ABSTRACT
Background
Recent studies suggest that respiratory syncytial virus (RSV) can cause severe illness in terms of in‐hospital outcomes and mortality. The degree to which RSV hospitalization is associated with cardiovascular outcomes, particularly those known to occur following acute respiratory infections, is poorly described.
Methods
We conducted a retrospective cohort study of adults aged ≥ 65 years hospitalized with a diagnosis of RSV, influenza, urinary tract infection (UTI), or fracture between 2011 and 2020 in Ontario, Canada. Outcomes included subsequent heart failure, myocardial infarction, stroke, or atrial fibrillation events up to 1‐year post‐discharge, as well as in‐hospital and acute outcomes.
Results
Cardiovascular events were subsequently identified in 18.5% (n = 474/2558) of patients who had an RSV‐related hospitalization, compared to 17.7% (2961/16,688), 12.1% (8908/73,587), and 8.4% (941/11,262) of patients initially hospitalized with influenza, UTI, or fracture, respectively. In matched analyses, RSV hospitalization was associated with a greater rate of subsequent heart failure events relative to all other patient groups (HR range, 1.48–3.74), both in patients with or without pre‐existing cardiovascular conditions. The rate of atrial fibrillation events was also higher in RSV patients, although this was dependent on pre‐existing cardiovascular conditions and the comparator group considered. RSV patients were also more likely to be transferred to intensive care (OR range, 1.48–3.55) and had a higher rate of mortality (HR range, 1.49–3.98).
Conclusion
Our findings suggest that RSV is an important determinant of serious post‐discharge cardiovascular outcomes in older adults. Further, they underline the importance of vaccination in this population, regardless of pre‐existing risk factors.
Keywords: aging, cardiovascular outcomes, hospitalization, respiratory syncytial virus, viral
Summary.
- Keypoints
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○Adults aged ≥ 65 years hospitalized for RSV experienced significantly higher rates of illness‐related outcomes such as length of stay, transfer to intensive care, and 30‐day mortality, as compared to patients hospitalized with influenza, urinary tract infection or fracture.
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○The rate of heart failure up to 1‐year post‐discharge, regardless of pre‐existing cardiovascular conditions, was significantly higher, as was atrial fibrillation.
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- Why does this paper matter?
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○Hospitalization for RSV is associated with more severe illness in‐hospital as well as long‐term cardiovascular outcomes, more so than influenza and non‐respiratory infection related admissions.
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○Our findings suggests that vaccine recommendations should be extended to all adults aged 65 years and older, not just those aged 75 years and older or those with pre‐existing cardiopulmonary conditions.
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1. Introduction
Respiratory syncytial virus (RSV) has traditionally been neglected as an important acute respiratory infection (ARI) outside of childhood, thus the perceived risk in adults aged ≥ 60 years is low. Vaccines (Arexvy, GSK; ABRYSVO, Pfizer; mRESVIA, Moderna) have recently been approved in the US, Canada, and Europe for adults aged ≥ 60 years. Findings from randomized trials [1] indicate they have similar safety profiles as the first and second doses of the Pfizer‐BioNTech COVID‐19 vaccine [2], although excess rates of Guillain‐Barré syndrome have been suggested from early analyses of safety monitoring [3] and administrative billing [4] databases. Although usually only 20%–30% as incident as influenza, evidence suggests that RSV is significantly more likely to cause severe disease in hospitalized older adults, particularly in terms of mortality [5, 6, 7, 8], need for mechanical ventilation and/or critical care [6, 9], and hospital length of stay [6, 9]. This appears to be compounded in the oldest old and those with comorbidities, as the hospitalization rate for individuals aged ≥ 80 years is approximately 8 per 1000 compared to 0.5 per 1000 for those aged 45–54 years, while the relative risk for hospitalization is 2–10‐fold higher for those with chronic obstructive pulmonary disease, asthma, heart disease, diabetes, and chronic kidney disease than individuals without those comorbidities [10].
Prior to the COVID‐19 pandemic, RSV, along with Streptococcus pneumoniae and influenza, had the greatest contribution to the global acute respiratory infection burden, accounting for approximately 1.2 million deaths per year and 22 million disability‐adjusted life‐years lost in adults aged ≥ 60 years [11]. Somewhat underappreciated is the substantial impact of these pathogens on the likelihood of cardiovascular outcomes. For example, the rate of myocardial infarction (MI) and stroke is significantly greater in the weeks following an influenza diagnosis or hospitalization [12, 13, 14], as is the rate of any acute cardiovascular event following a clinically diagnosed or laboratory‐confirmed influenza [15]. Others have shown the risk of ischemic heart disease or heart failure can be elevated for nearly a decade following pneumonia [16, 17]. These findings are supported by studies indicating that vaccination against influenza or pneumococcus is protective against cardiovascular events and related death [18], particularly in those who are already at high risk [19]. While it appears that many types of respiratory infections are associated with subsequent cardiovascular outcomes [20], and that cardiac events are a common complication of laboratory‐confirmed RSV hospitalizations, especially in severe cases [21], there is a paucity of data comparing outcomes among older adults hospitalized due to RSV compared to other types of hospital admissions.
We sought to estimate the subsequent rate of cardiovascular events and other serious outcomes in older adults hospitalized for RSV. We compared the incidence of these outcomes to the incidence in patients from three diverse groups: those hospitalized for influenza (another ARI), urinary tract infections (a non‐ARI infection), and fractures (not infectious related).
2. Methods
2.1. Study Design, Setting, and Population
We performed a cohort study of patients hospitalized in Ontario, Canada. Records of all hospital discharge summaries for patients aged ≥ 65 years from 2011 to 2020 were obtained from the Discharge Abstract Database (DAD) and Same Day Surgery (SDS) database. Four patient cohorts were established during this time period using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canadian Version (ICD‐10‐CA) codes recorded as admission diagnoses (Table S1): a primary cohort of patients hospitalized for RSV, and three comparator cohorts of patients hospitalized for influenza, urinary tract infection (UTI), and fracture. Patients were only included if admissions occurred during months when influenza and RSV circulated (Table S2), as confirmatory viral testing data is not always available for all patient records. Given that RSV tends to circulate earlier than influenza [22], this window represents 1 month prior to the week in which the percentage of individuals testing positive for influenza exceeded 5%, and ending the week in which cases fell below 5% [23]. Only the first instance of RSV, influenza, UTI, or fracture as an admitting diagnosis over the study period was selected as the index event for a given patient (i.e., subsequent hospitalizations were not included for the primary analysis). However, patients admitted with UTI or fracture as a diagnosis in the 3 months prior to the index RSV or influenza admission, or those admitted with multiple index conditions (e.g., RSV and fracture) were flagged for sensitivity analyses. An example diagram of patient follow‐up during a single RSV/influenza season can be found in Figure 1. Records were excluded for patients with an invalid identification number, or a missing or invalid birth date, death date, or any baseline characteristic used to calculate propensity scores. Records were also excluded if the patient was a non‐Ontario resident at the time of index admission, a long‐term care resident, or if they were hospitalized (both elective and non‐elective procedures) within 2 weeks prior to the index event. Long‐term care residents were excluded because they tend to exhibit distinct patterns of RSV incidence and comorbidities [24], health services use [25] and outcomes related to transitioning post‐discharge [26]. Since RSV testing practices vary by institution [27], only influenza, UTI, or fracture patients admitted to hospitals in which RSV cases were identified in the same year were included.
FIGURE 1.
An example of patient follow‐up with lookback windows in a given RSV/influenza season. Patient A represents an individual hospitalized for either RSV, influenza, UTI or fracture, and who was followed for 1‐year without death or a reported cardiovascular hospitalization. Patient B was hospitalized for a cardiovascular event approximately 4 months following discharge and patient C died or was hospitalized for a UTI or fracture approximately 7 months following discharge.
The study datasets were linked using unique encoded identifiers and analyzed at ICES. ICES is an independent, non‐profit research institute whose legal status under Ontario's health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation, planning, and monitoring. This study was approved by the Health Sciences North Research Ethics Board (#24‐3).
2.2. Patient Characteristics
The following information was obtained for patients: age, sex, rural residence, northern residence, neighborhood income quintile, frailty status, prior influenza vaccination, and chronic conditions. Rural residence was classified as living in a community with a population ≤ 10,000, and northern residence was classified as belonging to either the Northeast or Northwest regions of the province. Frailty status was defined using the hospital frailty risk score, calculated as described previously [28]. Influenza vaccination within 180 days prior to the index event was obtained from the OHIP physician claims and the Ontario Drug Benefit database. Prior medical conditions were identified using ICD‐9 and ICD‐10 diagnostic codes and included heart failure, myocardial infarction (MI), stroke, atrial fibrillation (AF), dyslipidemia, diabetes, chronic obstructive pulmonary disease (COPD), and asthma (Table S1). Heart failure, MI, stroke, and AF were identified using codes at any diagnostic position with lookback to the beginning of the DAD and SDS (i.e., April 1988), and National Ambulatory Care Reporting System (NACRS; July 2000) databases. Dyslipidemia was identified with lookback to the beginning of DAD and SDS (April 1988) in any diagnostic position or two visits within 2 years in the OHIP physician claims database. Diabetes, COPD, and asthma were identified using ICES‐derived cohorts, which began in 1991–1993.
2.3. Primary and Secondary Outcomes
Our primary outcomes included hospital admissions or emergency department visits for heart failure, MI, stroke, or AF coded as an admitting or main diagnosis up to 1 year following the index admission. Our classification was not mutually exclusive, meaning patients could be considered a case for all outcomes for which they were diagnosed. Diagnostic codes from either DAD, SDS, or NACRS were used for specification (Table S1).
Our secondary outcomes included death within 30 days of the index admission, readmission to hospital within 30 days of discharge, transfer to a specialized care unit (intensive care or step‐down unit) during the index admission, and length of stay (days) of the index admission. Patient mortality was obtained from RPDB, and the remaining outcomes from DAD and/or SDS.
2.4. Statistical Analysis
Patient characteristics were summarized as the median and interquartile range or the count and frequency. For testing differences in outcomes between RSV and influenza, UTI, or fracture cohorts, we employed pairwise exact matching on year and hospital, while also matching on propensity scores. Propensity scores were calculated using the patient characteristics listed in Table 1 and matching was performed using a caliper width of 0.2 times the standard deviation of the logit propensity scores [29]. Standardized differences were used to assess balance in matching. We also investigated differences in outcomes in patients without pre‐existing cardiovascular conditions (i.e., heart failure, MI, stroke, and AF), and only those with at least one of those conditions. For these analyses, stratification was performed prior to pairwise matching. For our primary (i.e., cardiovascular) outcomes, differences were estimated using proportional hazards models and a robust sandwich variance estimator to account for matching, with patients censored at either 1‐year post‐discharge or at the time of another index admission. Estimates were reported as the hazard ratio and 95% confidence interval (CI). For models that violated the proportional hazards assumption, we calculated piecewise HRs using restricted cubic splines. For our secondary outcomes, estimates were generated using hazard models (for mortality and readmission), conditional logistic regression (for ICU transfers, reported as odds ratio and 95% CI), or Poisson regression via generalized estimating equations with an exchangeable correlation structure (for length of stay, reported as incidence rate ratio and 95% CI).
TABLE 1.
Summary of RSV, influenza, UTI, and fracture patient groups after matching on year of admission, hospital, and propensity score.
| RSV (n = 2234) | Influenza (n = 2234) | d | RSV (n = 2308) | UTI (n = 2308) | d | RSV (n = 1612) | Fracture (n = 1612) | d | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Age | Mean ± SD | 80.80 (8.75) | 80.06 (8.56) | 0.09 | 80.66 (8.79) | 81.12 (8.90) | 0.05 | 79.66 (8.78) | 79.94 (8.63) | 0.03 |
| Sex | Female | 1281 (57.3%) | 1319 (59.0%) | 0.03 | 1345 (58.3%) | 1354 (58.7%) | 0.01 | 1018 (63.2%) | 1007 (62.5%) | 0.01 |
| Male | 953 (42.7%) | 915 (41.0%) | 963 (41.7%) | 954 (41.3%) | 594 (36.8%) | 605 (37.5%) | ||||
| Income quintile | 1 (lowest) | 539 (24.1%) | 567 (25.4%) | 0.03 | 563 (24.4%) | 610 (26.4%) | 0.05 | 389 (24.1%) | 386 (23.9%) | 0.00 |
| 2 | 504 (22.6%) | 484 (21.7%) | 0.02 | 516 (22.4%) | 523 (22.7%) | 0.01 | 356 (22.1%) | 370 (23.0%) | 0.02 | |
| 3 | 450 (20.1%) | 460 (20.6%) | 0.01 | 433 (18.8%) | 428 (18.5%) | 0.01 | 324 (20.1%) | 297 (18.4%) | 0.04 | |
| 4 | 373 (16.7%) | 364 (16.3%) | 0.01 | 401 (17.4%) | 365 (15.8%) | 0.04 | 273 (16.9%) | 293 (18.2%) | 0.03 | |
| 5 (highest) | 368 (16.5%) | 359 (16.1%) | 0.01 | 395 (17.1%) | 382 (16.6%) | 0.02 | 270 (16.7%) | 266 (16.5%) | 0.01 | |
| Rural residence | Yes | 67 (3.0%) | 78 (3.5%) | 0.03 | 93 (4.0%) | 83 (3.6%) | 0.02 | 51 (3.2%) | 74 (4.6%) | 0.07 |
| Northern residence | Yes | 40 (1.8%) | 45 (2.0%) | 0.02 | 48 (2.1%) | 47 (2.0%) | 0.00 | 31 (1.9%) | 31 (1.9%) | 0.00 |
| Hospital frailty risk score | Low (< 5) | 1370 (61.3%) | 1395 (62.4%) | 0.02 | 1319 (57.1%) | 1234 (53.5%) | 0.07 | 1002 (62.2%) | 974 (60.4%) | 0.04 |
| Mid (5–15) | 702 (31.4%) | 685 (30.7%) | 0.02 | 802 (34.7%) | 840 (36.4%) | 0.03 | 492 (30.5%) | 504 (31.3%) | 0.02 | |
| High (> 15) | 162 (7.3%) | 154 (6.9%) | 0.01 | 187 (8.1%) | 234 (10.1%) | 0.07 | 118 (7.3%) | 134 (8.3%) | 0.04 | |
| Influenza vaccination | Yes | 1198 (53.6%) | 1237 (55.4%) | 0.04 | 1227 (53.2%) | 1274 (55.2%) | 0.04 | 836 (51.9%) | 826 (51.2%) | 0.01 |
| Dyslipidemia | Yes | 1038 (46.5%) | 1050 (47.0%) | 0.01 | 1031 (44.7%) | 1098 (47.6%) | 0.06 | 698 (43.3%) | 703 (43.6%) | 0.01 |
| Asthma | Yes | 697 (31.2%) | 692 (31.0%) | 0.01 | 668 (28.9%) | 726 (31.5%) | 0.06 | 406 (25.2%) | 400 (24.8%) | 0.01 |
| COPD | Yes | 1047 (46.9%) | 1044 (46.7%) | 0.00 | 1029 (44.6%) | 1102 (47.7%) | 0.06 | 633 (39.3%) | 609 (37.8%) | 0.03 |
| Diabetes | Yes | 906 (40.6%) | 902 (40.4%) | 0.00 | 927 (40.2%) | 954 (41.3%) | 0.02 | 605 (37.5%) | 609 (37.8%) | 0.01 |
| Heart failure | Yes | 626 (28.0%) | 614 (27.5%) | 0.01 | 625 (27.1%) | 649 (28.1%) | 0.02 | 319 (19.8%) | 298 (18.5%) | 0.03 |
| Myocardial infarction | Yes | 348 (15.6%) | 376 (16.8%) | 0.03 | 360 (15.6%) | 360 (15.6%) | 0.00 | 205 (12.7%) | 206 (12.8%) | 0.00 |
| Stroke | Yes | 214 (9.6%) | 207 (9.3%) | 0.01 | 229 (9.9%) | 243 (10.5%) | 0.02 | 116 (7.2%) | 127 (7.9%) | 0.03 |
| Atrial fibrillation | Yes | 690 (30.9%) | 675 (30.2%) | 0.02 | 698 (30.2%) | 719 (31.2%) | 0.02 | 390 (24.2%) | 374 (23.2%) | 0.02 |
Note: Categorical data summarized as the count and frequency.
Abbreviations: d, standardized difference relative to RSV patients; RSV, respiratory syncytial virus; SD, standard deviation; UTI, urinary tract infection.
All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC).
3. Results
Prior to matching, a total of 104,095 patient admissions due to RSV (n = 2558), influenza (n = 16,688), UTI (n = 73,587), or fracture (n = 11,262) were identified (Table S3). After matching, 2234, 2308, and 1612 matched pairs remained to compare RSV patients to influenza, UTI, and fracture patients, respectively (Table 1). Within the matched pairs (e.g., RSV vs. influenza), the mean age was 80 years, approximately 60% were women, and about half had received influenza vaccination. Approximately 7% of patients were considered highly frail, and the prevalence of comorbidities tended to be high, especially chronic obstructive pulmonary disease (~45%), dyslipidemia (~45%), diabetes (~40%), AF (~30%), asthma (~30%), and heart failure (~28%). These conditions tended to be much more prevalent in RSV patients compared to other patient groups prior to matching (Table S3). Descriptive statistics pre‐ and post‐matching for patients stratified based on the absence (Tables S4 and S5) or presence of pre‐existing cardiovascular conditions (Tables S6 and S7) are provided in the Supporting Informations.
Prior to matching, 19% (n = 474) of patients hospitalized for RSV experienced a subsequent cardiovascular outcome, which was higher than for influenza (18%, n = 2961), UTI (12%, n = 8908) and fracture (8%, n = 941) patients (Table S8). In matched analysis, heart failure (10%–11%) was the most common outcome for RSV patients, followed by AF (5%–6%) (Table 2). Stratified analyses indicated that the incidence of either outcome, as well as MI, was at least two to three times higher in patients with a pre‐existing cardiovascular condition compared to those without.
TABLE 2.
Rates of cardiovascular outcomes following RSV hospitalization compared to other patient groups.
| All patients | Heart failure | Myocardial infarction | Stroke | Atrial fibrillation | |||||
|---|---|---|---|---|---|---|---|---|---|
| Incidence | HR (95% CI) | Incidence | HR (95% CI) | Incidence | HR (95% CI) | Incidence | HR (95% CI) | ||
| RSV vs. Flu (n = 2234) | RSV | 238 (10.65) | 1.65 a | 33 (1.48) | 0.82 | 22 (0.98) | 0.78 | 124 (5.55) | 0.95 |
| Influenza | 221 (9.89) | (1.14, 2.38) | 42 (1.88) | (0.52, 1.31) | 30 (1.34) | (0.45, 1.34) | 138 (6.18) | (0.75, 1.21) | |
| RSV vs. UTI (n = 2308) | RSV | 251 (10.88) | 1.92 | 31 (1.34) | 0.86 | 23 (1.00) | 0.79 | 128 (5.55) | 1.27 |
| UTI | 173 (7.50) | (1.28, 2.88) | 36 (1.56) | (0.53, 1.39) | 29 (1.26) | (0.46, 1.35) | 101 (4.38) | (0.98, 1.64) | |
| RSV vs. Frac (n = 1612) | RSV | 160 (9.93) | 1.81 a | 24 (1.49) | 1.26 | 19 (1.18) | 0.83 | 84 (5.21) | 1.50 |
| Fracture | 101 (6.27) | (1.41, 2.31) | 21 (1.30) | (0.70, 2.26) | 25 (1.55) | (0.46, 1.52) | 62 (3.85) | (1.08, 2.08) | |
| No prior CV conditions | |||||||||
| RSV vs. Flu (n = 925) | RSV | 50 (5.41) | 1.42 | 7 (0.76) | 0.62 | 9 (0.97) | 0.83 | 26 (2.81) | 1.30 |
| Influenza | 39 (4.22) | (0.93, 2.16) | 12 (1.30) | (0.25, 1.59) | 12 (1.30) | (0.35, 1.98) | 22 (2.38) | (0.74, 2.27) | |
| RSV vs. UTI (n = 1042) | RSV | 51 (4.89) | 2.51 | 7 (0.67) | 0.60 | 12 (1.15) | 2.04 | 33 (3.17) | 2.61 |
| UTI | 21 (2.02) | (1.52, 4.15) | 12 (1.15) | (0.23, 1.53) | 6 (0.58) | (0.76, 5.44) | 13 (1.25) | (1.39, 4.91) | |
| RSV vs. Frac (n = 760) | RSV | 40 (5.26) | 3.74 | < 6 b | 1.06 | 6–10 b | 3.64 | 25 (3.29) | 2.29 |
| Fracture | 12 (1.58) | (1.97, 7.08) | < 6 b | (0.27, 4.22) | < 6 b | (1.01, 13.21) | 12 (1.58) | (1.14, 4.58) | |
| 1+ prior CV conditions | |||||||||
| RSV vs. Flu (n = 1041) | RSV | 173 (16.62) | 1.02 | 23 (2.21) | 1.16 | 7 (0.67) | 0.41 | 83 (7.97) | 0.80 |
| Influenza | 179 (17.20) | (0.83, 1.25) | 21 (2.02) | (0.65, 2.08) | 18 (1.73) | (0.17, 0.98) | 109 (10.47) | (0.60, 1.06) | |
| RSV vs. UTI (n = 1128) | RSV | 188 (16.67) | 1.48 | 23 (2.04) | 1.08 | 8 (0.71) | 0.001 a | 94 (8.33) | 1.07 |
| UTI | 128 (11.35) | (1.19, 1.85) | 21 (1.86) | (0.59, 1.96) | 25 (2.22) | (< 0.001, 0.174) | 86 (7.62) | (0.81, 1.43) | |
| RSV vs. Frac (n = 507) | RSV | 87 (17.16) | 1.56 | 11 (2.17) | 1.50 | 7 (1.38) | 1.09 | 46 (9.07) | 1.25 |
| Fracture | 63 (12.43) | (1.14, 2.14) | 8 (1.58) | (0.60, 3.77) | 7 (1.38) | (0.38, 3.1) | 40 (7.89) | (0.81, 1.92) | |
Note: Sample sizes shown represent patient numbers in each matched cohort. Statistically significant estimates shown in bold. Hazard estimates for up to 1 year following admission.
Abbreviations: CV, cardiovascular; Frac, fracture; HR (95% CI), hazard ratio and 95% confidence interval; RSV, respiratory syncytial virus; UTI, urinary tract infection.
Relative hazard was not constant over time; piecewise estimate at 300 days shown.
Small event count suppressed to maintain patient privacy.
The rate of heart failure was higher for RSV patients compared to influenza (HR = 1.65 [1.14–2.38]), UTI (HR = 1.92 [1.28–2.88]), and fracture (HR = 1.81 [1.41–2.31]) patients (Table 2; Figure 2). This was similar for those without a pre‐existing cardiovascular condition and those with at least one, although differences between RSV and influenza were not significant (HR = 1.42 [0.93–2.16] and 1.02 [0.83–1.25], respectively). Hazards were significant when compared to UTI (HR = 2.51 [1.52–4.15] and 1.48 [1.19–1.85], respectively) and fracture (HR = 3.74 [1.97–7.08] and 1.56 [1.14–2.14]). The rate of AF was higher for RSV patients compared to fracture patients (HR = 1.50 [1.08–2.08]). In those without a pre‐existing cardiovascular condition, the rate in RSV patients was 2.61 (95% CI, 1.29–4.91) and 2.29 (1.14–4.58) times higher than UTI and fracture patients, respectively. The rate of stroke was also significantly different between RSV and UTI and fracture patients within strata, although the limited incidence resulted in wide confidence intervals.
FIGURE 2.
The rate of cardiovascular outcomes up to 1‐year post‐discharge for RSV patients as compared to influenza (Flu), urinary tract infection (UTI) or fracture (Frac). The hazard ratio (HR) and 95% confidence interval (CI) is presented for all patients, and within prior cardiovascular (CV) disease subgroups. Estimates for stroke between RSV and UTI patients with 1 or more prior CV condition is not shown due to an overly large 95% CI.
Regarding secondary outcomes, we observed higher rates of 30‐day mortality and ICU admission, and longer lengths of stay for RSV patients compared to other patient groups (Table 3; Table S8). Most notable was the odds for intensive care, which were higher for RSV patients regardless of whether pre‐existing cardiovascular conditions were present. In fact, when compared against UTI and fracture patients without pre‐existing cardiovascular conditions, the risk of ICU transfer was substantial (OR = 4.63 [95% CI, 3.26–6.58] and 3.75 [2.60–5.42], respectively). The rate of mortality in the first 30 days following admission was mostly higher for RSV patients as well, ranging from 1.49 to 3.98. Lastly, RSV patients tended to have lengths of stay that were 11%–32% longer; a notable exception was the comparison with fracture, for which length of stay was significantly shorter for all patients, regardless of the presence or absence of pre‐existing cardiovascular conditions. The risk of 30‐day readmission was significantly higher for RSV patients compared to fracture patients (1.36 [1.08–1.71]), but lower compared to UTI patients (0.73 [0.59–0.90]).
TABLE 3.
Risk of secondary outcomes following RSV hospitalization compared to other patient groups.
| All patients | Mortality (30 days) | Readmission (30 days) | ICU admission | Length of stay (days) | |||||
|---|---|---|---|---|---|---|---|---|---|
| Incidence | HR (95% CI) | Incidence | HR (95% CI) | Incidence | OR (95% CI) | Med (IQR) | IRR (95% CI) | ||
| RSV vs. Flu (n = 2234) | RSV | 255 (11.41) | 1.58 | 240 (10.74) | 0.95 | 417 (18.67) | 1.48 | 6 (4–11) | 1.11 |
| Influenza | 166 (7.43) | (1.3, 1.91) | 248 (11.10) | (0.79, 1.13) | 300 (13.43) | (1.26, 1.74) | 5 (3–10) | (1.02, 1.2) | |
| RSV vs. UTI (n = 2308) | RSV | 271 (11.74) | 1.49 | 252 (10.92) | 0.73 * | 445 (19.28) | 3.55 | 7 (4–12) | 1.21 |
| UTI | 186 (8.06) | (1.24, 1.80) | 342 (14.82) | (0.59, 0.90) | 154 (6.67) | (2.89, 4.37) | 4 (0–9) | (1.08, 1.35) | |
| RSV vs. Frac (n = 1612) | RSV | 179 (11.10) | 3.98 | 167 (10.36) | 1.36 | 309 (19.17) | 2.64 | 6 (4–11) | 0.65 |
| Fracture | 47 (2.92) | (2.88, 5.51) | 141 (8.75) | (1.08, 1.71) | 134 (8.31) | (2.11, 3.29) | 8 (3–18) | (0.59, 0.73) | |
| No prior CV conditions | |||||||||
| RSV vs. Flu (n = 925) | RSV | 91 (9.84) | 2.13 | 87 (9.41) | 0.95 | 157 (16.97) | 1.58 | 6 (3–11) | 1.09 |
| Influenza | 44 (4.76) | (1.48, 3.06) | 91 (9.84) | (0.71, 1.27) | 108 (11.68) | (1.2, 2.07) | 5 (3–9) | (0.95, 1.24) | |
| RSV vs. UTI (n = 1042) | RSV | 103 (9.88) | 0.47* | 100 (9.60) | 0.68 | 188 (18.04) | 4.63 | 6 (3–11) | 1.32 |
| UTI | 51 (4.89) | (0.16, 1.36) | 146 (14.01) | (0.53, 0.88) | 50 (4.80) | (3.26, 6.58) | 2 (0–7) | (1.14, 1.54) | |
| RSV vs. Frac (n = 760) | RSV | 71 (9.34) | 0.92* | 73 (9.61) | 1.23 | 144 (18.95) | 3.75 | 6 (3–11) | 0.75 |
| Fracture | 19 (2.50) | (0.18, 4.64) | 55 (7.24) | (0.86, 1.76) | 45 (5.92) | (2.6, 5.42) | 7.5 (3–16) | (0.67, 0.85) | |
| 1+ prior CV conditions | |||||||||
| RSV vs. Flu (n = 1041) | RSV | 133 (12.78) | 1.55 | 125 (12.01) | 0.88 | 214 (20.56) | 1.55 | 7 (4–12) | 1.11 |
| Influenza | 88 (8.45) | (1.18, 2.04) | 134 (12.87) | (0.69, 1.13) | 152 (14.60) | (1.23, 1.97) | 6 (3–11) | (0.97, 1.27) | |
| RSV vs. UTI (n = 1128) | RSV | 153 (13.56) | 1.50 | 139 (12.32) | 0.73 * | 239 (21.19) | 2.21 | 7 (4–13) | 1.18 |
| UTI | 105 (9.31) | (1.17, 1.93) | 206 (18.26) | (0.56, 0.97) | 130 (11.52) | (1.72, 2.84) | 5 (1–11) | (1.03, 1.35) | |
| RSV vs. Frac (n = 507) | RSV | 60 (11.83) | 2.71 | 55 (10.85) | 1.48 | 104 (20.51) | 2.07 | 7 (4–12) | 0.61 |
| Fracture | 23 (4.54) | (1.66, 4.44) | 57 (11.24) | (1.01, 2.19) | 58 (11.44) | (1.44, 2.98) | 11 (5–21) | (0.51, 0.72) | |
Note: Sample sizes shown represent patient numbers in each matched cohort. Statistically significant estimates shown in bold. Hazard estimates for mortality and readmission estimated up to 30 days following admission.
Abbreviations: 95% CI, 95% confidence interval; CV, cardiovascular; Frac, fracture; HR, hazard ratio; IRR, incidence rate ratio; OR, odds ratio; RSV, respiratory syncytial virus; UTI, urinary tract infection.
Relative hazard was not constant over time; piecewise estimate at 30 days shown.
4. Discussion
Between 2011 and 2020, we identified 2558 cases of adults aged ≥ 65 years admitted for an RSV infection. Regardless of the comparator group, RSV‐related admissions were more severe, including greater 30‐day mortality and transfer to intensive care, and longer length of stay, particularly for patients who did not have any pre‐existing cardiovascular conditions. This is supported by previous literature indicating that in both younger and older adults, RSV infection is associated with greater hospital admission from the emergency department, and for those hospitalized, greater risk of pneumonia, need for ventilation, and mortality compared to influenza [5, 6, 7, 8, 9]. However, our findings further suggest that hospitalization with an RSV infection substantially raises the rate of heart failure, with approximately of 11% of patients being readmitted within 1‐year of discharge. Interestingly, while the incidence of heart failure fell by more than one‐half when patients with pre‐existing heart failure, MI, stroke or AF were removed from analysis, the relative rate of heart failure did not. In fact, the hazard was higher in nearly all comparisons. The rate of heart failure for RSV patients also tended to be highest in comparisons against fracture patients, suggesting that the infectious component of the index admission could be an important contributor to the underlying pathogenesis, as has been previously suggested [30]. The rate of AF was also significantly higher in RSV patients compared to fracture patients when all patients were considered, and higher than both UTI and fracture patients when only those patients without any pre‐existing cardiovascular conditions were considered. These findings should be considered carefully, given that RSV testing practices have changed dramatically over time, and is more likely to occur in larger, urban hospitals [27]. This could lead to partial verification bias (i.e., “sickest of the sick”) [31] and as previously argued [32], could inflate estimates regarding severity and limit representativeness.
The biological mechanisms underlying RSV associations with long‐term risk of cardiac events in older adults and generally more severe disease has yet to be determined. The risk of heart failure related to ARI, particularly in patients with pre‐existing cardiopulmonary complications, is largely driven by significant hemodynamic disturbances. Specifically, pulmonary hypertension resulting from the infection leads to right ventricular strain, increased oxygen demand and subsequent demand ischemia, and diastolic dysfunction [33, 34]. Many have also suggested a prominent role for local and/or systemic inflammation, either as a byproduct of pervasive comorbid conditions or from the accumulation of immune cells such as monocytes and T‐cells in the myocardium, both of which can lead to cardiac remodeling [35, 36]. The ability of RSV to evade immunity via active subversion mechanisms [37] and a slower replication rate [38] may also contribute to a prolonged disease phenotype that features chronic inflammation [37]. More generally, RSV is known to commonly infect the lower airways, evident from wheezing [39] and other respiratory complications [40] present during hospitalization. Future longitudinal analyses of the dynamics of inflammatory factors during an RSV‐related admission and subsequent follow‐up for the incidence of cardiovascular outcomes such as heart failure could address these important questions.
Our study featured significant strengths and some weaknesses. First, our relatively large catchment area allowed us to include a reasonably large number of ARI hospitalizations across the province of Ontario, which has a 65‐year and older adult population of ~2.5 million. This provided considerable statistical power to test associations with the incidence of a number of important cardiovascular outcomes, while also offering reasonable generalizability to other high‐income nations. Second, we employed a conservative matching approach in our statistical design and only included cases if they fell within a time window coinciding with the circulation of RSV and influenza for that given year, which reduces the likelihood of confounding related to season. Our findings are limited given that we used administrative data to identify cardiovascular events in RSV and comparator patient groups, which precluded our ability to investigate associations with events occurring during the index admission due to an inherent lack of clarity around the actual sequence of events. We also categorized ARI admissions using administrative data and not laboratory‐confirmed diagnoses. Although classification algorithms such as the one we used for influenza [41] commonly exhibit reasonable sensitivity and specificity, they are nonetheless vulnerable to misclassification. Further, we cannot dismiss the possibility that there were unmeasured characteristics of RSV patients confounding the effect that we attribute to the virus itself. We also identified a relatively low number of RSV admissions (17% of influenza cases) compared to estimates of infection rates in the community [42] or hospitalization rates [9], which stand closer to 30% of influenza cases. Although older adult RSV hospitalizations are known to be underreported [43, 44], we may have further biased our sample by excluding potential healthcare‐related ARIs, of which RSV tends to be more commonly associated [45]. Our relatively low number of cases may also reflect the aforementioned nature of RSV testing practices [27].
In summary, our findings further substantiate the importance of RSV as a significant cause of short‐ and long‐term health outcomes in older adults, and in particular, the rate of heart failure. Given the variable nature of RSV testing over the past two decades, we cannot conclude that our findings are generalizable to all older patients hospitalized for an RSV illness. Nonetheless, increased monitoring in‐hospital and routine follow‐up with older RSV patients for cardiovascular symptoms indicative of decompensation (e.g., dyspnea, arrythmia, weight gain, etc.) may be beneficial to mitigate long‐term outcomes. Although RSV infections are less common than influenza in older adults, they remain a substantial source of economic burden to healthcare systems. Our findings underline the importance of robust and effective public health strategies regarding RSV vaccines.
Author Contributions
The following authors contributed significantly to the manuscript: Chris P. Verschoor conceived the study design, interpreted the findings, and prepared the manuscript. Joseph M. Caswell and Mark Tatangelo performed the statistical analysis. Joshua O. Cerasuolo, Joseph M. Caswell, and Jeffrey C. Kwong contributed to the study design, interpreted the findings, and contributed to the final manuscript. Atilio Costa‐Vitali and David W. Savage interpreted the findings and approved the final manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1.
Acknowledgments
This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long‐Term Care. This article used data adapted from the Statistics Canada Postal Code Conversion FileOM, which is based on data licensed from the Canada Post Corporation, and/or data adapted from the MOH Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. Parts of this material are based on data and information compiled and provided by MOH and the Canadian Institute for Health Information. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.
Verschoor C. P., Cerasuolo J. O., Caswell J. M., et al., “Respiratory Syncytial Virus (RSV)‐Related Hospitalization and Increased Rate of Cardiovascular Events in Older Adults,” Journal of the American Geriatrics Society 73, no. 9 (2025): 2685–2694, 10.1111/jgs.19591.
Funding: This work was supported by Northern Ontario Academic Medicine Association grant (#A‐19‐10) awarded to Drs. Josée Thériault and Janet McElhaney. Dr. Verschoor is supported as the HSN Foundation Research Chair in Healthy Aging.
Data Availability Statement
The datasets from this study are held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., health care organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at www.ices.on.ca/DAS (email, das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors on request, understanding that the computer programs may rely on coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1.
Data Availability Statement
The datasets from this study are held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., health care organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at www.ices.on.ca/DAS (email, das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors on request, understanding that the computer programs may rely on coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.