Healthcare resource use and costs following RSV-related hospitalizations among US adults aged 50 years and older

ABSTRACT

Respiratory syncytial virus (RSV), a common virus causing acute respiratory illness (ARI), can lead to severe disease among adults aged ≥50 y. We assessed healthcare resource utilization (HRU) and costs among United States (US) adults aged ≥50 y after hospitalization with RSV-ARI. Using 2015–2023 US claims data from the Optum® Clinformatics® Data Mart, three cohorts of patients aged ≥50 y were identified: patients with ≥1 RSV-ARI episode involving hospitalization (RSV-ARI cohort), patients with ≥1 influenza-ARI episode involving hospitalization (influenza-ARI cohort), and patients without recent ARI (control cohort). HRU and costs per-patient-per-month (PPPM) were assessed at 30 d, 3 months, and 1 y post-index. Adjusted regression models compared outcomes across cohorts. Overall, 14,759 patients were included in the RSV-ARI cohort, 77,468 in the influenza-ARI cohort, and 73,795 in the control cohort. The RSV-ARI cohort had significantly higher HRU vs. controls within 1 y post-index; adjusted incidence rate ratios (95% confidence interval) 30 d through 1 y post-index ranged from 81.07 (75.85, 86.65) to 11.56 (11.20, 11.93) for inpatient stays, 5.93 (5.58, 6.30) to 2.19 (2.09, 2.29) for emergency department visits, and 1.99 (1.95, 2.04) to 1.78 (1.75, 1.81) for outpatient visits. Adjusted total costs PPPM were higher for the RSV-ARI cohort vs. controls post-index (difference at 30 d: $37,025 [$36,345, $37,704]; 1 y: $6,699 [$6,476, $6,922]). HRU and costs among patients aged ≥50 y with RSV-ARI were higher vs. controls and generally similar between the RSV-ARI and influenza-ARI cohorts, demonstrating economic burden of severe RSV disease and the importance of RSV prevention.

GRAPHICAL ABSTRACT

Introduction

In adults, respiratory syncytial virus (RSV) is a common respiratory virus that often leads to acute respiratory illness (ARI), frequently accompanied by mild, cold-like symptoms.¹ However, RSV can lead to more severe disease, including hospitalization or even death, especially among certain increased-risk patients, such as adults aged ≥50 y, adults with underlying medical conditions (e.g. asthma, chronic obstructive pulmonary disease [COPD], heart failure [HF]) or weakened immune systems, and/or who reside in nursing homes.^2,3

Recent epidemiologic studies continue to demonstrate that RSV represents a substantial and underrecognized burden among adults in the United States (US). Analyses from the Centers for Disease Control and Prevention’s (CDC’s) Respiratory Syncytial Virus Hospitalization Surveillance Network (RSV-NET) surveillance system (2022–2023) report high rates of severe outcomes among adults aged ≥60 y, including intensive care unit admission and mortality.⁴ This evidence of the burden of RSV hospitalization is complemented by earlier evidence from a landmark prospective surveillance study conducted during the 1999–2003 winter seasons in Rochester, New York, US, which found that 3–7% of healthy adults aged ≥65 y and 4–10% of high-risk adults (aged ≥21 y with HF or chronic pulmonary disease) experienced RSV infection annually.⁵ The same study also estimated that RSV contributes to approximately 178,000 hospitalizations and 14,000 deaths each year in the US.⁵ In addition, more recent modeling studies suggest that RSV burden in adults aged ≥65 y has likely been historically underestimated due to under-ascertainment and limited testing, further emphasizing its public health impact.⁶ Consistent with this, a multicohort Markov model study with a 5-year time horizon estimated that, in the absence of RSV vaccination, RSV disease among US adults aged ≥60 y would result in nearly 827,000 hospitalizations and 66,000 deaths, specifically attributed to RSV-lower respiratory tract disease (LRTD).⁷

The introduction of RSV vaccines for adults aged ≥60 y in 2023, alongside updated Advisory Committee on Immunization Practices (ACIP) recommendations in 2025 to expand vaccination to increased-risk adults aged 50–59 y, has further increased interest in understanding the clinical and economic burden of RSV to inform prevention strategies.⁸ Real-world evidence from the 2023–2024 RSV season suggests that these vaccines are effective in reducing the risk of RSV-associated hospitalizations and emergency department encounters among adults aged ≥60 y.^9,10 However, vaccination uptake remains relatively limited, highlighting the continued need to better characterize the overall burden of RSV disease.¹¹

Previous studies have assessed the impact of severe RSV disease among adults on healthcare resource utilization (HRU) and costs. One retrospective, observational study of adults aged ≥18 y with RSV-LRTD highlighted the substantial costs of RSV-LRTD-attributable expenditures, such as hospitalization, emergency department (ED) visits, and outpatient visits, through 1 y post-ARI diagnosis. Overall annual HRU and cost expenditures summed to $95,127, with hospitalizations ($65,230) driving costs.¹² Another recent database analysis also identified an increase in mean weekly costs for adults aged ≥60 y and 18–59 y at high risk of severe RSV immediately before and following RSV diagnosis, compared with 2–8 weeks before RSV diagnosis.¹³ However, the descriptive nature and older data (2000–2020) used in this study represent an important limitation.¹³

Despite previous analyses of HRU and economic outcomes among adults aged ≥50 y with RSV-associated ARI (RSV-ARI), contemporary, real-world evidence including active comparator groups, such as adults aged ≥50 y with ARI associated with other vaccine-preventable respiratory diseases (e.g., influenza-ARI), remains limited. Prior research has suggested potentially worse health outcomes among adults hospitalized with RSV-ARI vs. those hospitalized with influenza-ARI, but these analyses did not include a control group without ARI, adequately adjust for confounding variables, nor account for influenza vaccination status.^14,15 More recent comparative analyses have similarly suggested that RSV may be associated with equal or greater severity than influenza among hospitalized adults, although important methodological limitations remain.¹⁶

The aim of this study was to assess and compare the HRU and economic outcomes of US patients aged ≥50 y after hospitalization with RSV-ARI, hospitalization with influenza-ARI, or no recent ARI. Clinical outcomes from this study have been previously described.¹⁷ Findings from this study shed light on the HRU and cost burden of RSV among adults aged ≥50 y and can help to guide future RSV prevention efforts and economic impact evaluations.

Methods

Study design, population, and data source

This retrospective, observational study utilized data from the Optum® Clinformatics® Data Mart (CDM),¹⁸ including claims data from patients enrolled in commercial or Medicare Advantage insurance plans, to evaluate the clinical and economic outcomes associated with severe RSV disease. Clinical outcomes from this study, and associated methodology and study design, have been previously reported.¹⁷

Empirical algorithms were used to identify patients with RSV or influenza and define the period of an ARI episode. A medically attended ARI episode was defined as a period with ≥1 inpatient, ED, or outpatient encounter with ARI diagnosis (Appendix A1). An RSV-ARI episode was defined as a medically attended ARI episode with ≥1 RSV diagnosis during the episode, or ≥1 positive RSV lab test within ±7 d of the start and end dates of the episode (Appendix A2). An influenza-ARI episode was defined as a medically attended ARI episode with ≥1 influenza diagnosis during the episode (Appendix A3). Influenza-ARI was defined using diagnosis codes alone, excluding laboratory-confirmed influenza-ARI episodes without a corresponding influenza diagnosis. Laboratory results, where available in the Optum® CDM, were included as qualifying criteria for defining RSV-ARI episodes to enhance case capture, given that RSV is often underdiagnosed or underidentified in routine clinical practice and administrative claims data (the occurrence of which has been reported in prior research).^19,20

Data between October 1, 2015 and June 30, 2023 were included in the analysis; the identification period for ARI episodes was October 1, 2016–June 2, 2023. Outcomes of interest were measured during the index ARI episode and during the post-index period at defined timepoints of 30 d, 3 months, and 1 y post-index (Figure 1).

Figure 1.

Study design schema.

Abbreviations: ARI, acute respiratory illness; CDM, Clinformatics® Data Mart; RSV, respiratory syncytial virus.

Cohort design & eligibility criteria

As described in Singer et al.,¹⁷ three cohorts of patients aged ≥50 y were constructed: 1) those who had ≥1 RSV-ARI episode involving hospitalization (RSV-ARI cohort), 2) those who had ≥1 influenza-ARI episode involving hospitalization (influenza-ARI cohort), and 3) those without a recent ARI (control cohort). Based on the date of the index RSV-ARI episode, five control patients were matched with each RSV-ARI cohort patient (Figure 1). Matching on index date distributions between cohorts was conducted for this study and has similarly been applied in recently published research on coronavirus disease 2019 (COVID-19).^21–23

Adults with influenza-ARI hospitalization were selected as an active comparator for disease burden as another vaccine-preventable, potentially serious viral respiratory illness. Controls with no recent ARI were used as a comparator group for disease burden, including cost and HRU, among adults aged ≥50 y. In the absence of severe RSV disease, study outcomes would be expected to occur at a background rate as observed in the control group, thereby making them an appropriate comparator (after appropriate adjustment for differences between baseline characteristics). Age ≥50 y was selected as part of the study eligibility criteria because the CDC recommends RSV vaccination for adults aged 50–74 y who are at increased risk for severe RSV disease (e.g., due to underlying health conditions, immunocompromised status, or long-term care facility residence) as well as for all adults aged ≥75 y, as of August 2026.²

Patients were included in the RSV-ARI or influenza-ARI cohorts if their ARI-episode occurred at age ≥50 y, and they had continuous claims enrollment for ≥1 y before the episode’s start. If a patient had >1 eligible RSV- or influenza-ARI episode (Appendix B), an episode was randomly selected, with its start date as the index date.

Patients were included in the control cohort if they had no RSV- or influenza-ARI episode at age ≥50 y ever observed for the patient in the data cut, an eligible index date at age ≥50 y matching the exact index date of a patient in the RSV-ARI cohort, ≥12 months of continuous claims enrollment before the index date, and no recent ARI, defined as no claims with an ARI diagnosis within 28 d before the index date.

Study measures and outcomes

During the index ARI episode, key HRU outcomes were captured and reported descriptively, including inpatient admission, ED visits, outpatient visits, invasive mechanical ventilation use or intensive care unit (ICU) admission, and discharge destination from the last inpatient admission during the ARI episode. Discharge destination outcomes were assessed among patients who had ≥1 inpatient admission during the ARI episode and were discharged alive. Total costs (i.e., medical and pharmacy costs) were also measured.

During the post-index period, HRU and total cost outcomes were reported per patient per month (PPPM) at 30 d, 3 months, and 1 y post-index. HRU PPPM, calculated as the total number of HRU events of a given type in the population by these time points, divided by the total number of person-months, included inpatient admissions, ED visits, and outpatient visits. Total costs PPPM were calculated using the same approach and included medical service costs (inpatient, ED, outpatient, and other costs) and pharmacy costs. Cost outcomes in the study were based on standardized costs (cost values adjusted by Optum® using proprietary algorithms to represent a consistent approximation of the allowed or reimbursed amounts) from claims. All costs were reported in 2023 United States dollars (USD).

Analytical approach

Patient characteristics (for all three cohorts) and outcomes during the ARI episode (for RSV-ARI and influenza-ARI cohorts) were summarized using descriptive statistics; detailed methodology on descriptive reporting of study measures has been previously described.¹⁷

PPPM HRU and cost outcomes up to 30 d, 3 months, and 1 y were described and compared for each of the three cohorts; however, patients were not required to have available follow-up data at each of these time points to be eligible, allowing for the capture of data from patients who were censored or died before such landmark timepoints. Count and continuous outcomes were summarized using mean and standard deviation (SD), which was derived as the SD of the patient-level PPPM outcomes in a cohort by a given time point. The total person-months used in the calculation for each PPPM outcome were reported. HRU outcomes post-index were analyzed as count variables and reported as PPPM. Binary outcomes were summarized using counts and proportions.

Unadjusted and adjusted generalized linear models were fitted to compare each type of outcome for the RSV-ARI vs. influenza-ARI and control cohorts and stratified by previously defined subgroups.¹⁷ Adjusted models controlled for demographics (age at index, sex, race, region, health insurance payer type), temporal trends (long-term trend using spline, and an indicator variable for before vs. after the COVID-19 pandemic), and risk factors for serious infection (e.g., chronic respiratory diseases, HF, coronary artery disease [CAD]), prior vaccination (influenza, COVID-19, or pneumococcal vaccination), and baseline HRU and cost measures.

A log-linked Poisson regression model was fitted to the HRU outcomes with the logarithm of the follow-up time truncated by each time point as an offset term. A Gaussian linear regression model was fitted to the healthcare cost outcomes with each patient weighted by the follow-up time truncated by each time point. Both models also used a robust sandwich estimator for the standard error estimation, which ensures correct statistical inferences even when a Gaussian or other distributional assumption is not perfectly met.²⁴ Accounting for the length of follow-up time as a weight allowed patients with longer follow-up lengths to contribute more to the estimation of the model parameters than patients with short follow-up lengths, mimicking the calculation of PPPM outcomes at the population level. Logistic regression modeling was utilized to compare binary outcomes within ARI episodes between RSV-ARI and influenza-ARI cohorts.

The sample size was designed to achieve 90% power with a two-sided type I error of 0.05. In consideration of the relative infrequency of RSV testing and diagnosis,^19,20 a minimum of 2,091 patients was required for the RSV-ARI cohort, and a selection ratio of 1:≥1 between the RSV-ARI cohort and each comparator cohort was applied.

Ethics

As this study was conducted under a data use agreement using a limited deidentified dataset that did not constitute human participants research as defined by the 45 CFR 46 Category 4 Common Rule (https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46),²⁵ institutional review board approval and informed consent were not required. This study followed the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) reporting guideline for cohort studies.

Results

Population and baseline characteristics

In total, 14,759 patients meeting the eligibility criteria were included in the RSV-ARI cohort, 77,468 in the influenza-ARI cohort, and 73,795 in the control cohort (Figure S1). Mean (SD) ages of patients in the RSV-ARI and influenza-ARI cohorts were higher than in the control cohort (76.5 [9.8] and 75.4 [9.9] vs. 69.5 [10.4] y, respectively). In all three cohorts, patients were majority White (70.2–73.5%) and female (55.0–60.6%). Baseline characteristics between the RSV-ARI and influenza-ARI cohorts were generally similar, although the RSV-ARI cohort had a higher comorbidity burden. The control cohort had the lowest comorbidity burden. Baseline characteristics for all three cohorts are detailed in Table 1.

Table 1.

Patient baseline characteristics by cohort^a.

	Cohort of RSV-ARI with hospitalization	Cohort of influenza-ARI with hospitalization	P-value	Control cohort	P-value
	N = 14,759	N = 77,468		N = 73,795
	(A)	(B)	(A) vs (B)	(C)	(A) vs (C)
Demographics as of the index date
Age (y), mean (SD)	76.5 (9.8)	75.4 (9.9)	<.001	69.5 (10.4)	<.001
Age (y), n (%)			<.001		<.001
50–59	945 (6.40%)	6,149 (7.94%)		15,372 (20.83%)
60–64	966 (6.55%)	5,703 (7.36%)		7,828 (10.61%)
65–74	3,986 (27.01%)	21,955 (28.34%)		26,094 (35.36%)
≥75	8,862 (60.04%)	43,661 (56.36%)		24,501 (33.20%)
Female, n (%)b	8,938 (60.56%)	43,296 (55.89%)	<.001	40,594 (55.01%)	<.001
Race, n (%)			<.001		<.001
White	10,847 (73.49%)	54,405 (70.23%)		52,178 (70.71%)
Black	1,512 (10.24%)	9,860 (12.73%)		7,214 (9.78%)
Asian	321 (2.17%)	1,652 (2.13%)		2,836 (3.84%)
Hispanic	1,225 (8.30%)	7,261 (9.37%)		7,488 (10.15%)
Unknown	854 (5.79%)	4,290 (5.54%)		4,079 (5.53%)
Geographic region of residence, n (%)			<.001		<.001
Northeast	2,796 (18.94%)	11,367 (14.67%)		8,809 (11.94%)
Midwest	3,810 (25.81%)	17,671 (22.81%)		16,260 (22.03%)
West	3,415 (23.14%)	15,027 (19.40%)		18,775 (25.44%)
South	4,729 (32.04%)	33,362 (43.07%)		29,349 (39.77%)
Unknown	<.1%	<.1%		602 (0.82%)
Months post-index, mean (SD)	18.8 (19.1)	23.0 (21.7)	<.001	26.2 (21.5)	<.001
Season at index, n (%)			<.001		1.0
Winter	8,161 (55.30%)	45,691 (58.98%)		40,805 (55.30%)
Spring	2,268 (15.37%)	17,310 (22.34%)		11,340 (15.37%)
Summer	986 (6.68%)	4,051 (5.23%)		4,930 (6.68%)
Autumn	3,344 (22.66%)	10,416 (13.45%)		16,720 (22.66%)
COVID-19 period at index, n (%)			<.001		1.0
Before COVID-19 pandemic	8,170 (55.36%)	53,797 (69.44%)		40,850 (55.36%)
After start of the COVID-19 pandemic	6,589 (44.64%)	23,671 (30.56%)		32,945 (44.64%)
Insurance payer type at index, n (%)c			<.001		<.001
Medicare	13,471 (91.27%)	69,450 (89.65%)		50,185 (68.01%)
Commercial	1,108 (7.51%)	7,042 (9.09%)		22,386 (30.34%)
Commercial and Medicare	167 (1.13%)	926 (1.20%)		1,190 (1.61%)
Risk factors for severe RSV disease during the 1 y baseline period, n (%)
Chronic cardiopulmonary diseasesd,e	12,111 (82.06%)	56,784 (73.30%)	<.001	23,794 (32.24%)	<.001
Chronic respiratory diseasesd	8,396 (56.89%)	37,344 (48.21%)	<.001	11,685 (15.83%)	<.001
COPD	6,713 (45.48%)	29,606 (38.22%)	<.001	6,949 (9.42%)	<.001
Asthma	2,766 (18.74%)	11,564 (14.93%)	<.001	4,328 (5.86%)	<.001
Chronic cardiac diseasese	9,602 (65.06%)	44,218 (57.08%)	<.001	17,289 (23.43%)	<.001
Heart failure	5,746 (38.93%)	24,067 (31.07%)	<.001	5,120 (6.94%)	<.001
CAD	6,000 (40.65%)	28,374 (36.63%)	<.001	10,589 (14.35%)	<.001
Cardiac arrhythmias	6,306 (42.73%)	26,567 (34.29%)	<.001	9,372 (12.70%)	<.001
Diabetes	6,379 (43.22%)	34,253 (44.22%)	<.05	17,595 (23.84%)	<.001
Chronic kidney disease	5,668 (38.40%)	26,102 (33.69%)	<.001	9,705 (13.15%)	<.001
Chronic liver disease	1,446 (9.80%)	6,740 (8.70%)	<.001	3,530 (4.78%)	<.001
Immunosuppressive conditionsf	534 (3.62%)	1,621 (2.09%)	<.001	487 (0.66%)	<.001
Prior RSV-ARI	324 (2.20%)	0 (0.00%)	–	0 (0.00%)	–
CCI, mean (SD)g	3.3 (2.5)	2.9 (2.4)	<.001	1.0 (1.6)	<.001
Preventive measures during the 1 y baseline period, n (%)
Influenza vaccination	5,359 (36.31%)	25,074 (32.37%)	<.001	18,787 (25.46%)	<.001
COVID-19 vaccination	542 (3.67%)	1,405 (1.81%)	<.001	2,358 (3.20%)	<.01
Pneumococcal vaccination	1,873 (12.69%)	9,357 (12.08%)	<.05	6,177 (8.37%)	<.001
HRU during the baseline period
Number of inpatient admissions, mean (SD)	0.9 (1.5)	0.7 (1.3)	<.001	0.1 (0.5)	<.001
Number of ED visits, mean (SD)	1.6 (2.9)	1.4 (2.8)	<.001	0.6 (1.6)	<.001
Number of outpatient visits, mean (SD)	40.1 (39.3)	34.3 (36.4)	<.001	15.1 (20.0)	<.001
Received care at long-term care facility, n (%)	1,787 (12.11%)	8,275 (10.68%)	<.001	1,371 (1.86%)	<.001
Received care at skilled nursing facility, n (%)	2,652 (17.97%)	12,034 (15.53%)	<.001	2,173 (2.94%)	<.001
Received home health services, n (%)	7,904 (53.55%)	36,397 (46.98%)	<.001	12,090 (16.38%)	<.001

Statistical significance based on P < .05.

^aBaseline characteristics were summarized for 14,759 patients in the RSV-ARI cohort and 77,468 patients in the influenza-ARI cohort with inpatient as their highest level of care in their selected ARI episode, and for 73,795 patients in the control cohort with their matched RSV-ARI patients having inpatient as the highest level of care in the selected ARI episode.

^bA total of <.1% of participants were reported with an unknown sex in the RSV-ARI, influenza-ARI, and control cohorts.

^cUnknown insurance payer type at index was <.1% across all cohorts.

^dAsthma, COPD, and other respiratory conditions including cystic fibrosis and interstitial lung disease.

^eHF, CAD, and cardiac arrhythmias.

^fImmunosuppressive conditions were defined as having any of the following procedures or conditions: hematopoietic stem cell transplant, solid organ transplant, or HIV.

^gThe CCI was defined based on criteria by Quan (2011).³⁴

Abbreviations: ARI, acute respiratory illness; CAD, coronary artery disease; CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; ED, emergency department; HF, heart failure; HIV, human immunodeficiency virus; RSV, respiratory syncytial virus; SD, standard deviation; vs, versus.

During the 12-month baseline period, patients in the RSV-ARI cohort had a mean (SD) of 0.9 (1.5) inpatient admissions, 1.6 (2.9) ED visits, and 40.1 (39.3) outpatient visits. Patients in the influenza-ARI cohort had 0.7 (1.3) inpatient admissions, 1.4 (2.8) ED visits, and 34.3 (36.4) outpatient visits, while control patients had 0.1 (0.5) inpatient admissions, 0.6 (1.6) ED visits, and 15.1 (20.0) outpatient visits. Mean (SD) total healthcare costs (2023 USD) during the 12-month baseline period in the RSV-ARI, influenza-ARI, and control cohorts were $77,409 ($135,793), $61,681 ($115,629), and $17,576 ($46,784), respectively.

Outcomes during ARI episodes

The mean (SD) duration of ARI episodes was 22.8 (27.6) days in the RSV-ARI cohort, compared with 21.9 (31.5) days in the influenza-ARI cohort. During ARI episodes, the RSV-ARI and influenza-ARI cohorts had similar outpatient visit percentages (54.0% vs. 50.8%, respectively), and ED visit percentages (18.7% vs. 20.6%, respectively). Both the RSV-ARI and influenza-ARI cohorts had a similar mean (SD) number of inpatient stays (1.1 [0.3] per patient) and mean (SD) total length of stay (15.9 [27.7] vs. 15.6 [31.6] days, respectively). Mean (SD) total healthcare costs (2023 USD) were $47,626 ($65,677) in the RSV-ARI cohort and $48,293 ($70,631) in the influenza-ARI cohort (Table S1). Clinical outcomes and healthcare costs between RSV versus influenza were generally similar during ARI episodes in the adjusted analyses.

Outcomes during the follow-up period

The RSV-ARI cohort had high HRU and healthcare costs PPPM over 30 d, 3 months, and 1 y post-index, predominantly driven by inpatient costs, compared with the control cohort with no recent ARI (Tables 2 and 3). The number of inpatient stays and outpatient visits PPPM were the highest in the RSV-ARI cohort, though generally numerically similar to the influenza-ARI cohort across the follow-up periods. HRU and healthcare costs PPPM were also generally comparable between the RSV-ARI and influenza-ARI cohorts.

Table 2.

HRU PPPM at the cohort level at 30 d, 3 months, and 1 y post-index.

	RSV-ARI Cohort			Influenza-ARI Cohort			Control Cohort
	(N = 14,759)			(N = 77,468)			(N = 73,795)
	30 d	3 months	1 y	30 d	3 months	1 y	30 d	3 months	1 y
Total person-time (months)	14,180	39,426	121,569	74,460	207,906	674,896	73,032	214,312	721,059
HRU during post-index period, PPPM, mean (SD)a
Inpatient admissions	1.160	0.480	0.212	1.144	0.466	0.191		0.013	0.013	0.013
	(0.550)	(0.388)	(0.264)	(0.516)	(0.370)	(0.245)		(0.174)	(0.093)	(0.055)
Emergency department visits	0.303 (0.708)	0.198 (0.443)	0.152 (0.302)	0.336 (0.733)	0.203 (0.424)	0.144 (0.269)		0.050 (0.402)	0.051 (0.236)	0.050 (0.152)
Outpatient visits	3.876	4.274	3.909	3.520	3.913	3.497		1.255	1.258	1.271
	(4.102)	(3.704)	(3.367)	(3.852)	(3.593)	(3.195)		(2.664)	(2.155)	(1.777)

^aThe mean of the HRU PPPM was calculated as the total number of relevant HRU events in a cohort by a given time point divided by the total person-months up to that time point in the cohort. The SD of the HRU PPPM was calculated as the SD of the patient-level HRU events PPPM in a cohort by a given time point, weighted by the patient-level follow-up length up to that time point in the cohort.

Abbreviations: ARI, acute respiratory illness; PPPM, per-patient-per-month; RSV, respiratory syncytial virus; SD, standard deviation.

Table 3.

Costs PPPM at the cohort level at 30 d, 3 months, and 1 y post-index.

	RSV-ARI Cohort			Influenza-ARI Cohort			Control Cohort
	(N = 14,759)			(N = 77,468)			(N = 73,795)
	30 d	3 months	1 y	30 d	3 months	1 y	30 d	3 months	1 y
Total person-time (months)	14,180	39,426	121,569	74,460	207,906	674,896	73,032	214,312	721,059
Costs during post-index period, PPPM, mean (SD)a
Total costs	$41,390	$22,636	$12,240	$41,813	$22,256	$11,181	$1,505	$1,587	$1,628
	($42,501)	($28,497)	($18,493)	($46,676)	($30,718)	($19,104)	($8,011)	($5,725)	($4,545)
Medical costs	$40,643	$21,859	$11,437	$41,210	$21,635	$10,548	$1,253	$1,334	$1,378
	($42,413)	($28,361)	($18,239)	($46,649)	($30,651)	($18,946)	($10,983)	($6,394)	($4,571)
Inpatient costs	$37,470	$18,558	$8,377	$38,062	$18,526	$7,778	$411	$486	$518
	($41,805)	($27,058)	($16,058)	($45,833)	($29,311)	($16,911)	($7,368)	($4,580)	($2,945)
Emergency department costs	$925	$634	$484	$1,079	$665	$476	$107	$108	$107
	($3,293)	($2,049)	($1,313)	($3,740)	($2,064)	($1,255)	($1,355)	($756)	($454)
Outpatient costs	$2,099	$2,474	$2,371	$1,922	$2,264	$2,109	$675	$685	$692
	($6,477)	($6,755)	($6,506)	($6,677)	($6,862)	($6,393)	($6,384)	($3,556)	($2,753)
Other costs	$150	$194	$205	$148	$180	$186	$59	$55	$61
	($1,395)	($1,090)	($676)	($1,646)	($1,085)	($772)	($2,061)	($708)	($552)
Pharmacy costs	$747	$776	$803	$603	$622	$633	$252	$253	$250
	($2,443)	($2,203)	($2,153)	($2,183)	($1,957)	($1,870)	($1,378)	($1,245)	($1,081)

^aCosts are presented in 2023 USD. The mean of the costs PPPM was calculated as the total number of relevant costs in a cohort by a given time point divided by the total person-months up to that time point in the cohort. The SD of the costs PPPM was calculated as the SD of the patient-level costs PPPM in a cohort by a given time point, weighted by the patient-level follow-up length up to that time point in the cohort.

Abbreviations: ARI, acute respiratory illness; PPPM, per-patient-per-month; RSV, respiratory syncytial virus; SD, standard deviation; USD, United States dollar.

HRU outcomes

At 30 d post-index, the RSV-ARI cohort had a higher HRU frequency PPPM vs. the control cohort for inpatient stays (adjusted incidence rate ratio [aIRR]: 81.07 [95% CI: 75.85, 86.65]), ED visits (aIRR: 5.93 [95% CI: 5.58, 6.30]), and outpatient visits (aIRR: 1.99 [95% CI: 1.95, 2.04]). The RSV-ARI and influenza-ARI cohorts had similar inpatient and outpatient visits PPPM, though ED visit rates were lower in the RSV-ARI cohort (aIRR: 0.88 [95% CI: 0.85, 0.92]; Figure 2).

Figure 2.

Adjusted association of HRU frequency PPPM with severe RSV-ARI at 30 d, 3 months, and 1 y post-index.

Note: Statistical significance based on P < .05.

Abbreviations: aIRR, adjusted incidence rate ratio; ARI, acute respiratory illness; CI, confidence interval; HRU, healthcare resource utilization; PPPM, per-patient-per-month; RSV, respiratory syncytial virus.

Similarly, at 3 months post-index, compared with the control cohort, the RSV-ARI cohort had higher rates of inpatient stays (aIRR: 31.24 [95% CI: 29.88, 32.67]), ED visits (aIRR: 3.22 [95% CI: 3.07, 3.38]), and outpatient visits (aIRR: 2.09 [95% CI: 2.05, 2.12]). The RSV-ARI and influenza-ARI cohorts maintained a similar pattern to 30 d post-index for inpatient, outpatient, and ED visit rates, though ED visit rates remained significantly lower in the RSV-ARI cohort (aIRR: 0.93 [95% CI: 0.89, 0.97]).

At 1 y post-index, the RSV-ARI cohort had higher rates vs. the control cohort for inpatient stays (aIRR: 11.56 [95% CI: 11.20, 11.93]), ED visits (aIRR: 2.19 [95% CI: 2.09, 2.29]), and outpatient visits (aIRR: 1.78 [95% CI: 1.75, 1.81]). The rate of inpatient stays for the RSV-ARI cohort vs. the control cohort remained high at 1 y post-index. As with previous follow-up points, rates for all three visit types at 1 y post-index were similar between the RSV-ARI and influenza-ARI cohorts. Although ED visit rates remained numerically lower in the RSV-ARI cohort at 1 y, a significant difference was no longer present at this time point (p-value: 0.143). While the differences between the RSV-ARI and control cohorts reduced in magnitude over time, differences in HRU rates remained statistically significant.

Total healthcare costs

Total, medical, and pharmacy costs PPPM during the 30 d post-index period were higher in the RSV-ARI cohort compared with the control cohort, with adjusted cost differences PPPM of $37,025 (95% CI: $36,345, $37,704), $36,953 (95% CI: $36,274, $37,632), and $72 (95% CI: $36, $107), respectively. Pharmacy costs PPPM were higher by a smaller magnitude. While statistically significant, at 30 d post-index the RSV-ARI cohort had total healthcare costs PPPM (-$1,412 [95% CI: -$2,119, -$705]) and medical costs PPPM (-$1,407 [95% CI: -$2,114, -$700]) that were lower than the influenza-ARI cohort by a smaller magnitude, while pharmacy costs were not different between the two cohorts. Higher total, medical, and pharmacy costs PPPM in the RSV-ARI cohort compared to the control cohort were similarly observed at 3 months (adjusted cost differences PPPM: $16,879 [95% CI: $16,469, $17,288], $16,811 [95% CI: $16,402, $17,220], and $68 [95% CI: $40, $96], respectively); however, incremental PPPM costs between the RSV-ARI and control cohorts were lower at 3 months than at 30 d post-index (Figure 3).

Figure 3.

Adjusted total, medical, and pharmacy cost differences PPPM for severe RSV-ARI compared to controls and severe influenza-ARI 30 d, 3 months, and 1 y post-index.

Note: Adjusted cost difference and 95% CI values shown. All costs were adjusted to 2023 USD using the medical care component of the Consumer Price Index; data reflect average cost PPPM. Linear regression models weighted by follow-up time were used to estimate the cost differences, and a robust sandwich estimator was used to estimate the standard errors and derive the 95% CIs and P-values. The analysis was conducted among patients in the combined sample of RSV-ARI cohort, influenza-ARI cohort, and the control cohort. Patients in RSV-ARI and influenza-ARI cohorts were restricted to those with IP as the highest level of care in their selected ARI episode. Patients in the control cohort were restricted to those with their matched RSV patients having IP as the highest level of care in the selected ARI episode.

*Statistically significant based on P < .05.

†CI crosses zero.

Abbreviations: ARI, acute respiratory illness; CI, confidence interval; IP, inpatient; PPPM, per-patient-per-month; RSV, respiratory syncytial virus; USD, United States dollars.

At 1 y post-index, the RSV-ARI cohort vs. the control cohort had higher total, medical, and pharmacy costs PPPM (adjusted cost differences PPPM: $6,699 [95% CI: $6,476, $6,922], $6,600 [95% CI: $6,379, $6,822], and $98 [95% CI: $70, $127], respectively). The RSV-ARI and influenza-ARI cohorts had similar total, medical, and pharmacy costs PPPM at 1 y post-index with no statistically significant differences in these outcomes.

Medical cost subcomponents

At 30 d post-index, the RSV-ARI cohort had higher adjusted inpatient, ED, and outpatient costs PPPM (adjusted cost differences PPPM: $35,796 [95% CI: $35,124, $36,467], $637 [95% CI: $579, $696], $494 [95% CI: $380, $609]) than the control cohort. Compared to the influenza-ARI cohort, the RSV-ARI cohort had lower inpatient (-$1,195 [95% CI: -$1,898, -$492]) and ED (-$161 [95% CI: -$222, -$100]) costs PPPM, and similar outpatient costs PPPM (Figure S2), though these adjusted cost differences PPPM were smaller than those estimated between the RSV-ARI and control cohorts.

At 3 months post-index, a similar trend to 30 d post-index was observed across medical cost subcomponents PPPM when comparing the RSV-ARI and control cohorts. RSV-ARI cohort inpatient, ED, and outpatient costs PPPM (adjusted cost differences PPPM: $15,739 [95% CI: $15,345, $16,133], $304 [95% CI: $269, $339], $707 [95% CI: $600, $813], respectively) continued to be higher than the control cohort. Compared to the influenza-ARI cohort, the RSV-ARI cohort still had lower inpatient costs PPPM (-$710 [95% CI: -$1,121, -$300]); ED and outpatient costs PPPM were numerically similar at this follow-up point, and outpatient costs were not statistically significantly different.

At 1 y post-index, the RSV-ARI cohort had higher inpatient, ED, and outpatient costs PPPM (adjusted cost differences PPPM: $5,821 [95% CI: $5,634, $6,008], $164 [95% CI: $142, $186], and $558 [95% CI: $462, $654], respectively) compared to the control cohort. The PPPM cost differences between RSV-ARI and control cohorts at 1 y post-index were smaller in magnitude compared to PPPM cost differences up to 30 d and 3 months post-index. The RSV-ARI cohort had similar costs PPPM across all medical cost subcomponents as the influenza-ARI cohort.

Subgroup analyses during the follow-up period

HRU and costs among the RSV-ARI, influenza-ARI, and control cohorts at 30 d, 3 months, and 1 y post-index stratified by age and comorbidity subgroups (i.e., diabetes, COPD, asthma, HF, and CAD) were largely consistent with those in the overall sample (Table S2, Table S3). The highest adjusted increases in inpatient visits PPPM at 1 y post-index were observed among patients with diabetes (aIRR: 7.44 [95% CI: 7.09, 7.81]) and asthma (aIRR: 7.39 [95% CI: 6.72, 8.13]) in the RSV-ARI cohort vs. the control cohort (Table S2).

At 1 y post-index, the subgroup of the RSV-ARI cohort with diabetes at baseline had higher total costs PPPM (adjusted cost difference PPPM: $7,319 [95% CI: $6,936, $7,702]) compared to the control cohort. The RSV-ARI cohort subgroups with COPD at baseline and asthma at baseline had higher total costs PPPM (adjusted cost differences PPPM: $6,793 [95% CI: $6,432, $7,155] and $5,724 [95% CI: $5,226, $6,223], respectively) than the control cohort. The RSV-ARI cohort subgroups with HF at baseline and CAD at baseline had higher total costs PPPM (adjusted cost differences PPPM: $8,262 [95% CI: $7,794, $8,730] and $7,511 [95% CI: $7,100, $7,922], respectively) compared to the control cohort. The subgroups of the RSV-ARI cohort with diabetes, COPD, asthma, HF, or CAD at baseline had similar total costs PPPM as the influenza-ARI cohort by respective baseline comorbidity (Table S3).

The RSV-ARI cohort had substantially increased HRU and costs PPPM compared to the control cohort across stratified subgroups, with the incremental economic burden maintained at 12 months post-index; in contrast, the RSV-ARI and influenza-ARI cohorts had smaller and mostly non-significant differences in HRU and costs PPPM over time. While the magnitude of total healthcare cost difference between the RSV-ARI and control cohorts in most subgroups was similar compared with the overall analysis, patients with asthma and HF at baseline had slightly smaller and slightly larger cost differences, respectively.

Discussion

This retrospective study using a large US claims database offers a novel evaluation of the long-term healthcare and economic burden among adults aged ≥50 y hospitalized with RSV-ARI, compared to those hospitalized for influenza-ARI and those without any recent ARI.

In an effort to bridge the gaps in the existing literature on the long-term impacts of RSV, the present study examined the relationship between severe RSV disease and economic outcomes, including HRU and costs, up to 30 d, 3 months, and 1 y post-index, adjusting for confounding variables to account for the differences in baseline characteristics observed between cohorts. Sample sizes for the RSV-ARI and influenza-ARI cohorts were the result of relative infrequency of RSV testing and diagnosis compared with influenza testing and diagnosis.^19,20 Compared to the control cohort, the RSV-ARI cohort had higher rates of HRU across visit types at 30 d post-index. Because the study focused on outcomes following an RSV-ARI episode involving hospitalization, requiring an inpatient stay during the ARI episode by design, the comparison of inpatient utilization rates may be less interpretable. Despite this design feature of the study, other types of HRU were consistently more frequent in the RSV-ARI cohort than the control cohort, and differences in inpatient utilization persisted well beyond short-term follow-up. A retrospective case–control study of patients with a claim for any RSV event between 2012 and 2013 found that RSV-attributable HRU, including hospital stays, ED visits, outpatient appointments, and prescriptions, was significantly higher for patients with RSV versus controls 1 y post-index, especially among older patients.²⁶ Our findings, based on 2015–2023 data, suggest that a significant HRU burden remains among adults aged ≥50 y who have been hospitalized with RSV in more recent years. The RSV-ARI cohort also had higher adjusted total and medical costs PPPM than controls, with adjusted cost differences PPPM of $37,025 and $36,953, respectively, and a substantial adjusted acute inpatient cost difference of $35,796. Notable differences in adjusted monthly costs persisted over time; over 1 y following the ARI episode, the RSV-ARI cohort had incremental costs of over $6,000 PPPM compared with the control cohort.

While this study’s findings provide further evidence of the significant economic burden of RSV, in alignment with previous studies,²⁶ they also suggest a long-term increased economic burden among adults aged ≥50 y with severe RSV disease, based on examining RSV-ARI episodes involving hospitalization. While previous studies have considered short-term outcomes and did not always include an appropriate comparator group, the present study analyzed an extensive list of both short- and long-term outcomes. Additionally, both an influenza-ARI cohort and a control cohort without any recent ARI were included as comparator groups in this study, thereby providing a rigorous assessment of the burden of severe RSV disease in contrast to those hospitalized with influenza and those with expected background HRU in the absence of a medically attended ARI. RSV outcomes could then be compared to expected outcomes in patients without severe RSV disease, providing useful data for real-world healthcare decision-making related to RSV prevention efforts. RSV immunization programs targeting adults aged ≥50 y may help address RSV-related HRU burden and cost.²⁷

In 2024, a population-based, multi-cohort model projected $15.2 and $9.7 billion 2023 USD in direct and indirect costs, respectively, among US adults aged ≥18 y with acute LRTD associated with RSV. Adults aged ≥65 y bore the majority of the economic burden for RSV-LRTD, accounting for 63% of direct medical costs (primarily driven by the high rate of hospitalizations [76%], the largest contributor to direct costs).²⁸ A cohort study estimated a total of $81,529 in healthcare expenditures among hospitalized RSV-lower respiratory tract illness patients aged ≥65 y during the year after the RSV-lower respiratory tract infection index, with $37,435 attributed to the acute phase and $44,094 attributed to the long-term phase.¹² Another model projected RSV-LRTD in adults aged ≥18 y incurred $25.0 billion in costs over five years, with $10.3 billion attributable to hospitalizations. In adults aged 65–74 y without chronic medical conditions, direct costs from hospitalizations were estimated at $12,670 per episode; this number rose to $20,537 if the patient had a chronic or immunocompromising medical conditions.²⁸ In 2020, an observational study also reported a mean cost of $16,034 associated with hospitalization among adults aged ≥60 y with RSV (comparable to influenza [$15,163]). However, the costs, estimated in 2013 USD, have not been adjusted for inflation since 2013 and are based on patients hospitalized in a single healthcare system, Kaiser Permanente Southern California, potentially limiting generalizability.²⁹ In a 2022 systematic literature review of HRU and cost data associated with RSV, of the 42 included studies, only three compared costs with influenza in the US and reported that RSV hospitalization costs were generally higher than influenza hospitalization costs, primarily associated with increased comorbidities.³⁰ Variations in methodology, patient populations, and adjustment factors may explain differences in RSV versus influenza hospitalization costs between the present study and the literature. Differences between RSV and influenza in readmission, all-cause mortality, and myocardial infarction risks were small in the RSV-ARI and influenza-ARI cohorts analyzed in this study, as reported previously.¹⁷

When evaluating HRU and cost outcomes stratified by comorbidity subgroup, patients in the RSV-ARI and influenza-ARI cohorts exhibited similar trends to the overall cohort samples, with similar HRU and costs maintained through 1 y post-index and substantially higher HRU and costs PPPM compared to the control cohort. Chronic conditions have been reported to place adults at a higher risk for hospitalization,³¹ and more complex hospital care.³² These findings highlight the substantial economic impacts among patients with an increased risk of severe RSV disease.²⁸

Meanwhile, despite statistically significant differences in some outcomes between the RSV-ARI and influenza-ARI cohorts at certain time points, HRU and costs were generally similar in magnitude overall. Differences that were observed during shorter follow-up periods were no longer present at 1 y. Between the RSV-ARI and influenza-ARI cohorts during ARI episodes, adjusted HRU and costs were similar with adjusted incidence rate ratios ranging from 0.90–1.08 across HRU visit type. With baseline differences accounted for in adjusted analyses, patients in the RSV-ARI cohort had slightly higher outpatient visit rates but similar total lengths of inpatient admissions. This contrasts with findings from a recent prospective multicenter study reporting that patients with RSV often had longer inpatient admissions compared with influenza patients.¹⁵ Of the study population with influenza, 50.6% had received the corresponding vaccine,¹⁵ which has been observed to attenuate the severity of influenza hospitalization, given the protective effect seasonal vaccination has against severe influenza outcomes.¹⁶ This protective effect was demonstrated in a cohort study of hospitalized ARI patients, which stratified RSV versus influenza disease severity comparisons by influenza vaccination status.¹⁶ RSV hospitalization was generally more severe than influenza hospitalization of influenza-vaccinated patients, but similarly severe when compared with influenza hospitalization of unvaccinated patients.¹⁶ In the present study, influenza vaccination status was recorded over a 1 y baseline period (32.4% among those in the influenza-ARI cohort) rather than based on seasonal administration, and analyses were not stratified by influenza vaccination status but did account for this as a covariate in adjusted analyses.

The consistently elevated HRU among patients with RSV-ARI generally aligned with the HRU among patients with influenza-ARI, highlighting the burden associated with severe RSV disease requiring hospitalization in US adults aged ≥50 y. Similarities in HRU and cost outcomes between RSV-ARI and influenza-ARI cohorts over long-term follow up in this study suggest that drawing on established influenza vaccination strategies may be beneficial in informing RSV vaccination practices to improve implementation of vaccination recommendations. During the 2023–2024 season, 46.2% and 69.7% of adults aged 50–64 y and ≥65 y, respectively, received an influenza vaccine,³³ while 10–25% aged ≥60 y received an RSV vaccine.^11,34 Given continued RSV knowledge and practice gaps among healthcare professionals (HCPs),^35,36 the similarities in disease burden may aid HCP and patient education efforts on RSV prevention, especially if education efforts highlight the effectiveness of RSV vaccination against RSV-associated hospitalizations and ED encounters for adults aged ≥60 y with and without immunocompromising conditions.^9,10,16 High vaccine effectiveness suggests that vaccinating adults aged ≥50 y can lower both hospitalization and ED visit rates, thereby lessening the substantial economic impact.

Limitations

Limitations of this study include typical biases of real-world retrospective analyses. The Optum® claims database used covers only commercially insured or Medicare Advantage patients. Study findings may therefore not be fully generalizable to other populations, such as uninsured patients or to those outside of the US. Detailed limitations of this retrospective study have been previously described.¹⁷

Data accuracy issues, such as imprecise death dates and possible misclassification of RSV and ARI diagnoses, may create imprecision in the follow-up time or lead to selection bias, respectively.^6,17

RSV diagnosis codes were anticipated to be highly specific for RSV cases, whereas influenza diagnosis codes might be less specific (but more sensitive) for influenza cases; because of these expected differences in coding patterns, ARI episodes with both diagnoses were classified as RSV-ARI, with likely influenza misclassification, assuming coinfection was rare. In the RSV-ARI cohort, cases with both influenza and RSV diagnoses were not excluded to avoid reducing the sample size. The proportion of RSV-ARI episodes with both an RSV and an influenza diagnosis was only 6% in the study population, aligning with findings from national surveillance studies that highlight the relatively infrequent occurrence of coinfection; RSV-NET reported low (2.2% [95% CI: 1.2%, 3.8%]) coinfection rates for hospitalized patients with RSV across 12 US states.⁴ Therefore, any potential measurement error from coinfection is expected to have had a minimal impact on the results.

To qualify as controls, patients could not have had an RSV- or influenza-ARI episode at age ≥50 y during the study period, which may have selected for a healthier cohort. However, since most adults in these plans are unlikely to have truly never experienced influenza- or RSV-ARI during the study period, the bias may be limited and not absolute. Baseline differences were also controlled through adjusted analyses. Additionally, follow-up duration was shortest in the RSV-ARI cohort relative to comparator cohorts, raising the possibility of informative censoring. That is, patients with the greatest disease severity, and potentially higher cumulative costs, may be observed for a shorter period due to increased mortality. If high-cost patients die before accruing longer-term HRU, PPPM estimates may be underestimated. Conversely, if costs are predominantly concentrated in the acute phase prior to death, PPPM estimates could be overestimated. Thus, while bias is possible, its direction is likely bidirectional. Given that PPPM estimates standardize costs by observed time, and that our study design did not require patients to have ≥1 month of follow-up to be eligible for HRU and cost calculations (avoiding bias due to excluding patients who censored or died before such landmark timepoints), the overall impact on results is expected to be limited.

The study period (2015–2023) included the COVID-19 pandemic (beginning March 2020); analyses were adjusted for respiratory virus seasonality and COVID-19 temporality. Temporal trends were also accounted for using splines in adjusted analyses. Changes in RSV testing patterns, possibly influenced by the pandemic, may have improved generalizability for patients with RSV-ARI identified in later years.

Since RSV vaccines are now available for use in certain US adults,³⁷ outcomes associated with RSV illness may improve as RSV vaccination uptake continues to increase.

Conclusions

HRU and costs among adults aged ≥50 y were substantially higher in the RSV-ARI cohort vs. controls. These findings support and expand upon previous literature describing the general US adult population with both hospitalized and non-hospitalized ARI associated with severe RSV disease, providing further evidence of the importance of RSV prevention in at-risk adults to reduce disease burden. Comparable costs between the RSV-ARI and influenza-ARI cohorts suggest that leveraging influenza prevention strategies and education may be useful in guiding future RSV prevention efforts to improve outcomes for adults aged ≥50 y at risk of RSV.

Biographies

David Singer is the Head of US Real World Evidence and Health Outcomes for Vaccines at GSK. He holds a PharmD from the University of North Carolina at Chapel Hill and an MS in applied health economics and outcomes research from Thomas Jefferson University.

Yan Wang is a Vice President at Analysis Group. He holds a ScD in environmental health and biostatistics and an MS in environmental health from the Harvard T.H. Chan School of Public Health.

Elizabeth M. La was a Director of US Real World Evidence and Health Outcomes for Vaccines at GSK at the time of this study. She holds a PhD in health policy and management from the University of North Carolina at Chapel Hill and an MSE in industrial and operations engineering from the University of Michigan.

Aozhou Wu is a Manager at Analysis Group. He holds a PhD and MHS in epidemiology, an MHS in biostatistics, and an MSE in computer science from Johns Hopkins University.

Susan I. Gerber is a Senior Medical Director for Adult and Respiratory Viral Vaccines, US Medical Affairs at GSK. She holds an MD from Loyola University Chicago Stritch School of Medicine.

Keith A. Betts is a Managing Principal at Analysis Group. He holds a PhD in biostatistics from Harvard University and an MA in biostatistics from University of California, Berkeley.

Appendix A. Key definitions and algorithms

Appendix A1. Medically-attended ARI episode

A medically-attended ARI episode was defined as a period with one or a cluster of inpatient, ED, or outpatient encounters with ARI diagnoses (the ICD-10-CM codes for ARI diagnoses are displayed in Appendix B).

• The start date of a medically-attended ARI episode (T₀) was identified as the first inpatient admission or non-inpatient encounter with an ARI diagnosis, after the beginning of one’s continuous claims enrollment and the end date of the previous ARI episode, whichever was later.

• The corresponding end date of the medically-attended ARI episode (T₁) was the latter of the following two dates:

  • Date of last non-inpatient encounter with an ARI diagnosis between T₀ and T₀ + 28 days (Figure A1a).
  • Date of discharge from the last hospitalization with an ARI diagnosis, with the admission date of the hospitalization falling between T₀ and T₀ + 28 days (Figure A1b).

The use of 28 days limited the period of an ARI episode to be 28 days (unless a hospitalization crosses the 28-day mark), which ensured relative consistency in the length across episodes, avoiding clinically implausibly long ARI episodes. The length of a medically-attended ARI episode varied and reflected different disease severity and the extent that medical attention was involved.

Figure A1.

Schema of a medically-attended ARI episode. (a) Scenario 1: T₁ ≤ T₀ + 28 days (one illustration with hospitalization; one illustration without hospitalization). (b) Scenario 2: T₁ > T₀ + 28 days (i.e., the discharge from the last hospitalization during the episode extended beyond T0 + 28 days).

Abbreviations: ARI, acute respiratory illness; D₀, first ARI diagnosis; D₁, outpatient with ARI diagnosis; D₂, discharge from inpatient with ARI diagnosis; dx, diagnosis; IP, inpatient; OP, outpatient; T₀, start date of the medically-attended ARI episode; T₁, end date of the medically-attended ARI episode.

Appendix A2. RSV-ARI episode

An RSV-ARI episode was identified as a medically-attended ARI episode where there was:

• ≥1 RSV diagnosis (ICD-10-CM for RSV diagnosis: B97.4, J12.1, J20.5, J21.0) during the medically-attended ARI episode, or

• ≥1 positive RSV lab test during a period from 7 days before the start date of the medically-attended ARI episode to 7 days after the end date of the medically-attended ARI episode (Figure A2).

RSV-ARI episodes included those episodes with only RSV diagnoses, those with only positive RSV tests, and those with both RSV diagnoses and positive RSV tests. ARI episodes with only a positive RSV test but no RSV diagnosis were qualified as an RSV-ARI episode under the current definition. Although lab values were only available for 30–40% of the patients in Optum® Clinformatics® Data Mart, the lab results were used as available to help improve the identification of RSV-ARI episodes. If an ARI episode was qualified as both an RSV-ARI episode and an influenza-ARI episode, the RSV-ARI episode took precedent for how the ARI episode was categorized (i.e., the episode was viewed as an RSV-ARI episode for the cohort assignment purposes).

Figure A2.

Schema of the testing window for an RSV-ARI episode. (a) Scenario 1: T₁ ≤ T₀ + 28 days (one illustration with hospitalization; one illustration without hospitalization). (b) Scenario 2: T > ₁ T₀ + 28 days (i.e., the discharge from the last hospitalization during the episode extended beyond T₀ + 28 days).

Abbreviations: ARI, acute respiratory illness; D₀, first ARI diagnosis; D₁, outpatient with ARI diagnosis; D₂, discharge from inpatient with ARI diagnosis; dx, diagnosis; IP, inpatient; OP, outpatient; T₀, start date of the medically-attended ARI episode; T₁, end date of the medically-attended ARI episode.

Appendix A3. Influenza-ARI episode

An influenza-ARI episode was identified as a medically-attended ARI episode where there was:

• ≥1 influenza diagnosis (ICD-10-CM for influenza diagnosis: J09–J11) during the medically-attended ARI episode.

Given the large number of influenza-ARI episodes and that influenza is better documented in claims, we required an influenza-ARI episode to have ≥1 influenza diagnosis, which excluded those ARI episodes with only a positive influenza lab test without a proper influenza diagnosis. If an ARI episode was qualified as both an RSV-ARI episode and an influenza-ARI episode, the RSV-ARI episode would take precedent for how the ARI episode was categorized (i.e., the episode would be viewed as an RSV-ARI episode for the cohort assignment purposes).

Appendix B. ARI diagnosis ICD-10-CM codes

ICD-10-CM	Description
A01.03	Typhoid pneumonia
A02.22	Salmonella pneumonia
A15.5	Tuberculosis of larynx, trachea and bronchus
A20.2	Pneumonic plague
A21.2	Pulmonary tularemia
A22.1	Pulmonary anthrax
A31.0	Pulmonary mycobacterial infection
A36.0	Pharyngeal diphtheria
A36.1	Nasopharyngeal diphtheria
A36.2	Laryngeal diphtheria
A36.89	Other diphtheritic complications
A37	Whooping cough
A37.0	Whooping cough due to Bordetella pertussis
A37.00	Whooping cough due to Bordetella pertussis without pneumonia
A37.01	Whooping cough due to Bordetella pertussis with pneumonia
A37.1	Whooping cough due to Bordetella parapertussis
A37.10	Whooping cough due to Bordetella parapertussis without pneumonia
A37.11	Whooping cough due to Bordetella parapertussis with pneumonia
A37.8	Whooping cough due to other Bordetella species
A37.80	Whooping cough due to other Bordetella species without pneumonia
A37.81	Whooping cough due to other Bordetella species with pneumonia
A37.9	Whooping cough, unspecified species
A37.90	Whooping cough, unspecified species without pneumonia
A37.91	Whooping cough, unspecified species with pneumonia
A42.0	Pulmonary actinomycosis
A43.0	Pulmonary nocardiosis
A48.1	Legionnaire’s Disease
A48.2	Nonpneumonic Legionnaires’ disease [Pontiac fever]
A52.72	Syphilis of lung and bronchus
A52.73	Symptomatic late syphilis of other respiratory organs
A54.5	Gonococcal pharyngitis
A54.84	Gonococcal pneumonia
A56.4	Chlamydial infection of pharynx
A70	Chlamydia psittaci infections
A78	Q fever
B00.2	Herpesviral gingivostomatitis and pharyngotonsillitis
B01.2	Varicella pneumonia
B05.2	Measles complicated by pneumonia
B06.81	Rubella pneumonia
B08.5	Enteroviral vesicular pharyngitis
B25.0	Cytomegaloviral pneumonitis
B37.1	Pulmonary candidiasis
B38.0	Acute pulmonary coccidioidomycosis
B38.2	Pulmonary coccidioidomycosis, unspecified
B39.0	Acute pulmonary histoplasmosis capsulati
B39.2	Pulmonary histoplasmosis capsulati, unspecified
B44.0	Invasive pulmonary aspergillosis
B58.3	Pulmonary toxoplasmosis
B59	Pneumocystosis
B77.81	Ascariasis pneumonia
B97.2	Coronavirus as the cause of diseases classified elsewhere
B97.4	Respiratory syncytial virus as the cause of diseases classified elsewhere
J00	Acute nasopharyngitis [common cold]
J01	Acute sinusitis
J01.0	Acute maxillary sinusitis
J01.00	Acute maxillary sinusitis, unspecified
J01.01	Acute recurrent maxillary sinusitis
J01.1	Acute frontal sinusitis
J01.10	Acute frontal sinusitis, unspecified
J01.11	Acute recurrent frontal sinusitis
J01.2	Acute ethmoidal sinusitis
J01.20	Acute ethmoidal sinusitis, unspecified
J01.21	Acute recurrent ethmoidal sinusitis
J01.3	Acute sphenoidal sinusitis
J01.30	Acute sphenoidal sinusitis, unspecified
J01.31	Acute recurrent sphenoidal sinusitis
J01.4	Acute pansinusitis
J01.40	Acute pansinusitis, unspecified
J01.41	Acute recurrent pansinusitis
J01.8	Other acute sinusitis
J01.80	Other acute sinusitis
J01.81	Other acute recurrent sinusitis
J01.9	Acute sinusitis, unspecified
J01.90	Acute sinusitis, unspecified
J01.91	Acute recurrent sinusitis, unspecified
J02	Acute pharyngitis
J02.0	Streptococcal pharyngitis
J02.8	Acute pharyngitis due to other specified organisms
J02.9	Acute pharyngitis, unspecified
J03	Acute tonsillitis
J03.0	Streptococcal tonsillitis
J03.00	Acute streptococcal tonsillitis, unspecified
J03.01	Acute recurrent streptococcal tonsillitis
J03.8	Acute tonsillitis due to other specified organisms
J03.80	Acute tonsillitis due to other specified organisms
J03.81	Acute recurrent tonsillitis due to other specified organisms
J03.9	Acute tonsillitis, unspecified
J03.90	Acute tonsillitis, unspecified
J03.91	Acute recurrent tonsillitis, unspecified
J04	Acute laryngitis and tracheitis
J04.0	Acute laryngitis
J04.1	Acute tracheitis
J04.10	Acute tracheitis without obstruction
J04.11	Acute tracheitis with obstruction
J04.2	Acute laryngotracheitis
J04.3	Supraglottitis, unspecified
J04.30	Supraglottitis, unspecified, without obstruction
J04.31	Supraglottitis, unspecified, with obstruction
J05	Acute obstructive laryngitis [croup] and epiglottitis
J05.0	Acute obstructive laryngitis [croup]
J05.1	Acute epiglottitis
J05.10	Acute epiglottitis without obstruction
J05.11	Acute epiglottitis with obstruction
J06	Acute upper respiratory infections of multiple and unspecified sites
J06.0	Acute laryngopharyngitis
J06.9	Acute upper respiratory infection, unspecified
J09	Influenza due to certain identified influenza viruses
J09.X	Influenza due to identified novel influenza A virus
J09.X1	Influenza due to identified novel influenza A virus with pneumonia
J09.X2	Influenza due to identified novel influenza A virus with other respiratory manifestations
J09.X3	Influenza due to identified novel influenza A virus with gastrointestinal manifestations
J09.X9	Influenza due to identified novel influenza A virus with other manifestations
J10	Influenza due to other identified influenza virus
J10.0	Influenza due to other identified influenza virus with pneumonia
J10.00	Influenza due to other identified influenza virus with unspecified type of pneumonia
J10.01	Influenza due to other identified influenza virus with the same other identified influenza virus pneumonia
J10.08	Influenza due to other identified influenza virus with other specified pneumonia
J10.1	Influenza due to other identified influenza virus with other respiratory manifestations
J10.2	Influenza due to other identified influenza virus with gastrointestinal manifestations
J10.8	Influenza due to other identified influenza virus with other manifestations
J10.81	Influenza due to other identified influenza virus with encephalopathy
J10.82	Influenza due to other identified influenza virus with myocarditis
J10.83	Influenza due to other identified influenza virus with otitis media
J10.89	Influenza due to other identified influenza virus with other manifestations
J11	Influenza due to unidentified influenza virus
J11.0	Influenza due to unidentified influenza virus with pneumonia
J11.00	Influenza due to unidentified influenza virus with unspecified type of pneumonia
J11.08	Influenza due to unidentified influenza virus with specified pneumonia
J11.1	Influenza due to unidentified influenza virus with other respiratory manifestations
J11.2	Influenza due to unidentified influenza virus with gastrointestinal manifestations
J11.8	Influenza due to unidentified influenza virus with other manifestations
J11.81	Influenza due to unidentified influenza virus with encephalopathy
J11.82	Influenza due to unidentified influenza virus with myocarditis
J11.83	Influenza due to unidentified influenza virus with otitis media
J11.89	Influenza due to unidentified influenza virus with other manifestations
J12	Viral pneumonia, not elsewhere classified
J12.0	Adenoviral pneumonia
J12.1	Respiratory syncytial virus pneumonia
J12.2	Parainfluenza virus pneumonia
J12.3	Human metapneumovirus pneumonia
J12.8	Other viral pneumonia
J12.81	Pneumonia due to SARS-associated coronavirus
J12.82	Pneumonia due to COVID-19
J12.89	Other viral pneumonia
J12.9	Viral pneumonia, unspecified
J13	Pneumonia due to Streptococcus pneumoniae
J14	Pneumonia due to Hemophilus influenzae
J15	Bacterial pneumonia, not elsewhere classified
J15.0	Pneumonia due to Klebsiella pneumoniae
J15.1	Pneumonia due to Pseudomonas
J15.2	Pneumonia due to Staphylococcus
J15.20	Pneumonia due to Staphylococcus, unspecified
J15.21	Pneumonia due to Staphylococcus aureus
J15.211	Pneumonia due to methicillin-susceptible Staphylococcus aureus
J15.212	Pneumonia due to methicillin-resistant Staphylococcus aureus
J15.29	Pneumonia due to other Staphylococcus
J15.3	Pneumonia due to Streptococcus, group B
J15.4	Pneumonia due to other streptococci
J15.5	Pneumonia due to Escherichia coli
J15.6	Pneumonia due to other Gram-negative bacteria
J15.7	Pneumonia due to Mycoplasma pneumoniae
J15.8	Pneumonia due to other specified bacteria
J15.9	Unspecified bacterial pneumonia
J16	Pneumonia due to other infectious organisms, not elsewhere classified
J16.0	Chlamydial pneumonia
J16.8	Pneumonia due to other specified infectious organisms
J17	Pneumonia in diseases classified elsewhere
J18	Pneumonia, unspecified organism
J18.0	Bronchopneumonia, unspecified organism
J18.1	Lobar pneumonia, unspecified organism
J18.2	Hypostatic pneumonia, unspecified organism
J18.8	Other pneumonia, unspecified organism
J18.9	Pneumonia, unspecified organism
J20	Acute bronchitis
J20.0	Acute bronchitis due to Mycoplasma pneumoniae
J20.1	Acute bronchitis due to Hemophilus influenzae
J20.2	Acute bronchitis due to Streptococcus
J20.3	Acute bronchitis due to coxsackievirus
J20.4	Acute bronchitis due to parainfluenza virus
J20.5	Acute bronchitis due to respiratory syncytial virus
J20.6	Acute bronchitis due to rhinovirus
J20.7	Acute bronchitis due to echovirus
J20.8	Acute bronchitis due to other specified organisms
J20.9	Acute bronchitis, unspecified
J21	Acute bronchiolitis
J21.0	Acute bronchiolitis due to respiratory syncytial virus
J21.1	Acute bronchiolitis due to human metapneumovirus
J21.8	Acute bronchiolitis due to other specified organisms
J21.9	Acute bronchiolitis, unspecified
J22	Unspecified acute lower respiratory infection
J36	Peritonsillar abscess
J39.0	Retropharyngeal and parapharyngeal abscess
J39.1	Other abscess of pharynx
J44.0	Chronic obstructive pulmonary disease with (acute) lower respiratory infection
J44.1	Chronic obstructive pulmonary disease with (acute) exacerbation
J85	Abscess of lung and mediastinum
J85.0	Gangrene and necrosis of lung
J85.1	Abscess of lung with pneumonia
J85.2	Abscess of lung without pneumonia
J85.3	Abscess of mediastinum
J86	Pyothorax
J86.0	Pyothorax with fistula
J86.9	Pyothorax without fistula
J95.851	Ventilator associated pneumonia
J96.0	Acute respiratory failure
J96.00	Acute respiratory failure, unspecified whether with hypoxia or hypercapnia
J96.01	Acute respiratory failure with hypoxia
J96.91	Respiratory failure, unspecified with hypoxia
U00	COVID-19
U07.1	COVID-19
U49	COVID-19
U50	COVID-19
U85	COVID-19

Abbreviations: ARI, acute respiratory illness; COVID-19, Coronavirus Disease 2019; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; SARS, severe acute respiratory syndrome.

Funding Statement

This study was sponsored by GlaxoSmithKline (Study identifier VEO-000616). Support for third-party writing assistance for this article, provided by Madeline Block, Costello Medical, US, was funded by GlaxoSmithKline in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022).

Disclosure statement

DS and SIG are employed by GSK and hold financial equities in GSK. YW, AW, and KAB are employees of Analysis Group, which received funding from GSK to conduct this study. EML was employed by GSK at the time of this study and holds financial equities in GSK.

Data sharing statement

For requests for access to anonymized subject-level data, please contact the corresponding author.

Prior presentation

The data in this manuscript are based on work that was also presented as posters at the Academy of Managed Care Pharmacy (AMCP) Nexus 2024, 14–17 October 2024, Las Vegas, Nevada, US; Infectious Diseases Week (IDWeek) 2024, 16–19 October 2024, Los Angeles, California, US; American Heart Association (AHA) Scientific Sessions 2024, 16–18 November 2024, Chicago, Illinois, US; and at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2025 Annual Conference, 13–16 May 2025, Montreal, Quebec, Canada.

Abbreviations

ACIP

Advisory Committee on Immunization Practices

ARI

acute respiratory illness

aIRR

adjusted incidence rate ratio

CAD

coronary artery disease

CDC

Centers for Disease Control and Prevention

CDM

Optum® Clinformatics® Data Mart

CI

confidence interval

COPD

chronic obstructive pulmonary disease

COVID-19

coronavirus disease 2019

ED

emergency department

HCP

healthcare provider

HF

heart failure

HRU

healthcare resource utilization

ICU

intensive care unit

LRTD

lower respiratory tract disease

PPPM

per patient per month

RSV

respiratory syncytial virus

RSV-NET

RSV Hospitalization Surveillance Network

SD

standard deviation

STROBE

STrengthening the Reporting of OBservational studies in Epidemiology

US

United States

USD

US dollars

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2720988