Respiratory Syncytial Virus Disease in Young Children and Older Adults in Europe: A Burden and Economic Perspective

Soon after the discovery that respiratory syncytial virus (RSV) was the major cause of bronchiolitis in infants, in 1956 [1], vaccines were developed to try and prevent both infection and severe disease caused by the virus, but such early preventive efforts failed [2]. A pivotal trial of an RSV hyperimmunoglobulin [3] in 1993, followed by the development and licensure in 1998 of an RSV-specific monoclonal antibody, palivizumab [4], paved the way for passive prophylaxis as a modality for the prevention of RSV in infants and young children. While RSV had been recognized as a cause of infection in adults and older adults as early as the 1970s, the advent of reverse-transcription polymerase chain reaction, allowed for the true recognition of the RSV burden in older adults in 2005 [5]. Elucidation of the structure of the prefusion form of the RSV F protein and the ability to stabilize it [6], as well as the demonstration that it was the major immunogenic moiety of the virus to which functional neutralizing antibody was directed [7], were the impetus for the rapid development of targeted vaccine and monoclonal antibody approaches against RSV, initially targeted for protecting infants [8]. Similarly, solving the structure and stabilization of the prefusion form of the spike protein of SARS CoV2 by the same group [9–11] rapidly led to the development of vaccines against coronavirus disease 2019 (COVID-19) [12–15], and the success of these vaccines, in part, propelled the explosion of RSV vaccine development targeting older adults [16–23]. Five years ago, while the RSV prevention field was clearly headed for success, the Innovative Medicines Initiative [24], the largest public private partnership funding health research and innovation, funded the REspiratory Syncytial vIrus Consortium in Europe (RESCEU) [25]. The RESCEU project aimed to develop robust evidence regarding RSV disease burden and economic impact with a multidisciplinary group, including academia, public health, scientific societies, patient organizations, regulatory agencies, and industry. This supplement presents the results of some of these studies targeting infants and young children as well as older adults. Globally it has been estimated that RSV hospitalization rates varied between 17.5 and 37.1 per 1000 infants, accounting for between 1.7 and 2.9 million hospitalizations in infants annually, of which about a third occur in the first 2 months of life (0.6–1.3 million) [26]. In this supplement, using a time series analysis and data available between 2006 and 2018 from Norway, Finland, Denmark, the Netherlands, Scotland, and England, the team found that in the first 2 months of life, the highest RSV hospitalization rates throughout life varied between 40 and 85 per 1000 infants annually, between 18 and 42 per 1000 for those aged 3–5 months, and between 7 and 20 per 1000 in older infants [27]. The lowest rates in all cases were in the Netherlands. This amounted to about 34 000 infant RSV hospitalizations annually. >75% of which were from England and Scotland. In the United States, the annual RSV hospitalization rates varied between 8.4 and 40.8 per 1000 infants, with a pooled rate of 19.4 per 1000 infants, amounting to 80 000–100 000 hospitalizations annually [28]. Given that the 2018 population of these countries (including the population of the United Kingdom as a proxy for England and Scotland) of 100 million is about 15% of the European population of about 700 million, if one extrapolates these rates to the rest of Europe (34 000 hospitalizations per 100 million population) it can be seen that (1) the rates in these 7 countries are similar to or slightly higher than that in the United States (population 332 million) [29] and (2) the overall infant burden of disease in Europe is potentially between 2 and 2.5 times that of the United States, if these rates hold true for the rest of Europe. The burden of RSV disease in infants in industrialized countries is primarily driven by hospitalization [30]. However, it is not only the rates of hospitalization that are important but also the duration of hospitalization that contributes to this burden. These rates are important while planning treatment and prevention trials of RSV, for understanding the direct as well as indirect costs to society and for cost-effective analyses, which are directly important for policies and recommendations concerning the use of these modalities. Wang et al [31] estimated the hospital burden in children <5 years of age, in the same 7 countries where the hospitalization rates were estimated, using routinely collected hospital databases from 2001–2018. The median length of stay varied between 2 and 4 days between countries, with more than two-thirds of hospital stays in infants, accounting for between 40.3–91.2 bed days per 1000 infants annually. The rates in older children were dramatically less, 1.1–7.1 bed days per 1000 children aged 12–59 months. Between 1993 and 1996, Glaxo SmithKline Beecham, when developing a monoclonal antibody against RSV, conducted a study in 9 industrialized countries to determine the average length of stay for RSV hospitalization [32]. That study found that the median duration of hospitalization was 4 days in Australia, Finland, the United Kingdom, and the United States, compared with 8–9 days in Belgium, France, Germany Italy, and the Netherlands. These differences have narrowed dramatically, as shown in this study [31] and others. For example, the median length of hospital stays from recent-year studies in the United States and France is now 3 days [33, 34]. Taken together, these studies show a convergence of not only hospitalization rates but also of the duration of hospitalization in the 7 countries studied, as well as in the United States [30], Canada [35], Australia [36], and other industrialized countries. The different rates in different countries used to be among the reasons often cited for not including hospitalization rates as the primary outcome in multinational clinical trials of RSV prevention in infants. Given the public health and socioeconomic impact, as well as the overall contribution of the hospitalization costs to the RSV burden, these studies provide impetus for making reduction of RSV hospitalization a primary rather than a secondary outcome in future phase 3 trials. In hospitalized children, between 15% and 20% are admitted to the intensive care unit (ICU), and a smaller proportion receive mechanical ventilation [30]. These are probably children who would die where such care is not available, especially in low middle-income countries where 97% of the estimated 84 500–125 000 annual RSV-attributable deaths occur [26]. Three articles in the current supplement address the severity of RSV lower respiratory tract infections (LRTIs) in infants and young children. The systematic review by Shi et al [37] identified 27 studies (15 from industrialized and 12 from developing countries) that examined risk factors for poor outcomes (prolonged hospitalization, oxygen supplementation, ICU admission or mechanical ventilation) [37]. Any comorbid condition, age <3 or <6 months, congenital heart disease, and prematurity (<37 weeks gestational age) were all found to be significant risk factors for poor outcome in multivariable analyses, with point estimates of the meta-estimates varying between 1.75 (prematurity) and 4.91 (age <3 months). Given the enormous importance of prematurity in the burden of RSV disease, a global burden of RSV disease in this population is planned [38]. Mortality risk factors were much more difficult to estimate, and only prematurity had a significant meta-estimate (odds ratio) of 3.81 on univariable analysis. However, most deaths occur in low-income countries [26], where very premature infants do not often survive beyond the first few months of life and prematurity and congenital heart disease are often unrecognized in the community, where most of these infants die. A study from Zambia [39] identified age <8 weeks and urban crowding as significant independent risk factors for RSV-attributable deaths in the community. While it is true that these medical and demographic factors are risks for severe disease, the major burden (>70%) of severe disease occurs in full-term infants without comorbid conditions [30], and a recent study from the United States shows that about 50% of RSV deaths occur in full-term infants [40]. A second approach to examining host risk factors for severe RSV disease, outside of medical (eg, prematurity, congenital heart disease, comorbid conditions) or demographic (eg, age at infection) factors, is to study the disease in well-developed, controlled animal models of infection. The article by McGinley et al [41] in this supplement is one of the few meta-analyses investigating animal models and infectious diseases, made possible by the collaboration of basic scientists, pediatricians, infectious disease experts, epidemiologists, and modelers. This analysis showed that RSV-specific antibody appeared to protect mice from RSV disease but not cows from bovine RSV. Strong T-cell (T-helper 1, 2, and 17, and CD4/CD8) responses and weak regulatory T-cell responses accompany severe disease in mice. McGinley et al, however, acknowledge that these biomarkers may not be directly applicable or relevant to the human clinical setting, and targeted human investigations should be revealing, especially those focused on mucosal immune responses [42], such as many ongoing studies using advanced immunologic cellular and mucosal assays, metagenomics, proteomics, and metabolomics. A third approach examined demographic and viral factors in a primary clinical observational study in 320 infants (14% with comorbid conditions) from the Netherlands, Spain, and the United Kingdom, to determine clinical and viral risk factors for disease severity in the short term and wheeze in the long term [43]. The clinical score based on feeding intolerance, respiratory difficulty, the general condition, fever, tachypnea, apnea, and medical intervention, geared to identify more severe disease, not surprisingly was correlated with hospitalization, ICU use, and mechanical ventilation. There were no significant differences in risk factors, clinical score, or clinical outcome among infants with RSV A or RSV B, and the initial or peak viral load was not correlated with either the clinical score or any of the severe outcomes. After 1 year of follow-up, fever, high clinical scores, and hospitalization and ICU use correlated with wheezing development. A long-term follow-up of this cohort for wheezing outcomes is planned, which, along with metagenomic and transcriptomic profiling, should provide interesting insights into the pathogenesis of this RSV-wheezing association. Two large studies from Denmark [44] and Scotland [27] examined the association between RSV hospitalization and subsequent wheezing or asthma. Both were large nationwide studies that used a cohort of children hospitalized for RSV, compared with control groups with unintentional accident admissions (Scotland and Denmark) or 5 other control groups (Denmark). The Danish study included index case patients up to 6 months of age, whereas the Scottish study included children up to 2 years of age. The Scottish study found a significant association between RSV and first asthma and wheeze admission up to 2 years of age, if the RSV hospitalization occurred in the first 6 months of life, but this association extended to 6 years if the hospitalization occurred between 6 and 23 months. The Danish study found a significant association between RSV and recurrent wheeze or asthma up to 6 years when the comparator cohort was the injury cohort. However, this difference between the injury cohorts was also significant when the comparator was the non-RSV acute upper respiratory tract infection or non-RSV pneumonia/other pathogen, non-RSV LRTI, and nonspecific respiratory infection groups. Both studies, however, failed to consider perhaps the most important risk factor for RSV hospitalization, that is, the atopic history in the mother and child [45]. A large Danish study using databases similar to those in the study reported here [46] that did include these risk factors found that maternal asthma/atopy increased the risk of RSV hospitalization, but prior or recurrent wheezing in the infant was the most significant risk factor for subsequent RSV hospitalization [45]. An atopic disposition and/or prior wheezing in older children hospitalized with RSV might be the explanation for the Scottish observation of that group having an increased risk for wheezing or asthma up to 6 years of age [27]. The Danish study found that the season of admission did not have an impact on the risk for wheezing or asthma [44]; however, a prior study from the United States clearly showed that the season of birth had an impact on subsequent asthma [46]. It is unclear what impact season of birth, maternal history of atopy/asthma, or prior wheezing in the infant would have had on the results of the Danish study. For most observational studies, the results must be viewed in the light of how the studies were designed, what factors were controlled for (if possible to do so), and other confounders. Likewise, metanalyses or interpretations of the data examining the RSV-wheeze-asthma connection, might arrive at different conclusions based on the studies included, methods of analyses, and controlling for confounders [47–49]. The issue of the role of RSV in recurrent wheezing and subsequent asthma is important because of the long-term health, quality of life, and economic burden of asthma. Even cost-effective analyses of RSV prevention increasingly find that the healthcare resource utilization costs following RSV are an important contributor to the overall burden of RSV disease [50]. There are significant differences in subsequent healthcare utilization costs after RSV hospitalization in both preterm and full-term infants for the first 6 years of life, but most of these differences occur in the first 2 years after hospitalization [51, 52]. Regardless of the causal role of RSV in recurrent wheeze/asthma, the important issue is whether preventing RSV in infants prevents subsequent recurrent wheezing and asthma. Two randomized placebo-controlled trials examined this association. The first one in Native American infants [53] had such a low rate of recurrent wheezing in the placebo population that it was clearly underpowered to show any effect [54]. The second Dutch trial in preterm infants showed a protective effect of palivizumab in the first year of life on wheezing [55] and an impact on parental report of asthma up to 6 years but no impact on pulmonary function [56]. The difference between this study and the Japanese study [57] that followed up children for a similar period of time [58] (aside from the latter being an observational study of preterm infants who received or did not receive palivizumab) was that in the Dutch study a history of recurrent wheezing was sought only in the fifth year of life of the subjects, whereas the Japanese study followed up children continuously for 6 years of life. Given that most observational and preventive studies find that recurrent wheezing occurs in the first few years of life and might disappear by age 6 years, that most of the healthcare utilization costs of RSV occur at least in the first 2 years of life and are related to wheezing/asthma, that it is very difficult to conduct randomized controlled trials (RCTs) of an effective prevention method once they are licensed, and that the major burden of RSV and recurrent wheezing is in full-term infants, it is very important when designing RCTs targeting the infant population that follow-up for wheezing and asthma not only include healthcare resource utilization but also measure the other direct and indirect societal costs, preferably for 3 years but for a minimum of 2 years. It is also important in these trials to show that there is a significant impact on RSV hospitalization. In the United States, 91% of the costs of the overall burden of RSV are related to hospitalization, and only 9% to outpatient and emergency room visits [59] In RCTs completed in recent years, a long-acting anti-RSV monoclonal antibody to infants and a RSV F protein maternal vaccine have been shown to protect infants in the first few months of life, from RSV severe RSV and RSV hospitalization In this supplement, et al report using the healthcare to the of and for both that of with of all infants after the was the most cost-effective at a more than that of other that included of infants in the RSV This was similar to the in the United States, which the burden of disease It is interesting that the overall costs in the study was estimated to be million annually compared with in the United States The study it to have a maternal other of the an analysis for countries that the most cost-effective for RSV maternal was It is interesting that these 2 analyses, with vaccine is well in industrialized countries, whereas it is not in developing countries. of these analyses into that be that maternal has been shown to severe RSV by in a trial that failed to the primary point that the might be as high as against and against severe or that the vaccine might be immunogenic that beyond 6 months These are results from a phase 2 but the much phase 3 trial is ongoing the same in a pooled analysis of the pivotal studies it was shown to by with hospitalization by and very severe by the recommendations of societies, societies, and public health such as the for are also to the use and of these potentially very effective That recommendations of is clearly shown in analysis of the 20 clinical for the prevention of RSV in children These were against the but only 1 of the 20 were after the was the that all of these prophylaxis for the groups heart disease and disease in groups where was lowest and it for groups where was highest in premature infants weeks gestational age without was the of recommendations from the per and the most for preterm infants from and Germany compared with the least from the countries with the lowest per in the and can whether this be followed for for use of RSV vaccines for older adults. of patient groups in making and as was 7 years in the for research would have more in and preventive to infants and young children who for RSV has been recognized as a major cause of in children discovery in but only in the 20 years has increasingly been recognized as a burden in older adults. of vaccines for older adults some of the for vaccine to develop vaccine for this The recent success of vaccines in preventing severe disease in older adults probably to the current in for preventing disease in this It must also be that most RSV disease occurs in the first year of life for it is a birth cohort per one that vaccines for older adults are probably targeted for annual of adults aged years, that to cohorts annually. the age is years, that to birth The major in RSV disease in older adults include the clinical recognition of clinical RSV disease and of a global burden of disease for this The has a robust global that of to to be for virus This was initially used only to identify adults more to have for at the global these data have been used to burden of disease for of RSV in children have clearly shown that occurs in only of children and RSV is if is the point for of A study in older adults was used to the for the of RSV respiratory tract infections in adults There were of RSV and of respiratory tract infections in this The had a of only which increased to if was with or without identified of RSV the While infectious may not be the for RSV of with such were RSV it would be important for to in vaccine trials and studies, where it is important to A second in RSV disease has been the rapid of RSV in older adults. In this same the of a rapid reverse-transcription polymerase chain The where the viral load was The study examining the estimates of hospitalization in 6 European countries in young children found rates in that population and to do the same for using a time series analysis estimated that there were no RSV hospitalizations in children in all 6 countries, in adults in 5 countries, and in adults in Denmark, of comorbid In a systematic review of disease burden in adults with comorbid conditions estimated that the annual rate of RSV in adults with comorbid conditions was per 1000 in industrialized countries and the only study of hospitalization rates in the United States found rates of per 1000 per year in adults aged years with heart or pulmonary disease These studies, by some of the by clinical which from that had varying of and in RSV and primary outcome one clinical disease and the burden in older The older to was also used to data on direct and indirect costs of RSV there were no RSV in the RSV the overall direct and indirect costs were estimated to be about per A much than the infant one found vaccine of between and for the including direct and indirect compared with between and in the United The study from a vaccine of for when it is to infants the season but the of to be cost-effective for with It that if this is to be an with a of be more for a monoclonal antibody against RSV than countries be to for a of per for the initial of vaccines from and a of or lower for the of This supplement a of data on the burden of RSV on the population and some of data on the older For example, for the RSV burden of disease were available from which to in to 20 studies on the burden of RSV in adults with comorbid at least 2 preventive to be available to infants in the year or and more in the as well as times the of for older adults. While the few years to be for the general and in industrialized countries, it is that to the most in developing countries that have not to the burden of disease in the older population and where vaccine in and older adults is an This article as of the supplement from RESCEU for by RESCEU has received funding from the Innovative Medicines Initiative 2 This from the European research and and The in this article only the and the is not for any use that may be made of the it