This cohort study assesses the incidence of respiratory syncytial virus–positive acute respiratory infection before and during the COVID-19 pandemic in adults aged 50 years or older in Minnesota.
Key Points
Question
What was the incidence of respiratory syncytial virus (RSV)–positive acute respiratory infections (ARI) before and during the COVID-19 pandemic and its outcomes in older adults?
Findings
In this cohort study, the prepandemic incidence rate of RSV-positive ARI was 48.6 per 1000 person-years with a 2.5% attack rate. While no RSV-positive ARI case was identified during the pandemic RSV season, 7 RSV-positive ARI cases were identified during the pandemic non-RSV season.
Meaning
While no RSV-positive ARI cases were identified during the pandemic, the burden after RSV-positive ARI in older adults during the pre-COVID-19 pandemic was substantial.
Abstract
Importance
Little is known about the burden and outcomes of respiratory syncytial virus (RSV)–positive acute respiratory infection (ARI) in community-dwelling older adults.
Objective
To assess the incidence of RSV-positive ARI before and during the COVID-19 pandemic, and to assess outcomes for RSV-positive ARI in older adults.
Design, Setting, and Participants
This was a community-based cohort study of adults residing in southeast Minnesota that followed up with 2325 adults aged 50 years or older for 2 RSV seasons (2019-2021) to assess the incidence of RSV-positive ARI. The study assessed outcomes at 2 to 4 weeks, 6 to 7 months, and 12 to 13 months after RSV-positive ARI.
Exposure
RSV-positive and -negative ARI.
Main Outcomes and Measures
RSV status was the main study outcome. Incidence and attack rates of RSV-positive ARI were calculated during each RSV season, including before (October 2019 to April 2020) and during (October 2020 to April 2021) COVID-19 pandemic, and further calculated during non-RSV season (May to September 2021) for assessing impact of COVID-19. The self-reported quality of life (QOL) by Short-Form Health Survey-36 (SF-36) and physical functional measures (eg, 6-minute walk and spirometry) at each time point was assessed.
Results
In this study of 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. The prepandemic incidence rate of RSV-positive ARI was 48.6 (95% CI, 36.9-62.9) per 1000 person-years with a 2.50% (95% CI, 1.90%-3.21%) attack rate. No RSV-positive ARI case was identified during the COVID-19 pandemic RSV season. Incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.42%; (95% CI, 0.17%-0.86%) were observed during the summer of 2021. Based on prepandemic RSV season results, participants with RSV-positive ARI (vs matched RSV-negative ARI) reported significantly lower QOL adjusted mean difference (limitations due to physical health, −16.7 [95% CI, −31.8 to −1.8]; fatigue, −8.4 [95% CI, −14.3 to −2.4]; and difficulty in social functioning, −11.9 [95% CI, −19.8 to −4.0] within 2 to 4 weeks after RSV-positive ARI [ie, short-term outcome]). Compared with participants with RSV-negative ARI, those with RSV-positive ARI also had lower QOL (fatigue: −4.0 [95% CI, −8.5 to −1.3]; difficulty in social functioning, −5.8 [95% CI, −10.3 to −1.3]; and limitation due to emotional problem, −7.0 [95% CI, −12.7 to −1.3] at 6 to 7 months after RSV-positive ARI [intermediate-term outcome]; fatigue, −4.4 [95% CI, −7.3 to −1.5]; difficulty in social functioning, −5.2 [95% CI, −8.7 to −1.7] and limitation due to emotional problem, −5.7 [95% CI, −10.7 to −0.6] at 12-13 months after RSV-positive ARI [ie, long-term outcomes]) independent of age, sex, race and/or ethnicity, socioeconomic status, and high-risk comorbidities.
Conclusions and Relevance
In this cohort study, the burden of RSV-positive ARI in older adults during the pre-COVID-19 period was substantial. After a reduction of RSV-positive ARI incidence from October 2020 to April 2021, RSV-positive ARI re-emerged during the summer of 2021. RSV-positive ARI was associated with significant long-term lower QOL beyond the short-term lower QOL in older adults.
Introduction
Respiratory syncytial virus (RSV)-positive acute respiratory infection (ARI) is the leading cause of bronchiolitis in children and is associated with substantial morbidity and mortality among older adults.1,2,3,4,5 In 2015, there were around 1.5 million (95% CI, 0.3 million-6.9 million) estimated episodes of RSV- positive ARI among older adults 65 years or older in industrialized countries.1 There are 1.15 million estimated medically attended RSV infections annually in the United States2 of which approximately 14.5% resulted in hospital admission.1 A significant proportion of older adults (30%-45%) with RSV-positive ARI were unable to carry out daily activities, compared with 54% to 60% for influenza.3,4 Lower respiratory symptoms were common (eg, 82% of patients after RSV-positive ARI).5 Therefore, RSV-positive ARI can pose major health threats to older adults and impact their daily activities and quality of life (QOL).
In the United States, Falsey et al3 assessed the incidence of RSV infection (3%-7%) based on reverse transcriptase polymerase chain reaction (RT-PCR) and serology in older adults from 1999 to 2003. No other prospective community-based studies have been conducted since 2003 to assess the incidence of RSV-positive ARI in older adults. Two independent community-based prospective cohort studies assessed the incidence of RSV infection among older adults, in the United Kingdom from 1992 to1994 (36 per 1000 person-years)1,5 and another in multiple European countries from 2017 to 2019 (4.2% to 7.2% based on both PCR and serology).6 Little is known about whether the incidence of RSV-positive ARI in older adults in the United States is consistent over time when compared with other studies covering different periods and geographies. Importantly, given the current COVID-19 pandemic, little is known about the association of the COVID-19 pandemic on RSV epidemiology. In addition, the literature supports that RSV-positive ARI is associated with significant morbidity and mortality in at-risk adults.1,7,8,9,10 However, almost all previous studies assessed only short-term morbidity and mortality of medically attended RSV-positive ARI, typically in a hospital setting 7 to 28 days after RSV-positive ARI. Thus, long-term outcomes after RSV-positive ARI, including QOL, in older adults are poorly understood.
To address these gaps, we assessed the current incidence and long-term outcomes of RSV-positive ARI in adults aged 50 years or older residing in southeastern Minnesota. While the primary aim of our study was to assess RSV incidence in older adults (aged 65 years or older), the inclusion of a younger group of adults (aged 50 to 64 years) in our study as a comparison group provides an important insight into interpreting our study results. Therefore, in this community-based, prospective cohort study, we followed up with adults aged 50 years or older for 2 consecutive RSV seasons from 2019 to 2021 (October 1 to April 30 for each year) as well as during 1 non-RSV season (May 1, 2021, to September 30, 2021) during the COVID-19 pandemic. As the COVID-19 pandemic unexpectedly broke out during our study period, our study was poised to assess the influence of the COVID-19 pandemic on the incidence of RSV-positive ARI in our study cohort.
Methods
Study Design and Cohort
This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies. The study was a prospective cohort study, which enrolled a community-based sample of adults aged 50 years or older residing in southeast Minnesota (eAppendix in Supplement 1) from July 23, 2019, to November 27, 2019. The study was approved by the Mayo Clinic institutional review board. We achieved enrolling 2326 participants in the given timeframe. Although we had planned to enroll 3000 participants, we had determined 2000 participants were sufficient to achieve the proposed precision for the incidence of RSV (eAppendix in Supplement 1). Inclusion and exclusion criteria were previously reported.11 The inclusion criteria were1: (1) residing in southeast Minnesota counties of Olmsted County and nearby counties, including Dodge, Fillmore, Goodhue, Mower, Wabasha, and Winona with residency established at least 1 year prior to consent2; (2) being age 50 years or older at the time of consenting with a cap of 25% of individuals aged 50 to 59 years (to enroll a larger proportion of participants age 60 years and older)3; (3) having a primary care physician at Mayo Clinic and a history of primary care visits to Mayo Clinic4; (4) authorization to use medical records for research; and5 (5) written informed consent to participate in the study. The exclusion criteria were1 (1) no authorization for the use of medical records for research2; (2) residence outside of southeast Minnesota at the time of enrollment3; (3) development of acute respiratory infection (ARI) after October 1, 2019, but prior to enrollment or lack of availability for enrollment and swabbing within 5 days of symptoms4; (4) opting out for swab test and other study procedures5; (5) inability to ambulate or bedridden status6; (6) known cognitive impairment7; evidence of an ongoing systemic bacterial, fungal, or viral infection within 7 days prior to enrollment;8 and (7) any reason in the opinion of the study principal investigators that someone would not be able to complete the requirements of the study for safety or other reasons. The first RSV season (October 1, 2019, to April 30, 2020) was partially affected by the COVID-19 pandemic, and we consider that the prepandemic RSV season. The second RSV season (October 1, 2020, to April 30, 2021) was completely affected by the COVID-19 pandemic, and we consider this the pandemic RSV season. With the COVID-19 pandemic starting in February 2020, the study was extended during the second RSV season (October 2020 to April 2021) to assess the influence of COVID-19 pandemic on the incidence of RSV-positive ARI. Participants continued to be followed up with (if consented) in the study during the pandemic non-RSV season (May 1, 2021, to September 30, 2021). Follow-up during the pandemic non-RSV season included only a subgroup of the original participants after reconsenting (n = 1682). The definition of ARI, lower respiratory tract disease (LRTD), and severity criteria are described in eTable 1 in Supplement 1, and the process for identifying and testing RSV-positive ARI is described in eFigure 1 in Supplement 1. Briefly, when study participants developed ARI symptoms, they informed our research staff to determine if they met ARI criteria. If so, the research staff requested an at-home self-swab sample,11 and specimens were returned to the lab within 72 hours for RSV testing by an FDA-cleared RT-PCR assay (eAppendix in Supplement 1). An in-house assay was used for the RSV-A and B subtyping at the GSK lab. When an incident RSV-positive case was identified, we identified and contacted 2 matched participants with RSV-negative ARI.
Baseline Data Collection
Following consent, baseline data were collected at the time of enrollment, including demographics, comorbidities, and patient-reported information (eTable 6 in Supplement 1). The Housing-Based Socioeconomic Status (HOUSES) Index, a validated, housing-based individual-level socioeconomic status measure, was assessed based on participants’ address of residence and publicly available property data. Race and ethnicity were classified as American Indian or Alaskan Native, Asian, African American, Hispanic or Latino, unknown, or White (non-Hispanic) based on known self-reported demographics from the electronic health record. If the patient indicated any Hispanic ethnicity, they were considered Hispanic; otherwise, they were classified as their race. If the documented race was other, we classified them as unknown. Race and ethnicity were collected as part of a comprehensive assessment to determine the characteristics of participants with RSV-positive ARI.
Rurality was classified based on the Census classification for urban and rural.11,12 Electronic health records were used to assess Charlson Comorbidity Index13,14,15 within 3 years of enrollment. Frailty was measured by validated questionnaires including Barthel activities of daily living (ADL) index16 and Lawton-Brody ADL scale17 as well as FRAIL Scale18 with the following scoring system—not frail (0 points); pre-frail (1-2 points), and frail (3-5 points). Quality of life (QOL) was measured by the 3-level version of EQ-5D19 and the Short Form Health Survey (SF-36), which was used to assess self-reported health-related QOL during the previous 4 weeks (scored 0 to 100 in 8 domains and a high score with each defines a more favorable health state).20
Identification of Comparative Groups (eg, Age- and Sex-Matched Controls)
When an incident index RSV-positive case was identified, we identified and contacted 2 matched participants with RSV-negative ARI from a pool of all participants with negative RSV tests within 4 weeks of identification of an index RSV case. These matched participants were in the same stratum as the index RSV-positive case from the sampling frame listing all study participants with RSV-negative ARI by age (SD, 5 years) and sex.
Outcome Data Collection
We assessed short-term complications (pneumonia and death) and health care uses (outpatient visits, emergency department visits, hospitalization, and intensive care unit [ICU] admission,) after ARI for all participants. Detailed outcome data, including the physical and self-reported frailty measures, which were all completed in-person (eMethods in Supplement 1), were collected for RSV-positive ARI cases and 2 matched RSV-negative ARI controls. The following clinical data were collected: (1) self-reported frailty and QOL by questionnaires18,20; (2) vital signs, including blood pressure, heart rate, respiratory rate, and temperature; (3) physical frailty measures, including hand grip strength (average for 3 measures), gait velocity (based on 5 meter walk), and total meters walked (6-minute walk), and 4) spirometry or peak flow meter (PFM; spirometry was replaced by self-measured PFM at home due to COVID-19–related restriction for aerosol-generating procedures). Either spirometry or PFM was available only at the short-term outcome measure. Outcomes for cases and controls were measured at short-term (within 4 weeks), intermediate-term (6-7 months), and long-term (12-13 months) interval postinfection.7,21
Statistical Analysis
We separately analyzed and reported the results for the prepandemic RSV season (October 1, 2019, to April 30, 2020) and those for pandemic RSV season (October 1, 2020, to April 30, 2021) because of the potential association of COVID-19–related public health measures. We also separately estimated the incidence of RSV-positive ARI cases during the pandemic non-RSV season (May 1, 2021, to September 30, 2021). The incidence rate is expressed as the number of first RSV-positive ARI cases per 1000 person-years of follow up with exact Poisson 95% CIs. The follow-up period used for calculating the incidence rate of the first RSV-positive ARI cases was defined as the duration from the start of the surveillance period until the symptom onset of RSV-positive ARI occurred during the time period, the end of the time period, or the last follow-up (eg, death, out of the study region for more than 2 weeks, the time when refused to follow the study procedures (eg, swab), or moving out of the region, whichever came first). The attack rate (ie, percentage of participants with at least 1 episode during the time period) was also computed and presented with Clopper-Pearson exact 95% CI. We also report incidence rates standardized to the United States White population based on the United States 2020 census by age and sex with 95% CIs based on the normal approximation.
For long-term outcomes collected over follow up (within 4 weeks, at 6-7 months, and at 12-13 post index date), we used mixed effect linear regression models to compare outcome between RSV-positive ARI and matched RSV-negative ARI by including matched sets as random effects, case-control status and potential confounders (age in years, sex, race and/or ethnicity, socioeconomic status, and Charlson Comorbidity Index) as fixed effects, and adding a timing component in the model as a fixed effect to account for the outcome variable collected at different time points (ie, repeated measures at 2 to 4 weeks, at 6 to 7 months, and at 12 to 13 months post-RSV index date). We adjusted for baseline values when available. Patient reported outcomes were available at enrollment, but physical frailty and spirometry measurements were not. Patient reported outcomes physical and frailty measurements were analyzed similar as above for short-term and intermediate-term outcomes except short-term outcomes did not include a timing component as only one outcome time point was available and for intermediate-term outcomes only 2 times were considered (repeated measure at 2 to 4 weeks and at 6 to 7 months). Spirometry results were only available at the short-term measurement, and analyses were similar to short-term physical frailty measurements. Adjusted β coefficients are reported to describe the adjusted mean difference between the RSV-positive cases and RSV-negative controls. Univariate mixed effect logistic regression models with case status as the outcome, matched sets as random effects and each baseline variable as a fixed effect was used to compare baseline characteristic differences between RSV-positive ARI and matched RSV-negative ARI. Two-sided P < .05 was considered statistically significant. However, these P values are exploratory and should be interpreted with caution considering that there is no adjustment for multiplicity for these comparisons and that the clinical relevance of the difference should be taken into account. All statistical analyses were completed in SAS statistical software version 9.4M6 (SAS Institute).
Results
In our study, 2326 participants consented, but 1 participant moved prior to our first follow-up period (eFigure 2 in Supplement 1). Of the 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. Chronic diseases were prevalent, the median (range) Charlson Comorbidity Index was 1 (0-9), and 1225 participants (53%) received pneumococcal vaccinations prior to the study. The reconsented participants were included in the pandemic non-RSV season analysis and their characteristics are summarized in eTable 2 in Supplement 1. Participants who reconsented to continue to be followed up in the study were in general younger with less comorbidity. Characteristics of study participants are summarized in Table 1.
Table 1. Characteristics of Study Participants.
| Characteristics | Overall (N = 2325) |
|---|---|
| Age at enrollment, y | |
| Mean (SD) | 67.7 (10.0) |
| Median (range) | 67 (50-98) |
| Age category at enrollment, No. (%), y | |
| 50-59 | 562 (24.2) |
| 60-69 | 799 (34.4) |
| 70-79 | 634 (27.3) |
| ≥80 or above | 330 (14.2) |
| Sex, No. (%) | |
| Female | 1380 (59.4) |
| Male | 945 (40.6) |
| Race and ethnicity, No. (%) | |
| American Indian or Alaskan Native | 4 (0.2) |
| Asian | 21 (0.9) |
| African American | 12 (0.5) |
| Hispanic or Latino | 14 (0.6) |
| Unknown | 34 (1.5) |
| White, non-Hispanic | 2240 (96.3) |
| Geographic location, No. (%) | |
| Dodge County | 148 (6.4) |
| Goodhue County | 85 (3.7) |
| Olmsted County | 2079 (89.4) |
| Wabasha County | 5 (0.2) |
| Other counties | 8 (0.3) |
| Rurality, No. (%) | |
| Living in rural area | 506 (21.8) |
| Socioeconomic status [HOUSES in quartile], No. (%) | |
| 1 (lowest) | 323 (14.7) |
| 2 | 549 (25.0) |
| 3 | 620 (28.2) |
| 4 (highest) | 705 (32.1) |
| Missing | 128 |
| Chronic illness [within 3-y of enrollment], No. (%)a | |
| Congestive heart failure | 118 (5.1) |
| Asthma | 251 (10.8) |
| Chronic obstructive pulmonary disease | 179 (7.7) |
| Any other heart or lung disease | 1394 (60.0) |
| Diabetes | 302 (13.0) |
| Immunosuppressed conditions | 222 (9.5) |
| Previous vaccination before enrollment, No. (%) | |
| Influenza vaccination (within 1 y) | 683 (29.4) |
| Pneumococcal vaccination (ever) | 1225 (52.7) |
| History of RSV infection before enrollment, No. (%)b | 6 (0.3) |
| Charlson Comorbidity Index | |
| Mean (SD) | 1.1 (1.4) |
| Median (range) | 1 (0-9) |
Abbreviation: HOUSES, housing-based individual-level socioeconomic status index; RSV, respiratory syncytial virus.
Individual conditions for chronic illness are listed in eTable 6 in Supplement 1.
History of RSV was based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes from medical record, which most likely underrepresents the true number of those with RSV infection.
Annual Incidence and Attack Rate of RSV-Positive ARI During Prepandemic RSV Season
During the prepandemic RSV season (October 1, 2019, to April 30, 2020), a total of 934 participants (40%) developed 1126 ARI episodes, of which 970 (86%) were tested for RSV. A total of 58 participants (2.5%) of the study cohort had RSV-positive ARI, of which 30 (1.3%) were caused by RSV type A and 26 (1.1%) by RSV type B (2 RSV cases were not typed). None developed recurrent RSV-positive ARI. The incidence rate of RSV-positive ARI per 1000 person-years was 48.6 (95% CI, 36.9-62.9), and the attack rate was 2.5% (95% CI, 1.9%-3.2%). The overall age- and sex-adjusted incidence rate of RSV-positive ARI per 1000 person-years was 50.2 (95% CI, 36.5-64.0). Of those with RSV-positive ARI, 41 (71%) developed LRTD. Specific incidence rates for RSV-positive ARI and RSV-positive LRTD are summarized in Table 2.
Table 2. Annual Incidence Rate of RSV-Positive ARI and Attack Rate by Age, Sex, RSV Type, and Severity and Annual Incidence of RSV LRTD by Age During Prepandemic RSV Season (October 1, 2019, to April 30, 2020).
| Characteristic | No. of patients | RSV positive ARI, No. (%) | Person-years | Value (95% CI) | |
|---|---|---|---|---|---|
| Incidence rate per 1000 person-years | Attack rate, % | ||||
| Specific incidence and attack rates of RSV positive-ARI | |||||
| Age category at enrollment, y | |||||
| 50-59 | 562 | 18 (3.2) | 284.61 | 63.25 (37.48-99.96) | 3.20 (1.91-5.02) |
| 60-69 | 799 | 19 (2.4) | 409.14 | 46.44 (27.96-72.52) | 2.38 (1.44-3.69) |
| 70-79 | 634 | 14 (2.2) | 327.15 | 42.79 (23.40-71.80) | 2.21 (1.21-3.68) |
| ≥80 | 330 | 7 (2.1) | 171.95 | 40.71 (16.37-83.88) | 2.12 (0.86-4.32) |
| Overall | 2325 | 58 (2.5) | 1192.85 | 48.62 (36.92-62.86) | 2.50 (1.90-3.21) |
| Sex | |||||
| Female | 1380 | 35 (2.5) | 707.91 | 49.44 (34.44-68.76) | 2.54 (1.77-3.51) |
| Male | 945 | 23 (2.4) | 484.94 | 47.43 (30.07-71.17) | 2.43 (1.55-3.63) |
| RSV subtypinga | |||||
| RSV A | 2325 | 30 (1.3) | 1200.27 | 24.99 (16.86-35.68) | 1.29 (0.87-1.84) |
| RSV B | 2325 | 26 (1.1) | 1201.93 | 21.63 (14.13-31.70) | 1.12 (0.73-1.63) |
| Severity | |||||
| Mild | 2325 | 0 | 1209.15 | 0 (0-3.05) | 0.00 (0.00-0.16) |
| Moderate | 2325 | 2 (0.1) | 1208.61 | 1.66 (0.20-5.98) | 0.09 (0.01-0.31) |
| Severe | 2325 | 56 (2.4) | 1193.39 | 46.93 (35.45-60.94) | 2.41 (1.82-3.12) |
| Specific incidence and attack rates of RSV positive-LRTD | |||||
| Age category at enrollment, y | |||||
| 50-59 | 562 | 15 (2.7) | 285.36 | 52.57 (29.42-86.70) | 2.67 (1.50-4.36) |
| 60-69 | 799 | 8 (1.0) | 412.18 | 19.41 (8.38-38.24) | 1.00 (0.43-1.96) |
| 70-79 | 634 | 12 (1.9) | 327.74 | 36.61 (18.92-63.96) | 1.89 (0.98-3.28) |
| ≥80 | 330 | 6 (1.8) | 172.25 | 34.83 (12.78-75.82) | 1.82 (0.67-3.92) |
| Overall | 2325 | 41 (1.8) | 1197.53 | 34.24 (24.57-46.45) | 1.76 (1.27-2.39) |
Abbreviations: ARI, acute respiratory infection; LRTD, lower respiratory track disease; RSV, respiratory syncytial virus.
An in-house developed assay was used for the RSV-A/B subtyping developed in GSK lab and available on research swabs, 2 patients were only tested in the clinic, so RSV subtyping was not available (Supplement 1).
Incidence and Attack Rate of RSV-Positive ARI During the Pandemic RSV Season and Pandemic Non-RSV Season
A total of 212 ARI episodes from 200 participants (9% of the full cohort of 2325 participants) were reported during the pandemic RSV season, and 120 of the 212 ARI episodes (57%) were tested for RSV (all RSV-negative ARI cases). During the pandemic non-RSV season, 211 participants (13%) reported 219 ARI episodes, 140 of 211 [64%] were tested for RSV) with 7 (5%) RSV-positive ARI cases. Of the RSV-positive ARI, 5 developed LRTD, and 6 developed severe ARI by severity criteria for ARI (eTable 1 in Supplement 1). Based on these numbers, the incidence rate of RSV-positive ARI per 1000 person-years was 10.2 (95% CI, 4.1-21.1), and attack rate was 0.42% (95% CI, 0.17-0.86) during pandemic non-RSV season. The overall age- and sex-adjusted incidence rate of RSV-positive ARI per 1000 person-years during RSV season and non-RSV season of the second year was 2.97 (95% CI, 0.70-5.24).
RSV-Positive ARI Complications and Health Care Use During Prepandemic RSV Season
As shown in Table 3, RSV-positive ARI episodes were more likely to be LRTD (41 of 58 [71%]) and severe ARI (56 of 58 [97%]), compared with RSV-negative ARI episodes, which met LRTD and severe ARI criteria 498 (55%) and 788 (87%) of the time, respectively. No differences in health care uses were observed between RSV-positive and RSV-negative ARI cases. Only 1 patient (1.7%) with RSV-positive ARI was hospitalized with pneumonia, confirmed by a physician diagnosis. The incidence of hospitalization for RSV-positive ARI was 0.83 (95% CI, 0.02-4.61) per 1000 person-years, and the attack rate was 0.04% (95% CI, 0.001-0.24). None of the patients with RSV-positive ARI were admitted to the intensive care unit (ICU) or died within a month after RSV-positive ARI episodes.
Table 3. Complications and Health Care Use Within 4 Weeks of ARI Onset of RSV-Positive ARI and RSV-Negative ARI During Prepandemic RSV Season.
| Characteristic | No. (%) | P value | |
|---|---|---|---|
| RSV positive-ARI episodes (N = 58) | RSV negative-ARI episodes (N = 909) | ||
| Complication during ARI | |||
| No ARI-related complications or hospitalizations | 57 (98.3) | 893 (98.2) | .98 |
| Pneumonia | 1 (1.7) | 11 (1.2) | .73 |
| Hospitalization | 1 (1.7) | 11 (1.2) | .73 |
| Death | 0 | 1 (0.1) | .80 |
| Health care uses | |||
| Outpatient visits | 13 (22.4) | 140 (15.4) | .16 |
| Emergency department visits | 2 (3.4) | 18 (2.0) | .45 |
| Hospitalization without ICU admission | 1 (1.7) | 8 (0.9) | .52 |
| Length of stay in hospital in days among those hospitalized without ICU | .39 | ||
| Mean (SD) | 1.0 (NA) | 2.8 (3.4) | |
| Median (range) | 1 (1-1) | 1.5 (1-11) | |
| Hospitalization with ICU admission | 0 | 3 (0.3) | .66 |
| Length of stay in hospital (including ICU), in days, among those hospitalized with ICU | |||
| Mean (SD) | 5.3 (1.5) | ||
| Median (range) | 5 (4-7) | ||
| Severity | .09 | ||
| Mild | 0 | 22 (2.4) | |
| Moderate | 2 (3.4) | 99 (10.9) | |
| Severe | 56 (96.6) | 788 (86.7) | |
| LRTD | 41 (70.7) | 498 (54.8) | .02 |
Abbreviations: ARI, acute respiratory infection; ICU, intensive care unit; LRTD, lower respiratory tract disease; RSV, respiratory syncytial virus.
Functional and QOL Impairment After RSV-Positive ARI During the Prepandemic RSV Season
Characteristics of participants with RSV-positive ARI and their matched participants with RSV-negative ARI were similar at enrollment, as summarized in eTable 3 in Supplement 1. The results on health-related QOL measured by SF-36 questionnaire are summarized in Table 4. Out of 8 domains, participants with RSV-positive ARI (vs matched RSV-negative ARI) were significantly more likely to have role limitation due to physical health (adjusted mean difference, −16.7; 95% CI, −31.7 to −1.8), lower energy-level or fatigue (adjusted mean difference, −8.37; 95% CI, −14.34 to −2.41), and decreased social functioning in short-term outcomes (adjusted mean difference, −11.9; 95% CI, −19.77 to −4.04), and lower energy level or fatigue (intermediate: adjusted mean difference, −4.90; 95% CI, −8.49 to −1.31; and long term: adjusted mean difference, −4.40; 95% CI, −7.29 to −1.51), decreased social functioning (intermediate: adjusted mean difference, −5.82; 95% CI, −10.32 to −1.31; long term: adjusted mean difference, −5.19, 95% CI, −8.69 to −1.68), and role limitation due to emotional problems (intermediate: adjusted mean difference, −6.98; 95% CI, −12.71 to −1.25; and long term: adjusted mean difference, −5.67; 95% CI, −10.7 to −0.63) in intermediate and long-term outcomes measured. No significant differences were found in other domains of SF-36 (Table 4). Compared with participants with RSV-negative ARI, those with RSV-positive ARI had no statistically significant differences in FEV1%, FEV1/FVC%, ADL, FRAIL Scale, QOL measure by EQ-5D-3L, and physical frailty measures in short-term outcomes (eTable 4 in Supplement 1).
Table 4. Assessment of the Association of RSV-Positive ARI Compared With Matched RSV-Negative ARI During Prepandemic RSV Season on Short-Term QOL in 8 Domainsa.
| Characteristic | Patients with RSV-positive ARI (n = 58) | Patients with RSV-negative ARI (n = 116) | Adjusted analysis | |
|---|---|---|---|---|
| Effect size, adjusted mean difference (95% CI) | P value | |||
| Physical function b | ||||
| Short-term outcomes | ||||
| Mean (SD) | 85.4 (15.6) | 86.0 (16.5) | −0.71 (−3.94 to 2.52) | .66 |
| Median (range) | 90 (25 to 100) | 90 (20 to 100) | ||
| Missing, No. | 7 | 11 | ||
| Role limitations due to physical health | ||||
| Short-term outcomes | ||||
| Mean (SD) | 50.0 (43.6) | 66.2 (41.2) | −16.73 (−31.69 to −1.76)c | .03 |
| Median (range) | 50 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 7 | 11 | ||
| Intermediate-term outcomes | ||||
| Mean (SD) | 88.5 (28.2) | 82.9 (31.4) | −7.27 (−15.71 to 1.17)c | .09 |
| Median (range) | 100 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 6 | 9 | ||
| Long-term outcomes | ||||
| Mean (SD) | 87.2 (29.6) | 85.6 (29.4) | −4.71 (−11.26 to 1.84) | .15 |
| Median (range) | 100 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 17 | 15 | ||
| Role limitations due to emotional problems | ||||
| Short-term outcomes | ||||
| Mean (SD) | 83.3 (33.3) | 85.8 (28.3) | −7.65 (−16.65 to 1.34) | .09 |
| Median (range) | 100 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 6 | 10 | ||
| Intermediate-term outcomes | ||||
| Mean (SD) | 89.1 (24.50) | 92.7 (20.1) | −6.98 (−12.71 to −1.25) | .02 |
| Median (range) | 100 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 6 | 11 | ||
| Long-term outcomes | ||||
| Mean (SD) | 86.5 (27.6) | 86.9 (27.7) | −5.67 (−10.71 to −0.63) | .03 |
| Median (range) | 100 (0 to 100) | 100 (0 to 100) | ||
| Missing, No. | 16 | 17 | ||
| Vitality (lower energy/fatigue) | ||||
| Short-term outcome | ||||
| Mean (SD) | 55.0 (21.0) | 62.80 (19.1) | −8.37c (−14.34 to −2.41) | .007 |
| Median (range) | 50 (15 to 100) | 63 (15 to 100) | ||
| Missing, No. | 7 | 10 | ||
| Intermediate-term outcome | ||||
| Mean (SD) | 66.6 (17.8) | 66.8 (17.7) | −4.90 (−8.49 to −1.31) | .008 |
| Median (range) | 70 (15 to 100) | 70 (25 to 100) | ||
| Missing, No. | 5 | 12 | ||
| Long-term outcome | ||||
| Mean (SD) | 65.9 (18.6) | 68.4 (17.50 | −4.40 (−7.29 to −1.51) | .003 |
| Median (range) | 65 (30 to 100) | 70 (30 to 100) | ||
| Missing, No. | 19 | 17 | ||
| Emotional b | ||||
| Short-term outcomes | ||||
| Mean (SD) | 83.8 (12.3) | 84.4 (12.6) | −1.41 (−4.81 to 1.99) | .41 |
| Median (range) | 88 (52 to 100) | 88 (32 to 100) | ||
| Missing, No. | 7 | 11 | ||
| Social functioning | ||||
| Short-term outcome | ||||
| Mean (SD) | 68.8 (28.0) | 80.2 (21.2) | −11.91 (−19.77 to −4.04) | .003 |
| Median (range) | 75 (13 to 100) | 88 (25 to 100) | ||
| Missing, No. | 6 | 10 | ||
| Intermediate-term outcome | ||||
| Mean (SD) | 92.2 (15.0) | 91.7 (14.9) | −5.82 (−10.32 to −1.31) | .01 |
| Median (range) | 100 (50 to 100) | 100 (13 to 100) | ||
| Missing, No. | 5 | 9 | ||
| Long-term outcome | ||||
| Mean (SD) | 88.7 (18.1) | 91.9 (14.7) | −5.19 (−8.69 to −1.68) | .004 |
| Median (range) | 100 (13 to 100) | 100 (38 to 100) | ||
| Missing, No. | 16 | 14 | ||
| Pain b | ||||
| Short-term outcomes | ||||
| Mean (SD) | 77.2 (21.4) | 76.1 (19.8) | 1.14 (−4.81 to 7.09) | .70 |
| Median (range) | 79 (23 to 100) | 78 (13 to 100) | ||
| Missing, No. | 6 | 10 | ||
| General health b | ||||
| Short-term outcomes | ||||
| Mean (SD) | 73.1 (15.9) | 71.8 (16.5) | −0.15 (−3.98 to 3.68) | .93 |
| Median (range) | 75 (35 to 100) | 75 (20 to 100) | ||
| Missing, No. | 6 | 11 | ||
Abbreviations: ARI, acute respiratory infection; QOL, quality of life; RSV, respiratory syncytial virus; SF-36, Short-Form Health Survey-36.
Measured by SF-36 (within 2-4 weeks after ARI) and further assessment of intermediate- (6-7 months after ARI) and long-term QOL (12-13 months after ARI) for those with significant impact on QOL at any point in the follow-up duration.
QOL domains without significant impact on short-term, intermediate-term, and long-term QOL as measured by SF-36 (patient reported functional outcome by SF-36 [scored 0 to 100 in 8 domains and a high score defines a more favorable health state in each domain]).
The expert panels of a Delphi method suggested the potential minimal clinically important difference based on their studied participants (individuals with asthma, COPD, and heart diseases) as follows: >5 for physical role functioning, >6.25 for role limitation by physical function, >8.3 for role limitation by emotional problem, >6.25 for vitality, >8.3 for emotional role functioning, >12.5 for social role functioning, >10 for bodily pain, and >5 for general health.22
Discussion
To our knowledge, this is the first and largest community-based prospective cohort study assessing the incidence of RSV-positive ARI before and during the COVID-19 pandemic and the short- and long-term outcomes of RSV-positive ARI in adults 50 years or older in the United States. Our study results suggest the overall incidence of RSV-positive ARI during the prepandemic RSV season was similar to the previously reported incidence rates in the United States and Europe, although the first RSV season of our study was partially affected by the COVID-19 pandemic (ie, March 2020 to April 2021). RSV-positive ARI poses significant long-term impacts on certain health-related QOL beyond the significant short-term outcomes of RSV-positive ARI in older adults. In the pandemic RSV season, RSV-positive ARI cases were undetected similar to very low or no RSV cases in our study setting and the State of Minnesota,23 but as the COVID-19 pandemic persisted, RSV-positive ARI reemerged during the non-RSV season in 2021.
Our estimated incidence rate and attack rate for RSV-positive ARI by RT-PCR for nasopharyngeal swabs during the prepandemic single RSV season were 48.6 (95% CI, 36.9-62.9) per 1000 person-years and 2.50% (95% CI, 1.9%-3.2%), respectively. These estimates might be similar to that reported by a previous United States study based on 4 RSV seasons from 1999 to 2003, (3% to 7% of attack rate by both RT-PCR and serology and 2.0% to 4.7% of estimated attack rate by only RT-PCR based on their provided information).3 Also, our incidence estimate appears to be similar to that from a previous United Kingdom study (36 per 1000 person-years) based on the 1992 to 1994 seasons and both PCR and serology1,5 and that from the more recent multisite European study based on the 2017 to 2019 seasons (4.2% to 7.2% of attack rate by both PCR and serology and 2.1% to 4.9% of estimated attack rate by PCR alone based on their provided information).6 These observations suggest that despite the large span of time (from 1992 to 2019) and different geographic regions, RSV-positive ARI incidence in older adults was consistent. Thus, RSV-positive ARI is likely to pose a major burden to older adults in a predictable manner as the global population ages unless such RSV epidemiology is interrupted by public health measures, which were undertaken during the worldwide public health crises, such as the COVID-19 pandemic.24
During the pandemic RSV season, RSV-positive ARI cases were undetected, and the number of ARI cases drastically decreased from 1126 in the prepandemic season to 212 in the pandemic RSV season. We postulate that this drastic change in the incidence of RSV and other viral ARI is likely to be due to changes in behaviors, in part, by following public health measures, especially during the early phase of the COVID-19 pandemic as we and others recently reported.11,24,25,26,27,28,29 However, as the COVID-19 pandemic persisted, RSV-positive ARI reemerged with the incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.4%; (95% CI, 0.17-0.86). The reemergence of RSV-positive ARI during the non-RSV season concurrent with the COVID-19 pandemic has been recognized at local and national levels.30,31,32 Given the upper respiratory airway has the same infection onset sites for various viral infections, including COVID-19, the mechanisms underlying the drastic reduction and reemergence of RSV-positive and other viral ARI during the COVID-19 pandemic remains to be determined. Additionally, the epidemiological course and association of the reemergence of RSV-positive ARI in older adults or those with high-risk conditions after the COVID-19 pandemic remains to be determined.
The literature supports that RSV-positive ARI causes significant morbidity and mortality in at-risk adults.1,7,8,9,10 Our study results indicated that large proportions of patients with RSV-positive ARI developed severe ARI (97%) and LRTD (71%). The RSV-positive ARI hospitalization incidence estimate of our study is similar to those from 3 previous studies.6,33,34 However, almost all previous studies assessed only short-term morbidity and mortality of medically attended RSV-positive ARI, typically in a hospital setting 7 to 28 days after RSV-positive ARI. As shown in Table 4, compared with those with RSV-negative ARI, our study results revealed previously unrecognized significant short-term, intermediate-term, and long-term impacts of RSV-positive ARI on health-related QOL.22,35 Importantly, these long-term impacts of RSV-positive ARI were independent of potential confounders (ie, age in years, sex, race and/or ethnicity, SES, Charlson Comorbidity Index, and baseline functional measures). A recent prospective cohort study of adult patients (mean age of 66 years) hospitalized with ARI at 40 centers across 12 countries during 2 consecutive RSV seasons (2017-2019) assessed clinical symptoms up to 3 months after RSV-positive ARI.7 At 3 months postdischarge from the hospital, patients with RSV-positive ARI were more likely to have shortness of breath (RSV, 16.1% vs influenza, 9.1%) and cough (RSV, 8.6% vs influenza, 3.5%), compared with those with influenza,7 suggesting the potential association of RSV-positive ARI beyond the ARI-related short-term outcomes. Our study results suggest that such clinical symptoms might persist beyond 3 months post-RSV-positive ARI and be associated with health-related QOL in older adults.
Our study has several strengths. It was the largest and most current community-based prospective cohort study, which followed 2325 adults aged 50 years or older for 2 consecutive RSV seasons from 2019 to 2021. Our study setting is a self-contained health care environment, which allows capture of almost all inpatient and outpatient health care services during the study period.
Limitations
This study had limitations. The primary limitation was that our main study results were based on a single RSV season since the second RSV season was affected by the COVID-19 pandemic. Changes in the proportion of participants who were tested prepandemic and during the pandemic is a major limitation. Another limitation is the lack of assessment for short-term outcome measures immediately after the onset of RSV-positive ARI (eg, underestimating the impact of RSV infection on QOL during the acute phase of RSV infection). Assessment of intermediate- and long-term outcomes did not consider other medical events after RSV-ARI. In this context, there might be additional potential confounders, which were not fully accounted for in our analysis. Finally, our study participants were disproportionately White, and our study was based on those enrolled in Mayo Clinic primary care practice, which may limit the generalizability of our study findings.
Conclusions
In conclusion, this cohort study found that the incidence of RSV-positive ARI in adults 50 years old or older during the pre-COVID-19 pandemic period was significant and consistent over time when compared with other studies covering different seasons and geographies. After a drastic reduction of RSV-positive ARI incidence during the first year of the COVID-19 pandemic, RSV-positive ARI reemerged from the typical RSV season as the pandemic persisted. RSV-positive ARI was associated with significant long-term impacts on health-related QOL beyond the acute infection in adults over 50. An effective RSV vaccine might be an important measure to mitigate the impact of RSV-positive ARI, especially in older adults.
eMethods.
eTable 1. Case Definitions of ARI, LRTD and Severity Definitions
eTable 2. Characteristics at Enrollment of Participants Who Reconsented and Those Who Were Not Reconsented
eTable 3. Characteristics of Participants With RSV-Positive ARI and Matched Participants With RSV-Negative ARI During Prepandemic RSV Season for Measurement of Outcomes at the Time of Enrollment
eTable 4. Assessment of the Association of RSV-Positive ARI Compared With Matched RSV-Negative ARI During Prepandemic RSV Season on Short-Term Frailty Outcomes
eTable 5. Instruction for Self-swab
eTable 6. Sources and Definitions of Variables
eFigure 1. Workflow for Identifying RSV Cases and Controls Including COVID-19 Era
eFigure 2. Flow Diagram for Participant Recruitment and Retention
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods.
eTable 1. Case Definitions of ARI, LRTD and Severity Definitions
eTable 2. Characteristics at Enrollment of Participants Who Reconsented and Those Who Were Not Reconsented
eTable 3. Characteristics of Participants With RSV-Positive ARI and Matched Participants With RSV-Negative ARI During Prepandemic RSV Season for Measurement of Outcomes at the Time of Enrollment
eTable 4. Assessment of the Association of RSV-Positive ARI Compared With Matched RSV-Negative ARI During Prepandemic RSV Season on Short-Term Frailty Outcomes
eTable 5. Instruction for Self-swab
eTable 6. Sources and Definitions of Variables
eFigure 1. Workflow for Identifying RSV Cases and Controls Including COVID-19 Era
eFigure 2. Flow Diagram for Participant Recruitment and Retention
Data Sharing Statement