Occurrence and disease burden of respiratory syncytial virus and other respiratory pathogens in adults aged ≥65 years in community: A prospective cohort study in Japan

Abstract Background The frequency and clinical profile of respiratory syncytial virus (RSV)–acute respiratory disease (ARD) in older adults in Japan has not been well‐characterized. Methods This was a multicenter prospective observational cohort study to evaluate the occurrence rate of ARD in 1000 older adult participants (≥65 years) for 52 weeks during the 2019 to 2020 season. A multiplex polymerase chain reaction panel was used for pathogen detection in nasopharyngeal swab from participants diagnosed with ARD. Symptoms and impact of ARD was assessed using the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™). The study was registered at UMIN (https://www.umin.ac.jp/ctr/): UMIN000037891. Results RSV–ARD was detected in 24/1000 (2.4%) participants and RSV‐lower respiratory tract disease in 8/1000 (0.8%) participants. The median duration of RSV–ARD was 18 days. All 24 participants had utilized the medical services of outpatient visits and only 1 (4.2%) participant was hospitalized for RSV–ARD. The most common viruses other than RSV that caused ARD (detected in >10 participants) were human rhinovirus/enterovirus, parainfluenza 3, coronavirus OC43, human metapneumovirus, and influenza A/H1. The most frequent symptoms of RSV–ARD were cough, sore throat, nasal congestion, and expectoration. Conclusions RSV was reported as a major pathogen for respiratory infections in older adults in Japan.


| INTRODUCTION
Respiratory syncytial virus (RSV) is a common pathogen responsible for mild cold-like symptoms to lower respiratory tract infection (LRTI).
Generally people recover within 2 weeks, but it can be serious in infants, children <5 years, older adults (especially ≥60 years), immunocompromised, or people with underlying cardio-pulmonary conditions. 1 Globally, in 2015, approximately 33.1 million children <5 years reported RSV-associated acute LRTI, of which 3.2 million were hospitalized and 59,600 died, while 336,000 older adults were hospitalized due to RSV-associated acute respiratory infection, of which 14,000 died. 2,3 Annually, over 177,000 older adults are hospitalized and 14,000 die in the United States (US) with RSV infection. 1 Older adults have higher risk of severe complications from RSV due to immunosenescence. 1 A 4-year prospective study in the US during 1999 to 2003 showed that 3%-7% of healthy older adults, 4%-10% of high-risk patients, and 8%-13% of hospitalized patients had RSV infection. 4 Another prospective observational cohort study in Europe (EU) during 2018 to 2019 showed that RSV infection is prevalent in community-dwelling older adults (≥60 years) with an annual incidence of 2.1%-4.9%; however, it rarely causes severe disease. 5 In long-term care facilities, RSV is estimated to infect 5%-10% of residents per year with significant rates of pneumonia (10%-20%) and death (2%-5%). 6 In the EU and the US, RSV is increasingly recognized, including impact on older adults; however, little is known about RSV infection in Japan. 7 Several prophylactic vaccines against RSV disease in older adult populations are currently under development. As Japan has a significant population over 60 years of age (35.6 million), 8 it is important to understand the burden of RSV disease in this population.
The objectives of this study were to estimate the occurrence rate of RSV infection, and to characterize the RSV disease outcome in older adults in Japan.

| Study population
Ambulatory adults (≥65 years) living in Japan in community or assisted-living or long-term care residential facilities, and who were, healthy or with clinically stable medical conditions, were enrolled.
Participants with acute respiratory disease (ARD) at consent and Week 0 (baseline), or who had received experimental antiviral drugs or vaccines for RSV within 6 months prior to the study, or had a life expectancy <1 year, were excluded.

| Study design
The study was conducted at 10 sites in Japan from April 2019 to July 2020. Participants were followed up bi-weekly (weekly during RSV season, predefined from 01 June 2019 to 30 November 2019) 9 through telephone to monitor ARD. Each participant was observed for 52 weeks from the day of registration or until withdrawal ( Figure 1).
The study was conducted in accordance with the principles defined in the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human Subjects, Japanese regulations, and sponsor policy. The occurrence rate of RSV infection in older adult population was conservatively estimated to be 2%. 4 A total of 1000 participants were expected to allow for precision of estimation of the true attack rate of 2%, as measured by the width of the two-sided 95% confidence interval (CI). The diagnosis and severity at ARD diagnosis by investigators, and the time from the onset day of ARD symptoms to the day of ARD diagnosis (ARD Visit Day 0) were also evaluated as post hoc analyses.

| Statistical analyses
This was an exploratory descriptive study; therefore, no hypothesis testing was conducted. The precision of the estimate of the occurrence rate was determined using the Clopper-Pearson exact 95% F I G U R E 1 Schematic diagram of the study. Greyed cells in the above figure indicate scheduled activities to be performed at home. White cells in the above figure indicate scheduled activities to be performed at the study site. *Of which >30% aged 65 to 74 years and >30% aged ≥75 years and older (including >5% of 85 years and older as possible). **In the case that participants recovered and symptoms recurred, ARD was defined as a single episode or a separate episode of respiratory illness by the clinical judgment of the investigator; however, the episodes of respiratory illness that occurred >28 days of each other as a separate episode of illness were to be counted. 10 Abbreviations: ARD = acute respiratory disease, ICF = informed consent form, RiiQ™ = Respiratory Infection Intensity Questionnaire, RSV = respiratory syncytial virus CI. All participants having baseline (Week 0) data were included in the analyses. All data were summarized descriptively.
The median (range) duration of RSV-ARD was 18.0 (10 to 33) days (Table S1). The most frequent symptoms recorded by the participants (mean change of >1.0 in symptom score from baseline) for RSV-ARD were cough, sore throat, nasal congestion, and expectoration. For most participants (n = 15), symptoms improved by Day 14; however, for few participants (n = 7), the symptoms lasted for 21 to 28 days after onset (data not shown). Respiratory tract symptoms tended to take longer to return to baseline for RSV and human metapneumovirus than for influenza A/H1 ( Figure S1). The body tempera-      Severe morbidity and mortality were seen in older adults hospitalized with RSV infection in an earlier study conducted in the US. 21 Another study conducted in EU confirmed that RSV is prevalent in community-dwelling older adults. 5 Hence, there is a need for vaccine T A B L E 5 Summary of diagnosis of ARD by investigators (pathogens detected in >10 samples)  This study has following limitations: the study was designed for only 1 RSV season in 2019 with 1000 participants, resulting that the relatively low numbers of cases reported in each pathogen make it difficult to compare disease characteristics among subgroups or pathogens; the impact of COVID-19 pandemic occurred in March 2020 was unknown on the occurrence of ARD by respiratory pathogens and the study site visits; there could be an underestimation of severe ARD cases requiring hospitalization given that 90% of participants were enrolled from general practitioner sites and a participant with severe symptoms could visit a hospital site other than study sites and such case was not recorded in the study.

| CONCLUSIONS
RSV was reported as a major pathogen causing respiratory infection and represents a burden as significant as influenza in elderly Japanese community setting. The evidence of medical needs for development of vaccine to prevent RSV infection was generated.