Economic burden of respiratory syncytial virus infection in adults: a systematic literature review

Abstract

Aims

To capture the economic and healthcare resource utilization (HCRU) burden in older adults due to respiratory syncytial virus (RSV) infection.

Methods

An electronic literature search of PubMed, Embase, the Cochrane Library, PsycINFO, and EconLit was conducted for studies of the cost and HCRU outcomes of RSV infection in adult patients, with no language or country restrictions. The search dates for the primary studies were January 1, 2002–May 18, 2022. The methodological quality of included studies was assessed using a modification of the Critical Appraisal Skills Programme (CASP) checklist for economic studies and the Drummond checklist.

Results

Forty-two studies were identified that reported cost or HCRU data associated with RSV infections, with geographic locations across North America, South America, Europe, Asia, and Oceania. Generally, hospitalization costs were highest in the United States (US). Driving factors of increased cost included older age, comorbidities, and length of stay. US studies found that the national direct cost burden of RSV hospitalizations was $1.3 billion for all adults and $1.5–$4.0 billion for adults aged ≥60 years (estimates for other countries were not identified). Studies estimating incremental costs for RSV cases versus controls and costs pre- and post-RSV infection demonstrated higher costs for RSV cases. Hospitalizations accounted for the majority of total costs.

Evidence Limitations and Gaps

The variability in definitions of cost outcomes, age groups, study seasons, and geographic locations was prohibitive of a meta-analysis and comparisons across studies. Cost and HCRU data were limited per country outside the US, per comorbidity, and in settings other than the inpatient setting. Only one study reported indirect costs, and only the US had national cost burden data.

Conclusion

Despite several data gaps, the economic burden of RSV infections on healthcare systems and payers was found to be substantial, globally, underscoring the need for RSV preventive strategies for reducing this burden.

Keywords:

• Respiratory syncytial virus
• respiratory infection
• economic burden
• cost
• healthcare resource utilization
• adults

JEL CLASSIFICATION CODES:

• I19
• I1
• I
• O50
• O5
• O
• O51
• O52

Introduction

Respiratory syncytial virus (RSV) is a seasonal virus that commonly affects infants and children, but the virus poses a risk for severe disease in adults as well^1,2. Most people experience an RSV infection as an infant or young child and have some immunity to further exposures during their lifespan, but the immunity from childhood exposure does not provide complete or sustained immunity³. In older adults, changes in the immune system and lung function regarding clearance of microbes lead to an inflammatory state that impairs responses to infection and prolongs inflammation after an infection has cleared⁴. Therefore, older adults in the general population or in long-term care facilities (LTCFs) are susceptible to severe RSV infection¹. In addition, adults with comorbidities such as chronic heart or lung disease, functional disability, frailty, and compromised immune systems are susceptible to severe RSV disease and are more likely to require hospitalization than healthy older adults^1,2,5–9. After older adult patients are diagnosed with RSV infection, their return to pre-RSV respiratory functioning and ability to perform activities of daily living may take several months¹⁰. Additionally, at hospital discharge, a substantial proportion of older adults or adults with comorbidities require discharge to a skilled nursing facility, rehabilitation facility, or assisted living facility not needed before RSV infection^11–14.

The annual incidence of RSV infection is estimated to be 3–7% in healthy older adults and 4–10% in high-risk adults based on prospective cohort studies conducted in the United States (US) and Europe^2,15. Among adults aged ≥60 years, RSV infection accounted for approximately 470,000 RSV-associated hospitalizations (attack rate: 0.15%) and 33,000 RSV-associated in-hospital deaths (in-hospital case fatality rate: 7.13%) in the community setting of high-income countries in 2019⁸. In low- or middle-income countries, there is a paucity of data on the burden of RSV disease in older adults; however, available data from prospective cohort studies in India and Thailand suggest a significant burden that increases with age and for persons with certain underlying conditions, such as cardiac and pulmonary diseases^16,17. Although a significant global RSV burden has been documented, the actual burden due to RSV may be even higher. A study estimating the incidence of RSV-associated hospitalization found that it may be 2.2-times that reported across 12 studies in high-income countries in adults ≥65 years of age¹⁸. This conclusion was obtained by adjusting for both the clinical specimen and clinical testing methods. In low- or middle-income countries, more limited access to care and more restricted care-seeking behaviors have been speculated to further underestimate the burden of RSV disease in older adults¹⁹.

RSV circulates year-round but typically peaks in a seasonal pattern, during winter in temperate climates and during the rainy season in tropical climates^20–24. The COVID-19 pandemic impacted the circulation of RSV²⁵. For example, in the 3 years immediately before the COVID-19 pandemic, the US RSV season spanned from October to March and peaked in December. The latest US RSV season (2022–2023) spanned from June to January and peaked in November²⁵.

Although RSV infections have decreased among adults during the COVID-19 pandemic^26,27, including adults aged ≥50 years²⁶, this decline is likely due to older adults’ adherence to public health infection prevention measures; whether it will be sustained as SARS-CoV-2 infections become endemic is currently unknown²⁶. More recently, in the US, following the COVID-19 pandemic, the reported peak rate of RSV hospitalization in older adults increased approximately twice as much as and occurred 2 months earlier than it did in older adults during the pre-COVID-19 pandemic years, 2017–2018 and 2019–2020²⁸.

A recent systematic literature review (SLR) reported that in approximately 33% of laboratory tests, RSV infection is under-detected in adults tested for RSV²⁹. This estimate may be conservative³⁰. Under-diagnosis from lack of testing in adults also contributes to the under-ascertainment of RSV infection in adults, although, to our knowledge, this has yet to be quantified in the current literature and may be changing as RSV vaccines become available^29,31.

The costs of management of acute respiratory infections (ARI) among older adults has been estimated in a recent meta-analysis³². However, this study did not report respiratory pathogen-specific management costs. With RSV vaccines for adults aged ≥60 years under development, there will be a need to better understand the cost and healthcare resource burden of RSV infection in adults. This information will be critical for policy decision-makers to assess the value and cost-effectiveness of vaccination strategies among those at risk for severe outcomes due to age and underlying comorbidities. Our objectives in this global SLR were to summarize the economic burden of RSV infection in adults and highlight any critical gaps in the existing literature. It was not designed to capture RSV hospitalization rates, which has been a focus of other recent SLRs^{8,9,19,29,33,34}.

Methods

Study selection, data extraction, and quality assessment

Based on a prespecified protocol (available upon request) and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a literature search of PubMed, Embase, the Cochrane Library, PsycINFO, and EconLit was conducted for studies of the economic and health-related quality-of-life (HRQoL) outcomes of RSV infection in adult patients (HRQoL findings will be examined in a forthcoming article). The search strategy incorporated Medical Subject Heading or Emtree terms and free-text terms for sources published in the past 20 years, with no language or country restrictions. Search dates for primary studies were January 1, 2002–May 18, 2022. The search included conference abstracts from select organizations (Figure 1) published between 2019 and 2022 that were indexed in Embase or available as abstract books or online, as well as from bibliographies of relevant SLRs.

Figure 1. PRISMA diagram. Abbreviations. ICU, intensive care unit; MV, mechanical ventilation; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ^aConferences and years indexed in Embase were as follows: American Thoracic Society (2019–2021 abstracts); CHEST annual meeting (2019–2021 abstracts); Infectious Diseases Society of America (IDWeek) (2019–2021 abstracts); ISPOR (2019–2021 abstracts); CHEST Congress (2019–2020 abstracts). ^bTwo publications^14,84 reported on the same population.

Unique titles and abstracts (level 1) and full texts (level 2) were independently reviewed by two reviewers, with consultation involving a third, senior-level researcher when consensus was not reached. Studies were included that reported economic outcomes for adults (aged ≥18 years) with or without comorbidities. There were no inclusion restrictions for interventions. Economic outcomes of interest were direct and indirect costs of RSV infection; healthcare resource utilization (HCRU) related to RSV infection, including intensive care unit (ICU) admission and mechanical ventilation (MV) use and the requirement for a higher level of care after hospital discharge. A broad range of study designs were included (Supplementary Table A1), but general reviews were excluded. For ICU admission and MV use, only studies with ≥100 patients with RSV infection were included.

Study details and data were extracted into tables and independently verified by a second reviewer not involved in the data extraction. Data extracted from the economic studies included study type and details; patient population characteristics (age, comorbidities); patient setting (inpatient, outpatient, any setting); follow-up period; cost outcomes; and proportions of patients needing ICU admission, MV, or a higher level of care at discharge. All cost outcomes were converted and inflated to 2022 US$ to compare costs. Cost conversions were calculated by multiplying reported costs by the corresponding inflation factor from the US Bureau of Labor Statistics Consumer Price Index Inflation Calculator (Supplementary Table A2). When currency year was not reported, it was assumed that it was the same as the publication year.

We included studies that reported HCRU even when the study’s purpose was about clinical outcomes instead of economic outcomes. Therefore, the quality assessment of included studies was evaluated using a modification of the Critical Appraisal Skills Programme (CASP) checklist for economic studies³⁵ and the Drummond checklist³⁶, which took into account the primary research aims as well as the cost and HCRU aims.

Results and discussion

A total of 828 sources were reviewed for eligibility, and 65 sources were included (55 articles and 10 conference abstracts or study registry entries) (Figure 1). Eligible studies were identified across North America, South America, Europe, Asia, and Oceania. This article summarizes 42 economic burden studies: 15 presented the cost burden of adult RSV infection^12,37–50, 28 presented ICU admission and/or MV use^{2,11,13,14,39,41,43,48,50–69}, and 12 presented the need for a higher level of care at discharge^{2,11–14,53,54,56,70–73}. Quality assessment of these 42 studies is presented in the Supplementary Material. Economic models were excluded from this manuscript because many of the cost inputs in the models were influenza costs, not RSV.

Cost studies

In this SLR, 15 studies reported the cost associated with RSV infection in adults in a primary study of general populations^12,37–50. The studies were conducted across one region and five different countries, with the majority being in the US: one in Europe⁴⁵ and nine in the US^{12,37–40,42,44,46,47}, two in Canada^43,49, one in China⁴¹, one in New Zealand⁴⁸, and one in the Republic of Korea⁵⁰ (Figure 2).

Figure 2. Countries included in cost studies. Abbreviation. US: United States.

Of the 15 studies, 12 were retrospective and three were prospective^42,43,45. For the studies that specified, RSV diagnosis was confirmed by either laboratory assessment (n = 8) or use of International Classification of Diseases (ICD) codes (n = 7) (Figure 3). In Bosco et al.⁴⁰, the study evaluated excess cardiorespiratory hospitalizations (ICD codes) during a time of high RSV circulation, and patients specifically did not have a diagnosis of RSV infection because the study aimed to evaluate sequelae of RSV infection. Five studies reported comorbidities, with the highest incidences being cardiovascular disease (CVD) and chronic pulmonary disease^{37,39,41,42,50}. Two studies reported costs for high-risk patients, characterized as older adults with chronic cardiopulmonary conditions and those who were immunosuppressed^12,46.

Figure 3. Design features of cost studies (n = 15). Abbreviations. ED, emergency department; LTCF, long-term care facilities; RSV, respiratory syncytial virus; US, United States.

Figure 4 identifies the cost studies by author (year) according to the types of cost outcomes reported.

Figure 4. Cost studies: Venn diagram of cost types, treatment settings, and outcome types. Abbreviations. Flu, influenza; RSV, respiratory syncytial virus; US, United States. ^aConference abstract.

Broad comparisons across the studies were difficult because of the wide variation in cost outcomes, period over which costs were collected, cost year, country, types of care setting, and patient characteristics, as well as the overall lack of consistency in metrics across studies (e.g. costs per hospitalization, costs per RSV case, pre- and post-RSV costs over a fixed period). Therefore, the studies were grouped into sections where they report similar cost outcomes (e.g. hospitalization costs or incremental costs versus control cohorts).

Direct national cost burden

Two studies estimated the national direct cost burden due to RSV hospitalizations in the US for two different age groups; no studies outside the US estimated national cost burden (Table 1).

Table 1. Direct US national cost burden.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Choi et al.^42; US; Inpatient	Multicenter, prospective cohort within a surveillance study; 15 October 2017–30 April 2018 and 15 October 2018–30 April 2019; Follow-up: not reported (appears to be the period of hospitalization)	Extrapolated national RSV hospitalization costs in adults in the US 18–49 years: $164,237,831; 95% CI, $46,330,606–$282,145,055 50–64 years: $290,202,254; 95% CI, $170,884,452–$409,520,054 ≥65 years: $810,932,993; 95% CI, $591,056,157–$1,030,809,829 Total (all ages): $1,265,409,170; 95% CI, $988,872,893–$1,541,945,445
Lonnet et al.^44 [conference abstract]; US; Inpatient	Retrospective database study; 2008–2017; Follow-up: not applicable	Total annual direct medical cost increase for RSV hospitalization events in 2008–2017 ≥60 years: $1,495–$1,796 million or $3,291–$3,955 million, depending on RSV incidence estimates

Abbreviations. CI, confidence interval; RSV, respiratory syncytial virus; US, United States.

^aConverted to 2022 US$. See Supplementary Table A3 for uninflated costs.

Choi et al.⁴² used the mean total cost of RSV hospitalization, RSV incidence rate/100,000 persons, and 2019 US population estimates to obtain an estimate of $1.3 billion in RSV hospitalization costs annually in the US for persons aged ≥18 years. Mean hospitalization costs were highest among the youngest age group (18–49 years), but the greatest national cost burden was for those aged ≥65 years ($810,932,993) (Table 1). This is a result of the RSV incidence for persons aged ≥65 years being 17-times that of 18–49-year-olds and 3-times that of 50–64-year-olds.

Lonnet et al.⁴⁴ used RSV hospitalization costs from 2008–2017 to obtain an estimate of $1.5–$1.8 billion or $3.3–$4.0 billion for persons aged ≥60 years, depending on RSV incidence estimates. The lower estimate agrees with Choi et al.⁴², but Choi et al.⁴² used only used two data years in their estimate versus the 10 data years in Lonnet et al.⁴⁴.

Incremental costs

Three US studies and one Canadian study presented incremental costs for patients with RSV, either comparing costs pre- and post-RSV diagnosis^12,46 or costs of RSV cases compared with those of a control group^38,49 (Table 2). Older patient populations had a significantly higher incidence of hospitalization, which was the driving factor for increased incremental costs^38,46.

Table 2. Incremental costs for RSV patients versus controls.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Costs pre- and post-RSV diagnosis
Mesa-Frias et al.^46; US;	Retrospective longitudinal database study;	Increases in mean weekly all-cause costs in week 1 pre-RSV diagnosis versus weeks 2–8 pre-RSV: •60–64 years: $1,163
All healthcare settings	2000–2020;	≥65 years: $1,456 ≥85 years: $945 18–59 years at high risk of severe RSV: $945
	Follow-up: N/A
		Increases in mean weekly all-cause costs in week 1 post-RSV diagnosis versus weeks 2–8 pre-RSV:
		60–64 years: $10,028 ≥65 years: $12,137 ≥85 years: $18,062 18–59 years at high risk of severe RSV: $8,349
		Estimates based on Optum data except those for 18–59 years at high risk of severe RSV, which were based on MarketScan data. Cost increases calculated based on reported costs week 1 pre-RSV diagnosis, weeks 2–8 pre-RSV diagnosis, and week 1 post-RSV diagnosis
Wyffels et al.^12;	Retrospective database study;	Mean (SD) total all-cause healthcare costs for 180 days pre-diagnosis and 180 days post-diagnosis of RSV; costs include outpatient costs, inpatient costs, pharmacy costs, and other costs (durable medical equipment, home health agency, hospice, and skilled nursing facility)
US;	January 2011–December 2015;
Inpatient and outpatient	Follow-up: N/A
					Patient risk		180 days pre-RSV diagnosis	180 days post-RSV diagnosis
		Hospitalized			High risk		$38,056	$49,108
					Non–high risk		$20,476	$43,445
		Outpatient			High risk		$17,398	$19,330
					Non–high risk		$7,016	$9,503
RSV vs controls
Rafferty et al.^49; Canada; Inpatient and ED	Retrospective case-control study; 2010–2019; Follow-up: N/A	Costs for both tables include hospitalization, ED visits, and physician billing.
		Incremental costs attributed to RSV are given by mean all-cause cost per RSV case minus controls’ mean all-cause costs per RSV case
			Mean all-cause cost per RSV case				Mean incremental all-cause cost per RSV case
		Age, years	30 days		365 days		30 days	365 days
		18–49	$21,530 ± $57,084		$104,182 ± $285,945		$21,241	$99,954
		50–64	$28,220 ± $72,114		$121,036 ± $211,619		$27,753	$113,938
		65–79	$25,303 ± $51,046		$146,290 ± $313,062		$24,807	$136,416
		≥80	$20,090 ± $35,888		$112,697 ± $203,969		$19,478	$101,702
		Incremental costs are given by mean all-cause cost per RSV-attributable ARI case minus controls’ mean all-cause cost per RSV-attributable ARI case
			Mean all-cause cost per RSV-attributable ARI case				Mean incremental all-cause cost per RSV-attributable ARI case
		Age, years	30 days		365 days		30 days		365 days
		18–49	$444 ± $2,463		$2,959 ± $10,456		$290		$914
		50–64	$752 ± $4,041		$4,890 ± $17,979		$517		$1,474
		65–79	$1,491 ± $5,675		$9,600 ± $26,540		$1,104		$3,600
		≥80	$2,878 ± $7,230		$16,918 ± $34,490		$2,379		$7,646
Amand et al.^38; US;	Retrospective case-control study; 2012–2013;	Incremental differences in annual healthcare utilization and costs between the RSV patients and the matched controls over the 12-month follow-up period
All healthcare settings	Follow-up: 12 months	Setting	18–49 years	50–64 years		65–74 years	75–84 years			≥ 85 years
		Inpatient	$2,861	$3,496		$7,744	$13,660			$3,592
		ED/UC	$721	$991		$790	$864			$856
		Ambulatory visit	$1,830	$2,609		$1,916	$1,217			$4,619
		Outpatient visit	$1,433	$1,914		$5,184	$14,142			$10,078
		Rx filled	$1,352	$1,495		$2,426	$1,499			$960
		Total costs	$8,198	$10,504		$18,060	$31,381			$20,102

Abbreviations. ARI, acute respiratory infection; ED, emergency department; N/A, not applicable; RSV, respiratory syncytial virus; Rx, prescription; SD, standard deviation; UC, urgent care; US, United States.

^aConverted to 2022 US$. See Supplementary Table A4 for uninflated costs.

Mesa-Frias et al.⁴⁶, a US-based study, found increases in mean weekly all-cause costs when comparing pre-RSV diagnosis in weeks 2–8 and post-RSV diagnosis in week 1 across patient age groups, with the highest increase ($18,062) among patients aged ≥85 years. Mesa-Frias et al.⁴⁶ reported a significant number of cardiovascular comorbidities in this age group, which may have resulted in more complex and costly RSV cases. Mesa-Frias et al.⁴⁶ also found increases in all-cause costs at 1 week pre-RSV diagnosis compared with 2–8 weeks pre-RSV diagnosis, which could be attributed to the latency between onset of symptoms, which resulted in HCRU, and diagnosis confirmation via ICD codes⁴⁶. Accounting for cost increases pre-RSV diagnosis, the total incremental cost of RSV from 1 week pre-RSV diagnosis to week 8 post-RSV diagnosis was found to be as high as $19,007 among those aged ≥85 years⁴⁶.

Wyffels et al.¹² reported mean total all-cause healthcare costs, comparing the 180-day period pre- and post-RSV diagnosis in patients with versus without high risk (chronic cardiac/pulmonary disease or immunocompromised) for RSV complications in an outpatient or hospitalized setting (see Costs among high-risk patients and patients with comorbidities). The largest incremental difference in total costs pre- and post-180 days from RSV diagnosis was incurred by hospitalized non-high-risk patients ($22,969), while the incremental difference in total costs among hospitalized high-risk patients was less than half that¹². A similar result was seen in the outpatient setting, with incremental costs pre- and post-180 days from RSV diagnosis of $1,932 and $2,487 for high-risk outpatients and non-high-risk outpatients, respectively. It is possible that the incremental costs for high-risk patients were lower than for non-high-risk patients due to higher mortality rates¹². The mortality rates for hospitalized high-risk patients were 4.2% during inpatient stay and 13.4% within 30 days of diagnosis versus 0.0% and 8.1%, respectively, for non-high-risk patients. Another possible explanation is that there may be an overlap in the healthcare resources that high-risk patients used pre- and post-RSV index, resulting in higher overall resource use but a smaller incremental cost, but this is yet to be explored in the literature. For more details on healthcare costs for high-risk patients, see the section Costs among high-risk patients and patients with comorbidities.

One US and one Canadian study calculated total incremental all-cause costs for patients within 12 months of RSV diagnosis versus a control group^38,49. The studies differed greatly in the costs reported, with Rafferty et al.⁴⁹ reporting costs up to almost 12-times those reported by Amand et al.³⁸. In both studies, the highest mean incremental all-cause cost per RSV case was incurred by older age groups: in Rafferty et al.⁴⁹, 65–79-year-olds incurred an incremental cost increase of $136,416 versus controls, and in Amand et al.³⁸, 75–84-year-olds incurred an incremental cost increase of $31,381 versus controls. These higher incremental costs among the older population could be attributed to the potential for RSV-related complications triggering additional healthcare visits⁴⁹. Rafferty et al.⁴⁹ noted several key differences between the two studies that could explain the markedly different costs: the US has higher healthcare costs than Canada, which affected the costs of the controls in Amand et al.³⁸; Rafferty et al.⁴⁹ gathered costs across five RSV seasons, while Amand et al.³⁸ used one RSV season; Rafferty et al.⁴⁹ used laboratory confirmation to diagnose RSV while Amand et al.³⁸ used ICD-10 codes; and Rafferty et al.⁴⁹ used a different methodology to match RSV patients with controls, including consideration for comorbidities and geographic location. For both studies, incremental cost increases 1 year after RSV diagnosis may be indicative of sequelae or other long-term health impacts^38,49.

Rafferty et al.⁴⁹ also reported shorter-term incremental costs, with all-cause cost increases up to $27,753 within 30 days of RSV diagnosis. Short-term incremental costs were the highest among adults aged 50–64 years. RSV infection is not as well recognized among this age group compared with children and older adults, which may result in a lack of testing and a delay in treatment. These patients may have had more serious RSV cases due to this delay, resulting in a higher incremental cost than other age groups⁴⁹.

Hospitalization costs

Four studies reported all-cause direct costs per RSV hospitalization within the US^37,39,42,47 (Table 3). Cost estimates varied substantially, ranging from as low as $8,049⁴² to as high as $58,117⁴⁷. Outside of the US, RSV hospitalization costs were reported in one study each from Canada⁴³, China⁴¹, New Zealand⁴⁸, and the Republic of Korea⁵⁰.

Table 3. Hospitalization costs.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Ackerson et al.^37; US; Inpatient	Observational, retrospective database study; January 2011–June 2015; Follow-up: NR	Adjusted mean cost per RSV hospitalization 60–74 years: $19,712 75–84 years: $20,884 ≥85 years: $17,222
Belk et al.^39 [conference abstract]; US; Inpatient	Retrospective, matched cohort study; 2016–2018; Follow-up: NR (appears to be admission to discharge or death)	Median hospitalization charges $27,757 (p < 0.001)
Pastula et al.^47;	Retrospective database study;	Adjusted (geometric mean) total (direct) cost of hospitalization during RSV event (total, includes immunocompromised and non-immunocompromised patients): 20–44 years: $49,442.40 45–59 years: $58,117.44 ≥60 years: $41,530.92
US;	1997–2012;
Inpatient	Follow-up: N/A
Choi et al.^42; US; Inpatient	Multicenter, prospective cohort within a surveillance study; 15 October 2017–30 April 2018 and 15 October 2018–30 April 2019; Follow-up: NR (appears to be the period of hospitalization)	Mean direct medical cost (includes ICU, nursing, pharmacy, therapy, emergency department, laboratory, radiology, and other) per RSV hospitalization 18–49 years: $12,125; 95% CI, $7,109–$18,951 50–64 years: $8,049; 95% CI, $6,260–$10,392 ≥65 years: $8,983; 95% CI, $7,583–$10,636
Chen et al.^41;	Multicenter, retrospective chart review;	Median cost of RSV hospitalization: $3,123.44
China;	1 January 2013–31 May 2019;
Inpatient	Follow-up: 30 days after discharge
Prasad et al.^48;	Retrospective surveillance study;	Median direct healthcare costs of RSV hospitalization for all adults: $3,420 per hospitalization
New Zealand;	2012–2015;
Inpatient	Follow-up: N/A
Yoon et al.^50;	Retrospective database study;	Median medical costs per admission by age group 19–49 years: $2,211.78 50–64 years: $2,391.57 ≥65 years: $3,314.48
Republic of Korea;	2012–2015;
Inpatient	Follow-up: N/A
El Sherif et al.^43;	Prospective surveillance study;	Mean direct cost of RSV hospitalizations (includes hospitalization, ICU, MV, other) per RSV case: All patients: $18,209; 95% CI, $17,568–18,852; provincial range: $16,538–$33,957 50–59 years: $16,683 60–79 years: N/R ≥80 years: $21,487
Canada;	2012–2015;
Inpatient	Follow-up: NR (appears to be during hospitalization)

Abbreviations. CI, confidence interval; ICU, intensive care unit; MV, mechanical ventilation; N/A, not applicable; NR, not reported; RSV, respiratory syncytial virus; US, United States.

^aConverted to 2022 US$. See Supplementary Table A5 for uninflated costs.

Of the four US studies, the lowest cost estimates were from Choi et al.⁴², with mean all-cause direct costs ranging from $8,049–$12,125 per RSV hospitalization, depending on the age group. The highest costs were incurred by the youngest age group of patients, aged 18–49 years. This was attributed to the concept that younger patients may have a higher threshold of illness severity for hospital admittance and would wait until they were sicker or had more complications before seeking hospitalization⁴². Belk et al.³⁹ reported all-cause direct costs of $27,757 per RSV hospitalization among elderly patients. (“Elderly” was not defined.) Ackerson et al.³⁷ also reported costs for older adults in a study population with a mean age of 78.4 years. Both Ackerson et al.³⁷ and Belk et al.³⁹ reported high incidence of comorbidities, including chronic heart conditions and chronic pulmonary conditions.

The analysis in Pastula et al.⁴⁷ captured the broadest timeline of data, with costs extracted across 15 years (1997–2012). The breadth of the data allowed for larger trends to be identified, and the findings are more easily generalized to the total US population than results of smaller studies⁴⁷. Additionally, a wider range of seasonal severity was captured, which could explain the difference in costs reported compared with the other two studies, which collected costs across 3.5 years³⁷ and 3 years³⁹. However, both Ackerson et al.³⁷ and Belk et al.³⁹ examined more recent costs from 2011–2015 and from 2016–2018, respectively, and Pastula et al.⁴⁷ did not report comorbidities.

Estimates of the cost burden in Canada were most similar to that in the US. El Sherif et al.⁴³ reported a mean direct medical cost of $18,209/RSV case for hospitalized patients of all ages, with the highest cost, $21,487, reported in the oldest age group (≥80 years), which is similar to that in multiple estimates in the US^37,42. Overall, cost burden for US patients hospitalized due to RSV infection was substantially higher than that for patients in all other countries, with Canada having the most similar costs to the US and China having the least similar.

Among studies reporting inpatient costs, China had the lowest cost burden, with a median cost of $3,123.44 per hospitalization for adults aged ≥18 years⁴¹. The Republic of Korea had the second lowest costs per hospitalization, with median medical costs up to $3,314.48 for patients ≥65 years⁵⁰.

Multiple care settings costs

Two studies reported costs for patients in multiple care settings^45,49 (Table 4).

Table 4. Multiple care settings costs.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Rafferty et al.^49;	Retrospective case-control study;	Costs below for both tables include hospitalization, ED visits, and physician billing
Canada;	2010–2019;		Mean all-cause cost per RSV case
Inpatient and ED	Follow-up: N/A	Age, years	30 days	365 days
		18–49	$21,530 ± $57,084	$104,182 ± $285,945
		50–64	$28,220 ± $72,114	$121,036 ± $211,619
		65–79	$25,303 ± $51,046	$146,290 ± $313,062
		≥80	$20,090 ± $35,888	$112,697 ± $203,969
			Mean all-cause cost per RSV-attributable ARI case
		Age, years	30 days	365 days
		18–49	$444 ± $2,463	$2,959 ± $10,456
		50–64	$752 ± $4,041	$4,890 ± $17,979
		65–79	$1,491 ± $5,675	$9,600 ± $26,540
		≥ 80	$2,878 ± $7,230	$16,918 ± $34,490
Mao et al.^45; Europe (Belgium, United Kingdom, and the Netherlands); Outpatient	Multicenter prospective observational cohort study; 1 October–1 May in 2017–2018 and 2018–2019; Follow-up: NR	Direct cost per RSV episode: Patient: $14.28 Healthcare provider: $17.82 Healthcare payer: $6.71 Total societal costs per RSV episode: $37.54 Societal costs included cost of productivity losses

Abbreviations. ARI, acute respiratory infection; ED, emergency department; N/A, not applicable; NR, not reported; RSV, respiratory syncytial virus; US, United States.

^aConverted to 2022 US$. See Supplementary Table A6 for uninflated costs.

In a European all-care-settings study that followed a community-based cohort, the direct cost to the patient was $14.28 and to the healthcare payer was $6.71/RSV case⁴⁵. This was the only study to report costs in all care settings (home, ambulatory, emergency department [ED], hospital) and to report societal costs ($37.54/RSV episode). However, the cohort was characterized as relatively healthy, with no hospitalizations during the observational period of two consecutive RSV seasons⁴⁵.

In contrast, much higher costs were reported in a Canadian study⁴⁹. The greatest mean all-cause cost per RSV case was incurred by patients aged 65–79 years during the observational period of 1 year ($146,290)⁴⁹. This age group also had the largest incremental cost increase when compared with controls (see Incremental costs). Patients aged 50–64 years had the second-greatest costs ($121,036). As previously noted, lack of recognition of RSV infection in these populations may have led to delays in receiving treatment and testing, resulting in more severe cases⁴⁹. Costs included hospitalization, ED visits, and physician billing, and costs were collected over a 365-day period.

Costs among high-risk patients and patients with comorbidities

One study reported costs for patients with cost breakouts by comorbidity⁴², one study reported costs for immunocompromised (IC) patients⁴⁷, and two studies reported mean all-cause costs for patients categorized as high risk^12,46 (Table 5). “High risk” in both studies was defined as adult patients aged ≥65 years with chronic cardiac disease and/or chronic pulmonary disease and those who were immunosuppressed, as classified by the Centers for Disease Control and Prevention⁷⁴. Additionally, Wyffels et al.¹² included patients who had prior pneumonia on or within 180 days before the date of RSV diagnosis.

Table 5. Costs among high-risk patients and patients with comorbidities.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Mesa-Frias et al.^46;	Retrospective longitudinal database study;	Increases in mean weekly all-cause costs in week 1 pre-RSV diagnosis versus weeks 2–8 pre-RSV: 18–59 years at high risk of severe RSV: $2,765 ‒ $1,820 = $945 Increases in mean weekly all-cause costs in week 1 post-RSV diagnosis versus weeks 2–8 pre-RSV: 18–59 years at high risk of severe RSV: $10,170 ‒ $1,820 = $8,349 (MarketScan data)
US;	2000–2020;
All healthcare settings	Follow-up: N/A
Wyffels et al.^12;	Retrospective database study;	Mean (SD) total all-cause healthcare costs for 180 days pre-RSV and 180 days post-RSV diagnosis, including outpatient costs, inpatient costs, pharmacy costs, and other costs (durable medical equipment, home health agency, hospice, and skilled nursing facility)
US; Inpatient and outpatient	January 2011–December 2015; Follow-up: N/A
			Patient risk	180 days pre-RSV diagnosis		180 days post-RSV diagnosis
		Hospitalized	High	$38,056		$49,108
			Non-high	$20,476		$43,445
		Outpatient	High	$17,398		$19,330
			Non-high	$7,016		$9,503
Choi et al.^42; US; Inpatient	Multicenter, prospective cohort within a surveillance study; 15 October 2017–30 April 2018 and 15 October 2018–30 April 2019; Follow-up: NR (appears to be the period of hospitalization)	Mean all-cause direct medical cost (includes ICU, nursing, pharmacy, therapy, emergency department, laboratory, radiology, and other) per RSV hospitalization Mean observed hospital cost per case (95% CI, unadjusted)^a
		Comorbidity			Yes		No
		Cardiovascular disease			$10,581* ($8,531–$12,967)		$7,344 ($6,282–$8,701)
		Chronic lung disease			$8,362 ($7,142–$9,775)		$9,931 ($7,801–$12,516)
		Diabetes			$8,280 ($6,961–$9,884)		$9,817 ($7,873–$12,139)
		Obesity			$8,513 ($6,434–$11,587)		$9,432 ($7,943–$11,117)
		Immunosuppression			$9,111 ($7,368–11,142)		$9,178 ($7,574–$11,084)
		Neurologic			$7,438* ($5,477–$10,278)		$9,705 ($8,211–$11,452)
		Chronic kidney disease			$9,834 ($7,669–$12,393)		$8,898 ($7,411–$10,709)
		Chronic liver disease			$14,630 ($7,771–$23,403)		$8,747 ($7,535–$10,181)
		*p < 0.05 vs. no comorbidity.
		^aSimple comparisons of patients with and without the specific comorbidity, without adjustment for other comorbidities or other patient characteristics.
Pastula et al.^47;	Retrospective database study;	Adjusted (geometric mean) total (direct) cost of hospitalization during RSV event for immunocompromised patients 20–44 years: $86,186.76 45–59 years: $88,675.80 ≥60 years: $70,378.56 Adjusted (geometric mean) total (direct) cost of hospitalization during RSV event for non-immunocompromised patients 20–44 years: $32,425.32 45–59 years: $43,155.45 ≥60 years: $34,542.96
US;	1997–2012;
Inpatient	Follow-up: N/A

Abbreviations. CI, confidence interval; ICU, intensive care unit; N/A, not applicable; NR, not reported; RSV, respiratory syncytial virus; SD, standard deviation; US, United States.

^aConverted to 2022 US$. See Supplementary Table A7 for uninflated costs.

Mesa-Frias et al.⁴⁶ limited high-risk patients to the youngest age group and compared their increases in direct medical costs with patients aged 60–64, ≥65, and ≥85 years. The study found that high-risk patients aged 18–59 years had the second highest weekly direct all-cause costs post-RSV diagnosis in week 1 ($10,170), as well as the second-greatest increase in mean weekly all-cause costs post-RSV diagnosis in week 1 versus pre-diagnosis in weeks 2–8 ($8,349), after any-risk patients aged ≥85 years.

Wyffels et al.¹² reported mean total all-cause healthcare costs pre- and post-180 days from RSV diagnosis for high-risk patients in both inpatient and outpatient settings. Unsurprisingly, the highest total costs were incurred by hospitalized high-risk patients, with a mean total all-cause healthcare cost of $49,108 post-180 days from RSV diagnosis¹². Outpatient high-risk patients incurred total all-cause post-180 days RSV diagnosis costs of $19,330¹².

Pastula et al.⁴⁷ reported mean total direct RSV hospitalization costs for IC patients, which were up to 2.5-times the costs incurred by non-immunocompromised (non-IC) patients: IC patients aged 20–44 years had mean total hospitalization costs of $86,186.76, while non-IC patients of the same age group incurred costs of $32,425.32. The highest mean hospitalization costs ($88,675.80) were among IC patients aged 45–59 years, who reported the highest MV use and longest length of stay (LOS)⁴⁷. For all patient age groups, IC patients had higher cost of hospitalization due to RSV infection compared with non-IC patients as well as patients with influenza⁴⁷. IC patients compared with non-IC patients had an increased death rate during hospitalization (7.3% vs 5.6%) and longer mean LOS (7.3 days vs 5.4 days)⁴⁷.

Choi et al.⁴² was the only study to report direct medical costs by comorbidity. Considering costs by comorbidity, patients with CVD incurred an additional $3,237 in costs when compared with patients without CVD. Patients with chronic liver disease had increased costs of $5,883, and patients with chronic kidney disease saw a cost increase of $936. Surprisingly, there was no substantial difference in costs among patients who were immunosuppressed and those who were not. Additionally, costs were lower in patients with chronic lung conditions and those with diabetes, with costs decreasing by $1,569 and $1,537, respectively. Choi et al.⁴² did not provide insight into the cause for these cost decreases but stated that the main predictors for cost increases were LOS, ICU admission, use of antibiotics, and the presence of four or more comorbidities. As these were simple comparisons of patients with and without a specific comorbidity and most patients (95%) had at least one comorbidity, it may be possible that the groups without chronic lung conditions and without diabetes have a higher prevalence of other expensive comorbidities, such as chronic liver disease.

Sequelae costs

Only one study reported RSV sequelae costs, as considered through RSV-attributable cardiorespiratory hospitalization costs (Table 6). It is possible that a primary diagnosis is actually a sequelae of RSV, but the downstream effects of RSV infection are unrecognized without prior testing to identify RSV infection. Due to a lack of routine testing, this may result in an underestimation of the true cost burden of RSV sequelae. Therefore, Bosco et al.⁴⁰ estimated cardiorespiratory hospitalizations attributable to RSV infection and influenza infection (separately and together) during times when these viruses were circulating, based on surveillance data. The cohort studied were residents of LTCFs who were enrolled in Medicare. National cost-burden estimates for cardiorespiratory hospitalizations attributable to both RSV infection and influenza infection were also reported.

Table 6. Sequelae costs.

Study, country(ies)	Study type, data dates, follow-up	Costs^a
Sequelae
Bosco et al.^40;	Retrospective cohort study;	Mean RSV-attributable cost per cardiorespiratory hospitalization 65–74 years: $11,348 75–84 years: $9,942 ≥85 years: $9,411 All age groups: $10,136 National RSV-attributable cost of cardiorespiratory hospitalization 65–74 years: $5,679,577; 95% CI, $2,171,656–$9,187,498 75–85 years: $8,662,411; 95% CI, $3,432,688–$13,892,134 ≥85 years: $45,401,614; 95% CI, $39,519,621 -$51,283,607 ≥65 years (total for all age groups): $59,743,602; 95% CI, $45,123,966–$74,363,238 Mean influenza-attributable cost per cardiorespiratory hospitalization 65–74 years: $11,348 75–84 years: $9,942 ≥85 years: $9,411 All age groups: $10,136 National influenza-attributable cost of cardiorespiratory hospitalization 65–74 years: $5,141,048; 95% CI, $2,256,756–$8,025,341 75–84 years: $18,148,748; 95% CI, $13,871,681–$22,425,814 ≥85 years: $43,329,667; 95% CI, $38,485,958–$48,173,376 ≥65 (total for all age groups): $66,619,462; 95% CI, $54,614,395–$78,624,529
US;	6 respiratory seasons (2011–2017);
Inpatient	Follow-up: until the end of the last respiratory season

Abbreviations: CI, confidence interval; US, United States.

^aConverted to 2022 US$. See Supplementary Table A8 for uninflated costs.

Bosco et al.⁴⁰ found no difference in the mean cost per cardiorespiratory hospitalization when comparing RSV and influenza sequelae, with an average of $10,136/hospitalization across all age groups. This finding is dissimilar to that in three US studies that compared RSV and influenza hospitalization costs^37,39,47, which trended toward sizeable direct cost increases in RSV infection when compared with influenza infection (no formal statistical analysis was done).

The national burden of RSV-attributable cardiorespiratory hospitalizations for those in LTCF on Medicare totaled $59.74 million, and the national burden of cardiorespiratory hospitalizations attributable to influenza for those in LTCF on Medicare was $66.62 million due to higher case numbers of influenza⁴⁰. These national cost estimates are limited to residents of LTCF on Medicare. The full national burden of RSV-attributable cardiorespiratory hospitalizations is likely to be much higher when including adults of all ages, those in other places of residence, and those with non-Medicare insurance coverage.

RSV infection costs compared with influenza infection costs

RSV infection costs compared with influenza infection costs were presented in three US studies^37,39,47, one Chinese study of hospitalized patients⁴¹, and one European study of outpatients⁴⁵ (Table 7). Cost comparisons among the US studies trended toward relatively higher costs for RSV infection than for influenza, with RSV hospitalization costs ranging from $713 to $38,800 more than influenza hospitalizations. The higher cost was attributed to the higher incidence of congestive heart failure, chronic pulmonary disease, bronchitis, respiratory failure, and LOS for patients with RSV infection^37,39. In contrast, comparisons among the Chinese and European studies trended toward relatively higher influenza costs (up to $480 increase per hospitalization for RSV infection; up to $45 for healthcare payers per RSV episode in all treatment settings for a relatively healthy cohort)^41,45.

Table 7. RSV costs compared with influenza costs.

Study, country(ies), setting	Study type, data dates, follow-up	Costs^a
Mao et al.^45; Europe (Belgium, United Kingdom, and the Netherlands); Outpatient	Multicenter prospective observational cohort study; 1 October–1 May in 2017–2018 and 2018–2019; Follow-up: NR	Direct cost per RSV episode: Patient: $14.28 Healthcare provider: $17.82 Healthcare payer: $6.71 Direct cost per influenza episode: Patient: $19.78 Healthcare provider: $32.09 Healthcare payer: $51.87 Total societal costs per episode: RSV: $37.54 Influenza: $91.02 Societal costs included cost of productivity losses
Chen et al.^41;	Multicenter, retrospective chart review;	Median cost of RSV hospitalization: $3,123.44
China;	1 January 2013–31 May 2019;	Median cost of influenza-related pneumonia hospitalization: $3,603.23
Inpatient	Follow-up: 30 days after discharge
Ackerson et al.^37;	Observational, retrospective database study;	Adjusted mean cost per RSV hospitalization: 60–74 years: $19,712 75–84 years: $20,884 ≥85 years: $17,222 Adjusted mean cost per influenza hospitalization: 60–74 years: $20,425 75–84 years: $18,803 ≥85 years: $15,676
US;	January 2011–June 2015;
Inpatient	Follow-up: NR
Belk et al.^39 [conference abstract];	Retrospective, matched cohort study;	Median RSV hospitalization charges: $27,757 Median influenza hospitalization charges: $22,164
US;	2016–2018;
Inpatient	Follow-up: NR (appears to be admission to discharge or death)
Pastula et al.^47;	Retrospective database study;	Adjusted (geometric mean) total (direct) cost of hospitalization during RSV event (total, includes immunocompromised and non-immunocompromised patients): 20–44 years: $49,442.40 45–59 years: $58,117.44 ≥60 years: $41,530.92 Adjusted (geometric mean) total (direct) cost of hospitalization during influenza event (total, includes immunocompromised and non-immunocompromised patients): 20–44 years: $15,152.88 45–59 years: $19,317.60 ≥60 years: $17,691.00
US;	1997–2012;
Inpatient	Follow-up: N/A

Abbreviations. CI, confidence interval; N/A, not applicable; NR, not reported; RSV, respiratory syncytial virus; US, United States.

^aConverted to 2022 US$. See Supplementary Table A9 for uninflated costs.

For two studies of hospitalized patients with RSV or influenza infection, HCRU outcomes were notably different and likely accounted for the higher cost of one virus over the other in China and the US. The Chinese study reported incidence of ICU admittance that was twice as high for patients with influenza-related pneumonia than for patients with RSV infection⁴¹. In the US study, the higher cost of RSV hospitalization versus influenza hospitalization was attributed to patients with RSV infection incurring more than double the mechanical ventilator use than patients with influenza infection, as well as patients with RSV infection having an average LOS nearly double that of patients with influenza infection⁴⁷. The greater cost of RSV hospitalization was seen in all three age groups studied (20–44, 45–59, and ≥60 years)⁴⁷.

HCRU studies

This SLR identified 33 studies that reported HCRU, specifically 28 studies reporting ICU admission rates and/or use of MV and 12 reporting discharge to a higher level of care. Of these, 30 < > used laboratory tests to confirm RSV infection in patients^{2,11,13,14,41,43,48,50–68,70–73}, two used diagnosis codes^12,39, and one included patients during an RSV outbreak separate from an influenza outbreak or non-RSV and non-influenza seasons⁶⁹. The majority of the studies were retrospective, with six being prospective^{2,13,43,53,55,57}. Study locations were primarily in the US, Europe, and Asia, with the US being the most represented country.

Supplementary Tables A10–A15 present the details of the studies, for example, the number of adults with RSV infection, the mean/median age or age categories of the adults by the RSV infection determination method, and setting (hospital vs. outpatient). Studies that report the percentages of patients with specific comorbidities report only the most frequent comorbidities and not the overall percentage of patients having any comorbidities.

ICU admittance

All the studies reporting ICU admission rates used laboratory testing to confirm the RSV diagnosis (Supplementary Table A10), except for Zhou et al.⁶⁹, which relied on ICD diagnosis codes for ARI during an RSV outbreak (Supplementary Table A11). In the mostly retrospective studies of adults hospitalized with RSV infection, the percentages of patients who were admitted to the ICU ranged from 4–33.5% (Supplementary Table A10). Among the US studies, ICU admission ranged from 13–33.5%^{2,11,14,54,59,61–63,65}. Within the US studies and all studies combined, ICU admission rates appeared to not be associated with age (no formal statistical analysis was done); however, most of the studies had high mean/median ages. There appears to be no clear trend in ICU admission with comorbidity across the studies. This informal analysis was based on categorizing the extent of comorbidities in the population by the highest single specific comorbidity reported, whereby studies were assigned to have high (≥50%), middle (>30%–< 50%), and low (≤30%) levels of comorbidity, since only two studies reported the overall level of comorbidities in patients with RSV infection^55,67.

MV Use

Mechanical ventilation can be invasive, involving endotracheal intubation⁷⁵, or non-invasive, which includes high-flow nasal oxygen, continuous positive airway pressure, or bilevel intermittent positive airway pressure⁷⁶. Most of the studies in this review reporting MV rates did not specify whether the mechanism was invasive or noninvasive (Supplementary Tables A12 and A13); those that did are shown in Supplementary Table A14.

Among all the studies with laboratory confirmation of RSV diagnosis (Supplementary Table A12), the percentage of patients requiring MV ranged from 3.8–23.1%^{2,11,14,43,50,51,53–56,58,61,63–68}. In most of the studies, the patients were either aged ≥50 years or the mean or median age was >60 years. The percentage of patients needing MV spanned a wide range, but overall MV was needed in a minority of patients.

Additionally, one US study found that 9.8% of 13,841 patients hospitalized with RSV infection, as determined by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes, required any MV³⁹.

Discharged to a higher level of care

The percentage of adults hospitalized with RSV infection who were discharged to a level of care not previously needed before RSV-related hospitalization ranged from 5–46% (Supplementary Table A15)^{2,11–14,53,54,56,70–73}. The high of 46% was for patients with healthcare-associated RSV infection, and this was significantly higher than the 17% of patients with community-onset RSV infection who required care at a skilled nursing or rehabilitation facility following discharge (p = 0.04)⁷¹. There was no pattern of patient subgroups needing greater care based on age or comorbidity. Because most of the studies were in the US, there is no clear pattern based on geography, except that the second highest rate of requirement for higher level care was reported by a 12-country study, in which 36.1% of patients required professional care at home or discharge to institutional care⁵³. None of the studies estimated the cost for discharging patients with RSV infection to a higher level of care.

Evidence limitations and gaps

Study design and reporting limitations

Several limitations exist due to either study design or reporting limitations. In general, overall rates of comorbidities were not typically reported, limiting our ability to analyze the studies by severity of underlying illness. Among the cost studies, about half identified the RSV-positive population by ICD diagnosis codes, without laboratory confirmation. Without a diagnostic test result to confirm the presence of RSV infection, it is unclear whether the physician made the RSV diagnosis based on local RSV infection trends or clinical parameters, when another virus may have been responsible for the infection. Studies may have excluded some cost types because of limitations in the data, resulting in an underestimation of the cost of RSV infection (e.g. Rafferty et al.⁴⁹ does not include pharmacy or laboratory costs). Despite the known association of older age with greater risk of more severe RSV disease, most studies presented HCRU for those aged ≥18 years and did not present HCRU by age subgroups. In studies that reported MV, invasive MV was usually not distinguished, so its use could not be determined. Only one study presented costs associated with sequelae associated with RSV infection⁴⁰.

Gaps in the economic literature

The gap analysis of RSV-associated costs revealed a lack of available direct-cost estimates for many countries, with most studies conducted in the US (Figure 5), and only one study reporting indirect costs⁴⁵. Cost studies were variable in their measurement by age groups and were mostly direct costs for hospitalized patients (Figure 5 and Supplementary Figure A2).

Figure 5. Economic gap analysis. Abbreviations: RSV, respiratory syncytial virus; US, United States. ^a Excluding transplant studies and economic models. ^b Belgium, United Kingdom, and the Netherlands. ^c Sequelae costs⁴⁰ or incremental costs of RSV when compared to a control group⁴⁹. ^d Numbers indicate total number of studies in which studied age ranges exactly match those specified here. Studies with outcomes for multiple age groups are counted more than once. ^e Bosco et al.⁴⁰ determined RSV-attributable cardiorespiratory hospitalizations (based on ICD coding) during RSV peaks.

Owing to the limited number of studies available and lack of uniformity across them, it was difficult to create a high-level overview of baseline patient characteristics to compare costs across studies and across patient groups. The main limitation in the economic literature was the lack of uniformity in metrics across the studies. Costs were reported either for a specified period (e.g. 30 days, 8 weeks, 1 year) or for a medical incident (e.g. per hospitalization, per RSV case). Studies that reported costs for medical incidents did not provide an average or estimated duration of each incident (e.g. how many days a hospitalization lasts); therefore, it was not possible to create a conversion factor between periods and medical incidents to compare the costs across similar timeframes. Only two studies compared pre- and post-RSV-infection costs^12,46. Comparing pre- and post-RSV-infection costs among the same cohort to estimate incremental cost differences due to RSV infection is informative for identifying patients at risk of incurring higher costs. Because of data limitations, pharmacy and laboratory costs were not included, resulting in an underestimation of the costs of RSV infection⁴⁹. Despite a high incidence of comorbidities that are associated with higher risk of developing serious RSV infection among the patient populations in the studies in this SLR, only one study reported costs by comorbidity⁴² and only two studies reported costs by high-risk versus non-high-risk patient categories^12,46. Additional gaps are highlighted in Figure 6.

Figure 6. Evidence limitations and gaps in the economic literature. Abbreviations: ICD, International Statistical Classification of Diseases; RSV, respiratory syncytial virus; US, United States.

Gaps in the HCRU literature

As with the cost studies, the gap analysis of HCRU in patients with RSV infection revealed a lack of available estimates for many countries; most studies were conducted in the US (Figure 7 and Supplementary Figure A2). One of the knowledge gaps identified in a meeting of experts at the Centers for Disease Control and Prevention on 16–17 May 2016 is the understanding of the short- and long-term outcomes of RSV infection, including the impact on those adults who may need nursing home or long-term facility-related care⁷⁷. While the rates of discharge to a higher level of care following an RSV-associated hospitalization were reported in several studies, the cost associated with that higher level of care has not been quantified.

Figure 7. HCRU gap analysis. Abbreviations: HCRU, healthcare resource utilization; ICU, intensive care unit; MV, mechanical ventilation; RSV, respiratory syncytial virus; US, United States. ^aAustralia, Argentina, Brazil, Canada, France, Germany, Japan, Malaysia, Mexico, Republic of Korea, South Africa, US. ^bCyprus, Italy, Portugal. ^c One US study⁶⁹ reported outcomes during an RSV surge for patients hospitalized with ARI. This study is not represented in this table. ^d Two studies had cohorts slightly different from ≥18 years: Hill-Ricciuti et al.⁷¹ included patients aged >18 years, and Falsey et al.² included high-risk adults aged ≥21 years, nine of whom were part of an 132 hospitalized cohort (age range not reported). ^e “Elderly” was not defined in Belk et al.³⁹. ^f In one US study¹¹, data were presented for age subgroups 60–74 years, ≥60 years, and ≥75 years.

Because adults are not routinely tested for RSV, studies evaluating HCRU during RSV seasons versus periods of lower RSV and influenza infection rates are informative for broader understanding of morbidity from RSV infection even though the number of RSV cases is not confirmed in these studies. A difficulty in these studies is that winter viral seasons often overlap, necessitating assumptions about RSV impact during RSV peaks. Additional gaps are highlighted in Figure 8.

Figure 8. Evidence limitations and gaps in the HCRU literature (for systematic HCRU outcomes only). Abbreviations: HCRU, healthcare resource utilization; ICU, intensive care unit; MV, mechanical ventilation; RSV, respiratory syncytial virus; US, United States. ^aBelgium, United Kingdom, and the Netherlands.

Conclusion

In adults, RSV infection represents a substantial economic burden, despite the under-ascertainment of RSV infections due to a lack of routine testing and limitations of current diagnostic testing^18,29,30. There is evidence of under-detection of RSV infection, as well as a lack of cost and HCRU studies, in individuals aged <50 years and those aged 50–64 years²⁹. The degree of under-ascertainment in those aged ≥65 years is greater for RSV than for influenza⁷⁸.

Globally, the population aged ≥65 years is rapidly increasing in high-, middle-, and lower-middle-income countries⁷⁹. A US study found that the population of persons aged ≥55 years continued to grow in the first half of 2020, despite the high mortality rate from COVID-19⁸⁰, indicating that the cost burden of RSV infection could continue to rise in the absence of an RSV vaccine and as transmission mitigation efforts for COVID-19 wane. RSV infection is also a significant concern in nursing homes because of high transmission rates among a concentrated, highly susceptible population⁴⁰. Based on economic models of RSV vaccination in adults aged ≥60 years, the current national direct medical costs of RSV infections are high and are estimated to be $1.70–$3.35 billion in the US, $196.43 million in the United Kingdom, and $14.61 million in the Netherlands (adjusted to 2022 USD, see Supplementary Table A2)^81,82.

Among large studies (RSV-positive cases, n ≥ 100), the percentages of hospitalized adults with RSV infection who require ICU admission and/or MV were substantial, with many studies reporting rates of 10–20%⁵³.

Given the substantial data gaps and variability across studies, further research is needed to provide additional cost and HCRU data for certain age groups; countries, including middle- and low-income countries; cost in outpatient care settings; indirect costs associated with RSV infection; and costs and HCRU in patients at risk for severe outcomes due to underlying comorbidities. It is important for these studies to account for under-reporting of RSV incidence and costs⁸³. Studies suggest that there are health and cost impacts beyond the acute phase of RSV infection^38,40,49, highlighting the need to assess the long-term economic and health impacts in future studies. Despite these data gaps, the economic burden of RSV infections was found to be substantial, underscoring the need for RSV preventive strategies for reducing this burden.

Transparency

Declaration of financial/other relationships

AC, MG, and SW are full-time employees of RTI Health Solutions. Their compensation is unconnected to the studies on which they work. PG and CP are employees of Moderna, Inc. and hold shares and/or stock options in the company.

Author contributions

AC, SW, CP, and PG were involved in the conception and design of this study. MG, AC, SW, CP, and PG were involved in the analysis and interpretation of the data. MG led the drafting of the paper, with all authors involved in revising it critically for intellectual content. All authors gave final approval of the version to be published, and all authors agree to be accountable for all aspects of the work.

Reviewer disclosures

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

Previous presentations

The manuscript, in whole or in part, has not been published nor is currently under consideration for publication by any other journal. Preliminary analyses were presented at RSVVW’23 (7^th Respiratory Syncytial Virus Foundation [ReSViNET] conference), in Lisbon, Portugal on 22–24 February 2023, and will also be presented at the Communicable Diseases & Immunisation Conference (CDIC 2023) in Perth, Western Australia on 19–21 June 2023.

Acknowledgements

The authors thank John Forbes of RTI-HS for medical editing assistance. Moderna, Inc. provided funding for publication support in the form of manuscript writing, styling, and submission.

Additional information

Funding

This study was conducted by RTI Health Solutions under the direction of and funded by Moderna, Inc. RTI Health Solutions, an independent nonprofit research organization, received funding under a research contract with Moderna, Inc. to conduct this study and provide publication support in the form of manuscript writing, styling, and submission.