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Infectious Disorders – Drug Targets, 2012, 12, 98-102
Respiratory Syncytial Virus Infection in Adult Populations
Edward E. Walsh* and Ann R. Falsey
University of Rochester School of Medicine and Dentistry, Rochester General Hospital, Rochester, New York, USA
Abstract: Respiratory Syncytial Virus, generally recognized for its role as the major respiratory pathogen in newborn infants and young children, is also a significant pathogen in adults. It is a frequent cause of upper and lower respiratory illness among all age groups, although it often goes unrecognized in adults unless highly sensitive molecular diagnostic tests
are used. All RSV infections in adults represent re-infection and are generally mild to moderate in severity, although persons with certain high-risk conditions are susceptible to severe disease. These include the frail elderly living at home or in
long term care facilities, those with underlying chronic pulmonary disease, and the severely immunocompromised. It is
estimated that between 11,000-17,000 adults die of RSV infection annually in the U.S, with ~ ten-fold more admitted to
hospital with respiratory symptoms. As in infants, wheezing is often noted during RSV infections and chest radiographs
are often normal despite significant lower respiratory symptoms and hypoxia. Treatment of RSV is directed at symptomatic relief, and only rarely is specific antiviral therapy recommended. Exceptions include the severely immunocompromised, in whom inhaled ribavirin has been recommended in hopes of reducing both mortality and long term pulmonary
compromise, especially in lung transplant recipients. Immunity to RSV is incomplete. Although there does not appear to
be a defect in humoral immunity, there is evidence that CD8+ T cell immunity may be impaired with age. Currently a
vaccine for RSV is not available, and many challenges to developing a successful vaccine must be overcome.
Keywords: Respiratory Syncytial Virus, Respiratory infections, Adults.
INTRODUCTION
Not long after a novel virus was isolated from chimpanzees in 1956, and aptly called Chimpanzee Coryza Agent, it
was renamed Respiratory Syncytial Virus (RSV) reflecting
the characteristic cytopathology of this virus in cell culture
and in the lungs of infected infants (syncytial giant cells) and
its association with respiratory illness in infants [1,2].
Frequently overlooked, however, is the fact that the first
human identified as infected with this new agent was an
adult handler of experimentally-infected primates. In the
next few years reports by Kravetz, Johnson and Mufson, in
collaboration with Chanock, described the clinical illness
due to RSV in both experimentally-exposed and naturallyinfected adults [3-6].
Despite these early descriptions of illness in adults, the
role of RSV in this population was largely overshadowed by
its paramount importance in pediatric populations. It was not
until approximately twenty years later that other investigators began to systematically describe the significant impact
of RSV infection in adult populations. The high incidence
and clinical significance of RSV infection in adults has been
well documented in several distinct subpopulations of adults,
including elderly persons residing in long term care facilities, healthy young adults, healthy elderly individuals, those
with underlying cardiopulmonary disease, and in immunocompromised adults [7-13]. Each of these distinct groups
display unique clinical and epidemiologic characteristics of
RSV infection and present specific management problems. Undoubtedly as the population ages and the use of
*Address correspondence to this author at the 1425 Portland Avenue, Rochester, New York 14621, USA; Tel: 585-922-4331; Fax: 585-922-5168;
E-mail: [email protected]
2212-3989/12 $58.00+.00
immunosuppressive therapies for malignancies and inflammatory disorders increases, the overall impact of RSV infection in adults will continue to increase.
LABORATORY DIAGNOSIS
Unlike infants in whom primary infection is often distinctive (classically described as bronchiolitis), the clinical
features of RSV infection in adults are non-specific and not
readily distinguished from other common respiratory viral
infections [14]. Thus, laboratory confirmation is required to
be confident of a specific diagnosis of RSV infection. However, identification of RSV in adults is challenging as several
studies have demonstrated that virus titers are lower in respiratory secretions and the duration of shedding shorter than in
infants and young children [10,15].Typically, nasal secretions contain ~10-1000 plaque forming units (pfu) per ml of
sample, which is 1000-fold lower than titers in infants. In
severely ill hospitalized elderly adults viral titers, as measured by quantitative reverse transcription-polymerase chain
reaction (RT-PCR) in nasal secretions, averaged 2.7 ± 1.4
pfu/ml [15]. Even in severely immunocompromised adults,
Englund found that viral titers measured in cell culture
ranged from <5 to 104 pfu/ml (geometric mean titer 35
pfu/ml) [16]. Due to the low levels of virus shed and the instability of viable virus, antigen detection with enzyme immunoassays or immunofluorescent tests, and cell culture are
insensitive in adults, and optimal diagnosis requires RT-PCR
assays or serology. In one study of 60 elderly persons diagnosed by culture, RT-PCR or serology, the sensitivity of
rapid antigen detection ranged from 10-23% depending on
the commercial antigen assay used [17]. In 144 RSV infected
hospitalized patients, RSV was identified by culture in 39%,
while RT-PCR had a sensitivity of ~73% and a specificity of
99% Fig. (1) [9,18]. Curiously, the utility of serology is age© 2012 Bentham Science Publishers
Respiratory Syncytial Virus Infection in Adult Populations
Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 2
dependent in adults, as those >65 years of age develop more
robust RSV-specific IgG responses than younger adults [19].
Although not available outside of the research laboratory, it
may also be possible to diagnose infection acutely by detection of RSV-specific, antibody-secreting cells in whole blood
using ELISPOT technology. Lee noted that 36 of 40 (90%)
RSV RT-PCR positive adults had positive assays, although
the specificity of this assay has not been evaluated [20].
# RSV Cases
Method of RSV Diagnosis
200
150
100
50
0
Culture
PCR
Serology
RSV total
Fig. (1). Diagnostic yield of culture, RT-PCR and serology in 160
adults with RSV infection.
EPIDEMIOLOGY, CLINICAL FEATURES AND IMPACT
The number of reports describing the epidemiology and
clinical impact of RSV in various adult populations has increased considerably in the past decade [21-26]. Zambon
reported that of adults seen by general practitioners in the
U.K. for acute respiratory illness, 20% and 15% of nasal
secretions were RT-PCR positive for RSV in 45-64 and >65
year old ages groups, respectively [23]. The incidence was
only slightly lower than that of influenza. During a comprehensive study of RSV infection in 294 young adults (ages
21-40), the average annual RSV attack rate was 7.4% (Falsey
and Walsh, unpublished data). Although none of these young
persons required hospitalization or developed severe disease,
the clinical impact was significant as 10% visited a doctor
and 15% were prescribed antibiotics. In another study spanning 20 years, Hall diagnosed RSV in 7% of 2960 respiratory illnesses in otherwise healthy working adults ages 18-60
[11]. Illnesses lasted 9.5 days on average and one-quarter
developed lower respiratory symptoms, most notably wheezing, and 38% missed work (in contrast to 66% with influenza). Typically, nasal congestion and mild sore throat are
followed several days later by lower respiratory symptoms
with a productive cough. In patients with reactive airway
disease wheezing often occurs. Even in previously normal
young adults, RSV is associated with reactive airway disease, and pulmonary function abnormalities can be demonstrated many weeks after the illness has clinically resolved
[27]. However, it is elderly adults, especially frail persons or
those with underlying high-risk conditions (i.e., congestive
heart failure [CHF] or chronic obstructive pulmonary disease
[COPD]), that experience the most serious effects of RSV [9,
24, 28]. In a prospective cohort of 608 healthy elderly persons (mean age 75 years, each followed for two years) 46
RSV infections were identified [9]. The average illness duration was 16 days, and 32% sought medical advice via phone
99
or from a doctor. During the same study, 56 RSV infections
were noted in 540 high-risk persons (mean age 70 years).
Although illness duration was similar to the healthy elderly
group, the use of medical care was significantly greater in
the high-risk group: 51 percent called or visited the doctor,
9% visited an emergency room and 16% required hospitalization. During the four year period of the surveillance study
RSV infection rates ranged from 3-7% and 4-10% in the
healthy elderly and high-risk cohorts, respectively. Others
have also reported that RSV is relatively common in exacerbations of COPD and asthma, although in this instance rhinovirus infections outnumber both RSV infections as well as
that of the other common respiratory pathogens [29].
The incidence of RSV infection among adults hospitalized with acute respiratory symptoms has been reported by a
number of investigators [9, 25, 26, 28, 30, 31]. In two of the
larger studies the incidence of RSV during the winter ranged
from 4.4 to 9.5% [9, 31]. Overall, RSV infection rates were
only slightly lower than those for influenza and mortality
was similar at 7-8%. Using statistical methods, Thompson
estimated that 11,000 elderly persons die annually of RSV in
the U.S., a number similar to that derived from prospective
estimates based on virus-specific diagnosis [9,26]. Recent
estimates using similar methodology suggest that RSVrelated hospitalizations in adults above age 50 are ~40% of
those estimated for influenza [25]. Upper respiratory signs
and symptoms and wheezing were common features of RSV
infection in hospitalized persons [14]. Compared to patients
with influenza, adults hospitalized with RSV have less fever
and more frequent rhinorrhea, wheezing and dyspnea, yet in
individual patients the two illnesses are indistinguishable
[14].
The chest radiographic findings in RSV infected adults,
even among severely ill hospitalized persons, are generally
unimpressive [14]. Approximately half are clear or unchanged, while the rest generally reveal minimal basal
atelectesis or small infiltrates.
RSV outbreaks have long been reported among elderly
residents living in congregate settings such as nursing homes
and adult day care facilities [7, 32-37]. Illness is often severe
in this population, with hospitalization and other morbidity
due to respiratory failure noted in 10-20%. The incidence of
RSV infection reported is variable, and likely dependent
upon the method of diagnosis. Studies using serology or RTPCR are more apt to measure incidence rates accurately
[7, 34]. An advantage of RT-PCR is that it does not underestimate incidence due to failure to obtain convalescent serum
samples from patients who die. Although clinical manifestations are similar to those described in community dwelling
elderly, with relatively minimal fever and high frequency of
wheezing, the illness is often mistaken for influenza outbreaks unless specific viral diagnostic tests are performed.
Transmission of RSV in these hospital settings appears to
require close contact as infections tend to cluster on certain
floors in the hospital, suggesting patient-to-patient spread by
younger health care workers or by direct contact between
residents.
Adults with severe immunodeficiency are at particular
risk of severe RSV infections [12, 13, 38-44]. A number of
100 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 2
Walsh and Falsey
investigators have described the impact of RSV in patients
with leukemia, hematopoietic stem cell transplant (HSCT)
recipients, and solid organ transplant patients. Infection usually begins with typical upper respiratory symptoms, but in a
significant number, progresses to lower respiratory disease,
with mortality rates ranging from 30-70% depending upon
the study. Infection is most serious in HSCT recipients during the pre-engraftment period. Illness is characterized by
radiographic sinusitis in many patients, and this is a useful
clue to distinguish RSV from cytomegalovirus infection
[43]. In this report 6 of 8 (75%) of bone marrow transplant
recipients with RSV pneumonia also had radiographic sinusitis, while reports of CMV sinusitis are rare in this population. In addition to the acute morbidity and mortality, RSV
can lead to long-term detrimental effects on pulmonary function [45-47]. Attention to infection control measures is important in transplant centers, and have been demonstrated to
limit RSV infections [48].
There is little information regarding RSV infection in
adults with HIV infection. In HIV infected infants, virus
shedding is prolonged and this may be true in adults as well,
although data in this regard is lacking [49]. Interestingly,
influenza virus infection does not seem to be more severe in
HIV infected adults.
IMMUNITY AND DISEASE PATHOGENESIS IN
ADULTS
Immunity to RSV is incomplete and all infections in
adults represent re-infection. Most adults, including the very
old, have relatively high levels of serum RSV neutralizing
antibody although there is an inverse correlation between
both serum and nasal antibody levels and risk of infection in
elderly frail and high-risk adults [50]. Mills had demonstrated a similar relationship in an experimental RSV challenge model in young adults four decades earlier, and subsequently confirmed by others [51]. In addition, high levels of
serum neutralizing antibody to RSV are associated with less
severe infection in elderly adults Fig. (2) [52]. However, a
fully-protective level of serum antibody has not been identified. Following infection, serum antibody titers rise rapidly,
consistent with an anamnestic response, but then slowly return to pre-infection levels by 16-20 months [53]. Although
long lasting immunity to RSV infection seems unlikely, we
have rarely observed sequential re-infection during two consecutive years in over 1000 elderly persons suggesting that
recent infection does confer temporary immunity. (E Wash
& A Falsey, unpublished data). The role of cellular immunity in adults, either in protection or in disease pathogenesis
is unknown. Looney found an age-related decline in interferon- production by peripheral blood mononuclear cells
after in vitro RSV stimulation [54]. Lee found that the ratio
of RSV-stimulated CD8+ to CD4+ T cells was diminished in
all adults, regardless of age, when compared to influenza
stimulation, while de Bree reported that elderly adults had
lower numbers of circulating RSV tetramer positive CD8+
memory cells than younger adults [55, 56]. The importance
of these findings in the incomplete immunity to RSV reinfection has not been documented.
The relationship of viral load to disease severity in adults
has not been extensively studied, in contrast to the situation
in infants. However, one report found that elderly RSVinfected, hospitalized persons who developed respiratory
failure had significantly higher RSV viral load in both nasal
and pulmonary secretions than hospitalized persons who did
not develop respiratory failure [15].
TREATMENT AND PREVENTION
Treatment of RSV infection in adults is generally supportive, with bronchodilators and inhaled corticosteroids often
prescribed for wheezing especially in asthmatics or those
with COPD. For those requiring hospitalization, fluids and
supplemental oxygen are often prescribed. The presence of
45
No. of
subjects
40
hospitalized
35
non-hospitalized
30
25
20
15
10
5
0
<8
>8-9
>9-10
>10-11
>11-12
>12-13
>13
Log 2 serum neutralizing titer
Fig. (2). Distribution of serum neutralizing antibody titers in RSV infected patients who were hospitalized (gray bars) or non-hospitalized
(black bars) during their infection. As shown, RSV hospitalized persons have a lower titer distribution than ambulatory RSV infected persons, suggesting that more severe RSV disease is associated with low serum neutralizing antibody. Reproduced with permission of Oxford
University Press and the Infectious Diseases Society of America original publication J. Infect Dis 2004;189:233-238.
Respiratory Syncytial Virus Infection in Adult Populations
bacterial co-infection should be sought in those with severe
illness and with infiltrates on chest radiographs, although
bacterial pathogens are often not recovered. Despite the
common use of antibiotics in hospitalized persons, they may
not be necessary in many cases, as radiographs only rarely
demonstrate consolidation suggestive of bacterial pneumonia. Among hospitalized patients with RSV, bacterial pathogens in sputum were also identified in 15%.
Ribavirin, the only licensed antiviral agent for RSV infection, is rarely used in adults, even those with respiratory
failure with the exception of severely immunocompromised
persons. In this latter group there are no controlled trials
demonstrating benefit of inhaled ribavirin in adults infected
with RSV, although anecdotal reports and expert opinion
suggest that early therapy prior to the onset of lower respiratory symptoms may be beneficial [45, 57]. There remains a
need for an active oral treatment, especially for immunocompromised patients and high-risk elderly persons.
Currently, a vaccine for adults is not available, although
several approaches have been considered. Subunit purified
fusion protein vaccines have been shown to be immunogenic
in a high proportion of young and older adults, including
those significant frailty or COPD [58, 59]. Difficulties designing large scale efficacy trials because of low attack rates
have hindered progress to a licensed vaccine. Similar to influenza, live-attenuated RSV vaccines have not been immunogenic in older adults, likely in part due to partial immunity
[60].
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[6]
[7]
[8]
[9]
[10]
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CONCLUSIONS
RSV infects between 3-7 percent of adults annually, affecting all age groups. Infection is especially troublesome for
those with underlying cardiopulmonary disease and frail
individuals, and results in a significant burden as measured
by hospitalization and mortality. Illness generally goes unrecognized as clinical features are indistinct and available
diagnostics are insensitive due to low virus shedding. There
remains a need in certain adult populations for effective
therapeutic agents and a safe and efficacious vaccine.
CONFLICT OF INTEREST
[17]
[18]
[19]
[20]
[21]
None declared.
ACKNOWLEDGEMENTS
[22]
None declared.
[23]
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Accepted: November 30, 2011
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