases per 1000 children per season) being in infants 6–11 months of age and rates of 238 and 135 cases per 1000 children per season among those aged 12–23 and 24–59 months, respectively [9]. The study by Heikkinen et al in this issue of The Journal of Infectious Diseases extends these observations to older children up to 13 years of age [10]. Heikkinen et al followed 2231 children under the age of 13 years over 2 respiratory illness seasons, with the primary goal of estimating the burden of RSV-associated disease. Overall, there were 86 cases/ 1000 person-years (95% confidence interval [CI], 71–103 cases/1000 persons) in the first respiratory illness season and 209 cases/1000 person-years (95% CI, 180–242 cases/1000 person-years) in the second. For all age groups, the incidence in the first season was at least 2–3-fold lower than that in the second, with values of 177 and 373 cases/1000 person-years during 2000–2001 and 2001–2002, respectively, among children <3 years of age; 61 and 173 cases/1000 personyears, respectively, among those 3–6 years of age; and 7 and 84 cases/1000 person-years, respectively, among those aged 7–13 years. This quasi-biennial periodicity has been well described in other North European countries and North America [11] and emphasizes the necessity for conducting epidemiologic and clinical trials that last at least 2 or 3 seasons. These rates are not dissimilar to the rates found in North America [9], despite completely different settings under which the study was done. Unique to the study by Heikkinen et al, and probably directly related to the excellent and free follow-up of subjects, was the ability to obtain a record of daily symptoms from >2000 children over a whole season. Rates of RSV-related emergency department visits (9 events per 2231 child-seasons of follow-up [ie, 4.03 cases per 1000 child-seasons of follow-up]) and hospitalization (3 events per 2231 child-seasons of followup [ie, 1.34 events per 1000 child-seasons of follow-up]) are relatively low overall. However, 6 of the emergency department visits and all of the hospitalizations involved 1-year-old children, which translate to 21.1 and 10.6 events per 1000 children, respectively, in that age group. There were no emergency department visits or hospitalizations in the 80 infants, perhaps reflecting the very small number in the study. These rates also probably reflect the study design, since children were recruited from day care or schools. Thus, although the data from infants (amply studied in numerous other settings) are not representative, the larger number of subjects and the extension of data up to 13 years of age with the intensive follow-up make for a compelling story of the burden of outpatient RSV illness among older children. Another lesson to be gleaned from this study is the importance of the simultaneous use of viral culture and PCR to establish an etiology of illness in burdenof-disease studies. All too frequently, in hospital-based studies or field-based burden-of-disease studies from North America [12], Europe [13], Australia [14], Africa [15], Asia [14, 16, 17], or Latin America [14], investigators exclusively use PCR to establish the burden of disease. In this study, 302 children received a diagnosis of RSV illness, with the diagnosis in 30 established on the basis of viral culture alone (PCR results were negative for 13 children, and PCR was not performed for 17). The authors do not explain why PCR was not performed for 17 children, but the estimates have increased by 10% or 5% if one excludes the samples in which PCR was not performed. Conducting viral cultures is becoming a lost art, since most diagnostic laboratories in industrialized countries are switching to molecular detection methods, and results can now be obtained in an hour. However, for critical burden-of-disease studies [3], especially those using invasive lung puncture to establish etiology, such as the PERCH study, which was conducted in 7 countries [18], or the new CHAMPS study [19], viral culture should play an important role in etiologic diagnosis, as illustrated in the study by Heikkinen et al. Finally, why is it important to establish an outpatient burden of disease in older children up to the age of 13 years? The authors imply that knowledge of the burden of disease is important for economic considerations in treatment and vaccinerelated preventive strategies, However, they do not provide compelling evidence for an economic burden in children older than 2 years, since the direct burden of hospitalizations and emergency department visits in the older child are scant, if not absent. Treatment strategies are currently aimed at preventing lower respiratory tract infection in children and, thereby, preventing their hospital admission [20]. In this population, the burden of lower respiratory tract disease is not clearly established, although there were 9 cases of radiographically confirmed pneumonia (4 in children 1 year of age, and 5 in those 2–6 years of age). The main cost that could be potentially prevented is related to otitis media. However, monoclonal antibodies have not been shown to influence otitis media [21–23], and it is unlikely that subunit vaccines will ever be used in young children because of the experience with the formalin-inactivated RSV vaccine in the 1960s [24]. Maternal immunization is the current strategy and is being pursued by several vaccine manufacturers, but it is likely to provide protection only for the first few months of life [25]. Live attenuated vaccines have recently not been able to protect the upper respiratory tract sufficiently to prevent upper respiratory tract infection. These vaccines could potentially affect otitis media; however, the main goal in the development of the current strains for use in live vaccines is the production of a robust serum neutralization response to protect the lung, rather than a local immunoglobulin response to protect the upper respiratory tract [26]. There are several vaccines being developed for elderly individuals that could potentially be used in older school-aged child. Family transmission studies, such as those being done in Kenya, suggest that this cocooning strategy, while directly reducing the burden of disease and protecting older children, could also have a substantial impact on the youngest infants, who are at highest risk for morbidity and mortality [27]. It is likely that subunit RSV vaccines will become available for use in elderly individuals in the near future, but these will not be tested in young, RSV-naive infants. Such studies, in older children and adolescents and extending to adults, along with indirect cost data, as were collected in this study, could be critical to providing burden-of-disease information that could provide economic justification for future preventive and treatment options. Note Potential conflicts of interest. E. A. F. S.’s institution (the University of Colorado, Denver) has received grant funding from Astra Zeneca, Regeneron, and Pfizer and institutional funds for consulting from Abbvie. The author has 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. Hall CB , Simoes EA , Anderson LJ . Clinical and epidemiologic features of respiratory syncytial virus . Curr Top Microbiol Immunol 2013 ; 372 : 39 - 57 . 2. 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 . 3. 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 . 4. 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 . 5. Régnier SA , Huels J. Association between respiratory syncytial virus hospitalizations in infants and respiratory sequelae: systematic review and metaanalysis . Pediatr Infect Dis J 2013 ; 32 : 820 - 6 . 6. Stockman LJ , Curns AT , Anderson LJ , FischerLangley G . Respiratory syncytial virus-associated hospitalizations among infants and young children in the United States , 1997 - 2006 . Pediatr Infect Dis J 2012 ; 31 : 5 - 9 . 7. Emukule GO , Khagayi S , McMorrow ML , et al. The burden of influenza and RSV among inpatients and outpatients in rural western Kenya , 2009 - 2012 . PLoS One 2014 ; 9 : e105543 . 8. Ambrose CS , Anderson EJ , Simoes EA , et al. Respiratory syncytial virus disease in preterm infants in the U .S. born at 32-35 weeks gestation not receiving immunoprophylaxis . Pediatr Infect Dis J 2014 ; 33 : 576 - 82 . 9. Simpson MD , Kieke BA Jr, Sundaram ME , et al. Incidence of medically attended respiratory syncytial virus and influenza illnesses in children 6-59 months old during four seasons . Open Forum Infect Dis 2016 ; 3 : ofw081 . 10. Heikkinen T , Ojala E , Warris M. Clinical and socioeconomic burden of respiratory syncytial virus infection in chlidren . J Infect Dis 2017 ; 215 : 17 - 23 . 11. Zachariah P , Shah S , Gao D , Simoes EA . Predictors of the duration of the respiratory syncytial virus season . Pediatr Infect Dis J 2009 ; 28 : 772 - 6 . 17. Saha S , Pandey BG , Choudekar A , et al. Evaluation of case definitions for estimation of respiratory syncytial virus associated hospitalizations among children in a rural community of northern India . J Glob Health 2015 ; 5 : 010419 . 18. Murdoch DR , O'Brien KL , Driscoll AJ , Karron RA , Bhat N. Laboratory methods for determining pneumonia etiology in children . Clin Infect Dis 2012 ; 54 (suppl 2): S146 - 52 . 19. CHAMPS. Available at: http://champshealth.org/ collaborating-partners/. Accessed 3 October 2016 . 20. Mazur NI , van Delden JJ , Bont LJ . Respiratory syncytial virus trials and beyond . Lancet Infect Dis 2015 ; 15 : 1363 - 5 . 21. Group TI-RS . Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group . Pediatrics 1998 ; 102 : 531 - 7 . 22. Carbonell-Estrany X , Simoes EA , Dagan R , et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial . Pediatrics 2010 ; 125 : e35 - 51 . 23. O'Brien KL , Chandran A , Weatherholtz R , et al. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised doubleblind placebo-controlled trial . Lancet Infect Dis 2015 ; 15 : 1398 - 408 . 24. Killikelly AM , Kanekiyo M , Graham BS . Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus . Sci Rep 2016 ; 6 : 34108 . 25. Glenn GM , Fries LF , Thomas DN , et al. A randomized, blinded, controlled, dose-Ranging study of a respiratory syncytial virus recombinant fusion (F) nanoparticle vaccine in healthy women of childbearing age . J Infect Dis 2016 ; 213 : 411 - 22 . 26. Karron RA , Luongo C , Thumar B , et al. A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children . Sci Transl Med 2015 ; 7 : 312ra175 . 27. 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 .


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Eric A. F. Simões. The Outpatient Burden of Respiratory Syncytial Virus Infections in Older Children, Journal of Infectious Diseases, 2017, 1-3, DOI: 10.1093/infdis/jiw483