Systematic literature review of the signs and symptoms of respiratory syncytial virus

Abstract Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year. Despite the risk RSV poses to young children, older adults, and individuals with comorbidities or suppressed immunity, there is limited understanding of RSV symptom presentation across these at‐risk groups, and there is no vaccine for RSV. We conducted two systematic literature reviews (SLRs) of studies that document signs and symptoms (S&S) of RSV in (1) children aged ≤5 years and (2) immunocompromised adolescents and adults, and adults at high risk for severe RSV due to age or comorbidities. Symptom duration and hospital length of stay (LOS) were explored. Electronic database searches were performed following PRISMA guidelines. Studies captured RSV S&S across community and hospital settings. Clinicians and caregivers reported (n = 25 studies) nasal discharge/congestion, cough, shortness of breath, feeding abnormalities, and fever in ≥40% of children across studies and settings. Median hospital stays for children ranged from 2 days in the United States to 7.5 days in China. High‐risk adults with RSV (n = 6 studies) commonly (≥40% of adults) reported cough, sputum, dyspnea, and fever/feverishness. Median length of hospital stay in adults ranged from 6 to 15 days across studies. Caregivers and clinicians reported similar RSV S&S in young children, including upper and lower respiratory and systemic symptoms. In high‐risk and immunocompromised adults, the most frequent (in multiple publications) and commonly reported RSV S&S were primarily LRTI symptoms. RSV symptoms could last for weeks and are variable based on geography.

Evidence suggests that RSV hospitalizations are on the rise among adults in the US, particularly those aged over 65 years. 5 Respiratory syncytial virus is known to exacerbate some serious health conditions, including asthma, chronic obstructive pulmonary disease (COPD), congestive heart failure, arrythmia, and myocardial infarction and is one of the most common causes of mortality among hematopoietic stem cell transplant recipients. 6,7 In children who contract RSV in their first 3 years of life, the risk of developing asthma is nearly three times greater than in children who do not. 8 All of these long-term effects related to RSV lead to significant socioeconomic burden and detriment to health-related quality of life. 9 Given the health risks and mortality associated with RSV, there has been decades-long demand for effective therapeutics to treat or prevent RSV infections and related illness. In 1998, the US Food and Drug Administration approved ribavirin, an antiviral agent, but ribavirin has minimal clinical benefit in RSV and is not routinely prescribed. 10,11 The monoclonal antibody palivizumab has been approved by the US Food and Drug Administration for prevention of severe RSV in certain high-risk pediatric patients, but none of the indications for this drug are for children over 2 years of age or for adults. 12,13 Most patients with active infections receive supportive care only. Currently, there is a great deal of ongoing research, including clinical trials, aimed at treating or preventing RSV. 13 While there are promising products in development, [14][15][16] there are currently no vaccines approved to reduce the risk of RSV, leaving only effective hygiene techniques as a prevention for most persons at this time.
Because of this lack of effective treatments and preventions, and the vulnerable populations RSV affects, a clear understanding of how RSV presents is important for identifying individuals most at risk for disease progression, identifying treatment targets, and evaluating treatment efficacy in each of these populations. To provide a comprehensive examination of the signs and symptoms (S&S) of RSV in the most at-risk populations, two systematic literature reviews (SLRs) of patientreported S&S were conducted, one in young children and one in highrisk adults (older adults or those with comorbidities) and immunocompromised adults and adolescents. Because young children are not able to report their symptoms, the literature review for this population focused on studies that included reports by clinicians and caregivers of children with RSV. This study can provide researchers and clinicians with the tools necessary to identify and adequately treat RSV infections based on the unique needs of each of these vulnerable populations.

| METHODS
We performed two separate systematic reviews of literature published in English-language journals indexed in the MEDLINE, Embase, Psy-chINFO, and Cochrane Library medical databases: One review of the literature from 22 June 2011 to 22 June 2021 on caregiver-or clinicianreported RSV S&S in children aged ≤5 years, and one review of the literature from 21 June 2011 to 21 June 2021 on self-reported RSV S&S in adults at high risk for RSV-related disease progression (i.e., adults aged ≥65 years; adults with congestive heart failure, COPD, or asthma) and adults or adolescents who are immunocompromised. Additional searches of conference abstracts indexed in Embase and bibliographies of SLRs identified in the literature were performed. Included studies were limited to qualitative, focus group, and real-world studies; clinical trials were included if they assessed patient-reported S&S and if they included caregiver-reported, questionnaire, measurement, or assessment terms in the title, abstract, or Medical Subject Headings (MeSH) or Emtree indexing. All sources were identified, screened, and included in this review on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 17

as shown in
Figures S1 and S2. Screening took place in two stages against the inclusion and exclusion criteria laid out in Table 1. Data on study design and characteristics, patient demographics and clinical characteristics, and outcomes of interest were then extracted from the relevant publications. Outcomes of interest included caregiver-and clinician-reported RSV S&S in young children and patient-reported RSV S&S in high-risk adults and immunocompromised adults and adolescents in both outpatient/community and hospitalized settings. Signs and symptoms were considered common if they were reported in 40% or more of the study population. Symptom duration and hospital length of stay (LOS) for the populations of interest were extracted from articles collected in our systemic review of S&S as an exploratory objective; the literature was not searched systematically for these outcomes.

| Eligible studies
We identified 651 unique publications on pediatric RSV infections through our literature search. After two levels of manual screening following the PRISMA guidelines and our inclusion and exclusion criteria (see Table 1), we found 33 publications eligible for inclusion in the pediatric review (Table S1). Eligible studies were identified across North America, western Europe, Asia, and the Middle East, as well as parts of Africa. Twenty-five studies reported on RSV S&S in the target pediatric population. In addition, 13 studies reported symptom duration, [18][19][20][21][22][23][24][25][26][27][28][29][30] including nine studies that also presented RSV S&S.

Population
• Studies that include • High-risk adults (i.e., ≥65 years of age,* or ≥18 years of age with congestive heart failure, COPD, or asthma) or • Immunocompromised adults or adolescents with RSV • Studies that combine these populations and other populations but report data separately for adults and immunocompromised adolescents with RSV • Studies that focus on another population that also includes the populations of interest with RSV but whose results are not separated by population • Studies that recruit or include only patients with a different disease or condition from that of RSV • Studies of only children aged < 13 years • Studies that include adult, adolescent, and pediatric patients but that do not report data separately for adults or adolescents

Interventions and comparators
None; not specific to a particular treatment None • Articles published prior to the past 10 years • Conference abstracts from older conferences (those held more than 3 years ago, i.e., before 2019) Abbreviations: COPD, chronic obstructive pulmonary disease; RSV, respiratory syncytial virus. a Reviews of qualitative research were included at level 1 screening, used for identification of primary studies, and then excluded at level 2 screening. b Upon review of the articles, studies with adults aged ≥60 years were included in the systematic literature review.
reported S&S in the intensive care unit (ICU). 24,51 The studies we identified varied considerably in the types of S&S evaluated, age group, treatment setting, and geographical location. Nasal discharge, nasal congestion, cough, shortness of breath, feeding abnormalities, and fever were the most commonly reported S&S by both clinicians and caregivers, occurring in at least 40% of children across multiple studies and treatment settings (Tables S1 to S3). 19 (Table S2). 20,21,39,41 All four studies were prospective and enrollment ranged from 361 to 923 children. One of these studies reported solely on wheezing. 20 In the other three studies evaluating a range of RSV symptoms ( Figure 1), cough was reported in all of the studies and in 94% to 99% of children. 21,39,41 Nasal congestion or discharge and fever were reported across all three of these studies as well. 21,39,41 Feeding abnormalities, reported as poor appetite, were reported by caregivers in two studies, occurring in 72% of children aged 6 to 35 months with signs of acute otitis media 41 and 45.5% of children aged ≤24 months. 21 Although only reported by caregivers in one study, shortness of breath was reported in infants more frequently in the emergency department (64%) than in outpatient clinics (43%). 39

| Caregiver-reported S&S in the hospital setting
Four publications representing three studies presented S&S reported by caregivers of children hospitalized with RSV ( Figure 1 and  Table S3 shows RSV S&S commonly reported by clinicians in the community or mixed settings. The RSV-positive (RSV+) populations in these studies ranged in size from 11 to 311. Figure 2 shows the most common S&S across age groups, which include nasal discharge/congestion, cough, fever, and feeding abnormalities. In infants, cough (96%) and wheezing (52%) were common in one study, 49 but cough was uncommon (3%-4%) in another study, 27 (Figure 2 and Table S4). 19,26,28,34,35,37,39,40,43,44,46,48 Studies in the ICU setting are summarized separately below. The most common S&S (≥40% of patients) reported by clinicians in the hospitalized pediatric population were cough, nasal discharge or congestion, dyspnea, and feeding abnormalities. 28,34,35,37,43,46,48 Fever was also a commonly identified symptom of RSV by clinicians in the hospitalized pediatric population, 34 reported, the median overall duration of any symptoms reported in studies in the community setting included in this SLR ranged from 4 to 12 days (Table S5).

| Eligible studies
Our search identified 234 unique studies of RSV infections in high-risk or immunocompromised adults. Through the PRISMA-guided screening process outlined in Figure S2, eight studies were included in this literature review (Table S1). 47 55 Both were retrospective cohort studies that reviewed electronic and paper medical records to obtain the data for the study. The following symptoms were reported in both studies: cough, sputum, fever, and weakness ( Figure 3). In addition, Volling et al 54

| S&S in high-risk adults in mixed settings
Three studies included patients in both hospital and outpatient settings. 56

| S&S in immunocompromised patients
Only two studies presented S&S in exclusively immunocompromised populations 58,61 ; in one study, all but two patients were hospitalized, 58 and another study took place in a mixed setting. 61 While one of these studies of immunocompromised patients (after lung transplant) included adolescents aged >15 years, the mean age of the sample was 49, 58 so no inferences can be made about the RSV S&S experienced by immunocompromised adolescents.
Of the two studies, one was a retrospective analysis of adult lung transplant patients infected with RSV receiving oral or inhaled ribavirin. This study did not report proportions of patients experiencing each of the RSV S&S, but did report fever, cough, dyspnea, wheezing, rhinorrhea, pharyngitis, and headache as present in both treatment groups. 58 The second study, Marcelin et al, 61 was the only study to report the proportions of immunocompromised patients with each RSV symptom; cough was reported in 94% of patients, fever was seen in 62% of patients, and dyspnea was seen in 59%.

| Length of hospital stay and symptom duration
In addition to reporting S&S of RSV, six of the identified studies exam- Among studies of caregiver-and clinician-reported RSV S&S in children, regardless of setting or age group, RSV signs or symptoms that were commonly reported (≥40%) and also reported by at least three studies of each study type (caregiver-reported or clinicianreported) were cough, fever, and feeding abnormalities. While wheezing is also considered a prominent symptom of RSV in children, 65 we found that it was commonly reported in children by clinicians, but not by caregivers; it is possible that caregivers may have captured wheezing as part of reporting "breathing difficulties" rather than using the term wheezing.
Symptom trends based on age or treatment setting in the pediatric population were overall not robust. The most salient trend identified in this review was related to fever. Both clinicians and caregivers more commonly reported fever in hospitalized children as their age increased. 29,34,35,37,40,44,46,48  found in adults in this review, and the relative lack of reporting on duration of symptoms, the prolonged evidence of symptoms following discharge may be of concern to the thousands of adults who contract RSV each year and whose quality of life may be impacted for months following infection.
A recent prospective cohort study of adults with respiratory tract infections across 12 countries that was published after our literature review was completed also found that LRTI symptoms are commonly associated with RSV infections in adults, particularly cough, wheezing, and shortness of breath. 66  This study has some limitations. We identified common RSV S&S in multiple populations but did not capture the severity or burden of those symptoms on patients; less common S&S may be more burdensome. We limited our search to English-language studies published between 2011 and 2021, so global studies in a non-English language would have been missed in our search. We therefore may have overrepresented studies in English-speaking countries. Despite the availability of studies on RSV S&S, data on the duration of symptoms or the LOS in hospitals was less readily available. Studies that did report symptom duration used different criteria for evaluating duration, so it is challenging to draw conclusions. However, duration of S&S and LOS were exploratory and were not part of the search terms for this study. An SLR focused on these outcomes may provide additional details. Although we initially included immunocompromised adolescents in our literature search strategy, the lack of data on S&S separately in this population in this SLR may have been caused by our requirement that included studies were either questionnaires or clinical trials to ensure that patients were being queried about the reported S&S. Observational studies in adults likely were also omitted.
Due to the resulting limited number of studies in adult and adolescent populations, as well as the variation in the list of S&S reported, firm conclusions may not be drawn on the presentation of RSV in these populations.

| CONCLUSION
Cough was reported in the majority of RSV patients across all age and risk groups assessed in this study. The most frequent commonly reported RSV S&S in the pediatric population were consistent across caregivers and clinicians and across settings (nasal discharge/congestion, cough, shortness of breath, fever, feeding abnormalities). The most frequent commonly reported RSV S&S across settings in highrisk and immunocompromised adult patients were primarily LRTI symptoms (e.g., cough, sputum, and shortness of breath). Duration of RSV S&S in children was reported as up to 12 days in this review. In high-risk and immunocompromised adults, RSV S&S were found to last several weeks (17)(18)(19)

ACKNOWLEDGMENTS
The authors thank Sara Musetti Jenkins, PhD, of RTI Health Solutions for medical writing assistance.

CONFLICT OF INTEREST
AC and JC are full time employees of RTI Health Solutions, an independent nonprofit research organization, which was retained by Janssen to conduct the research, which is the subject of this manuscript.
Their compensation is unconnected to the studies on which they work. KB and KK are employees of Janssen and may hold shares and/or stock options in the company. KM was an employee of Janssen at the time the research was conducted and may hold shares and/or stock options in the company.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article, as no new data were created or analyzed in this study.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13100.