Respiratory syncytial virus infection and the need for immunization in Korea

ABSTRACT

Introduction

Respiratory syncytial virus (RSV) infection is one of the most common causes of acute respiratory tract infections in young children and the elderly. Infants and young children aged <2 years and the elderly are at particular risk of severe infections requiring hospitalization.

Areas covered

This narrative review summarizes the epidemiology of RSV infection in Korea, with a particular focus on infants and the elderly, where possible, and highlights the need for effective vaccinations against RSV. Relevant papers were identified from a search of PubMed up to December 2021.

Expert opinion

RSV infection is associated with a significant burden of illness in infants and the elderly worldwide and accounts for a substantial number of hospital admissions due to severe lower respiratory tract infections in both of these age groups in Korea. Vaccination has the potential to reduce the burden of acute RSV-associated disease and long-term consequences such as asthma. Increased understanding of the immune response to RSV, including mucosal immunity, and the innate and adaptive immune responses is needed. Technological advances in vaccine platforms could provide better approaches for achieving a safe and effective vaccine-induced immune response.

KEYWORDS:

• Immunization
• Korea
• respiratory syncytial virus
• vaccine

1. Introduction

Human respiratory syncytial virus (RSV) infection is one of the most common causes of acute respiratory tract infections (RTIs) in infants and young children [1]. RSV infection is the second leading cause of lower RTI (LRTI)-associated deaths globally, after Streptococcus pneumoniae infections [2]. RSV accounted for 76,612 deaths in 2016, of which 54% were in children aged <5 years [2]. Most deaths occur in resource-limited regions [3]. In 2015, it was estimated that RSV was associated with 28% of all acute LRTI episodes in children under 5 years of age and accounted for 13–22% of all acute LRTI-associated mortality [4].

It is also increasingly recognized as a pathogen in adults, especially the elderly [5–8], and it is associated with a substantial burden for healthcare systems [9,10].

Following a general introduction to RSV, this narrative review summarizes the epidemiology of RSV infection in Korea, with a particular focus on infants and the elderly where possible, and highlights the need for effective vaccinations against RSV.

Relevant papers were identified by searching the PubMed database up to December 2021. Search terms included ‘respiratory syncytial virus,’ ‘RSV,’ ‘epidemiology,’ ‘Korea,’ ‘immunization.’ Additional papers were identified from the bibliographies of papers found through the database search.

2. Respiratory syncytial virus infections: general overview

2.1. Respiratory syncytial virus

RSV is an enveloped non-segmented negative strand RNA virus from the Pneumoviridae family [11]. The viral envelope contains three membrane proteins, including the G glycoprotein, which is involved in attachment to the host cell; the F glycoprotein, which is involved in fusion with, and entry into, host cells; and the SH protein [12]. There is one RSV serotype, which is divided into two antigenic groups, A and B [12]. Within each group, antigenic and genetic variants have been identified [13–15].

RSV spreads via respiratory secretions and is highly communicable, with an incubation period of 2–8 days. The two main routes of transmission are via aerosol particles and through touching infectious secretions on contaminated environmental surfaces [9,16]. The principal points of entry for the virus are the nose, upper airway and, to a lesser extent, the eyes; transmission requires close proximity to airborne droplets or direct contact with contaminated surfaces [9]. Estimates of the basic reproduction number (the average number of secondary infections generated by a single primary case) for RSV vary from approximately 1 to >10 [17,18]. In temperate climates, RSV infections generally follow a seasonal pattern, with most cases developing between late autumn and late spring, peaking in mid-winter [9,12]. In tropical and subtropical regions, cases tend to peak in the wet season [19]. However, there can be variations within regions [9]. RSV is a common pathogen in young children, with almost all having been infected at least once within the first 2 years of life [20]. Immunity after infection is short-lived and reinfection is common throughout life [20,21]. Reinfection may occur as early as a few weeks after recovery, but usually occurs during subsequent annual outbreaks. Antigenic variation is not required for reinfection. The immune response of infants is poor in quality, magnitude, and durability. The severity of illness during reinfection in childhood is lower than that in the first infection. The infection rate amongst adults is not clear as it is generally underdiagnosed in this age group, but a recent meta-analysis found that RSV accounted for 1–10% of acute RTIs in adults [22].

2.2. Clinical features

In adults and most children, RSV typically causes a mild, self-limiting upper respiratory tract infection (URTI), with symptoms such as rhinorrhea, sneezing, nasal congestion, cough, and sometimes fever [23]. However, in infants and young children aged <2 years who experience primary infections it commonly causes an LRTI in the form of bronchiolitis or pneumonia [24]. Affected children develop dyspnea, tachypnea, cough, and wheezing, with increased respiratory effort [24]. In severe cases, apnea and respiratory failure may develop. Some adults, particularly the elderly and those with comorbidities, can also develop severe LRTIs associated with RSV [23].

Most patients with an RSV infection make a good recovery. Individuals who are at greatest risk of severe illness and death include premature infants, the elderly, and those with preexisting cardiac, lung, and immunosuppressive disorders [25–31]. Deaths due to RSV are uncommon in industrialized countries (generally <0.5%), where they tend to occur in patients with comorbidities [32,33]. Deaths are more common in low-resource settings [3]. RSV infection at a very young age may increase the risk of wheezing and asthma later in life [34, 35]. The prevalence of asthma/recurrent wheezing at age 18 years was 39% in a cohort who had had RSV bronchiolitis in the first year of life compared with 9% in a control group [35]. Neurological complications develop in approximately 2% of children after RSV infection [36], and can include seizures, encephalopathy, strabismus, and cognitive impairment [36–40].

2.3. Risk factors

The most important risk factor for RSV infection is age, and infants (aged <1 year) and the elderly are at greatest risk of severe illness [41]. In the pediatric population, risk factors for severe RSV infection requiring hospitalization include young age (<6 months), male sex, prematurity, low birthweight, birth during the first half of the RSV season, having older siblings, overcrowding/daycare, and exposure to tobacco smoke [1,32,42]. Children with hemodynamically significant congenital heart disease (HS-CHD) are also at risk for severe RSV disease [43].

In adults, low levels of serum and nasal RSV-specific antibody are independent risk factors for RSV infection [44]. Among adults with chronic obstructive pulmonary disease, risk factors for symptomatic RSV illness include concurrent congestive heart failure and exposure to children [29]. Among adults hospitalized with RSV infection, advanced age (>75 years) and the presence of comorbidities were independently associated with longer hospitalization [28]. Independent predictors of life-threatening illness among adults with RSV infection (defined as admission to the intensive care unit [ICU], need for ventilator care, or in-hospital death) included the presence of chronic respiratory disease, LRTI, fever ≥38°C, and bacterial co-infection [30]. The factors that specifically make elderly people more susceptible than other adults to RSV are not clear [7,13]; however, immunosenescence may play a role [45].

2.4. Prophylaxis and treatment

No vaccines against RSV are currently available. Several vaccines are under development and further information is provided in Section 8. Passive immunization is possible using palivizumab, a humanized murine monoclonal antibody directed against the F membrane protein. When administered monthly throughout the RSV season it can reduce the risk of hospitalization and serious complications in high-risk children and has been shown to be safe [46]. The American Academy of Pediatrics (AAP) guidelines recommend it is used in infants in the first year of life who were born premature (≤29 weeks gestational age), or have chronic lung disease of prematurity, CHD, or neuromuscular disorders; it may also be considered for those aged <2 years who are immunocompromised [47]. The Korean National Health Insurance Service indicates that candidates for palivizumab include high-risk preterm infants (those born at <32 weeks of gestation and aged ≤6 months during the October–March RSV season or those born at <36 weeks of gestation during the RSV season who have older siblings), as well as patients with bronchopulmonary dysplasia or HS-CHD aged <2 years [48]. More recently, nirsevimab, a long-acting monoclonal antibody directed against the F protein, has been approved in some countries for the prevention of RSV LRTI in infants after it was shown to be efficacious at preventing medically attended RSV-associated LRTIs in healthy late-preterm and term infants [49].

Treatment for RSV infection is generally supportive and may involve antipyretics and hydration. Patients with severe illness may require hospitalization and respiratory support. The antiviral drug ribavirin is licensed for the treatment of RSV in some countries, but there are concerns over its efficacy and safety in this population, and it is generally only considered for certain immunocompromised patients such as hematological patients [13,23].

3. Epidemiology of RSV among all ages in Korea

In Korea, RSV is a national notifiable infectious disease that is classified by the Korea Centers for Disease Control and Prevention as Category 4, along with other viruses causing acute respiratory infection, such as adenovirus, human bocavirus, human metapneumoviruses, parainfluenza viruses, human coronaviruses, human rhinoviruses, and influenza viruses [50]. These respiratory infections are monitored by a passive surveillance network in designated sentinel medical institutions such as Severe Acute Respiratory Infection (SARI) and Korea Influenza and Respiratory Viruses Surveillance System (KINRESS); however, no RSV-specific nationwide active surveillance is available.

A meta-analysis of 20 Korean studies published from 2000 to 2017 found that among respiratory samples collected from patients of any age with acute RTI, LRTI or influenza-like illness, 18.05% (95% confidence interval [CI] 13.84–22.67%) were positive for RSV [19]. By comparison, the overall positivity for the entire Western Pacific Region was 16.73% [19].

A nationwide surveillance study of patients of any age with acute RTIs from 2013 to 2015 in Korea found that 3.6% of nasopharyngeal samples were positive for RSV [51]. Smaller studies involving patients of any age have reported higher rates of RSV detection [52,53]. For example, in a regional study covering 2006–2010, RSV was detected in 31.7% of patients with acute RTIs [52]. A study of patients with URTI or LRTI in 2004–2006 reported an RSV detection rate of 37.2% [54]. Among inpatients with respiratory symptoms at a university hospital in 2012–2018, the RSV detection rate was 12.8% [55]. A study of hospital-acquired viral respiratory infections in 2012–2015 found that RSV accounted for 12.7% of identified viruses [56].

The study that evaluated samples from inpatients of any age with respiratory symptoms in 2012–2018 found that RSV-A (7.1%) was detected more often than RSV-B (5.8%) [55]. Both RSV groups were present every year, but they tended to dominate in alternate years. The overall rate of RSV detection was highest in December (36.5%) and lowest in June (0.2%), and this pattern was generally consistent for both groups.

Genetic sequencing of G genes of RSV-positive samples obtained over a 6-year period from 2009 to 2014 found that among 131 RSV-A samples from patients of any age, the most common genotype overall was NA1 (46.8%), followed by ON1 (43.3%), GA5 (2.1%) and GA1 (0.7%) [57]. Prior to 2010, the NA1 genotype was predominant. The ON1 genotype was first detected in December 2011, after which a shift from the NA1 genotype to the ON1 genotype was seen, such that from the 2013–2014 season, NA1 was no longer observed. Among 31 RSV-B samples, the most common genotypes were BA9 (87.9%) and BA10 (6.1%).

4. Epidemiology of RSV in infants and children in Korea

4.1. Prevalence and detection rate

Much of the pediatric data on RSV infection in Korea comes from studies on RTIs requiring hospitalization. RSV was one of the most common viral etiological agents identified among children with severe RTI in Korea (Table 1) [58–70]. In the first study reported for Korea, which involved 712 children with acute LRTI, 85% of whom were aged <2 years, RSV was the most common virus isolated (27.2%) [58]. Most cases of pneumonia (53.7%) and bronchiolitis (74.6%) in this study were caused by RSV.

Table 1. Prevalence and detection rate of respiratory syncytial virus among children hospitalized with acute respiratory tract infections in Korea.

Study	Period	Age	Reason for hospitalization	Diagnostic test method	Total N/Confirmed viral etiology N	Prevalence of RSV in patients with acute RTI (%)	RSV detection rate in patients with positive viral samples (%)	Other results
Yun et al. 1995 [58]	Nov 1990–Apr 1994	2 weeks-14.4 years (median 9 months)	Acute LRTI	VC, IF	712/369	27.2	59.3	85% of RSV patients were <2 years
Ahn et al. 1999 [59]	Mar 1996–Feb 1998	≤15 years	Acute LRTI	IF	1070/237	–	21.5	RSV predominantly isolated in infants aged ≤1 year; no cases seen in children aged >5 years
Kim et al. 2000 [60]	Jan 1994 – Aug 1998	1 month – 10.75 years (RSV: mean 11.4 ± 4.6 months)	Acute RTI	IF	1389/360	–	41.8^a	69.9% of RSV cases were aged <1 year
Choi et al. 2006 [61]	Sep 2000–Aug 2005	≤5 years	Acute LRTI	RT-PCR	515/312	23.7	39.1^b	RSV accounted for 77% of LRTIs in infants aged ≤3 months
Chung et al. 2007 [71]	Feb–Nov 2006	≤5 years	Acute wheezing	IF	231/142	13.8	22.5^b	Among RSV cases, 71.9% were aged <1 year, 28.1% were aged 1 to <3 years and none were ≥3 years
Kim et al. 2008 [62]	Mar 2004–Dec 2005	<15 years	LRTI	VC, RAD	400/na	–	48	RSV most common at age <2 years (almost twice as common vs children aged 2 years)
Chun et al. 2009 [63]	Nov 2007–Apr 2008	<5 years (RSV: median 13 months, range 2–66)	Acute LRTI	RT-PCR, VC	296/147	29.4^b	52.7
Kim et al. 2010 [72]	Dec 2003–Apr 2008	1–150 months (RSV: mean 15 ± 27 months)	Acute RTI-wheezing illness	IF	1008/na	26.0	–	82.2% of RSV-positive patients were diagnosed with wheezing illness. RSV more common than HMPV at age <12 years (p < 0.05)
Baek et al. 2012 [64]	Oct 2008–Feb 2010	90 days–6 years	Respiratory illness	RT-PCR	965/na	30.8	–	60% of RSV cases were aged <2 years. Among RSV-positive samples, 67% were RSV-A, 33% were RSV-B
Seo et al. 2014 [65]	Jan 2005–Dec 2008	<19 years	Acute RTI	VC, IF	21,641^c/5257^c	7.3	30.0^b
Cho et al. 2013 [66]	Jan 2009–May 2010	<1 month	Acute LRTI	RT-PCR	140/108	–	42.6	Detection rate for RSV-A 26.9%, RSV-B 15.7%
Kwon et al. 2014 [67]	May 2010–Apr 2011	Median 26 months (IQR 16–39)	Acute LRTI	RT-PCR	309/309^d	–	34.9	Mean age of RSV cases was 23 ± 20 months. RSV was present in 57.6% of bronchiolitis cases
Seo et al. 2014 [68]	Jul 2009–Apr 2012	<15 years	Acute febrile respiratory illness	RT-PCR	3865^c/2800^c	–	RSV-A 17.4% RSV-B 11.7%
Lee et al. 2015 [73]	Apr 2009–Mar 2010	Preterm infants (GA 22–32 weeks) discharged from neonatal ICU	Readmission for respiratory problems	Not specified	431/na	16.2	30.3^a	Among infants who attended the emergency room with respiratory problems, 9.8% were diagnosed with RSV infection, and RSV accounted for 32.4% of laboratory-detected viruses
Choi et al. 2018 [69]	Jan 2013–Dec 2015	<15 years	Acute RTI	RT-PCR	2424/2424^d	–	RSV-A 17.0^e RSV-B 12.1^e	RSV was the most common pathogen in infants <1 year old
Lee et al. 2020 [70]	Jan 2010–Dec 2015	<18 years	CAP	RT-PCR	30,994/30,994 ^f	20.3	–	RSV was detected in 34.0% of children aged <2 years (most common pathogen in this age group). 2.6% of RSV pneumonia cases required ICU admission

a Detection rate amongst total number of viral isolates identified.

b Estimated based on data in the associated publication.

c Number of respiratory samples (patients may have had more than one sample collected).

d Only patients with a confirmed virologic cause were included in the analysis.

e Among single-virus cases.

f Patients with a confirmed virologic/bacteriologic cause were included in the analysis.

CAP = community-acquired pneumonia; GA = gestational age; HMPV = human metapneumovirus; ICU = intensive care unit; IQR = interquartile range; IF = immunofluorescent staining; LRTI = lower respiratory tract infection; N = number; na = not available; RAD = rapid antigen detection; RSV = respiratory syncytial virus; RTI = respiratory tract infection; RT-PCR = reverse transcription-polymerase chain reaction; VC, viral culture; wks = weeks

The results of subsequent studies were consistent. Overall, among children hospitalized with an acute RTI (generally LRTI), RSV was identified in 7.3–30.8% of patients (Table 1). Among samples obtained from children in whom a viral cause for the LRTI was confirmed, RSV accounted for 21.5–59.3% of the pathogens identified. RSV was detected in 13.8% of children aged ≤5 years admitted with acute wheezing [71] and in 26.0% of children aged 1 month to 12.5 years admitted with an acute RTI-associated wheezing illness [72] (Table 1). RSV was the most common viral cause of pediatric community-acquired pneumonia (CAP) requiring hospitalization and was the second commonest pathogen overall, after Mycoplasma pneumoniae [70].

RSV infection necessitating hospitalization was particularly common in children under the age of 2 years, and several studies found that around 70% of hospitalized RSV cases were aged <1 year (Table 1). RSV was a common cause of bronchiolitis in young children in Korea; among hospitalized children who tested positive for RSV, 24.0–79.5% had bronchiolitis, with the highest rates seen in those aged <2 years [58–61,63,64,67,72]. Another study found that RSV was the most common cause of CAP in children aged <2 years (34%) [70].

Among previously healthy neonates, RSV was the most common viral cause of acute LRTI leading to neonatal ICU admission (13.8%), and it was associated with more severe illness than other viral infections [66]. Among preterm infants (born at gestational age 22–32 weeks) who were later readmitted to hospital for any reason, 3% were diagnosed with RSV infection; among the subset of patients admitted with respiratory problems, 16.2% had RSV detected [73].

Other studies have focused specifically on patients with RSV infection. An analysis of 92 RSV-related admissions to pediatric ICUs in the period 2008–2013 found that the median age at admission was 6.6 months (range 0.5–210.4 months); 75% were aged <2 years and 48.9% were aged <6 months [74]. Overall, 89.1% had an LRTI and 10.9% had an URTI. Among 62 children who were aged <2 years at the start of the RSV season, 53.2% were high-risk for severe RSV infection, most commonly because of CHD (22.6%), chronic lung disease (11.3%), congenital abnormality of the airway/neuromuscular disease (11.3%) or prematurity (8.1%).

Several studies focused on subgroups of children at high risk of severe RSV, including those born prematurely or with CHD. A single-center study found that among preterm infants (born at gestational age <35 weeks) without chronic lung disease who did not receive palivizumab prophylaxis, 4.5% were hospitalized due to suspected RSV infection during the first year after their initial discharge from the neonatal ICU [75]. However, not all patients had RSV laboratory testing performed, and it was estimated that the hospitalization rate for RSV illness could range from 4.3% to 8.8%, depending on whether all or none of the untested patients were RSV-positive. In a nationwide study conducted in 2012–2013, after palivizumab became widely available, 8.4% of preterm infants (born at gestational age <34 weeks) were readmitted to hospital with an RSV infection within 1 year of discharge from the neonatal ICU [76]. Palivizumab prophylaxis reduced the risk of RSV-associated readmission (3.3% versus 41.1%; odds ratio 0.06, 95% CI 0.03–0.13). In studies involving preterm infants with bronchopulmonary dysplasia, reported rates of hospitalization due to RSV infection were 5.2% and 22.6% in the absence of palivizumab prophylaxis compared with 0.7% and 4.0%, respectively, among those who received prophylaxis [77,78]. Another study reported an RSV hospitalization rate of 8.9% in infants with a history of very low birthweight and bronchopulmonary dysplasia who received prophylaxis and were aged <2 years at the start of the RSV season [79].

Another study found that, prior to the palivizumab era, 48.9% of CHD patients hospitalized with LRTI due to RSV required ICU care compared with 9.7% of non-CHD patients [80]. A more recent study found that even after palivizumab prophylaxis, 12.2% of patients with CHD were hospitalized with RSV-associated bronchiolitis, and 24.6% of the hospitalized patients required ICU admission [81].

Finally, as would be expected, RSV infections in children generally peaked during autumn/winter in Korea [59,62–65,68–70,72].

4.2. Outbreaks

Several reports of RSV outbreaks in postpartum/neonatal care centers in Korea have been published. A large outbreak occurred in a postpartum center, where 35 of 59 neonates (58.3%) developed respiratory symptoms; 12 of 15 cases submitted to laboratory testing were confirmed as having RSV-B infection [82]. Eight parents and two staff were also found to be RSV-B–positive. All of the neonates in the postpartum center were healthy at birth and there were no differences between RSV cases and non-cases with respect to gender, gestational age, or birthweight. The only independent risk factor for RSV infection was longer length of stay in the unit (≥1 week) (relative risk 8.10, 95% CI 1.84–35.62). Another report described four cases of RSV infection that occurred in neonates in a 6-bed special-care newborn nursery facility, two of which were probably acquired nosocomially, presumably via nursery staff [83].

A study of 108 neonates hospitalized with acute viral LRTI found that those with RSV infection were more likely to have contracted it from a neonatal daycare center compared with infants with other viral infections (odds ratio 16.5, 95% CI 2.06–132.6) [66]. No other differences were found with respect to patient demographics, such as gestational age or birthweight. A study of 156 neonates admitted to a neonatal ICU due to respiratory symptoms, most of whom were born at full-term, also found that patients in the RSV group were more likely to have contracted the infection in a postnatal care center compared with infants with other viruses (46.6% versus 24%, p = 0.0243) [84].

Overall, these data suggest that low-risk neonates can be exposed to RSV infection in settings such as postpartum care centers.

4.3. RSV group and genotype analyses

A study covering the period 2008–2010 found that among RSV-positive samples obtained from children hospitalized with respiratory illness, 67% were in the RSV-A group and 33% were RSV-B [64]. Other studies have also found that the RSV-A group was more common than RSV-B [66,69]. One reported a detection rate of 26.9% for RSV-A and 15.7% for RSV-B [66]; the other reported detection rates of 17.0% for RSV-A and 12.1% for RSV-B among single-virus cases [69].

In studies conducted during 9 consecutive epidemics from November 1990 through to February 1999, strains with distinct genotypes of G or F genes circulated simultaneously, and there was a gradual shift in the dominant genotypes over time, especially in the RSV-A group [15,85]. A recent molecular epidemiology study evaluated genotype changes of the G gene over time in RSV isolates obtained from children over 28 consecutive seasons (1990–2018) in Korea [86]. In most of the seasons both RSV-A and RSV-B circulated, but in some seasons isolates belonging to only one group were identified. RSV-A was isolated more often than RSV-B except for seven (25%) seasons and RSV-A was dominant in three times as many seasons as RSV-B. In seasons when RSV-A was predominant, a median 89.8% (range 61.8–100%) isolates were RSV-A; in seasons when RSV-B was dominant, a median 66.7% (range 59.1–100%) of isolates were RSV-B. For the RSV-A group, genotypes GA2 and GA7 were predominant up to the 2003/2004 season, and the NA1 genotype was predominant from the 2004/2005 season to the 2011/2012 season. The ON1 genotype was first detected in November 2011 and from the 2013/2014 season onwards replaced all other RSV-A genotypes. For the RSV-B group, genotypes GB2, GB4 and SAB2 were identified from the 1990/1991 season to the 1998/1999 season, and GB3 was most common from the 1999/2000 season to the 2005/2006 season (44.2%). BA genotypes appeared in the 2005/2006 season (the first was BA9, isolated in November 2005), and from then onwards replaced all other genotypes, with BA9 found in particularly high numbers during the seasons 2015/2016 to 2017/2018. It was found that the duplication region of the G gene of ON1 and BA genotypes evolved each season.

5. Epidemiology of RSV in adults in Korea

5.1. Prevalence and detection rate

As would be expected, RSV infection is less common among adults than children in Korea. However, it is still an important pathogen, particularly in the elderly and those with underlying comorbidities. Most studies in Korea have included adults of all ages, although the mean/median age was generally around 65 years.

RSV infection was found in 1.1% of adults hospitalized with acute RTIs [65] and 2.3% of adults hospitalized with suspected viral respiratory infections (mean age of population 70 years) [87] (Table 2). RSV accounted for 2.8% of viruses detected in adults who visited an emergency department with an influenza-like illness (median age 43 years) [88], and was detected in 7–9% of virus-positive samples obtained from patients hospitalized with acute RTIs [65,68].

Table 2. Prevalence and detection rate of respiratory syncytial virus among adults hospitalized with acute respiratory tract infections in Korea.

Study	Period	Age	Reason for hospitalization	Diagnostic test method	Total N/Confirmed viral etiology N	Prevalence of RSV in patients with acute RTI (%)	RSV detection rate in patients with positive viral samples (%)	Other results
Seo et al. 2014 [65]	Jan 2005–Dec 2008	≥19 years	Acute RTI	VC, IF	2165^a/255^a	1.1	9.0^b
Seo et al. 2014 [68]	Jul 2009–Apr 2012	>19 years (53.9% ≥65 years)	Acute febrile respiratory illness	RT-PCR	763^a/205^a	–	RSV-A ~ 4^b RSV-B ~ 3^b
Kwon et al. 2017 [67]	Jan 2013–Dec 2015	≥18 years (mean 70 ± 12 years)	Suspected respiratory viral infection	RT-PCR	3743/–	2.3	–	20-day mortality in RSV patients 18.4% (adjusted hazard ratio vs influenza 2.32, 95% CI 1.17–4.58)
Noh et al. 2013 [88]	Sep 2011–Jun 2012	≥18 years (median 43 years, IQR 31–63; 23.2% ≥65 years)	Influenza-like illness^c	RT-PCR	1983/1100^d	–	2.8^d
Choi et al. 2012 [89]	Mar 2010–Feb 2011	≥18 years (mean 65.4 years, range 17–96)	Severe CAP^e or severe HCAP^e	RT-PCR	198/72	5.1 RSV-A 2.0 RSV-B 3.0	13.9	RSV more common in CAP than HCAP (10.9% vs 2.2% patients, p = 0.01). RSV-associated mortality 20.0%
Hong et al. 2014 [90]	Mar 2010–Feb 2012	Mean age 64.5 ± 13.5 years	Severe HAP^e	RT-PCR	262/59	6.1 RSV-A 4.2 RSV-B 1.9	27.1 RSV-A 18.6 RSV-B 8.5	Median 20 days’ hospitalization prior to pneumonia diagnosis. RSV-associated mortality 37.5%
Kim et al. 2018 [91]	Jan 2008–Dec 2015	Median 64 years (IQR 56–73)	Severe CAP^e, severe HCAP^e or severe HAP^e	RT-PCR	515/69	RSV-A 4.1 RSV-B 1.8	–

a Number of respiratory samples (patients may have had more than one sample collected).

b Estimated from data/graph in the associated publication.

c Requiring emergency room visit.

d Total number of detected viruses (1100). RSV detection rate among total number of viral isolates detected is reported.

e Requiring ICU admission.

CAP = community-acquired pneumonia; CI = confidence interval; HAP = hospital-associated pneumonia; HCAP = healthcare-associated pneumonia; ICU = intensive care unit; IF = immunofluorescent staining; IQR = interquartile range;; N = number; RSV = respiratory syncytial virus; RT-PCR = reverse transcription-polymerase chain reaction; RTI = respiratory tract infection; VC = viral culture.

Among adults (mean/median age approximately 65 years) with severe pneumonia who were admitted to ICUs, RSV was identified in 5.1–6.1% of patients (Table 2) [89–91]. RSV was detected in 13.9–27.1% of virus-positive samples obtained in these studies. One of these studies found that RSV was more common in patients with CAP than in those with healthcare-associated pneumonia (HCAP) (10.9% versus 2.2%, p = 0.01) [89].

Among Korean adult asthmatics (mean age 56 years) with LRTIs who had sputum samples that were positive for respiratory viruses, RSV was found in 11.8% of samples from patients with an LRTI plus an exacerbation and 25.0% of samples from patients with an LRTI but no exacerbation (p = 0.22) [92].

Other Korean studies have focused specifically on adults with RSV infection. A study that evaluated 204 adults hospitalized with RSV infection in 2012–2015 compared three age groups (19–49, 50–64 and ≥65 years) [93]. Almost two-thirds of patients with RSV were aged ≥65 years (64.7%). In all age groups, most patients had underlying diseases (85% overall). Overall, 57.8% of patients had pneumonia and 10.8% died in hospital, with no significant differences between the age groups. The rate of ICU admission was higher in the older-age group than in the middle-age or young adult groups (25.0% versus 11.5% versus 10.0%), as was the need for mechanical ventilation (11.4% versus 5.8% versus 0%), but the differences did not achieve statistical significance. Solid cancers and hematologic malignancy were identified as risk factors for RSV-associated pneumonia.

A comparison of adults hospitalized with RSV infection (n = 87) or influenza (n = 312) found that RSV patients were older (70 versus 62 years, p < 0.01), were more likely to be residents of long-term care facilities (10.3 versus 1.9%, p < 0.01) and were more likely to have chronic obstructive pulmonary disease (12.6 versus 4.8%, p < 0.01) than those with influenza [87]. RSV patients were also more likely to have pneumonia, respiratory bacterial superinfection, and hypoxemia. RSV infection was associated with a significantly higher risk of 20-day mortality compared with influenza (18.4% versus 6.7%; hazard ratio 2.32, 95% CI 1.17–4.58).

Risk factors for life-threatening RSV infections in adults were identified in a study of 227 patients with RSV who visited an emergency room in 2013–2015 [30]. The median age of participants was 65 years (range 19–99). Life-threatening RSV infection was seen in 34 (15%) patients and the overall in-hospital mortality rate was 7.9%. Independent predictors of life-threatening RSV infection were the presence of LRTI, chronic respiratory disease, bacterial coinfection, and fever ≥38°C.

One of the studies in adults hospitalized with acute RTIs (53.9% of whom were aged ≥65 years) noted that comorbidities were common in patients with RSV infection (75–80%), that patients with RSV-A tended to be older than those with RSV-B, and that compared with other viral infections, patients with RSV-A had longer hospital stays (mean 16.1 days), more often required ICU admission (20.0%) and had a high mortality rate (20.0%) [68].

Co-infection with other organisms in addition to RSV was more common in adults than in children (e.g. 44.4% versus 3.0% for RSV-A coinfection) [68]. In that study, co-infecting organisms included viruses (e.g. coronavirus, influenza A, rhinovirus) and bacteria (Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus). A study involving inpatients of any age with respiratory symptoms found that RSV co-infection rates with other viruses (e.g. rhinovirus) were highest in patients aged >80 years [55]. The clinical implications of co-infection in patients with RSV vary, but it may lead to longer hospitalization, and bacterial co-infection has been associated with an increased risk of life-threatening infections [30,68].

Finally, the pattern of seasonality for RSV infection in adults was similar to that seen in children, with RSV infections peaking during autumn/winter [30,65,68,69,88,92,93].

5.2. Outbreaks

No specific reports describing RSV-associated outbreaks among elderly adults in Korea have been published. However, one study reported that patients hospitalized with RSV infection were more likely than patients with influenza to be residents of long-term care facilities (10.3 versus 1.9%, p < 0.01) [87]. Evaluation of an outbreak of acute febrile illness among healthy young men at a military training camp in 2011, in which 588 of 3750 recruits (15.7%) were affected, identified the causative agent as RSV (based on reverse transcription-polymerase chain reaction testing of 5 subjects). Most patients had upper respiratory tract symptoms, but 4 developed pneumonia [94].

5.3. Seroprevalence data in adults

Most adults will have experienced RSV infection in childhood. Adequate levels of neutralizing antibody must be maintained in order to prevent further RSV infections, and so it is important to have information on RSV seroprevalence in adults. A study evaluating healthy young men in their early twenties confirmed that almost all had encountered RSV before reaching adulthood [95]. This study enrolled new recruits (mean age 20.25 years, range 18.5–28.0) entering Korea Air Force basic training in 2012, and found that 98.4% were RSV immunoglobulin G seropositive, 0.4% were negative and 1.2% were equivocal when tested with a commercial RSV diagnostic reagent.

5.4. RSV group and genotype analyses

RSV-A is more common than RSV-B in Korean adults. Among Korean adults hospitalized with RSV infection, RSV-A was more common than RSV-B in all age groups including 19–49 years (65.0% versus 35.0%), 50–64 years (69.2% versus 21.2%) and ≥65 years (68.9% versus 22.0%) [93].

Based on analyses of virus-positive samples, RSV-A and RSV-B detection rates were 2.4% and 0.4% in adults who visited emergency rooms with influenza-like illnesses [88], ~4% and ~3% in adults hospitalized with acute febrile respiratory illness [68], and 18.6% and 8.5% in patients with severe hospital-associated pneumonia (HAP) [90].

Few genotype data are available for Korean adults. A study that sequenced the G gene in RSV samples obtained from 2009 to 2014 from 183 patients of all ages, including 3 adults aged ≥20 years, found that 1 of these adults had RSV-A genotype ON1 and 2 had RSV-B genotype BA9 [57].

6. Medical need for RSV vaccines in Korea

6.1. Unmet medical needs

As a leading cause of severe LRTI in infants and the elderly, RSV infection is associated with substantial morbidity and mortality. Improved measures to prevent RSV infection and reduce the severity of illness are needed in Korea and worldwide.

Prophylaxis with the monoclonal antibody palivizumab in high-risk infants can reduce RSV-associated hospitalizations; this has been demonstrated in several studies involving preterm infants in Korea [76–78]. However, one study found that despite administration of palivizumab, RSV infection was still associated with significant morbidity/mortality in another high-risk group – children with CHD [81].

In the future, RSV vaccination could be an effective and economic method of providing immunity against RSV, with the principal goal being to reduce disease severity [96,97]. Considering the risk population of the disease, the target vaccination population for preventing RSV infections in children can be split into the primary population (neonates and young infants <6 months) and the alternative target population. The main goal is to prevent severe RSV disease in young infants and to provide protection against reinfection. However, immunizing neonates is difficult. Therefore, alternative approaches may need to be considered. These include immunizing pregnant women, or the parents, grandparents and siblings of young infants. As described, the disease burden in the elderly is also significant and the vaccination strategy for the elderly population should be considered based on the existing immunity in this age group and the potential risk and benefit profile of mass vaccination. The potential role of vaccination is discussed further in Section 7.

6.2. Economic burden

Only a few studies have reported on the use of medical resources and the costs associated with RSV infection in Korea.

A study involving neonates admitted to the neonatal ICU with LRTI found that those with RSV had a longer hospital stay than infants with LRTI due to other viruses (9.41 versus 7.34 days, p = 0.011) [66]. Evaluation of RSV-related admissions to the pediatric ICU in 2008–2013 found that for children aged <2 years (n = 28) the median cost of healthcare was US$2,284 (range 705–98,243) for high-risk patients and US$1,899 (range 556–30,449) for those not considered high-risk [74]. Median costs for the subgroup who required mechanical ventilation were US$15,346 (range 2,576–91,546) for high-risk infants and US$4,634 (range 2,312–30,449) for low-risk patients.

Among adults hospitalized with acute viral respiratory infections, patients with RSV-A tended to have a longer length of hospital stay than patients with other viral infections (mean 16.1 versus 6.9–8.9 days) and were more likely to require admission to the ICU (20.0% versus 0–12.7%) [68]. A study involving Korean adults hospitalized with RSV pneumonia in 2012–2015 found that 22% of patients needed ICU care and the median medical cost per RSV pneumonia admission was US$2,855 [93]. Patients aged >65 years were more likely to need ICU care than younger adults (26.7% versus 8.3–16.1%) and had higher median medical costs per admission (US$2,933 vs US$1,957–2,116), although the differences were not statistically significant. Additional data on the economic burden of RSV infection in Korea are needed.

Prevention of RSV infection is likely to reduce use of resources, including medical resources (related to hospital or outpatient treatment) and the parental/family burden (such as the cost of medical payments and loss of work hours). Of relevance, studies in infants who were born preterm, had very low birthweight, or had bronchopulmonary dysplasia, showed that palivizumab prophylaxis reduced the rate of hospitalization due to RSV [76–78].

Data pertinent to the burden of disease associated with RSV in Korea are summarized in Table 3.

Table 3. Data relevant to quantifying burden of disease associated with RSV in Korea.

Outcome	Available data
PEDIATRIC POPULATION
Incidence/Prevalence
RSV rate among children hospitalized with acute RTI	- 7.3–30.8% [58–70]
Proportion of neonatal ICU admissions due to viral LRTI caused by RSV among previously healthy neonates	- 13.8% [66]
RSV-associated hospitalization by age	- Most common in children aged <2 years; around 70% of hospitalized RSV cases aged <1 year [58–62,64,69,70]
RSV-related admissions to pediatric ICU by age	- 75% aged <2 years and 48.9% aged <6 months [74]
Risk factors
Prematurity	- Among preterm infants (born gestational age 22–32 weeks) later readmitted to hospital for any reason, 3% had RSV infection (16.2% among those who had respiratory problems) [73] - 4.5% of preterm infants (born gestational age <35 weeks; no chronic lung disease; no palivizumab prophylaxis) readmitted to hospital with suspected RSV infection during the first year after initial discharge from neonatal ICU [75] - 8.4% of preterm infants (born gestational age <34 weeks) readmitted to hospital with an RSV infection within 1 year of discharge from neonatal ICU (3.3% after palivizumab prophylaxis; 41.4% no prophylaxis) [76]
Bronchopulmonary dysplasia	- RSV hospitalization rate 5.2% [77] or 22.6% [78] with no palivizumab prophylaxis and 0.7% or 4.0%, respectively, with prophylaxis - RSV hospitalization rate 8.9% among infants with history of very low birthweight and BPD (and aged <2 years at start of RSV season) who received prophylaxis [79]
Congenital heart disease	- Prior to the palivizumab era, 48.9% of CHD patients hospitalized with RSV-LRTI required ICU care versus 9.7% of non-CHD patients [80] - After palivizumab prophylaxis, 12.2% of CHD patients were hospitalized with RSV-associated bronchiolitis, and 24.6% of the hospitalized patients required ICU admission [81]
Medical resources/Costs
Length of hospital stay	- Among neonates admitted to neonatal ICU with LRTI, RSV was associated with longer hospital stay versus other viral causes (9.41 versus 7.34 days, p = 0.011) [66]
Healthcare cost	- For children aged <2 years admitted to the pediatric ICU with RSV infection, median cost US$1,899 (range 556–30,449) for those not considered high-risk and US$2,284 (range 705–98,243) for high-risk patients [including median US$1,866 for those with chronic lung disease, US$3,730 for those with congenital heart disease and US$9,929 for those with neuromuscular disorder/congenital abnormality of airway]) (years 2008–2013) [74]
ADULT POPULATION
Incidence/Prevalence
RSV rate among adults hospitalized with acute RTIs	- 1.1% (mean/median age of study population not reported) [65]
RSV rate among adults hospitalized with suspected viral RTIs	- 2.3% (mean age of study population 70 years) [87]
RSV rate among adults attending emergency room with influenza-like illness	- RSV accounted for 2.8% of viruses detected (median age of study population 43 years) [88]
RSV rate among adults with severe pneumonia admitted to ICU	- 5.1–6.9% (mean/median age of study population 65 years) [89–91]
RSV-associated hospitalization by age	- 64.7% were aged ≥65 years; ICU admission rate higher for age ≥65 years (25%) versus 50–64 years (11.5%) or 19–49 years (10.0%); need for mechanical ventilation also higher (11.4% versus 5.8% versus 0%) (both p = NS) [93]
Mortality
Adults with RSV attending emergency room	- Median age 65 years (range 19–99); 15% had life-threatening infection; in-hospital mortality 7.9% [30]
Hospitalized adults with RSV infection	- In-hospital mortality 13.6% (adults with RSV pneumonia) [93] - 20-day mortality 18.4% (significantly higher than with influenza; hazard ratio 2.32, 95% CI 1.17–4.58) [87]
Risk factors
Older age	- Among adults hospitalized with RSV infection mean age was 70 years (significantly higher than for influenza patients) [87]
Comorbidities	- Among adults hospitalized with acute RSV infection, 75–80% had comorbidities [68] - Among adults hospitalized with RSV infection, 12.6% had chronic obstructive pulmonary disease (significantly higher than influenza patients) [87] - Among inpatients of any age with respiratory symptoms, the rate of co-infection with RSV plus other viruses was highest in those aged >80 years (80%) [55]
Medical resources/Costs
Length of hospital stay	- Mean 16.1 days among adults hospitalized with RSV-A–associated acute RTI (median age 71 years) [68] - Mean 19.4 days among adults hospitalized with RSV pneumonia; mean 20.4 days for those aged >65 years (versus 17–19 days for younger age groups) [93]
Rate of ICU admission among adults hospitalized with RSV pneumonia	- 20% among adults hospitalized with RSV-A–associated acute RTI [68] - 22% among all adults hospitalized with RSV pneumonia; 26.7% among those aged >65 years (versus 8.3–16.1% for younger age groups) [93]
Healthcare costs	- Median medical cost per adult RSV pneumonia hospital admission US$2,855; median US$2,933 for patients aged >65 years (versus US$1,957–2,116 for younger age groups) (years 2012–2015) [93]

BPD = bronchopulmonary dysplasia; CHD = congenital heart disease; CI = confidence interval; ICU = intensive care unit; LRTI = lower respiratory tract infection; NS = not significant; RSV = respiratory syncytial virus; RTI = respiratory tract infection.

7. Conclusion

RSV poses a significant health problem in Korea and other countries, particularly for young infants and the elderly. It places a substantial burden on healthcare resources and costs. Improved methods to prevent and treat RSV infection are needed.

8. Expert opinion

RSV infection is a worldwide health problem, associated with a significant burden of disease in infants and the elderly. In 2015, RSV was estimated to have caused 3 million hospitalizations and 59,600 deaths in children under 5 years of age [4]. Elderly patients with RSV infection are at risk of severe illness requiring hospitalization, and the burden of hospitalization due to RSV amongst the elderly is similar to that of seasonal influenza [28]. Resource utilization is greatest for elderly patients [41], and the burden on healthcare systems is likely to increase in the future because of the global aging population [98]. Indeed, the aging population in Korea has gained increased focus in recent years; due to the decreasing birth rate and increased life expectancy, Korea became an aged society in 2017, with elderly individuals comprising more than 14% of the total population [99].

Consistent with this global picture, RSV infection accounts for a substantial number of hospital admissions due to severe LRTI in both infants and the elderly in Korea. Additional data are needed in order to obtain a full picture of RSV infection in Korea. Further studies providing data that could be used to quantify the burden of disease associated with RSV in Korea would be useful. For example, data on the incidence of RSV for inpatients according to months post-delivery, RSV-specific pediatric mortality data, and RSV epidemiology data specifically for elderly patients would be of interest. In addition, information on patient-/caregiver-reported outcomes, such as quality of life, functional decline, and emotional distress caused by RSV infection, would be helpful to understand the true burden of the disease.

The development of effective and safe vaccines against RSV is considered a global health priority [97,100]. Vaccination has the potential to reduce both the burden of acute RSV-associated disease and also long-term consequences such as asthma [97,100]. Multiple challenges need to be overcome for the development of RSV vaccines, including issues around inefficient protective natural immunity and inadequate immune response in young infants, concerns about the potential for vaccine-enhanced respiratory disease when vaccinated RSV-naïve children subsequently become exposed to RSV, and the need to target populations of different ages (infants aged <4–6 months, children aged 6–24 months, and elderly people) [97].

Nonetheless, there are currently more than 40 vaccines in development, with 19 having entered clinical trials [97,100,101]. They include protein vaccines (particle-based or subunit vaccines) and live vaccines (vector-based or live-attenuated). The majority of protein vaccines target the prefusion conformation of the F membrane protein (pre-F), since antibodies that bind to pre-F are particularly efficient at neutralizing RSV, although some target the G or SH membrane proteins [97]. Live vaccines under development target pre-F, post-fusion F, or other viral antigens such as N, M2 and G proteins [97]. Among the most advanced vaccines, a recombinant adjuvanted pre-F nanoparticle maternal vaccine (ResVax) failed to meet the primary endpoint of a reduction in medically significant RSV LRTI during the first 90 days of life in infants in a phase 3 study, although it did reduce hospitalization and had a favorable safety profile [102]. An adjuvanted vaccine containing the F protein stabilized in its trimeric prefusion conformation (RSVPreF3), which is being developed as a vaccine for adults aged ≥60 years [103], has been submitted for regulatory review in the USA, Europe and Japan [104].

Monoclonal antibodies offer an alternative approach to provide protection. Following the introduction of palivizumab for use in high-risk infants and nirsevimab for use in healthy late-preterm and term infants, several other monoclonal antibodies are being evaluated in clinical trials involving premature and full-term infants [97].

Different approaches to vaccination may be required, depending on the age of the target population (and associated immune system status) and whether or not they have been exposed to RSV previously [100,101]. For infants, one approach might be to combine passive immunization (via maternal vaccination) followed by active immunization of the child [97]. In elderly patients, the challenge is to restore age-related losses in humoral and cellular immunity against RSV [98]. Therefore, studies clarifying the seroprevalence of RSV infection among adults, and especially the elderly, in Korea, would be helpful with respect to building a vaccination strategy targeting the elderly population in the country.

The high burden of RSV in infants, young children and the elderly needs to be addressed. It is expected that over the next 5 years understanding of the immune response to RSV, including mucosal immunity, and the innate and adaptive immune responses will increase. It is also anticipated that RSV vaccines will start to become available within this timeframe. Technological advances in the manufacture of vaccine platforms may provide better approaches for achieving a safe and effective vaccine-induced immune response. Finally, additional studies evaluating the impact of RSV in elderly patients can be expected.

Article highlights

• RSV is a common cause of acute respiratory tract infections (RTIs) in young children and the elderly.

• RSV can cause severe lower respiratory tract infections in infants and young children <2 years old and in elderly people.

• RSV is one of the most common viral etiological agents in children with severe RTI in Korea.

• Approximately two-thirds of Korean adults hospitalized with RSV were aged ≥65 years.

• Improved measures to prevent RSV infection and reduce the severity of illness are needed.

• Several RSV vaccines are in clinical development globally.

Declaration of interest

H Young Kim is employed by Pfizer Korea. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Under the direction of the authors, medical writing assistance was provided by Kathy Croom BM and David P. Figgitt PhD, ISMPP CMPP™, Content Ed Net, with funding from Pfizer Korea

Additional information

Funding

This manuscript was funded by Pfizer Korea.