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NFID Clinical Updates

Respiratory Syncytial Virus in Older Adults

A Hidden Annual Epidemic

Talbot, H. Keipp MD, MPH*; Belongia, Edward A. MD; Walsh, Edward E. MD; Schaffner, William MD*

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Infectious Diseases in Clinical Practice: November 2016 - Volume 24 - Issue 6 - p 295-302
doi: 10.1097/IPC.0000000000000455
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Respiratory syncytial virus (RSV) is a common cause of acute respiratory illness in older adults, with the risk of serious infection increasing with age.1–4 The virus circulates along with many other winter respiratory viruses, most notably seasonal influenza, and is largely indistinguishable from influenza based on clinical presentation alone.2,5,6 Respiratory syncytial virus is second only to influenza as a cause of medically significant respiratory tract illnesses in adults7,8 and is estimated to cause 177,000 hospitalizations and 14,000 annual deaths in US adults aged 65 years and older.2,9

There is no specific treatment for RSV and currently no licensed vaccine to prevent the disease. However, several promising candidate vaccines are on the horizon to protect populations at increased risk of serious RSV outcomes, including older adults.10 Respiratory syncytial virus epidemiology and burden of disease suggest vaccines should target infants younger than 6 months, infants and children aged 6 to 24 months, pregnant women (to provide passive immunity to newborns), and adults aged 65 years and older.11 The focus of this report is on the older adult population.

Recognizing and defining the impact of RSV in older adults is important to evaluate the impact of new prevention and treatment options that will likely be available in the United States soon. Public health and health care professionals need to educate themselves about RSV so they can advise the general public and older patients about the importance of prevention.


Respiratory syncytial virus is an RNA virus that was isolated in the mid-1950s from a captive chimpanzee with upper respiratory tract illness.12 It is classified in the Paramyxoviridae family, which includes parainfluenza, metapneumovirus, and measles viruses. Humans are the only known reservoir.

The RSV subtypes A and B cocirculate. Some data indicate that RSV subtype A may cause more severe disease. Two surface glycoproteins, F and G, are responsible for initiation and propagation of RSV infection in the host. The G protein differs on the RSV A and B subtypes, but the F protein is antigenically stable with minimal difference between subtypes (Fig. 1).7,13

The RSV structure. Reprinted from Current Opinion in Immunology, Volume 35, Graham BS, Modjarrad K, McLellan JS. Novel antigens for RSV vaccines, pp 30–38, 2015, with permission from Elsevier.13

Respiratory syncytial virus epidemics occur annually during the winter months in temperate regions, with most US infections occurring in a 22-week period from November to May.14 By 2 years, almost all children have been infected with RSV, and approximately half have been infected twice.15 Immunity is fleeting, and reinfection is common throughout the lifespan.

Hall et al16 challenged 15 healthy young adults with RSV at 2, 4, 8, 14, 20, and 26 months after natural infection. The rate of reinfection was highest after the first challenge (~50%) showing that just 2 months after RSV infection, otherwise healthy adults were already susceptible to reinfection. The cumulative reinfection rate was two thirds by 8 months, and, during the course of the approximately 2-year study, 73% had 2 or more and 47% had 3 or more infections.


The pathogenesis of disease associated with RSV is well described in young children, but little is known about the pathogenesis in older adults. In children, RSV usually begins as an infection in the nasal mucosal epithelial cells.17 The RSV virion attaches to and penetrates ciliated nasal epithelial cells by fusing with the cell membrane, entering and replicating in the cytoplasm. Infectious virus buds from and exits the infected cells via apical membrane on the lumenal side (the same side of entry) of the airway and is not released into the systemic circulation through the basement membrane. This restricted replication may be why RSV is not a systemic virus, making it difficult for the immune system to mount a very strong and durable systemic response.

Virus replication results in epithelial cell sloughing, inflammatory cell infiltration, edema, increased mucous secretion, and impaired ciliary action. The sloughed cells create an obstruction; during inhalation the airway opens, but on exhalation when the lungs deflate, the airway can become obstructed, causing air trapping and wheezing.


Respiratory syncytial virus is associated with the most severe disease at the extremes of age.2,6,18,19 In infants, RSV causes bronchiolitis, pneumonia, tracheobronchitis, and otitis media, whereas in older adults, it can cause pneumonia as well as exacerbation of chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF). For healthy older children and young adults, clinical presentation of RSV resembles the common cold, with mild to moderate cough and nasal congestion.

When RSV presents similar to the common cold, it is unlikely to cause significant fever, giving patients no signal that they should self-isolate. If they go to work in day cares, nursing homes, hospitals, and other locations, they may unknowingly spread RSV to others who may be more vulnerable to severe outcomes.


Gradual deterioration of the immune system due to aging (immunosenescence) is one of several reasons why older adults are at increased risk from viral respiratory disease.20 Even the most vital and active older adult will experience some immunosenescence as a consequence of aging, but it is important to note that age alone is not the only determining factor. Frailty, marked by a lack of physiologic reserve,21 may predict immunosenescence and response to immunization better than age.22,23

As adults age, cellular immunity changes include decreased naïve T cells, increased memory T-cell count, decreased T-cell proliferation with Th1 and Th2 imbalances, and increased levels of inflammatory mediators. Older adults also have decreased B-cell responses to new antigens and decreased cytotoxic T-cell activity, resulting in less effective natural killer cells in the immune system.

Anatomically, older adults have decreased strength of the respiratory muscles and diaphragm, which impede lung expansion. Older adults also have decreased protective mucus levels, lung compliance, and elastin.


Based on data from a 4-year study, the Centers for Disease Control and Prevention estimates 14,000 annual deaths in the United States caused by RSV in adults aged 65 years and older.9 A statistical model by Thompson et al1 encompassing a 10-year period estimated more than 11,000 annual respiratory and circulatory deaths due to RSV in the United States with 78% in patients aged 65 years and older. During the surveillance period, RSV was associated with more deaths in this age group than influenza B or the influenza A (H1N1) strain, but fewer deaths than the more severe influenza A (H3N2).

Whereas a hallmark of influenza is its annual seasonal variability, RSV is more consistent in its attack rate and severity. According to a study by Falsey et al2 during 4 winter respiratory seasons (1999–2003) in Rochester, NY, RSV infection developed annually in an average of 5.5% (range, 3%–7%) of healthy adults aged 65 years and older (ie, without COPD or CHF) and 4% to 10% of high-risk adults aged 21 years and older (ie, diagnosed with chronic heart or lung disease). The number of patients with RSV in this study was approximately double the number of patients with influenza, but a high level of influenza vaccination coverage was noted in the study population.

The investigators also evaluated all adults aged 65 years and older and those with underlying cardiopulmonary disease at any age who were admitted to a local hospital with a spectrum of acute cardiopulmonary symptoms. Respiratory syncytial virus and influenza were responsible for 9.6% and 10.5% of these hospitalizations, respectively. Based on discharge diagnosis, RSV accounted for 10.6% of hospitalizations for pneumonia, 11.4% for COPD, 7.2% for asthma, and 5.4% for CHF.2


There are limited data on the cost of RSV in adults. A study published in 2000 estimated the annual cost of RSV-related acute respiratory infection in adults aged 65 years only at almost $103 million.24 Based on Social Security Administration estimates of an additional 19 to 21 years life expectancy for individuals reaching 65 years today,25 a progressively aging population, and rising health care costs, the US price tag for RSV in the 65-years-and-older population is likely much greater and may be well into the billions of dollars.

A striking finding in this study was that nearly half of the total cost of RSV was for outpatient oral antibiotics,24 which would only be medically appropriate for patients with bacterial coinfection. Another study by Falsey et al2 found that only 10% of older and high-risk adults hospitalized with RSV infection had concomitant bacterial infection. In addition to adding to unnecessary costs, overuse of antibiotics is the single most important risk factor leading to antibiotic resistance.26

Preventing RSV in this older population (≥65 years) could reduce both short- and long-term disability and reduce the burden on the US health care system resulting in fewer acute illnesses and exacerbations of chronic conditions; less contact with health care facilities, especially during the winter respiratory season; fewer unnecessary antibiotic prescriptions; and less financial burden.


Respiratory syncytial virus and influenza A present with strikingly similar symptoms in adults, making it “nearly impossible,” according to Walsh et al,6 to distinguish between the 2 infections based on clinical presentation alone.2,3,5,6 Nearly all RSV-infected adults (89%) exhibit some combination of acute respiratory symptoms (Table 1).2

Symptoms in Outpatients with Laboratory-Confirmed RSV Versus Influenza A Through 4 Seasons, 1999–2003—Rochester, NY

Testing for RSV is not performed routinely in outpatient settings because it is not widely available, it is expensive, and there is no clinical application for the results because there are no targeted RSV treatments.3,6,27 The similarity of RSV and influenza symptoms combined with infrequent laboratory confirmation of RSV infection have contributed to a lack of awareness of the true impact of RSV in older adults among both health care professionals and the public. However, with the recent introduction of multiplex real-time polymerase chain reaction (PCR) for viral testing, the identification of RSV in adults has begun to increase.

RSV illness usually starts with nasal congestion and rhinorrhea, which progress through several days. Cough, often with sputum production, is common and can be accompanied by dyspnea and wheezing, a hallmark of RSV infection across all ages. On average, patients with RSV present to a doctor or the emergency department on day 5 to 7 of the illness.6

There is little difference in RSV and influenza symptoms in adults with high-risk conditions (eg, chronic heart or lung disease) at any age and those aged 65 and older without high-risk conditions (Tables 1 and 2).2,3 Healthy adults with RSV tend to report less fever and dyspnea, and more wheezing, than adults with influenza. Among hospitalized adults with RSV, a substantial proportion report wheezing with both RSV (73%) and influenza infection (53%).6 Absence of fever in patients with RSV seems to be one of the few clues differentiating RSV from influenza.

Factors Associated With RSV Infection Compared With Influenza in Adults Aged 50 Years and Older Over 6 Seasons, 2004-2010—Marshfield, WI

Although patients with RSV and influenza report similar symptoms, albeit with differing frequencies, patients with RSV do not seek medical attention as quickly and experience a longer time from symptom onset to hospitalization.3,28 The more rapid symptom onset of influenza combined with higher fever likely drives these patients to seek medical care sooner than patients with RSV.

Although the data show a milder course of illness for RSV compared with influenza, it is worth noting that influenza severity can vary substantially by season according to the circulating strain. In the 6-year Sundaram et al3 study, the first 4 seasons were marked by either dominant or cocirculation of the influenza A (H3N2) virus, which causes more severe illness than influenza A (H1N1) and B viruses.

Patients hospitalized with RSV have similar outcomes as patients hospitalized with influenza. In the Falsey et al2 study, 8% of those hospitalized with RSV died compared with 7% for influenza. In a study by Lee et al,28 9% of those hospitalized with RSV died compared with 10% hospitalized with influenza.

Patients hospitalized with either influenza or RSV are typically admitted under a wide range of diagnoses, similar across both groups.2 These include pneumonia (39%–46%), acute exacerbation of COPD (23%–35%), CHF (9%–13%), asthma (7%–8%), bronchitis (1%–6%), and myocardial infarction (1%–3%).


Because the clinical syndrome is nonspecific, laboratory testing is required for accurate RSV diagnosis. Currently, PCR is the diagnostic test of choice with approximately 85% sensitivity in adults. Viral shedding starts soon after infection in adults and peaks at approximately day 3, followed by a 2- to 3-day plateau and then a steady decline (Fig. 2).29 Nasal shedding can last 10 days or more, making it possible to detect RSV by PCR for at least 10 or more days in the average adult patient. Adults aged 65 years and older tend to shed slightly higher titers than younger adults (2.8 ± 1.0 vs. 2.0 ± 1.3 log10 PFU [plaque-forming unit]/mL) and for a longer duration (11.3 ± 5.2 vs. 8.7 ± 4.3 days).

Composite nasal shedding in 111 RSV-infected adults. Adapted from Walsh et al (J Inf Dis. 2013;207:1424–1432).29

Unfortunately, currently available point-of-care rapid antigen tests, especially those based on enzyme immunoassay, which are widely used for infants, have very poor sensitivity in adults because of the relatively low titer of virus shed in respiratory secretions. Serology is slightly more sensitive than PCR testing for detecting RSV in older adults (85% vs. 82%, respectively).30 Unfortunately, serologic testing results do not return in a timely manner to help with clinical care. In adults, RSV infection is associated with lower viral loads, making detection difficult, especially by rapid antigen tests and viral culture. It is expected that technological advances will soon provide more rapid and equally sensitive PCR-based point-of-care tests with costs that allow more widespread use. This is critical because it will be important to accurately test for and diagnose RSV once RSV-specific treatments become available.


The RSV treatment in adults is supportive, including antipyretics, supplemental oxygen, and intravenous fluids as needed.31 Inhaled or systemic corticosteroids and bronchodilators may be used for elderly patients or patients with preexisting pulmonary conditions (eg, asthma, COPD) with acute wheezing. As referenced earlier, antibiotics are not indicated for patients with RSV except in cases of concomitant bacterial infection, which occurs in 10% to 30% of RSV infections in hospitalized adults. Bacterial complication rates in outpatients with RSV have not been studied.


The RSV surface F protein mediates the virus entry into the host cell and is the major target for vaccines currently in late-phase clinical trials. The F protein undergoes a conformational change during the fusion process, elongating from its prefusion active version to a nonfunctional postfusion state. This may be important for vaccine development because the prefusion F carries a unique neutralizing epitope that is absent in the postfusion F. Currently, both pre- and postfusion forms of F are being assessed as vaccine candidates.

The F protein is relatively well conserved, unlike the hemagglutinin on influenza virus or the G protein (attachment protein) of RSV. F is very stable, with little antigenic change through time. An anti-F monoclonal antibody (palivizumab) is protective when administered prophylactically to premature infants, suggesting that induction of neutralizing antibodies against the F protein by immunization may be protective in adults. The F protein also carries CD8+ T-cell epitopes that may be important in protection from disease severity.

The RSV G glycoprotein mediates virus attachment to respiratory epithelial cells and also can generate neutralizing antibodies, although they are less frequent than with F immunization. The G glycoprotein has a short central conserved domain, but the majority of the protein carries hypervariable domains with a wide range of antigenic diversity. It also determines RSV subtype (A or B) and it is highly glycosylated, which may impair antibody binding to the antigen. Unlike F, the G protein does not contain CD8+ T-cell epitopes. These factors have made the F protein the favored target for vaccine-induced immunity.


More than 3 dozen RSV vaccines for a range of patient populations are currently in preclinical development and more than a dozen are in clinical trials.10 Vaccines currently in phase 1 include gene-based vector, subunit, particle-based, and live-attenuated vaccines. Live-attenuated vaccines are of particular interest for use in infants because the evidence to date suggests they do not pose a risk for inducing more severe enhanced respiratory disease in RSV-naïve children, which occurred after use of an inactivated whole-virus RSV vaccine given to very young infants in the 1960s.32 There is less concern that an inactivated vaccine could be associated with enhanced disease in adults. Two candidate vaccines for older adults have moved beyond phase 1 trials.

A phase 2b randomized, double-blind, placebo-controlled trial is evaluating the efficacy of a vaccine from MedImmune (MEDI7510; MedImmune, LLC, Gaithersburg, Md), a single-dose RSV F antigen with a GLA-SE adjuvant, a TLR4 agonist (GLA) in oil and water emulsion (SE) that boosts cellular and humoral immune response for prevention of acute RSV-associated illness in adults aged 60 years and older.33 All subjects receive an inactivated influenza vaccine, and subjects in the intervention arm also receive 120 μg of the RSV F antigen with adjuvant.

The primary efficacy outcome measure is incidence of acute RSV-associated respiratory illness assessed by clinical symptoms along with PCR confirmation. Efficacy is assessed in season 1, with data available at the end of 2016. In season 2, subjects who received MEDI7510 in the northern hemisphere will be rerandomized to receive MEDI7510 or placebo (all subjects receive influenza vaccine) to assess the safety and immunogenicity of repeat dosing (efficacy is not assessed in season 2). The trial enrolled approximately 1900 participants in North America, Europe, South Africa, and Chile (subjects with significant ongoing illness were permitted to enroll; subjects with autoimmune disorders and significant immunosuppression were excluded).

In the phase 1b trial (N = 264), MEDI7510 seemed to be safe and immunogenic with no reports of related serious adverse events; however, at the highest dose of the adjuvant, 54% of the subjects reported local pain and tenderness at the injection site, a rate similar to inactivated influenza vaccine.34,35

A phase 3 randomized, double-blind, placebo-controlled trial is evaluating the efficacy of a vaccine from Novavax, Inc (Rockville, Md), a single dose of a recombinant subunit RSV F vaccine at a dose of 135 μg for the prevention of moderate to severe RSV-associated lower respiratory tract disease in adults aged 60 years and older.36 The primary efficacy outcome measure is number and percent of subjects with moderate to severe RSV-associated lower respiratory tract disease assessed by clinical symptoms (≥3 of the following: cough; new or worsening wheezing; new or increased sputum production; new or worsening dyspnea; and observed tachypnea) along with PCR confirmation. The primary safety outcome measure is number and percent of patients with solicited local and systemic adverse events through 1-year postdosing. This study enrolled close to 12,000 US subjects and is scheduled to be completed in 2016.

The phase 2 trial of the Novavax vaccine (N = 1599) randomized subjects to placebo or 135 μg RSV F antigen.37 All subjects received inactivated influenza vaccine. The randomization was stratified based on age (60–75 and >75 years) and presence of ischemic heart disease or CHF (yes/no). The study is complete, but results have not yet been published.


A 2015 article from Simões et al38 reported on ongoing challenges and opportunities in development of RSV-specific therapies and pointed out that whereas the impact of RSV in infants is widely recognized, the misperception that RSV is of little to no consequence in adults has slowed drug development for this age group. Development was delayed for all ages because of lack of adequately sensitive point-of-care diagnostic tests, but this challenge has been overcome in recent years.

A review at shows that multiple drugs are currently in phase 2 trials for treatment and prevention of RSV in adults including monoclonal antibodies and small molecules. Antiviral drugs mainly target the RSV F (fusion) protein. Two phase 3 trials that are underway are focused on RSV treatment in stem cell and bone marrow transplant patients.


Experts at the National Foundation for Infectious Diseases roundtable discussed gaps in current knowledge about RSV in older adults as well as limited awareness of the impact of RSV in older adults among health care professionals, public health officials, and the public that must be addressed before prevention strategies including vaccines are available.

Improved surveillance is needed to collect better data about the incidence and burden of RSV, including hospitalizations and intensive care unit admissions, in older adults and in adults with high-risk conditions such as COPD. It will be important to collect comprehensive data that will allow public health experts to stratify risk by age (ie, by younger and older seniors) and by underlying condition to help drive the best public health vaccination policy.

The question that will need to be addressed is, “Should RSV vaccination policy be driven by age or other measures of frailty and susceptibility (or both)?” Experts pointed out the difficulty in implementing recommendations based on identifying high-risk conditions versus the much simpler implementation of age-based recommendations.

It will be essential to gather data on the duration of vaccine protection and the issue of reimmunization. Aligning RSV vaccination recommendations with influenza immunization recommendations (ie, annual vaccination before the start of the winter respiratory season) would simplify implementation in many ways. However, there are additional practical considerations, such as how delivery of RSV vaccine will impact delivery of other vaccines targeted for older adults and whether the public will accept 2 annual immunizations: influenza and RSV. Public health policy must be shaped by what will optimize health outcomes but will need to take into consideration these practical implementation issues.

Vaccine trials should provide some valuable information on correlates of protection and on the clinical predictors of serious outcomes. We need to know more about the predictors of serious outcomes beyond what is already known about CHF, COPD, and compromised immune systems.

Since the use of a new vaccine grading system at the Advisory Committee on Immunization Practices (ACIP), cost-effectiveness will be a consideration for RSV vaccines in development. It will be essential to define the overall impact of vaccination on the burden of RSV illness in older and at-risk adults and on reducing costly inpatient and intensive care unit stays as well as long-term disability.

Finally, RSV vaccines must be safe and provide adequate protection. Optimally, vaccines will be moderately or highly effective against serious RSV outcomes and provide sustained protection through at least 1 season.

Successful implementation of a new vaccine will rest on raising health care professional awareness levels about RSV and its impact on older adults. It will also depend on educating the public about the benefits of vaccination. The impact of RSV on older adults has been all but invisible in a sea of winter respiratory viruses; it will take a concerted effort to raise awareness of this serious threat to the older US adult population. Widespread availability of fast and relatively inexpensive RSV diagnostic tests in the clinical setting would help improve awareness.

Once vaccines are licensed and recommended, additional questions will need to be answered, including cost and payment for the vaccine itself and administration (eg, coverage under Medicare Part B or under the more complex Medicare Part D, private insurance coverage for a vaccine approved for individuals younger than 65 years, etc.) Medical practice infrastructure, including seemingly mundane issues such as stocking, storage and handling, and recording the immunization in state-based immunization registries will also need to be considered and addressed to maximize vaccine uptake.


Increasing recognition of the considerable burden of RSV illness in older adults (65+) coupled with potential new preventions and treatments on the horizon should change the way health care professionals focus on RSV now. It is important to build awareness and consensus among public health and immunization communities about the need to protect older adults from RSV infection. This will help ensure that when vaccines and other prevention options become available to protect this population from RSV, they are used optimally and according to public health recommendations.


1. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179–186.
2. Falsey AR, Hennessey PA, Formica MA, et al. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med. 2005;352(17):1749–1759.
3. Sundaram ME, Meece JK, Sifakis F, et al. Medically attended respiratory syncytial virus infections in adults aged ≥50 years: clinical characteristics and outcomes. Clin Infect Dis. 2014;58(3):342–349.
4. Widmer K, Griffin MR, Zhu Y, et al. Respiratory syncytial virus-and human metapneumovirus-associated emergency department and hospital burden in adults. Influenza Other Respir Viruses. 2014;8(3):347–352.
5. Widmer K, Zhu Y, Williams JV, et al. Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. J Infect Dis. 2012;206(1):56–62.
6. Walsh EE, Peterson DR, Falsey AR. Is clinical recognition of respiratory syncytial virus infection in hospitalized elderly and high-risk adults possible? J Infect Dis. 2007;195(7):1046–1051.
7. Collins PL, Melero JA. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res. 2011;162(1-2):80–99.
8. Mullooly JP, Bridges CB, Thompson WW, et al. Influenza- and RSV-associated hospitalizations among adults. Vaccine. 2007;25(5):846–855.
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10. PATH. RSV vaccine and mAb snapshot. Available at: Accessed July 12, 2016.
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17. Meissner HC. Viral bronchiolitis in children. N Engl J Med. 2016;374(1):62–72.
18. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588–598.
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Self Assessment Examination

A minimum assessment score of 80% is required.

  1. What is the estimated annual attack of RSV in healthy adults aged 65 years and older in the United States?
    1. 2.5%
    2. 4%
    3. 5.5%
    4. It varies too much by season to estimate.
  2. What proportion of adults with RSV is symptomatic?
    1. Approximately 30%
    2. Approximately 50%
    3. Approximately 70%
    4. Approximately 90%
  3. In US adults aged 65 years and older, RSV is estimated to cause:
    1. Approximately 100,000 hospitalizations and approximately 2000 deaths annually
    2. Approximately 125,000 hospitalizations and approximately 8000 deaths annually
    3. Approximately 150,000 hospitalizations and approximately 12,000 deaths annually
    4. Approximately 175,000 hospitalizations and approximately 14,000 deaths annually
  4. Which populations are targets of future RSV vaccination strategies?
    1. Infants and children up to 24 months
    2. Pregnant women
    3. Adults with high-risk conditions
    4. Adults aged 65 years and older
    5. All of the above
  5. Adults who require hospitalization for RSV have similar death rates to adults hospitalized with influenza.
    1. True
    2. False


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