Severe Morbidity and Short- and Mid- to Long-term Mortality in Older Adults Hospitalized with Respiratory Syncytial Virus Infection

Abstract

Background

We describe the clinical epidemiology and outcomes among a large cohort of older adults hospitalized with respiratory syncytial virus (RSV) infection in the United States.

Methods

Hospitalized adults aged ≥60 years who tested positive for RSV between 1 January 2011 and 30 June 2015 were identified from Kaiser Permanente Southern California. Patient-level demographics, comorbidities, clinical presentation, utilization, complications, and mortality were evaluated.

Results

There were 664 patients hospitalized with RSV (61% female, 64% aged ≥75 years). Baseline chronic diseases were prevalent (all >30%); 66% developed pneumonia, 80% of which were radiographically confirmed. Very severe tachypnea (≥26 breaths/minute) was common (56%); 21% required ventilator support and 18% were admitted to intensive care unit. Mortality during hospitalization was 5.6% overall (4.6% in 60–74 year olds and 6.1% in ≥75 year olds). Cumulative mortality within 1, 3, 6, and 12 months of admission was 8.6%, 12.3%, 17.2%, and 25.8%, respectively.

Conclusion

RSV infection in hospitalized older adults often manifested as severe, life-threatening lower respiratory tract illness with high rates of pneumonia, requirement for ventilatory support, and short- and long-term mortality. Increased recognition of the substantial RSV disease burden in adults will be important in evaluation and use of urgently needed interventions.

(See the Editorial Commentary by Falsey and Walsh, on pages 1245–6.)

Respiratory syncytial virus (RSV) infection is a leading cause of respiratory disease-related morbidity and mortality in infants and young children [1, 2]. Recently, there has been increasing recognition that RSV can be serious among healthy, community-dwelling and high-risk older adults [3–8]. In the United States, an annual estimated 61 000–177 000 hospitalizations and 10 000–14 000 deaths are attributable to RSV in adults ≥65 years [4, 9, 10].

RSV infection in older adults often presents as a nonspecific respiratory syndrome with lower respiratory tract involvement with signs and symptoms that frequently overlap with other causes of acute viral respiratory illness. When compared to influenza, RSV infections are more commonly associated with underlying chronic lung disease [6], wheeze [6, 7], and dyspnea [6, 8], while influenza infections are more likely to present with fever and myalgias [3, 6, 8]. Rates of complications and severe outcomes in older adults, including mortality, have been reported to be similar between RSV and influenza patients [4, 6, 11]. In a seminal, prospective study of community-dwelling adults ≥65 years, Falsey et al reported that RSV infection was associated with a disease burden similar to that of nonpandemic influenza with annual community rates of RSV infection ranging between 3% and 7% in healthy individuals and 4% and 10% in high-risk individuals (ie, those with baseline cardiopulmonary disease); 16% of the high-risk infected individuals were hospitalized [4].

Nonetheless, RSV remains underrecognized as a cause of severe respiratory disease in adults [3, 12]. With the increasing prospect of interventions to prevent and treat RSV, detailed data on the clinical burden of severe disease are critical to increase clinical understanding and provider awareness, to design appropriate trials, and to support policy discussions and health economic analyses on the rational use of RSV vaccines and antivirals [13]. In this context, we previously undertook a study to compare the morbidity and mortality associated with RSV versus influenza infection in hospitalized older adults [11]. However, notwithstanding several notable publications, there is a relative absence of recent, large-scale, longitudinal, or comprehensive data on severe RSV infection in a representative US older adult population [6, 8, 14, 15]. Our aims were to comprehensively characterize the clinical epidemiology, signs and symptoms, and outcomes of severe RSV, and identify independent risk factors associated with short- and mid- to long-term mortality among older adults hospitalized with RSV infection.

METHODS

Study Setting, Population, and Source of Data

The details of the study setting, population, and source of data were described previously [11]. Briefly, the study population consisted of hospitalized Kaiser Permanente Southern California (KPSC) members aged ≥ 60 years at the time of admission who had a positive RSV polymerase chain reaction (PCR) or culture test result that was ordered between 1 January 2011 and 30 June 2015 during a hospitalization or an emergency department encounter resulting in hospitalization. For any patients with multiple, separate hospitalizations associated with a positive RSV test, only the first RSV hospitalization was used for analysis. Necessary information, including baseline characteristics, membership history, signs and symptoms, comorbidities, utilization, and outcomes were extracted from the electronic medical records (EMRs). This study was different from our previous publication [11], in which only electronic data were captured and compared between the RSV and influenza patients. In the current study, we focused on the RSV cohort. Detailed RSV signs and symptoms and additional outcome variables were collected by chart review conducted by research associates (Z.S. and C.A.F.) and physician (B.A.). Because the additional information was not collected for the influenza cohort, the influenza cohort was not included in this publication. The study was reviewed and approved by the KPSC Institutional Review Board.

Chart Review Process

Automated data were collected from structured data in the EMR and additional detailed data were abstracted by trained chart abstractors. A full list of variables can be found in Supplementary Table 1. For the chart abstracted data, a chart abstraction form in REDCap and a chart abstraction manual were developed to ensure quality and consistency of data collection among the chart abstractors. All abstraction forms were quality checked by a second person, and a 10% sample of all abstraction forms were additionally reviewed by a third person.

Signs and Symptoms

Fourteen respiratory and 19 nonrespiratory signs and symptoms were collected from medical notes recorded in EMRs for the period beginning 14 days prior to admission and up to (and including) inpatient history and physical examination or history of present illness on the day of admission. The earliest symptom onset date of any of the respiratory signs and symptoms was considered to be the RSV onset date. Those symptoms with onset dates greater than 30 days prior to admission were not considered to be associated with the RSV episode. Moderate-to-severe lower respiratory tract disease (msLRTD) was defined as having ≥3 of the following signs or symptoms of lower respiratory tract infection: cough, wheeze, sputum production, shortness of breath/difficulty breathing/dyspnea, or tachypnea. The case definition of msLRTD was similar to an endpoint used in 2 recent RSV vaccine trials in older adults (ClinicalTrials.gov NCT02266628 and NCT02608502).

Hospitalization Outcomes

A detailed list of hospitalization outcomes and definitions is provided in Supplementary Table 1. Threshold values for clinical parameters or outcomes such as tachypnea and hypoxia were defined by study physicians. In addition to using International Classification of Diseases, Ninth Revision (ICD-9) codes to identify outcomes, chart reviews were conducted to confirm diagnoses as current events, to search for undercoded conditions (eg, exacerbations of chronic conditions), to identify radiographically confirmed pneumonia, and to ascertain the specific details of ventilator support.

Statistical Analysis

Patient demographics, prehospital course, comorbid conditions, signs and symptoms, and outcomes of hospitalization were described. The demographic and clinical characteristics were stratified by age (60–74 years and ≥75 years). The differences in distribution between patients of different age groups were tested by χ² test or Wilcox rank-sum test.

To identify the factors associated with the short-term (≤60 days after admission) and the mid- to long-term (61–365 days after admission) mortality, 2 Cox proportional hazard models, 1 for each outcome, were created to estimate the hazard ratios (HR) and 95% confidence intervals (CI) associated with the factors. In the first step, a bivariate model was used to evaluate the association between each of the patient demographics, prehospital course, comorbid conditions, signs and symptoms, and complications during hospitalization and the outcome (either short- or mid- to long-term mortality). Characteristics that applied to less than 1% of the total number of subjects were not included in the model to avoid unstable estimation. In the second step, variables with a P value less than .05 in the first step were included in a stepwise multivariate model to estimate the adjusted HRs and CIs. Age and sex were forced into the final adjusted model, while additional variables with an associated P value less than .2 were included.

One-year survival rates were estimated using the Kaplan-Meier method, and survival rates among subgroups were compared using the log-rank test. The subgroups within the RSV hospitalized cohort included age (60–74 vs ≥75 years), community-acquired pneumonia during hospitalization (yes/no), baseline presence of chronic obstructive pulmonary disease (COPD)/chronic bronchitis/emphysema (no, yes with no current exacerbation, or yes with current exacerbation), and baseline presence of congestive heart failure (CHF; no, yes with no current exacerbation, or yes with current exacerbation).

To estimate the RSV test positive rate of hospitalized patients during the RSV season (from 1 October 1 to 30 April of the next year) over the study period, we calculated the proportion of those who tested positive for RSV among those who were tested during the RSV season. The RSV test positive rates and their 95% binomial CI are presented overall and stratified by RSV season, age, and sex. All analyses were performed using SAS Enterprise Guide version 5.1 and higher (SAS Institute Inc.).

RESULTS

There were 690 hospitalized patients ≥60 years of age who tested positive for RSV during the study period; 26 (3.8%) did not meet the 6-month prior membership requirement and were excluded. RSV was detected by multiplex PCR in 91.8% of the patients and the rest by viral culture. The distribution of demographic characteristics, medical history, and comorbidities is presented in Table 1. Approximately two-thirds of the population was ≥75 years, and 60.5% were female. Current smoking was prevalent (35.1%). More than 85% of the patients resided at home prior to admission, 7.8% resided in residential care or a nursing home, and 5.9% resided at a skilled nursing facility. Baseline ischemic heart disease, CHF, diabetes, and COPD/chronic bronchitis/emphysema were common (each >30%). Numbers of outpatient visits, emergency department visits, and hospitalizations during the 6 months prior to admission with RSV were high. Coinfection with other respiratory viral pathogens was uncommon; only 2.6% were coinfected with another viral respiratory pathogen within 7 days of the RSV test order date.

The median number of days from onset of the first respiratory symptom to the first health care encounter, to admission, and to a positive test were 3, 5, and 6 days, respectively. The majority (>86%) had symptom onset within 14 days of admission. Notably, approximately 75% of the patients had ≥6 respiratory signs/symptoms, with a median of 7. The signs/symptoms noted to be present prior to admission, separately by age group, are described in Figure 1. The most common presenting respiratory symptoms were cough, tachypnea (≥20 breaths per minute), and shortness of breath/difficulty breathing/dyspnea. More than 90% of the patients met the case definition of msLRTD (91.2% vs 93.0% in the 60–74 vs ≥75-year-old age group). Fifty-one (7.7%) patients were admitted without msLRTD, nonetheless, they were very ill. Many had underlying conditions that increased their risk of poor outcomes or had other serious reasons for admission but were found to have RSV, nearly always at the time of admission or shortly thereafter. Finally, common nonrespiratory signs/symptoms included feverishness, lethargy, and weakness.

The pattern of clinical outcomes associated with hospitalization, separated by age group, are presented in Figure 2. The median length of stay from admission to discharge or death was 5 days. Approximately half of the patients (48.7% vs 55.9% aged 60–74 vs ≥75 years) had radiographically confirmed pneumonia. An additional 84 patients (10.5% vs 13.8% aged 60–74 vs ≥75 years) had possible pneumonia (ie, physician-diagnosed clinical pneumonia without radiographic confirmation). A diagnosis of bacteremia/sepsis during the RSV hospitalization encounter was identified in 189 patients (30.3% vs 27.5% aged 60–74 vs ≥75 years); among them, 18 had blood culture-confirmed bacteremia. Myocardial infarction occurred in 25 (3.8%) patients during hospitalization. One hundred and fifteen patients (14.7% vs 18.8% aged 60–74 vs ≥75 years) were noted to have acute renal failure during hospitalization. Almost all patients had some level of tachypnea during hospitalization (highest measured respiratory rate ≥20 breaths per minute), with 374 (56.3% vs 56.3% aged 60–74 vs ≥75 years) experiencing very severe tachypnea (highest measured respiratory rate ≥26 breaths per minute) during hospitalization. Eighty percent of the patients experienced hypoxia (77.7% vs 81.2% aged 60–74 vs ≥75 years) with 21.5% (23.1% vs 20.7%) having very severe hypoxia. Approximately 21.4% (23.1% vs 20.4% aged 60–74 vs ≥75 years) required ventilator support during hospitalization (median 4 days), 17.9% (18.9% vs 17.4%) were admitted into the intensive care unit (median stay of 4 days), and 16.7% (14.3% vs 18.1%) were readmitted within 30 days of discharge. The mortality during hospitalization was 5.6% overall (4.6% vs 6.1% aged 60–74 vs ≥75 years). Overall, the cumulative mortality within 30 days, 3 months, 6 months, and 12 months of admission was 8.6%, 12.3%, 17.2%, and 25.8%, respectively, and was higher in patients aged ≥75 years across all follow-up durations.

Among patients with CHF, COPD/chronic bronchitis/emphysema, or asthma at baseline, 38.2%, 80.4%, and 49.5%, respectively, experienced exacerbation during the RSV hospitalization. Approximately half of all patients (65.5% vs 39.9% aged 60–74 vs ≥75 years) were discharged home without need for additional home health services, with 2.6% (0.8% vs 3.5% aged 60–74 vs ≥75 years) discharged to hospice and 10.4% to a skilled nursing facility (6.3% vs 12.7%). Among survivors at discharge, high utilization of health care services during the 6-month postdischarge period was observed.

The factors associated with short- and mid- to long-term mortality are presented in Table 2. Variables independently associated with increased short-term mortality included having 2 or more hospitalizations in the 6 months prior to RSV hospitalization, tachypnea (adjusted HR [aHR], 5.28; 95% CI, 1.23–22.60 for very severe tachypnea vs no tachypnea), altered level of consciousness, lymphoma in 12 months prior to admission, community-acquired pneumonia during hospitalization (aHR, 2.98; 95% CI, 1.55–5.74), acute renal failure during hospitalization (aHR, 2.62; 95% CI, 1.57–4.38), atrial fibrillation during hospitalization (aHR, 1.66; 95% CI, 1.01–2.71), and neurovascular complication during hospitalization (aHR, 6.28; 95% CI, 2.17–18.2). Presence of nasal congestion or chills was associated with a lower short-term mortality.

Variables independently associated with increased mid- to long-term mortality included advanced age, having any hospitalizations in the 6 months prior to RSV hospitalization, weakness, lymphoma, dementia, end-stage renal disease (ESRD) in 12 months prior to admission, or exacerbation of CHF during hospitalization (aHR, 1.86; 95% CI, 1.11–3.13). Presence of cough, vomiting, or dizziness was associated with decreased mid- to long-term mortality.

Estimated survival during the year following admission was significantly poorer among those with advanced age, pneumonia during hospitalization, or presence of CHF exacerbation or CHF at baseline, but not by COPD/chronic bronchitis/emphysema status (Figure 3).

Table 3 presents the overall and age- and sex-stratified RSV test positive rate among all KPSC adults ≥60 years old who were hospitalized and tested for RSV during the RSV season. The RSV test positive rate was higher in women and in adults ≥85 years old. During the study period, the seasonal average test positive rate was 5.40% (range, 3.28%–7.58%).

DISCUSSION

In this clinically comprehensive report, we describe detailed data—stratified by age (60–74 years and ≥75 years)—on patients’ demographics, chronic medical conditions, health care utilization, development of respiratory and nonrespiratory signs and symptoms, pattern of complications, and, notably, estimates of short-term and long-term mortality associated with an RSV hospitalization, with long-term mortality being unique in published descriptions of serious outcomes associated with severe viral or bacterial respiratory infections. Our data confirm and expand several reports of the burden and severity of illness during an RSV-associated hospitalization episode in older adults, and, most importantly, extend recognition of the clinical sequelae of severe RSV significantly beyond the acute hospitalization episode [4, 6, 8]. We noted high proportions of patients requiring home health services or nursing facility placement upon discharge, high levels of hospital readmission within 30 days of discharge, substantial health care utilization (outpatient, emergency department, and hospital visits) in the 6 months following discharge, and increasing mortality during 1-year posthospital admission in association with advanced age, presence of concomitant pneumonia, and presence of baseline CHF or CHF exacerbation.

In a population of hospitalized older adults, RSV infection manifested predominantly as a severe and life-threatening lower respiratory tract illness. During hospitalization, 56% of patients with RSV infection had very severe tachypnea (≥26 breaths per minute), >65% had radiographically or clinically confirmed pneumonia, >20% required ventilator support, and 18% were admitted to intensive care. Similar rates of intensive care unit admission have been reported in previous studies [4, 8, 16, 17].

We documented substantial mortality throughout the 1-year period following an RSV-associated hospitalization with markedly higher mortality rates in selected high-risk groups. In a 2013 study from Hong Kong, Lee et al reported similar levels of all-cause mortality within 30 days and 60 days of an RSV hospitalization (9.1% and 11.9%, respectively, median age 80 years) [6]. Falsey et al estimated an 8% in-hospital mortality rate for RSV in those aged ≥65 years, and based on those observations, extrapolated an estimated 14 000 RSV-associated deaths each year in the United States [4]. Remarkably, we found a profound age-dependent increase in the short- and long-term mortality trajectory of an RSV-associated hospitalization. Almost one-third of hospitalized RSV patients aged ≥75 years died within 1 year of admission and only approximately 40% of the patients in this age group were discharged home without the need for home health services or a higher level of postdischarge care (hospice or skilled nursing facility). Uniquely, in this study, we were able to separately assess independent risk factors for both short- and mid- to long-term mortality among older adults hospitalized with RSV. We found that patients presenting with very severe tachypnea (respiratory rate ≥26 breaths per minute) or with community-acquired pneumonia— both markers indicative of significant acute lower respiratory tract pathology—had a nearly 5-fold and 3-fold increased risk of death within 60 days of admission, respectively. Not surprisingly, potential markers of increasing frailty, such as multiple prior hospitalizations in the prior 6 months, were also independent risk factors for increased 60-day mortality. Mid- and long-term mortality trajectory through 1 year following admission was most heavily predicted by advanced age, followed by the presence of long-standing chronic underlying medical conditions such as CHF, lymphoma, ESRD, and dementia.

Consistent with findings from other studies [18–20], our results indicate that baseline cardiopulmonary diseases, including ischemic heart disease, CHF, COPD/chronic bronchitis/emphysema, and asthma are prevalent chronic conditions among patients hospitalized with RSV. Perhaps not surprisingly, we noted that RSV infection triggered clinically consequential deterioration of underlying cardiopulmonary diseases. We estimated that 80% of patients with COPD/chronic bronchitis/emphysema at baseline experienced an exacerbation during hospitalization; similarly, approximately 50% of patients with baseline asthma, and 38% of patients with baseline CHF, experienced exacerbations. Of note, those with CHF exacerbation at the time of RSV hospitalization had amongst the worst 1-year survival of any subgroup (approximately 57%). For patients with a history of COPD, significant ongoing clinical sequelae may result from a permanent decline in lung function following clinical recovery from an acute exacerbation that appears to be particularly severe following RSV infection [21, 22]. This potential for serious clinical decline underscores the importance of heightened clinical monitoring of long-term complications in certain high-risk older adults following recovery from an acute RSV-associated hospitalization.

Recent studies of adult patients hospitalized with acute respiratory illnesses have reported incidence proportions of RSV infection of 3%–12% [4–6, 8, 23]. In this study, we found a seasonal average test positive rate of 5.40% (range, 3.28%–7.58%) for RSV among all hospitalized KPSC patients aged ≥60 years tested during the US national RSV transmission season. Similarly, Widmer et al reported an average RSV test positive rate of 6.7% (19/282) among patients ≥65 years hospitalized with an acute respiratory illness [8]. Falsey et al reported an RSV test positive rate of around 10% in patients hospitalized with acute cardiopulmonary conditions [4, 16]. A large international influenza vaccine clinical trial conducted during the 2008–2009 and 2009–2010 winter seasons identified a RSV test positive rate of 12.5% (8/64) among patients aged ≥65 years who were hospitalized with moderate-to-severe influenza-like illness (ILI) [5]. As in our study, they reported that the RSV test positive rate among ILI cases increased with age, from 6.1% in 65–69 year olds to 8.5% in those older than 85 years [5].

The lower RSV test positive rates reported in retrospective observational studies compared to rates reported in prospective studies could, in part, be explained by the general lack of clinical awareness among adult health care providers of the burden of RSV disease in older adults and a resulting lack of routine diagnostic testing for RSV infection in many clinical settings [3, 12]. In prospective trial settings, molecular diagnostic testing is systematically performed on participants meeting a respiratory illness case definition, while in retrospective studies of routine clinical practice, noninfluenza viral respiratory pathogens including RSV are detected opportunistically because diagnostic testing is usually ordered to confirm a suspected influenza virus infection. Local circulation of influenza virus in the community, and clinical suspicion for influenza infection, may therefore drive testing patterns among the hospitalized older adult population. These testing patterns are likely to underestimate the relative frequency of other viral respiratory pathogens, including RSV, which may have either nonoverlapping or broader periods of circulation within the same community. In addition, rates of RSV are likely to be underestimated in prospective studies using traditional ILI or severe acute respiratory infection definitions that typically include fever [13]. In our study, only 56% of hospitalized RSV patients had fever. Additionally, when testing is performed many days after symptom onset, RSV replication can progress to the lower airways and become undetectable in upper airway nasal secretion samples [3]. This may lead to potentially false-negative results and an underestimation of true rates of RSV. As the routine use, cost, and availability of multiplex molecular diagnostic testing continues to improve, driven initially by a clinical and research interest in severe influenza, it will set the stage for further characterization of the incidence and burden of RSV.

In conclusion, these comprehensive data help to fill critical knowledge gaps, further underscore a significant unmet medical need, and can inform future planning for the research agendas of RSV vaccines and antivirals in the United States and worldwide. The burden of severe RSV in a hospitalized older adult population is significant and likely underrecognized by health care providers, patients, and policy makers in the United States. With a growing aging population, RSV-associated morbidity and mortality in the older adult population poses a significant health and economic burden. Additional prospective studies are needed to evaluate the totality of the long-term impact of RSV infection and to quantify the overall medical and societal burden, particularly the potential long-term decline in functional status that may follow a severe RSV-associated hospitalization.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors acknowledge the following individuals from Kaiser Permanente Southern California for their contribution to medical chart abstraction: Dwayne Agpalo, Brittany Brown, Laura Dilanchian, Nidia Golla, Peggy Hung, Claire Jang, Lindsay Lyons, Mercedes Munis, Laura Sirikulvadhana, and Melena Taylor; and Songyue Chen for his contribution to programming. The authors thank the patients of Kaiser Permanente for helping us improve care through the use of information collected via our electronic health record systems.

Author contributions. H. F. T. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. J. S. and Y. L. conducted and are responsible for the data analysis. V. S. participated in the design and conduct of the study, interpretation of the data, and review of the manuscript.

Financial support. This work was supported by Novavax.

Potential conflicts of interest. H. F. T., L. S., B. A., C. F., J. S., Y. L., and Z. S. report receiving research support from Novavax for this study. H. F. T., L. S., B. A., C. F., J. S., Y. L., and Z. S. report receiving research support from GlaxoSmithKline for studies unrelated to this study. L. S., B. A., J. S., and Z. S. report receiving research support from Dynavax for studies unrelated to this study. H. F. T., L. S., B. A., and Y. L. report receiving research support from Seqirus for studies unrelated to this study. V. S. is an employee of Novavax.

References