Epidemiology and Disease Burden of Respiratory Syncytial Virus Infection in Adults

Abstract

Respiratory syncytial virus (RSV) constitutes a significant cause of respiratory illness and mortality among older adults, a demographic that is expanding with considerable impact on healthcare systems worldwide. The actual burden of RSV in this population may still be underestimated, owing to factors such as low awareness and suboptimal diagnostic sensitivity in adults, the lack of robust RSV surveillance systems, and the infrequent use of diagnostic testing. Recent advancements in respiratory virus detection have spurred further exploration into appropriate preventive and therapeutic strategies. The recent approval of two vaccines highlights the critical need for the precise estimation of the RSV disease burden to optimize the effectiveness and cost-efficiency of immunization programs. This narrative review aimed to summarize the existing knowledge of the RSV burden in adults with a particular focus on older adults, incorporating data from Korea. Overall, current estimates indicate that the annual RSV attack rate in the general adult population ranges from 1 - 7%, increasing to approximately 4 - 10% among elderly and high-risk groups. The in-hospital mortality rate can be estimated to be around 7 - 10%, rising up to 40% among intensive care unit-admitted patients. To elucidate RSV’s disease burden, further continuing research, including population-based studies, is necessary.

Introduction

Historically, respiratory syncytial virus (RSV) infection has been one of the most common causes of lower respiratory tract infections in infants and young children. The global incidence of RSV-associated lower respiratory tract infections is estimated at over 30 million cases in children under the age of five, resulting in 3.2 million hospitalizations [1]. However, RSV infection also constitutes a substantial disease burden in older adults. The number of RSV-attributable deaths is considerably higher in older adults than in infants [2]. In the United States (US), RSV is responsible for an estimated 6,000 - 10,000 annual deaths among older people [3].

In the temperate regions of the Northern hemisphere, including Korean peninsula, RSV transmission generally commences in the fall and peaks in the winter [4]. It has been postulated that the surge in RSV cases correlates with declining temperatures, which may be attributable to increased indoor gatherings that facilitate viral transmission. Lower temperatures can also increase viral stability and host susceptibility, leading to an escalation in viral transmission rates [5,6].

Recently, the coronavirus disease 2019 (COVID-19) pandemic has modified the usual seasonality of respiratory viruses, including RSV [7,8]. Changes in individual behaviors and viral interference, along with control measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), might have postponed the RSV outbreak in the 2021–2022 season [7,9]. Notably, as of 2023, two RSV vaccines have been licensed for use in adults aged 60 years and older [10]. These epidemiologic changes, coupled with the approval of vaccines for older adults, underscore the need for a detailed understanding of the epidemiology and disease burden of RSV infection.

Over the past two decades, there has been increasing emphasis on the burden of RSV infection in adults, yet its true impact on older adults and other at-risk adult populations remains underappreciated. This underestimation is partially attributed to the reliance of RSV surveillance on the existing influenza surveillance system and case definitions [11]. To our knowledge, there has not been a comprehensive review focused specifically on RSV infection across different adult age groups. Hence, this narrative review aimed to collate and present the existing body of knowledge regarding the burden of RSV in adults, with a specific emphasis on older adults.

Epidemiological overview of RSV infection across all age groups

1. Global Epidemiology of RSV infection

RSV is distinguished as the predominant viral agent in lower respiratory tract infections (LRTI) among infants, with its etiological association with bronchiolitis being well-documented since 1957 [12]. Nearly all humans are infected with RSV during early childhood, yet the immunity conferred post-infection is neither sustained nor complete [13]. Consequently, recurrent infections occur frequently, impacting as many as 10% of young adults each year, typically presenting with only mild symptoms [14]. It was not until 1970s that RSV began to be recognized as a pathogen of potential seriousness among adults [15,16,17].

Few studies have addressed the overall age distribution of RSV at a global level, partly due to the lack of dedicated surveillance systems for this virus [18]. In an effort to fill this gap, the Global Epidemiology of RSV (GERi) network was launched in 2019 to elucidate the global epidemiology and temporal patterns of RSV epidemics based on virological surveillance data [18]. Recent data published from the GERi network, incorporating surveillance data from 12 countries, reported 501,425 RSV cases over 210 seasons spanning from 2000 and 2020 [19]. In most temperate countries, RSV epidemics predominantly occurred in winter, with a median duration of 10 - 21 weeks. In contrast, countries with subtropical or tropical climates showed more variation in the timing of these epidemics. When analyzing the impact of RSV subtype A or B-dominant seasons on the timing of RSV seasons using data from 18 seasons in four different countries, no substantial differences were found in the duration, start, or end of the RSV epidemics. Another study from the GERi network delved into the global epidemiology of RSV and found that the majority of cases (n = 9,287, 55.6%) occurred in children aged less than one year, with 8% of cases reported in those aged 65 years and older [20].

A recent systematic analysis using the global burden of RSV infection across different age groups assessed the global temporal trends and further stratified the analysis according to the Socio-demographic Index [21]. This study disclosed that, in 2019, the global age-standardized rate of mortality (ASMR) was 4.79 per 100,000 population (95% uncertainty interval [UI], 1.82 - 9.32), and the age-standardized disability-adjusted life years (ASR-DALYs) was 218.34 per 100,000 population (95% UI, 92.1 - 376.8). Notably, the highest ASMR (10.26/100,000; 95% UI, 3.8/100,000 - 20.2/100,000) and ASR-DALYs (478.7/100,000; 95% UI, 202.4/100,000 - 840.9/100,000) were observed in regions with low Socio-demographic Index. Although there has been a global decline in both mortality and DALYs across all age groups globally, the rate of this decrease was not uniform. Notably, in 2019, the mortality rate in the elderly over 70 (34.5/100,000) surpassed that in children under 5 (18.7/100,000), with an increased ratio of mortality rates between individuals over 70 years and those under 5 years (0.57 in 1990 to 1.85 in 2019). These disparities underscore the urgent need to ameliorate the disease burden of RSV, particularly in low Socio-demographic Index regions and amongst the elderly over 70 years.

2. Epidemiology of RSV infection in Korea

In Korea, a nationwide, active surveillance system dedicated to RSV is not in place. There is a passive surveillance network, the Respiratory Viruses Surveillance System, which monitors respiratory viruses, including adenovirus, human bocavirus, human metapneumoviruses, parainfluenza viruses, human coronaviruses, human rhinoviruses, influenza viruses, and RSV [22]. However, the utility of this system is hindered by the lack of clinical data such as hospitalization rates and patient outcomes. A meta-analysis, which included 20 Korean studies published from 2000 to 2017, revealed that RSV was identified in 18.1% (95% confidence interval [CI], 13.8 - 22.7%) of respiratory specimens collected from patients of any age with acute respiratory infection, lower respiratory infection, or influenza-like illness [23]. However, the wide range of RSV detection rates — from 3.6% to 37.2% — reported by surveillance studies of acute respiratory tract infections in Korea indicates inconsistencies [24,25,26,27,28,29]. These variations may be attributed to factors including different settings, such as inpatient populations, potentially unreliable testing practices in adult demographics, and studies conducted over short timeframes with varying temporal contexts.

A recent molecular epidemiology analysis assessed the temporal evolution of the G gene in RSV strains isolated from children over 28 consecutive seasons (1990 - 2018) in Korea [30]. RSV is categorized into two subgroups, RSV-A and RSV-B, based on antigenic variability of the G protein. It was found that both RSV-A and RSV-B co-circulated in most seasons; however, in certain seasons, only one group was identified. RSV-A was isolated more often than RSV-B, with the exception of seven seasons (25.0%), during which RSV-A was threefold more likely to be the dominant strain. During RSV-A-dominant seasons, the median percentage of RSV-A isolates was 89.8% (range, 61.8 - 100%), while in seasons when RSV-B was dominant, it was 66.7% (range, 59.1 - 100%). Until the 2003/2004 season, the GA2 and GA7 genotypes of RSV-A were the most predominant, followed by the dominance of the NA1 genotype from the 2004/2005 season through the 2011/2012 season. Starting in November 2011 with its first detection, the ON1 genotype became the sole genotype of RSV-A observed from the 2013/2014 season onwards. Within the RSV-B group, the GB2, GB4, and SAB2 genotypes were prevalent from the 1990/1991 season to the 1998/1999 season. Subsequently, the GB3 genotype emerged as the predominant strain from the 1999/2000 season to the 2005/2006 season, representing 44.2% of the RSV-B isolates. The BA genotypes were initially detected in the 2005/2006 season, starting with the BA9 in November 2005. Subsequently, the BA genotypes, particularly BA9, dominated in the seasons between 2015/2016 to 2017/2018. The duplication region of the G gene in both the ON1 and BA genotypes demonstrated evolutionary changes with each season. This complete genotypic replacement by ON1 and BA9 in both RSV-A and RSV-B was observed in a cohort of Korean adults admitted to the intensive care unit (ICU) for severe pneumonia [31]. This phenomenon has been corroborated by parallel studies conducted in various other countries [32,33].

Disease burden of RSV infection in adults

1. Global burden of RSV infection in adults

A recent systematic review and meta-analysis, including 95 studies published that involved adults aged ≥18 years from January 1970 to February 2017, reported the incidence rates of RSV-related acute respiratory infection requiring hospitalization [34]. The incidence rates of hospitalized RSV acute respiratory infection (ARI) in adults >65 years old ranged from 7.3 - 13.0/100,000 population in developing countries to 190 - 254/100,000 population in the US. In addition, the US exhibited higher incidence rates in emergency department settings, ranging from 128 to 340/100,000 population, particularly among adults aged ≥50 years. The proportions of RSV-attributable illnesses among ARI/influenza-like illness (ILI) or community-acquired pneumonia (CAP) were higher in Europe and the US, at 10% and 7% respectively, in contrast to 1 - 2% reported in lower-income regions, such as Africa and Asia [32]. Furthermore, that review found that RSV accounts for 1 - 7% of ARI/ILI cases in the general adult population and 1 - 10% in individuals aged ≥50 years old. The aforementioned study indicated that adults over 65 years old exhibited higher incidence rates compared to younger age groups (7.3 - 13.0/100,000 population in adults >65 years vs. 0.9 - 4.1/100,000 in 29 - 49 years).

According to Centers for Disease Control and Prevention, RSV is responsible for an estimated 60,000 - 160,000 hospitalizations and 6,000 - 10,000 deaths annually among US adults aged ≥65 years [35]. A comprehensive analysis of existing literature calculated the incidence of RSV-ARI in the elderly population (≥65 years) for the year 2015 within developed nations, identifying roughly 1.5 million instances (95% CI, 0.3 million - 6.9 million) [36]. Out of these episodes, an estimated 14.5% (214,000 cases; 95% CI, 100,000 - 459,000) resulted in hospital admissions. From another meta-analysis focused on developed countries, it was deduced that in the elderly demographic, RSV was responsible for 4.7% (95% CI, 3.3 - 6.5%) of symptomatic ARI annually and 7.8% (95% CI, 5.8 - 10.5%) seasonally [37]. The case fatality proportion (CFP) associated with RSV was 8.2% (95% CI, 5.5 - 11.9%). Among high-risk adults with chronic diseases or functional impairment, RSV was found to cause 7.0% (95% CI, 5.2 - 9.5%) of symptomatic respiratory infections in yearly studies, and 7.7% (95% CI, 6.2–9.5%) in studies conducted during specific seasons. The CFP was 9.9% (95% CI, 6.7 - 14.4%). Other researchers estimated the RSV disease burden in adults ≥ 60 years in high-income countries as 1.6% (95% CI, 0.8 - 3.1%) for the RSV-ARI attack rate, 0.2% (95% CI, 0.1 - 0.2%) for the hospitalization attack rate, and 7.1% (95% CI, 5.4 - 9.4%) for the in-hospital case fatality rates [38].

The seminal work by Falsey et al. was pivotal in assessing the RSV burden in elderly (≥65 year), as well as in individuals with chronic cardiac or pulmonary conditions [39]. This study encompassed 608 older adults in good health and 540 adults at high risk. Within the observed cohorts, RSV was confirmed in 102 patients. The incidence of RSV infection occurred annually in 3 - 7% of the robust elderly participants and 4 - 10% of those within the high-risk category. More recently, a US study documented the seasonal rate of RSV cases requiring medical attention among individuals aged 60 and above, who sought outpatient care for ARI, as 139 per 10,000 persons during the period from 2006 to 2016, noting a decline in cases beginning in the 2011 - 2012 season [40]. Significantly, the incidence of RSV was markedly greater in patients with underlying cardiopulmonary diseases (rate ratio, 1.9; 95% CI, 1.4 - 2.5). Furthermore, severe outcomes were notably more prevalent among individuals aged 75 and older compared to 60 - 64 years old, and those suffering from chronic obstructive pulmonary disease (COPD) or congestive heart failure [40].

In a recent community-based longitudinal study by Juhn et al., which observed adults over 50 in Minnesota for two RSV seasons (2019 - 2021), it was found that before the pandemic, the incidence of RSV-related ARI was 48.6 per 1,000 person-years, with an attack rate of 2.5% [41]. Although there were no cases of RSV-positive ARI detected during the pandemic season, the impact of RSV on older adults prior to the COVID-19 pandemic was considerable.

To evaluate the community impact of RSV on the elderly in Europe, the RESCEU, an observational cohort conducted across various European nations, included 1,040 participants with a median age of 75 [42]. These individuals were tested for acute respiratory tract infection (ARTI) symptoms at home within three days of onset. The RSV infection rate was 4.2% in the 2017 - 2018 season and rose to 7.2% in the 2018 - 2019 season. The data from this study suggest that RSV infections in older adults within community settings are generally mild and do not necessitate aggressive treatment. When compared to influenza-associated ARTI, RSV-ARTI led to fewer healthcare visits (30.6% vs. 60.0%, P = 0.006) and resulted in less frequent antibiotic prescriptions (5.6% vs. 30.5%, P = 0.004) [42].

A Japanese multicenter prospective observational cohort study evaluated the occurrence rate of acute respiratory disease (ARD) in 1,000 older adult participants (≥65 years) during the 2019/2020 season [43]. RSV-ARD was detected in 24/1,000 (2.4%) participants and RSV-lower respiratory tract diseases in 8/1,000 (0.8%) participants. Only 1 (4.2%) participant was hospitalized for RSV-ARD.

2. Burden of RSV infection in Korean adults

In Korea, while RSV infections are less prevalent in adults than in children, the virus is still a significant pathogen, particularly in the elderly population and those with comorbidities [4]. Studies conducted in Korea have typically included adults of all ages, yet the mean or median age was generally around 65 years. In the setting of emergency departments, RSV has been detected in 2.8% of adults presenting with an ILI (median age, 43 years) [44]. Among Korean adult asthmatics with a mean age of 56 years and LRTIs, RSV was found in 11.8% of sputum samples from patients experiencing an exacerbation and in 25.0% of samples from those without an exacerbation (P = 0.22) [45]. The seasonal pattern of RSV infection in adults paralleled that observed in children, with a peak in cases during the autumn and winter months [44,46,47].

Incidence and outcome of RSV infection in hospitalized adults

1. American and European studies

According to a retrospective study of hospitalizations among adults ≥20 years from the 1997 -2012 National Inpatients Sample of the US, an estimated 28,237 adult RSV hospitalization occurred, compared with 652,818 influenza hospitalizations; 34% were immunocompromised individuals [48]. RSV hospitalization rates increased from 1997 to 2012, particularly for those ≥60, increasing from 0.5 to 4.6 per 100,000, whereas unspecified pneumonia admission rates decreased significantly. Immunocompromised patients had significantly higher inpatient mortality, use of mechanical ventilation, mean length of stay, and mean cost than non-immunocompromised RSV hospitalizations. Although there were fewer hospitalizations, the severity and the burden of hospitalization, including in-hospital mortality (6.2% vs. 3.0%), mechanical ventilation (16.7% vs. 7.2%), length of hospital stay (6.0 vs. 3.6 days), and mean cost ($38,828 vs. $14,519), were higher in RSV than in influenza.

A retrospective study assessing the disease burden and outcomes associated with RSV infection in US adults hospitalized between 2014 and 2016 revealed that the majority of patients (73%) presented to the emergency department, with a mean age of 60 years [49]. The median length of stay was 6.0 days (Interquartile range [IQR], 3.0 - 9.0). Over half of the patients received antibiotic prescriptions during their hospitalization. Another recent retrospective study analyzed the characteristics and outcomes of 489 hospitalized adults with RSV infection from 2009 to 2015 in Chicago; about a quarter of patients (26.9%) required ICU level care, and death was more common among those with recent cancer treatment and age >65 years [50].

In the earlier prospective cohort study by Falsey et al., which included three distinct cohorts (608 healthy elderly, 540 high-risk adults, and 1,388 hospitalized older patients with acute respiratory symptoms), 142 patients (10.2%) from the hospitalized cohort were found to have RSV infection [39]. A recent systematic review and meta-analysis, encompassing 16 observational studies and 762,084 older participants, showed that the incidences of hospitalization and mortality were similar for RSV and influenza [51].

An observational study conducted across five French university hospitals between 2017 and 2019 included hospitalized adults presenting with ILI. Among 1,428 hospitalized adults with ILI, RSV was detected in 8.0% and influenza virus in 30.6%. The analysis found that those admitted due to RSV were older than those with influenza (average age, 73.0 years vs. 68.8 years). In addition, a higher prevalence of comorbidities was reported among the RSV-infected patients, including chronic respiratory or cardiac conditions (51.8% vs. 38.5% and 51.8% vs. 40.8%, respectively), along with a longer duration of hospital stay (median stay, 8 days vs. 6 days) [52].

In another recent French study evaluating hospitalized adult patients with RSV infection, the in-hospital mortality rate was found to be 6.6% (77/1,668) [53]. Notably, a higher rate of 12.8% (37 of 288) was observed among patients necessitating ICU admission. The predictive factors for the need for invasive mechanical ventilation included chronic heart conditions (adjusted OR [aOR], 0.98), respiratory failure (aOR, 2.83), and co-infection (aOR, 2.62) [53]. A Swiss-retrospective cohort study comparing hospitalized patients infected with RSV (n = 79) to influenza (n = 479) reported an increased risk of ICU admission or death among patients with RSV (19% vs. 10% for patients with influenza) [54]. In this study, combined reverse transcriptase real-time polymerase chain reaction (RT-PCR), detecting both RSV and influenza, was used for diagnosis in hospitalized patients presenting with symptoms and signs of ARTI.

The aforementioned systematic review with meta-analysis estimated the global rates and found there are approximately 336,000 hospitalizations annually for RSV-ARI among older adults (uncertainty range [UR], 186,000 - 614,000) [36]. Additionally, the study estimated around 14,000 in-hospital deaths (UR, 5,000 - 50,000) related to RSV-ARI globally. Both the hospital admission rate and hospital case fatality ratio were found to be higher in individuals aged ≥65 years compared to those aged 50 - 64 years. Another systematic review that estimated the RSV hospitalization burden of older adults in high-income countries included 12 studies and showed that the adjusted rate could be translated into 787,000 (460,000 - 1,347,000) RSV-associated hospitalizations in high-income countries in 2019 [55]. Stratified analysis by age group showed that the adjusted rate increased with age, from 231 per 100,000 in adults aged 65 - 74 years to 692 per 100,000 in adults aged >85 years. The in-hospital case fatality ratio of RSV was 6.1% (95% CI, 3.3 - 11.0) and the total RSV-associated in-hospital deaths in high income countries in 2019 could be between 22,000 and 47,000.

In a study from the United Kingdom, it was determined that RSV led to an estimated 71 hospital admissions annually per 100,000 individuals aged 65 - 74 for ARTIs, and 251 admissions for those aged over 75 [56]. From a patient sample in the US, 21% of the 664 patients hospitalized with RSV required mechanical ventilation, and 18% were admitted to the ICU [57]. Another American study examining 302 adults aged 60 and older with confirmed RSV infections found that hospital stays due to RSV often resulted in both immediate and lasting functional impairment. Specifically, 14.2% needed a higher level of care upon discharge, and roughly a third showed a decline in their ability to perform instrumental and basic activities of daily living scores half a year post-discharge [58]. A retrospective cohort study conducted over five consecutive winters in the US, which included hospitalized adults aged ≥60 years, established that RSV is a significant contributor to serious and potentially life-threatening respiratory illness in this population [59]. That study found that the morbidity and mortality associated with RSV were comparable to, or exceeded, those related to influenza. This was evidenced by greater odds of length of stay ≥7 days, pneumonia, ICU admission, COPD exacerbation, and greater mortality within 1 year of admission.

2. Studies from developing countries

Compared to developed countries, data on the disease burden of RSV in developing countries data are limited. A recent review of RSV hospitalization rates in adults ≥65 years of age estimated them to be 1/1,000 and 0.3/1,000 person-years in industrialized and developing countries, respectively, in 2015 [36].

3. Korean studies

In Korea, studies have revealed that 1.1% of adults admitted to hospitals for ARTIs tested positive for RSV [60], and RSV infections were identified in 2.3% of the older adult population (average age 70) hospitalized with suspected viral respiratory illnesses [61]. RSV was responsible for 7.3 – 9.0% of the viruses detected in samples from patients hospitalized with ARTIs [60,62].

An investigation focusing on adult patients hospitalized due to RSV between 2012 and 2015 assessed 204 individuals and stratified them into three age categories (19 - 49, 50 - 64, and ≥65 years) [47]. A majority of these RSV patients were in the oldest age bracket (64.7%). Across all age groups, the majority had pre-existing health conditions (90.2%), and pneumonia was diagnosed in 57.8% of cases. The hospital mortality rate stood at 10.8% and did not differ significantly between the age groups. The rate of ICU admission and the need for mechanical ventilation were higher in the older age group compared to the middle-aged or younger adult (25.0% vs. 11.5% vs. 10.0% for ICU admission and 11.4% vs. 5.8% vs. 0% for mechanical ventilation, respectively), but these differences did not reach statistical significance. The median medical cost for hospitalization due to RSV pneumonia in Korean adults was $1,562 - $5,380 (IQR, USD). In addition, it was noted that adults ≥65 years accounted for approximately 65% of hospitalizations related to RSV, incurring higher median costs per episode compared to younger and middle-aged adults [47]. Solid cancers and hematologic malignancy were identified as risk factors for RSV-associated pneumonia.

In a study contrasting adults admitted to hospitals with either RSV (n = 97) or influenza (n = 312), those with RSV were on average older (70 vs. 62 years old), more frequently from long-term care facilities (10.3% vs. 1.9%), and had a higher prevalence of COPD (12.6% vs. 4.8%) compared to the influenza patients [61]. Additionally, the incidence of pneumonia, secondary bacterial respiratory infections, and hypoxemia were higher in RSV patients. Those with RSV showed a significantly greater 20-day mortality rate than those with influenza (18.4% vs. 6.7%; hazard ratio, 2.32; 95% CI, 1.2 - 4.6). Another study involving hospital patients of all ages with respiratory symptoms indicated that coinfections with other viruses, such as rhinovirus, were most frequent in patients over 80 years of age [28]. While the outcomes of such coinfections with RSV are variable, they can lead to extended hospital stays, and bacterial coinfections have been linked to a heightened risk of fatal infection [62,63].

The Korean RSV studies, conducted predominantly in tertiary or university hospitals, have notable limitations. To date, there has been no comprehensive population-based study on RSV, underscoring the significant gap in understanding its impact across diverse community settings.

Outcomes of patients with severe RSV infection requiring ICU admission

Even in recent investigations regarding the burden and outcomes of RSV infection in hospitalized adults, limited attention has been given to the role of RSV in severe pneumonia. A French group recently conducted a multicenter matched cohort study comparing adult ICU patients with RSV infection to those affected with influenza [64]. The findings demonstrated that patients with RSV had a higher incidence of pre-existing medical conditions (60.2% vs. 40.1%) and were more frequently immunocompromised (35.0% vs. 26.2%). Despite these differences, the in-hospital mortality rate was comparable between the two groups (23.9% vs. 25.6%; aOR, 0.8; 95% CI, 0.5 - 1.3).

In cohort studies of Korean adults (mean/median age approximately 65 years) with severe pneumonia admitted to ICUs, RSV was identified in 5.1 - 6.1% of the patients [65,66,67]. Among virus-positive samples from these studies, RSV was detected in 13.9 - 27.1%. In one study, RSV was significantly more common among patients with CAP compared to those with healthcare-associated pneumonia (HAP) (10.9% vs. 2.2%) [65], a finding that was supported by another cohort study [67]. In addition, an analysis of extended data from a previous prospective ICU cohort study [65], encompassing severe pneumonia cases through to the year 2019, indicated that RSV accounted 3.6% (102/747) of the identified viral pneumonia pathogens [31]. Among 1,589 patients with severe CAP, 3.4% were attributed to RSV and 8.1% to influenza virus, whereas out of 1,276 cases of severe HAP, the rates were 3.8% for RSV and 3.5% for influenza virus. Immunocompromise (57.6% vs. 34.4%) and hospital acquisition (47.8% vs. 23.9%) were significantly more common in the RSV group. Notably, the 90-day mortality rates were high and comparable between the two groups (39.1% for RSV vs. 40.5% for influenza) [31].

RSV transmission among high-risk patients

Outbreaks identified in long-term care facilities in the late 1970s and early 1980s first drew attention to RSV as a potential cause of serious respiratory disease in older adults [68]. More recently, RSV outbreaks have predominantly been reported among immunocompromised adults, particularly in patients residing in hematology or oncology wards [69,70,71,72].

Research from Korea revealed that hospitalized patients with RSV were more frequently from long-term care facilities compared to those with influenza (10.3% vs. 1.9%) [61]. In another incident, an outbreak of acute febrile illness at a military base in 2011 affected 588 of 3,750 trainees (15.7%), and RSV was identified as the infectious agent through RT-PCR tests [73]. While the majority of the patients presented with upper respiratory tract symptoms, four cases developed pneumonia. Despite these findings, to date, there have been no specific reports published that described RSV-associated outbreaks among elderly populations in Korea.

Epidemiology of RSV infection in the post COVID-19 era

An Italian study that assessed the prevalence of different respiratory viruses during the COVID-19 pandemic, spanning January 2017 to May 2021, reported a significant decrease in overall multiplex PCR positivity rates for respiratory viruses (excluding SARS-CoV-2), declining from 14.6% in the pre-pandemic period to 2.7% after the pandemic onset [74]. There was also a significant reduction in RSV cases, with the positivity rate falling from 5% to 0.14% during the same period. This cessation of RSV circulation following the emergence of SARS-CoV-2 has been reported by various global surveillance initiatives [8]. Following this marked decrease, substantial outbreaks of RSV have occurred in many regions, especially during the easing of non-pharmaceutical measures in the 2022 - 2023 winter season. One theory is that the initial drop in respiratory virus circulation during the early days of the COVID-19 pandemic may have expanded the group of vulnerable individuals, thereby facilitating their spread. An additional theory posits that the resurgence of these viruses could have heightened the interplay between different respiratory viruses, leading to an increase in concurrent viral infections or secondary infections. The effects of these viral interactions can either compound or diminish one another, as shown in experimental, clinical, and epidemiological studies [7].

Similarly, in a recent nationwide ecologic study from Korea, it was reported that there was an RSV epidemic, suggestive of endemic transmission, which was delayed by 1 - 2 months during the 2021 - 2022 season in the absence of concurrent influenza activity [9]. That study noted that the RSV infection positivity rate was 1.8 times higher than in the pre- nonpharmaceutical intervention (NPI) period and 1.5-times higher than the predicted value. The hospitalization rate for RSV was reported to be 20.0% of the rate in the pre-NPI period, which was 17.6% of the predicted value. In contrast to RSV, influenza showed a significant decrease in both positivity rate (0%) and hospitalization rate (1.0%), thus highlighting the re-emergence of RSV with endemic transmission patterns during the study’s observation period.

Discussion

In this review, we have summarized the disease burden of RSV infection, with a particular focus on older adults. RSV is now recognized as a significant health threat not only to infants and children but also to older adults. Despite a global decline in the incidence of RSV, this decrease is not uniformly observed, especially in older patients and populations in developed countries. The COVID-19 pandemic has further altered the epidemiology and the disease burden of respiratory viruses, including RSV. Notwithstanding, the specific burden of RSV within adult populations at risk, as exemplified by limited data from Korea, has not been adequately quantified, highlighting a necessity of population-based research studies.

This under-recognition of RSV infection in adults may stem from a myriad of factors. First, there is a low level of awareness among healthcare providers and the general public regarding RSV infection in adults, leading to a low index of suspicion and clinical diagnosis. For instance, RSV may not be suspected, or it may no longer be detectable, when it precipitates an exacerbation of an underlying chronic cardiac or pulmonary condition [75]. Case detection in many studies is contingent upon testing for RSV in patients presenting with clinical syndromes such as ILI, ARI, or SARI. A substantial number of RSV cases in adults might not be captured in these studies because RSV infection in older children and adults is often mild and afebrile, with non-specific symptoms, and tends to resolve in less than a week [40].

Second, older adults frequently have atypical or delayed clinical presentations with much lower viral loads in nasal secretion compared to infants and children [68], which further decreases the sensitivity of the most widely used diagnostic tests (i.e., nasal swab PCR). They may not have a detectable virus when they seek medical care, owing to a shorter duration of viral shedding, delay in seeking care, or improper specimen collection [76]. Rapid antigen tests, which have known limitations in sensitivity, are not considered optimal for the detection of RSV in older adults [77,78]. Currently, RT-PCR is the reference diagnostic method for detecting RSV [79,80]. While RT-PCR increases RSV detection sensitivity in comparison to other testing modalities, the type of specimen used for the diagnostic test can impact the sensitivity of RSV detection. For instance, a single nasopharyngeal multiplex PCR might yield lower viral titers, leading to an underestimated RSV infection [81]. Most studies of RSV infection among older adults rely solely on nasal swab testing to identify RSV infection. However, a recent systematic review and meta-analysis revealed that, compared to nasal swab PCR testing alone, adding sputum specimen PCR or blood testing increased the detection of RSV infections by 52% and 44%, respectively [82]. The addition of mouth/throat swab PCR testing further increased the detection of RSV infections by 28%.

Third, the lack of robust data collection and surveillance systems for RSV means that several studies, particularly in Europe, were reliant on influenza surveillance platforms, which may not be ideally suited for estimating the burden of RSV in adults [18,83]. Fourth, there is often a failure to distinguish between annual rates and seasonal rates in the literature, resulting in underreported rates that do not specifically target the peak respiratory virus season. Lastly, routine virological diagnostics for RSV in adult patients, especially in out-patient settings, are not commonly performed, partly due to the absence of targeted treatment and the relatively high costs associated with multiplex PCR analysis. This was particularly the case before the 2009 - 2010 influenza pandemic and during the 2019 - 2022 COVID-19 pandemic, as well as in low- and middle-income countries. Such practices have led to the underestimation of RSV rates in most retrospective studies.

Fortunately, we have entered a golden era of RSV vaccine development, with two licensed vaccines for use in older adults. This advancement has led policymakers to pose critical questions about how we will use these new pharmaceutical arsenals to enhance the health of older populations. Key considerations include whether to conduct seasonal vaccination campaigns, the necessity of an annual booster, the age groups that should be prioritized, the risk factors that should be given precedence to improve outcomes of RSV infection, and how to diagnose RSV infection accurately to avoid underestimation.

There is a growing body of evidence regarding the RSV burden in adults. As the landscape of preventive and therapeutic strategy rapidly evolves, the approval or forthcoming approval of vaccines highlights the need for effective virological and clinical surveillance of RSV infections, mirroring efforts implemented for SARS-CoV-2 and influenza. Discussions should also focus on improving diagnostic strategies to accurately ascertain the RSV disease burden, assess the public health impact of preventative interventions (including vaccines), and develop precise economic models that can estimate the economic value of RSV immunization in adults. The upcoming years hold great potential for advancement in the realm of RSV prevention. The optimal use of emerging preventive, diagnostic, and therapeutic tools must be delineated. Moreover, understanding viral evolution and resistance is critical to guide the development of new vaccines, monoclonal antibodies, and antivirals, particularly for at-risk populations, such as the elderly.

In summary, elderly patients with RSV infection face a significant risk of severe illness requiring hospitalization, with the hospitalization burden in this population being comparable to that of seasonal influenza. Resource utilization among the elderly is notably higher, and this trend is expected to exacerbate the burden on healthcare systems globally, particularly as the global population ages. This issue is more evident in Korea, where the rapidly aging population has become a critical concern in recent years. RSV infection accounts for a substantial number of hospital admissions due to severe LRTI among both infants and the elderly. It is critical to collect data that highlight the burden of RSV in older adults to develop-targeted prevention programs. There is a pressing need for comprehensive studies to enhance understanding and effectively address the current burden of RSV in adults.