The disease burden of respiratory syncytial virus in older adults

Purpose of review To highlight the respiratory syncytial virus (RSV) disease burden and the current developments and challenges in RSV prevention for older adults ≥60 years through analysis of RSV epidemiology and the effectiveness of emerging vaccines. Recent findings In industrialized countries, RSV incidence rates and hospitalization rates among older adults are estimated to be 600.7 cases per 100 000 person-years and 157 hospitalizations per 100 000 person-years, respectively. Yet, accurately determining RSV morbidity and mortality in older adults is challenging, thus resulting in substantially under-estimating the disease burden. The in-hospital fatality rates vary substantially with age and geographies, and can be as high as 9.1% in developing countries. Two promising RSV vaccines for the elderly have been approved, demonstrating efficacies of up to 94.1%, signifying considerable advancement in RSV prevention. However, concerns over potential side effects remain. Summary RSV is associated with a significant burden in older adults. While the landscape of RSV prevention in older adults is promising with the licensure of vaccines from two companies, current trial data underscore the need for additional studies. Addressing the real-world effectiveness of these vaccines, understanding potential rare side effects, and ensuring broad inclusivity in future trials are crucial steps to maximize their potential benefits.


INTRODUCTION
Respiratory syncytial virus (RSV), first identified by Robert Chanock in 1956, is a single stranded RNA virus.RSV is a common respiratory pathogen and almost all children are infected by the age of 3 years [1].RSV is a member of the Pneumoviridae family, characterized by enveloped viral particles.This envelope contains key surface glycoproteins such as the G protein, which allows the virus to attach to and enter host cells and stimulates neutralizing antibodies [2].The F protein, another crucial component, facilitates attachment and fusion to the host cell membrane.The F protein also undergoes a shift from a prefusion to a postfusion form and remains a central target for vaccine and passive prophylactic measures development [3].There are two subgroups -A and B. RSV is transmitted primarily through droplets released by coughing and sneezing and involves direct contact with infected persons and contact with contaminated surfaces.Some infants may remain contagious for longer and those with immunocompromised status may remain contagious up to 4 weeks [4].RSV exhibits distinct seasonality in most parts of the world [5] and causes severe disease in the very young (infants <1 year) and the older adults !60 years [6,7 RSV infection can result in upper respiratory and/ or lower respiratory tract symptoms.The most prevalent upper respiratory tract infection (URTI) symptoms in older adults with RSV include sore throat, runny noses, and nasal congestion (Table 1).In those with lower respiratory tract infections (LRTI) symptoms, cough is predominant, along with shortness of breath and sputum.Among the gastrointestinal symptoms, nausea, vomiting, or diarrhea have been reported.Other common symptoms include fever, fatigue or weakness, disturbed sleep, and general malaise.The symptoms are mild and self-resolving in most cases with symptoms usually resolving in one to two weeks.However, a small proportion of cases may result in more severe acute LRTI leading to serious outcomes such as hospitalizations and death [7 & ,8

&&
].The incidence rates, however, show marked variability in any given year (across regions and countries) due to factors like inadequate testing and the potentially suboptimal sensitivity of conventional diagnostic specimens and tools in adults [9

&&
].There is also marked variability in RSV activity year on year [5].People with chronic conditions such as chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, among others, are more likely to experience hospitalizations and death caused by RSV [11][12][13] ].The purpose of this article is to examine burden of disease caused by RSV in older adults (60 years and above).

EPIDEMIOLOGY OF RESPIRATORY SYNCYTIAL VIRUS
The primary source of RSV infection in older adults are frequently their grandchildren in the community and staff in nursing care homes [16  & ].Regardless of the region, the variations in RSV season onset, duration, and offset are relatively consistent yearon-year [5,17].RSV outbreaks have a consistent duration, averaging 4.6-4.8months.In temperate areas, RSV epidemics predominantly occur in the winter, but they usually precede influenza outbreaks by about 0.3 months.The influenza season, by contrast, tends to be shorter in temperate zones,

KEY POINTS
Respiratory syncytial virus (RSV) represents a substantial health burden for older adults, with high incidence and hospitalization rates that are often underestimated.
Emerging vaccines for RSV show promising efficacies up to 94.1%, marking significant progress in prevention efforts for the older adults.
Despite vaccine approvals, ongoing challenges include the need for further studies to assess real-world effectiveness and understand rare side effects.] to report that the annual estimates RSV hospitalizations in adults !65 years industrialized countries could be as high as 787 000 (460-1347).Similarly, the in-hospital annual mortality in this region could be as high as 47 000.Communitybased studies provide a varied picture compared to inpatient studies (Tables 2 and 3).While community-based studies provide valuable insights into the range of prevalence/incidence of RSV-ARI in the general older adult population, hospital-based studies offer more precise data on the hospitalization rate, in-hospital deaths, and healthcare impact of RSV.].No cases were identified during the pandemic RSV season, though cases re-emerged in the summer of 2021.

CHALLENGES TO IDENTIFYING MORBIDITY BURDEN IN OLDER ADULTS
Studies in industrialized countries among outpatients aged 60 years and above have reported that RSV positive proportions among those seeking care with ARI varied from 5.2% to 14.9% [26, [29][30][31][32][33][34][35][36].Studies in United States where a reliable population denominator could be estimated have reported an incidence rate of 500.9 to 2300.2 per 100 000 person-years for RSV-ARI in outpatient settings [37,38].About 11.9% of these RSV-positive older adults in outpatient settings were subsequently hospitalized [30].In two studies conducted in United States and a multicentre European study, the RSV positive proportions across age groups were relatively consistent [30,31].Those aged 60-64 years had a proportion of 10% [30].For the 60-74 years age group, proportions were recorded at 5.18% and 10.78% [30,31].In the same studies, individuals aged 75 years and above, 8.4% and 11.3% of those with ARI tested positive for RSV [30,31].In a study conducted in the United States in emergency departments, those aged 65 and over had an RSV incidence rate of 330.9 per 100 000 person-years (95% CI: 110.7-9000.8).

HOSPITAL BURDEN
There is substantial variability in the estimates for RSV hospitalizations in older adults.The RESCEU investigators reported a pooled hospitalization rate of 157 (95%CI 98-252) per 100 000 persons per year for industrialized countries [8 && ] (Table 3).This translates to about 356 000 (222-572) hospitalizations in industrialized countries in 2019.Another meta-analysis by Savic et al. [39]  ].The hospitalization rate of RSV-ARI in older adults per 100 000 per year increases with age: for those aged !65 years, the rate ranges from 10 to 320; for !70 years, it varies from 10 to 460; for !75 years, it spans from 0.0 to 710; and for those aged !80 years, it's between 0.0 and 1410 [27].A meta-analysis from industrialized countries reported that the odds ratio for RSV-ARI hospitalization in patients with comorbidities (asthma, CHF, COPD, diabetes, and immunocompromised) compared to those without was 4.1 (95% CI: 1.6-10.4).[12].Moyes et al. [41] from South Africa reported that the hospitalization rates for RSV-ARI in adults with HIV (in 2012) were 400.8, 200.0, and 200.0 per 100 000 persons/year for age groups !65 years, 45-64 years, and 18-44 years, respectively.Falsey et al. [42] from the United States reported a hospitalization rate of 1300.2 per 100 000 persons/ year for adults aged !65 with chronic heart failure or chronic obstructive pulmonary diseases due to RSV-ARI.

COMPARISON WITH INFLUENZA BURDEN
Several reports have shown that while RSV disease burden is well recognized in young children, it is under appreciated in older adults.Therefore, seasonal influenza that causes substantial morbidity and mortality in older adults, offers a useful anchor point for comparing disease burden and impact on healthcare systems.Studies have shown that in general RSV disease burden may be slightly lower or even comparable to influenza.For example, Falsey et al. [20] analyzed data over four consecutive winters from their cohort in Rochester, New York and reported that although RSV infection generated fewer clinic visits than influenza (17% and 29% in healthy and high risk older adults respectively, compared to 42% and 60% respectively for influenza A), use of healthcare services by high-risk adults was similar in both groups (9% and 16% for emergency room visits and hospitalizations respectively for RSV compared to 16% and 20% respectively for influenza A).In the hospitalized cohort, RSV and influenza A infections resulted in similar lengths of stay, rates of use of intensive care (15% and 12% respectively), and mortality (8% and 7%, respectively).A timeseries modelling study from the United Kingdom using data from the Public Health England (PHE) weekly pathogen surveillance for influenza and RSV, the Clinical Practice Research Datalink (CPRD), the Hospital Episode Statistics (HES), and the Office of National Statistics (ONS) databases for the period 1997 to 2009 showed that the RSV: Influenza ratio for GP episodes and hospitalizations for respiratory disease in adults !65 years was 1.6 : 1 and 0.8-0.9: 1 [45].The antibiotic prescriptions ratio for RSV and influenza was 2 : 1.A recent timeseries including data over a 20 year period from US reported that mean excess respiratory and circulatory deaths associated with RSV in adults !65 years was 12604 (95% CI 11808-139999) compared to 14496 (13465-15528) for influenza [46].In the UK, ratio of deaths due to respiratory and cardiorespiratory disease in adults !65 years from RSV and influenza was broadly comparable (0.9 : 1) [45].

CONCLUSION
The prevalence and severity of RSV among older adults, particularly those aged 60 and over, are becoming increasingly recognized, with several studies highlighting its widespread nature both in industrialized and developing countries.The disease burden is likely to be comparable to seasonal influenza.The frail elderly and those with multimorbidities are at substantial risk of severe disease (including prolonged hospitalization) and death.As a result, RSV vaccines displaying efficacies of up to 94.1% with duration of protection extending at least two seasons offer hope.However, concerns about possible side effects require continued monitoring and rigorous research to ensure the safe and effective management of RSV among the older adults.This study advances the understanding of RSV detection in adults, showing that diagnostic rates increase significantly when multiple specimen types are used alongside traditional nasopharyngeal swab RT-PCR.With a nearly two-fold higher detection rate using a combination of NP swab, saliva, sputum, and serology, the research suggests current RSV incidence rates are underestimated and highlights the need for a multifaceted diagnostic approach to accurately assess RSV burden in hospitalized older adults.
vaccines demonstrated similar efficacies in adults !75 years as well as those with comorbidities.Concerns emerged regarding certain side effects, such as Guillain-Barr e syndrome and atrial fibrillation, observed postvaccination in trials of both vaccines [55 && ].Based on the safety and efficacy data as well as current disease burden data, the US Centres for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) has recommended single dose of RSV vaccine in adults !60 years based on shared clinical decision-making considering individual risk factors, health status, and preferences [55 &&

Table 1 .
Respiratory syncytial virus signs and symptoms in older adults averaging around 3.8 months, but extends to 5.2 months in the tropics.RSV epidemics typically start in tropical regions around July, with the onset delayed until January in high-latitude areas.Subtropical areas display more varied seasonality with peaks at different time of the year depending on the region.The dominant RSV subtype in circulation does not affect the epidemic's timeline or span[18 & ].

Table 2 .
RSV burden among older adults in community studies

Table 3 .
RSV burden among older adults in inpatient studiesVery few community-based studies have reported RSV disease burden in older adults.These are largely from industrialized countries.A meta-analysis by RESCEU investigators identified five studies (with a clear denominator population at risk) from industrialized countries in older adults and reported that the pooled estimate of RSV related acute respiratory infections (ARI) incidence rate was 600.7 [95% confidence interval (CI): 100.4-3100.5]casesper 100 000 person-years [19] (Table2).Other studies, without a clear denominator population at risk have reported the proportion of older adults with ARI cases testing positive for RSV in community settings; these are highly variable and range from 3.4% to 8.8% depending on the study settings[20][21][22][23][24][25][26].
&& ] 9.1% (95% CI: 2.6--31.8%)[8&& ] !60 years Industrialized countries 7.1% (95% CI: 5.4--9.3)[21]CI, confidence interval; RSV, respiratory syncytial virus.The disease burden of respiratory syncytial virus in older adults Kenmoe and Nair 0951-7375 Copyright © 2024 The Author(s).Published by Wolters Kluwer Health, Inc. www.co-infectiousdiseases.com MORBIDITY BURDEN Community burden The proportion of ARI cases testing positive for RSV in community and subsequently hospitalized ranged from 0% to 19.5% [21-23].There is a clear age dependent increase in incidence of RSV-ARI in older adults.The incidence rate of RSV-ARI in older adults per 1000 per year varies by age group: for those aged !65 years it ranges from 0.7 to 151.1, for !70 years it ranges from 1.6 to 175.0, for !75 years it ranges from 6.6 to 175.4, and for those aged !80 years, the rates span from 0.9 to 259.7 [27].In a meta-analysis from industrialized countries examining the incidence of RSV-ARI in adults with comorbidities, the annual incidence rate was found to be 3700.6(95% CI: 20.1-70.3)per 100 000 persons, while the seasonal incidence rate was 2800.4 (95% CI: 11.4-70.9)per 100 000 persons [12].In a community-based cohort study involving older adults aged 50 years or older in United States across two RSV seasons (2019-2021), the incidence of RSV-positive ARI before the COVID-19 pandemic was found to be substantial at 4800.6 per 100 000 person-years [28 & [40imated that the hospitalization attack rate for RSV-ARI in older adults in industrialized countries was 0.15% and this translates to about 466 000 (302-720) hospitalizations in industrialized countries in 2019.They estimate about 274 000 (177-423) and 109 000 (71-168) hospitalizations in Europe and USA in 2019.By contrast, Osei-Yeboah et al.[40 Cong B, Dighero I, Zhang T, et al.Understanding the age spectrum of respiratory syncytial virus associated hospitalisation and mortality burden based on statistical modelling methods: a systematic analysis.BMC Med 2023; 21:224.The study informs a crucial deficit in recognizing the RSV burden among older adults, with statistical models showing notably high mortality rates for those 75 and older.The study also highlights the inadequacy of clinical databases in capturing the true extent of RSV hospitalizations for adults, particularly those over 50, suggesting that current data significantly underreports the disease burden.8. Moreo LM, Menon S, et al.Underascertainment of respiratory syncytial virus infection in adults due to diagnostic testing limitations: a systematic literature review and meta-analysis.J Infect Dis 2023; 228:173-184.This study provides insights into the underascertainment of adult RSV infections, demonstrating that RT-PCR remains the most sensitive diagnostic test.It reveals that the inclusion of additional specimen types, beyond nasal/nasopharyngeal swabs, significantly increases RSV detection rates.10.Carrico R, Wilde A, et al.Diagnosis of respiratory syncytial virus in adults substantially increases when adding sputum, saliva, and serology testing to nasopharyngeal swab RT-PCR.Infect Dis Ther 2023; 12:1593-1603.
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