Abstract
Introduction
Adult respiratory syncytial virus (RSV) burden is underestimated due to non-specific symptoms, limited standard-of-care and delayed testing, reduced diagnostic test sensitivity—particularly when using single diagnostic specimen—when compared to children, and variable test sensitivity based on the upper airway specimen source. We estimated RSV-attributable hospitalization incidence among adults aged ≥ 18 years in Ontario, Canada, using a retrospective time-series model-based approach.
Methods
The Institute for Clinical Evaluative Sciences data repository provided weekly numbers of hospitalizations (from 2013 to 2019) for respiratory, cardiovascular, and cardiorespiratory disorders. The number of hospitalizations attributable to RSV was estimated using a quasi-Poisson regression model that considered probable overdispersion and was based on periodic and aperiodic time trends and viral activity. As proxies for viral activity, weekly counts of RSV and influenza hospitalizations in children under 2 years and adults aged 60 years and over, respectively, were employed. Models were stratified by age and risk group.
Results
In patients ≥ 60 years, RSV-attributable incidence rates were high for cardiorespiratory hospitalizations (range [mean] in 2013–2019: 186–246 [215] per 100,000 person-years, 3‒4% of all cardiorespiratory hospitalizations), and subgroups including respiratory hospitalizations (144–192 [167] per 100,000 person-years, 5‒7% of all respiratory hospitalizations) and cardiovascular hospitalizations (95–126 [110] per 100,000 person-years, 2‒3% of all cardiovascular hospitalizations). RSV-attributable cardiorespiratory hospitalization incidence increased with age, from 14–18 [17] hospitalizations per 100,000 person-years (18–49 years) to 317–411 [362] per 100,000 person-years (≥ 75 years).
Conclusions
Estimated RSV-attributable respiratory hospitalization incidence among people ≥ 60 years in Ontario, Canada, is comparable to other incidence estimates from high-income countries, including model-based and pooled prospective estimates. Recently introduced RSV vaccines could have a substantial public health impact.
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Avoid common mistakes on your manuscript.
Why carry out this study? |
Respiratory syncytial virus (RSV) burden is underestimated in adults due to non-specific symptoms, lack of or delayed testing during clinical presentation, and lower sensitivity of diagnostic testing compared to infants. |
We estimated adult RSV-attributable hospitalization incidence in Ontario during 2013–2019 using a retrospective time-series model-based approach. |
What was learned from the study? |
RSV-attributable hospitalization incidences are high and increase with age. |
RSV contributes to both respiratory and cardiovascular hospitalizations. |
RSV vaccines could have a substantial public health impact. |
Introduction
Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections [1] and is estimated to cause 787,000 RSV-related hospitalizations among older adults in high-income countries worldwide [2]. In temperate climates, such as Canada, seasonal surges in RSV disease correlate with low temperatures and high humidity during winter [3]. When progressing from an upper respiratory infection to a more severe clinical presentation in adults, RSV may exacerbate underlying medical conditions or cause severe cardiovascular complications, presenting as heart failure exacerbations, arrhythmia, or myocardial infarction, even in individuals without pre-existing cardiovascular disease [4,5,6].
High-risk groups in adults, defined as patients with underlying comorbidities, including immunocompromising conditions [6], chronic respiratory [7] or cardiovascular [4] disease, diabetes, neurological, kidney, or liver disease, and blood disorders, are at higher risk of hospitalization and death [8,9,10,11]. Due to immunosenescence [12] and inflammaging, a state of chronic pro-inflammation [13, 14], as well as an increased frequency of comorbidities, age is an important predictor of severe clinical manifestations and mortality in patients hospitalized with RSV [6, 11, 15].
Recently, two vaccines were authorized in Canada to prevent RSV-associated lower respiratory tract disease in adults aged 60 years and older [16]. To inform vaccine programs and facilitate public health policies, robust estimates of RSV incidence in adults are needed. Although the burden of RSV is well established in young children [17], the incidence of RSV infections in adults is often underestimated due to non-specific symptoms and the resolution of clinical signs before seeking medical attention [18]. In addition, lack of standard-of-care RSV testing, use of case definitions that exclude some RSV illnesses (e.g., influenza-like illness or community-acquired pneumonia), low diagnostic capacity, and low diagnostic sensitivity due to the use of a single respiratory swab lead to under-ascertainment of cases [18,19,20,21,22]. However, a growing body of evidence emphasizes the considerable burden of RSV infections in adults, particularly in older adults. Recent meta-analyses estimated an incidence rate of 347 RSV-related acute respiratory infection (ARI) hospitalizations per 100,000 [2] after adjustment for diagnostic testing-based under-ascertainment and an in-hospital case fatality proportion of 6‒9% in patients 65 years and older in high-income countries [2, 5]. A study using nationwide Canadian healthcare administrative data from 2003 to 2014 reported an annual RSV-attributable incidence rate of 53 respiratory hospitalizations per 100,000 in patients aged over 65 years [23], which is several-fold lower than other model-based and prospective study results from the US, UK, and globally [2, 8, 18].
Model-based incidence estimates approximate prospective study estimates and considerably exceed those based on International Classification of Diseases (ICD)-coded administrative data that depend on standard-of-care testing, and consequently suffer from substantial underestimation [8]. Thus, time-series model-based approaches have been increasingly used to indirectly estimate the number of events attributable to RSV. Such time-series models take undiagnosed RSV-related events into account and compare the temporal variability of the RSV indicator with the variability in the outcome (e.g., respiratory hospitalizations) to predict the portion of events attributable to RSV while accounting for seasonality and co-circulation of other pathogens [18, 24,25,26,27,28,29,30,31,32,33,34].
The aim of this study was to estimate the population-based RSV-attributable counts and incidence of respiratory, cardiovascular, and cardiorespiratory hospitalizations among adults in Ontario, Canada, between 2013 and 2019 using a retrospective time-series model-based approach.
Methods
Study Design
This study was an observational retrospective database analysis to estimate the incidence rates of RSV-attributable hospitalizations among adults in Ontario, Canada, using a quasi-Poisson regression model. The study design was selected after reviewing the literature on modeling methods used to estimate RSV disease incidence from electronic medical records or claims databases. The full study protocol can be found in the following publication [35].
Data Sources
Data on demographics and aggregated weekly hospitalizations of the Ontario population eligible for universal health coverage were obtained from the Discharge Abstract Database (DAD) and Registered Persons Database, which are included in the Institute for Clinical Evaluative Sciences (ICES) data repository [36, 37]. Individuals aged 18 years and over residing in Ontario, Canada, registered in these databases with a documented hospitalization were included. Data were captured from January 1, 2013 through December 31, 2019. Only data from pre-COVID-19 pandemic years, i.e., before 2020, were included in the study, given the potential distortion of RSV incidence data caused by the pandemic. Implementation of non-pharmaceutical interventions as well as host- and viral-related factors may have contributed to reported changes in RSV incidence and seasonality during the pandemic period [38]. Nevertheless, seasonal patterns of RSV circulation and, thus, RSV burden, are returning to the pre-pandemic state [39].
Hospitalizations for disease outcomes of interest were counted based on any occurrence of selected ICD, 10th revision [40], Canada adaptation (ICD-10-CA) codes, excluding pre-hospitalization comorbidities (e.g., if a patient with chronic obstructive pulmonary disease was admitted for surgery, this was not considered as an event). Three main disease outcomes were selected: all respiratory diseases (ICD-10-CA codes: J00‒J99), all cardiovascular diseases (ICD-10-CA codes: I00‒I99), and all cardiorespiratory diseases (ICD-10-CA codes: I00‒I99, J00‒J99), with the first two being subsets of the latter. A hospitalization was defined as an overnight stay in a hospital and was characterized by the date of admission. Subsequent hospitalization with the same ICD-10-CA code occurring within 30 days was considered a single hospitalization.
Based on the age at admission date, individuals were categorized into the following age groups: 18‒49, 50‒59, 60‒74, and ≥ 75 years. This categorization of age was motivated by prior literature [18, 27, 29] and to align with the current target group for RSV vaccination in the older adults in Canada [16]. Data on risk factors for RSV were collected to construct the binary risk group variable. This variable was defined as groups with and without a risk factor, determined by any mention of a set of selected ICD-10-CA codes (Table S1) during a 1-year look-back period before hospitalization. The selection of these codes was based on established risk factors for influenza [41], which are consistent with the more limited literature on risk factors for severe RSV disease [11].
Hospital-based viral activity proxies accounting for the circulation of RSV and influenza in the population were defined as the weekly number of hospitalizations with ICD-10-CA codes related to RSV in children < 2 years (B97.4, J12.1, J20.5, J21.0, J21.9) or influenza in adults ≥ 60 years (J09, J10, J11). We used pediatric RSV activity for the RSV activity proxy because testing is frequent among young children, allowing for consistent measurement of RSV activity, as has been done in other studies [18, 27, 34]. In addition, the temporal association between RSV waves in children and adults (after different lags) has been demonstrated before and is related to both infections and hospitalizations [42, 43]. We included acute bronchiolitis, unspecified (J21.9), because RSV is responsible for the majority of bronchiolitis hospitalizations in this age group [44,45,46]. Correspondingly, we used influenza-specific hospitalizations in older adults aged 60 years and over for the influenza activity proxy, as the largest burden of influenza and most consistent testing is evident among older adults [31].
Statistical Analysis
For each outcome of interest (i.e., respiratory, cardiovascular, or cardiorespiratory disease), weekly hospitalizations, stratified by age and risk group, were modeled using a quasi-Poisson regression model when a seasonal pattern was observed. The model was constructed following the published time-series model-based analysis protocol for the estimation of RSV incidence rate in adults [35]. In brief, the quasi-Poisson model considers probable overdispersion in count data. It is based on periodic and aperiodic time trends, as well as viral activity. In this study, RSV and influenza were included in the model, assuming they are the only circulating pathogens, with RSV hospitalization in children below 2 years and influenza in adults aged 65 years or older used as proxies. It is worth noting that the periodic trend and the overdispersion parameter of the model are expected to substantially account for other pathogens that may be related with RSV hospitalizations besides RSV and influenza. The identity link function was used in the model, representing biological plausibility, as it allows hospitalizations to increase proportionally with increase of viral activity. Finally, the most plausible aperiodic trend and viral proxy lag were selected by employing model building techniques.
The yearly model-based number of RSV-attributable hospitalizations was obtained by summing over the included weeks per age and risk group. To determine the proportion of RSV-attributable hospitalizations, the yearly model-based number of RSV-attributable hospitalizations was divided by the yearly observed number of hospitalizations (such as respiratory hospitalizations).
Age-specific yearly incidence rates of hospitalizations attributable to RSV were calculated by adding up all model-based hospitalizations attributable to RSV across risk groups and dividing the sum by the age-specific population at risk of the event, derived from Ontario census data. To capture the changes in the population (due to immigration) as accurately as possible, the census data were composed by the combination of the preceding and subsequent censuses. For 2013‒2015, the average between the 2011 census and 2016 census was used. For 2016, the 2016 census was used, while for 2017‒2019, the average between the 2016 census and 2021 census was used. The resulting rates were expressed as the number of events per 100,000 person-years. As the number of individuals at risk (denominator) was not available by risk group, risk-specific incidence rates were not estimated. Data management and statistical analysis were performed in SAS Enterprise Guide (SAS Institute, Cary, NC, USA) version 7.15, and R version 4.2.2.
Ethical Approval
The study received ethics approval from the Advarra Institutional Review Board (Study number Pro00068118). The study was conducted in accordance with legal and regulatory requirements and research practices described in the Good Epidemiological Practice guidelines issued by the International Epidemiological Association [47].
Results
Recorded Hospitalizations
A total of 0.75 million respiratory, 1.23 million cardiovascular, and 1.66 million cardiorespiratory hospitalizations during 2013‒2019 in adults aged 18 years or older were registered in the ICES database in Ontario, Canada. The oldest group (≥ 75 years) accounted for 49% of the hospitalizations, followed by those aged 60‒74 years (31%).
Estimated RSV-Attributable Hospitalizations
The estimated annual numbers and proportions of RSV-attributable respiratory, cardiovascular, and cardiorespiratory hospitalizations stratified by age and risk group are presented in Table 1. The estimated absolute numbers of RSV-attributable hospitalizations across all outcomes and age groups were higher in patients without risk factors than in those with risk factors (Table 1). However, the proportions of RSV-attributable hospitalizations were not consistent across age groups and outcomes. Among respiratory hospitalizations, the proportion of RSV-attributable hospitalizations was approximately twofold higher among persons without risk factors (approximately 11%) compared to those with risk factors (approximately 6%) in the 50‒59 years age group. A similar difference was observed in the proportion of RSV-attributable cardiovascular hospitalizations for the age group 60‒74 years (3% in the group without risk factors vs. 1.5% in the group with risk factors).
The annual incidence rates of RSV-attributable hospitalizations and corresponding proportions for the respiratory, cardiovascular, and cardiorespiratory hospitalizations stratified by age group are presented in Table 2. Among patients aged ≥ 60 years, the overall RSV-attributable incidence rates were highest for cardiorespiratory hospitalizations (range [mean] in 2013–2019: 186–246 [215] per 100,000 person-years, 3‒4% of all cardiorespiratory hospitalizations), followed by respiratory (144–192 [167] per 100,000 person-years, 5‒7% of all respiratory hospitalizations) and cardiovascular hospitalizations (95–126 [110] per 100,000 person-years, 2–3% of all cardiovascular hospitalizations). The overall incidence rates of RSV-attributable cardiorespiratory hospitalizations increased with age, from 14–18 [17] hospitalizations per 100,000 person-years among those aged 18‒49 years to 317–411 [362] among those aged ≥ 75 years.
Respiratory and cardiorespiratory hospitalizations exhibited a seasonal pattern and good model fit across all age and risk groups, which were particularly prominent in the older age groups (Figure S1, Figure S2, Figure S5, Figure S6). The age group 18‒49 years without and with risk factors (Figure S3—A, Figure S4—A) and the age group 50‒59 years with risk factors (Figure S4—B) lacked a discernible seasonal pattern for cardiovascular hospitalizations and thus were not suitable for modeling. A seasonal pattern was observed for the remaining age groups, although weaker than those observed for the respiratory hospitalizations (Figure S3—B, C, D, Figure S4—C, D).
Discussion
The burden of RSV-attributable hospitalizations in adults in Ontario, Canada—expressed as hospitalization counts and incidence rates—increased with age and was highest among older age groups. The overall incidence rates were highest for cardiorespiratory hospitalizations, followed by their subgroups of respiratory and cardiovascular hospitalizations.
Our incidence rates of RSV-attributable respiratory hospitalizations in people aged ≥ 60 years (144‒192 [167] per 100,000 person-years) are comparable to those reported in a recent meta-analysis of prospective observational studies, namely an annual incidence of RSV-associated acute respiratory infections of 145 per 100,000 individuals aged ≥ 60 years [48]. Also, they are in line with the pooled hospitalization rates of observational studies in people aged ≥ 65 years from high-income countries (157 cases per 100,000), without adjusting for case under-ascertainment [2]. In contrast, they are lower than pooled estimates of prospective US studies for adults aged ≥ 65 years (282 per 100,000 persons) adjusted for an additional specimen type to enhance diagnostic sensitivity [8]. Our incidence rates are also lower than the hospitalization rate when applying a more comprehensive adjustment for case under-ascertainment from another SLR of observational studies on RSV-associated ARI hospitalizations in high-income countries (347 hospitalizations per 100,000 individuals) [2]. However, these two SLRs adjusting for under-ascertainment focused on the slightly older group of patients aged ≥ 65 years, which would explain in part these high estimates.
This study’s estimated RSV-attributable respiratory hospitalization incidences for adults aged ≥ 60 years are modestly higher compared to a recent prospective observational nationwide study in Canada analyzing ARI hospitalization data and surveillance data, which reported an estimated incidence of 73‒146 per 100,000 persons for the same age-group [49]. The difference in results may be explained by the latter study being limited to ARI rather than a broader outcome, including all respiratory diseases used in our study [49]. Time-series modeling methodology used in our study is able to estimate the proportion of the broader respiratory hospitalization outcome group that is attributable to RSV (e.g., including a hospitalization due to RSV-related asthma exacerbation or unspecified respiratory failure). Our results were also substantially higher than estimates of another Canada-based study, which employed modeling techniques similar to our study, especially for the younger age groups, specifically reporting 1, 5, and 53 RSV-attributable annual respiratory hospitalizations per 100,000 persons among those aged 17‒44, 45‒64, and over 65 years, respectively [23]. This study included only primary diagnoses of respiratory conditions from hospital discharge information [23], however, the use of primary diagnosis only has been shown to underestimate the LRTI burden [50]. We used both primary and secondary diagnoses, as has been done in other time-series studies [34, 51], given that the model is able to determine which events are RSV-attributable. In addition, differences in definitions of viral proxies, as well as model specification choices, may have contributed to the lower incidence rate in this study [23].
The contribution of RSV to cardiovascular and cardiorespiratory hospitalizations has been studied to a lesser extent in comparison to respiratory hospitalizations. Potential mechanisms of RSV-related cardiovascular manifestations include the development of atherosclerosis, inflammatory response, pulmonary hypertension, or even direct myocardial injury [4, 52,53,54]. Our findings on RSV-attributable cardiovascular hospitalizations are comparable to estimates from a US model-based study reporting an annual incidence of 199 cases per 100,000 person-years for adults over 75 years, similarly about 30% lower than the corresponding respiratory hospitalizations [27]. Given the high global morbidity and mortality associated with cardiovascular diseases [55] and our findings of RSV contribution to cardiovascular hospitalizations in older adults, it may be expected that RSV vaccination programs could potentially avert cardiovascular hospitalizations and related poor long-term survival [56], as has been seen with influenza vaccination programs.
The increasing incidence rates with age in adults agree with a systematic analysis of RSV-burden studies [57]. In addition, the sharp increase after 60‒65 years in RSV-attributed respiratory hospitalizations is consistent with findings from two nationwide Canadian studies assessing the RSV burden across a wide spectrum of ages in adults [23, 49]. This suggests that these older age groups may benefit from vaccination against RSV.
Our study suggests that individuals in the high-risk group have, in general, similar proportions of RSV-attributable hospitalizations compared to their counterparts without risk factors. In addition, in our study, the estimated RSV-attributable hospitalization counts in all age groups and outcomes were highest in people without risk factors. The risk group in our study was derived from inpatient medical records with a look-back period limited to one year prior to hospital admission, potentially leading to decreased sensitivity in identifying people with risk factors. This is supported by the fact that the numbers of reported hospitalizations were highest in people without risk factors, also in the oldest age group. Unfortunately, due to the lack of population denominators, we could not obtain the incidence rates by risk group.
Our study presented several strengths. Firstly, this is one of the first studies in Canada estimating the population-based burden of RSV-attributed hospitalizations based on three outcomes, investigating respiratory, cardiovascular, and cardiorespiratory hospitalizations. Secondly, comprehensive statistical modeling was applied, which was based on an extensive literature review and experts’ input.
However, the findings of this study should be interpreted in the context of some limitations. Firstly, we cannot exclude the possibility for selection bias due to inclusion of cases with severe disease requiring hospitalization, likely leading to underestimation of the total RSV burden in the population. Secondly, as an inherent limitation of retrospective database analysis, there is a chance for misclassification of outcomes, which may result in overestimation—when ICD codes are defined as rule-out diagnosis—or underestimation—when ICD codes are omitted when the outcome is present. Thirdly, the data were only sourced from Ontario; thus, our estimates may not be generalizable to Canada. The number of patients with risk factors, defined based on a look-back window of one year, is most likely underestimated, given that some risk factors might not require annual hospital visits. Nevertheless, this window was selected to balance an adequate assessment of risk factors, while allowing for sufficient follow-up to not exclude many patients (e.g., moving in/out of Ontario)), which would reduce representativeness. In addition, risk-specific incidence rates could not be obtained, due to risk-specific denominator data not being available. Moreover, a discernible seasonal pattern could not be detected for the cardiovascular hospitalizations in the younger age groups; therefore, it was unfeasible to model and obtain the corresponding RSV-attributable hospitalizations and incidence rates. No other potentially relevant circulating pathogens besides influenza and RSV were accounted for in the model. However, to a great extent, these would be indirectly accounted for in the model through the periodic component and the overdispersion parameter. Lastly, as an RSV proxy, hospitalization data from children below two years may not precisely reflect the temporality of viral circulation among adults. However, this approach has been successfully used in multiple other studies [18, 27, 34], and the best lag in time between the proxy in children and the outcome in the adult population was selected to represent the expected spread from children to adults. Future research could involve sensitivity analyses to evaluate the impact of the decisions made in this modeling approach.
Conclusions
Our study demonstrated that the incidence of RSV-attributable respiratory hospitalizations among people aged ≥ 60 years in Ontario, Canada, is considerable and comparable to other high-income countries. RSV contributes to both respiratory and cardiovascular hospitalizations, especially in the older adults. Our findings support that recently introduced RSV vaccines could have a substantial public health impact by reducing the risk of RSV-associated cardiorespiratory hospitalizations. Further research is warranted to assess the impact of assumptions made in this model-based study.
Data Availability
The datasets generated and/or analyzed in the current study are not publicly available due to restrictions of the data provider. Pfizer Canada ULC has provided funding to IQVIA Canada to obtain the data from ICES.
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Acknowledgements
The authors acknowledge Juan Luis Ramirez Agudelo, epidemiologist at P95, for his support during the preliminary phase of the data analysis. We also acknowledge the Real World Solutions team from IQVIA Canada and the ICES DAS Program for data extraction, management, and analytic support. No endorsement by IQVIA Canada is intended or should be inferred. This study made use of de-identified data from the ICES Data Repository, which is managed by the Institute for Clinical Evaluative Sciences with support from its funders and partners: Canada’s Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results, and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by the Canadian Institute For Health Information and the Ontario Ministry of Health. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada.
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Editorial assistance in the preparation of this article was provided by Dr. Somsuvro Basu of P95. Support for this assistance was funded by Pfizer Ltd.
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This study was funded by Pfizer Ltd. Pfizer funded the journal’s Rapid Service Fee.
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Bradford D. Gessner and Elizabeth Begier conceived the study. Marianna Mitratza, Malak Elsobky, Caihua Liang, Robin Bruyndonckx, Aleksandra Polkowska-Kramek, Charles Nuttens, Ana Garbiela Grajales, and Elizabeth Begier designed the study and its statistical analysis. Thao Mai Phuong Tran, Worku Biyadgie Ewnetu, and Pimnara Peerawaranun conducted the statistical analysis. Marianna Mitratza, Robin Bruyndonchx, and Aleksandra Polkowska-Kramek wrote the manuscript, with Malak Elsobky, Caihua Liang, Worku Biyadgie Ewnetu, Pimnara Peerawaranun, Thao Mai Phuong Tran, Charles Nuttens, Ana Gabriela Grajales, Sazini Nzula, Bradford D. Gessner, and Elizabeth Begier providing critical feedback and revisions. All authors reviewed and approved the final version of the manuscript.
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Marianna Mitratza, Robin Bruyndonckx, Aleksandra Polkowska-Kramek, Worku Biyadgie Ewnetu, Pimnara Peerawaranun, and Thao Mai Phuong Tran are employees of P95 Epidemiology & Pharmacovigilance, which received funding from Pfizer to conduct the research described in this manuscript and for manuscript development. Malak Elsobky, Caihua Liang, Charles Nuttens, Ana Gabriela Grajales, Sazini Nzula, Bradford D. Gessner, and Elizabeth Begier are Pfizer employees and may own Pfizer stock.
Ethical Approval
The study received ethics approval from the Advarra Institutional Review Board (Study number Pro00068118). The study was conducted in accordance with legal and regulatory requirements and research practices described in the Good Epidemiological Practice guidelines issued by the International Epidemiological Association.
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Prior Presentation: Poster presentation at RSVVW’24 8th Global ReSViNET Conference on Novel RSV Preventive and Therapeutic Interventions; 13th to 16th Feb 2024, Mumbai, India.
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Mitratza, M., Elsobky, M., Liang, C. et al. Estimated Incidence of Hospitalizations Attributable to RSV Infection Among Adults in Ontario, Canada, Between 2013 and 2019. Infect Dis Ther (2024). https://doi.org/10.1007/s40121-024-01018-w
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DOI: https://doi.org/10.1007/s40121-024-01018-w