Pediatric Pulmonology 46:324–347 (2011)

Respiratory Syncytial Virus Prevention and Therapy:

Past, Present, and Future
Melvin Wright, DO and Giovanni Piedimonte, MD*
Summary. Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants
and young children worldwide. More than 50 years after its discovery, and despite relentless
attempts to identify pharmacological therapies to improve the clinical course and outcomes of
this disease, the most effective therapy remains supportive care. Although the quest for a safe
and effective vaccine remains unsuccessful, pediatricians practicing during the past decade have
been able to protect at least the more vulnerable patients with safe and effective passive
prophylaxis. This review summarizes the history, microbiology, epidemiology, pathophysiology,
and clinical manifestations of this infection in order to provide the reader with the background
information necessary to fully appreciate the many challenges presented by the clinical
management of young children with bronchiolitis. The last part of this article attempts an
evidence-based review of the pharmacologic strategies currently available and those being
evaluated, intentionally omitting highly experimental approaches not yet tested in clinical trials
and, therefore, not likely to become available in the foreseeable future. Pediatr Pulmonol. 2011;
46:324–347. ß 2010 Wiley-Liss, Inc.

Key words: bronchiolitis; asthma; apnea; humanized antibodies; paramyxovirus;

pneumonia; wheezing.

Funding source: none reported.

INTRODUCTION AND HISTORICAL PERSPECTIVE
Acute bronchiolitis is the most common lower respira-
tory tract illness in infants and young children, and is most
frequently caused by respiratory syncytial virus (RSV). The
earliest medical description of acute bronchiolitis was
published by Eberle,1 who described a ‘‘catarrhal affec-
tion’’ of infants under 1 year with labored breathing, cough,
and wheeze that resembled a ‘‘violent attack of asthma.’’
Since that time, much has been discovered about RSVas the
primary etiology of acute bronchiolitis. In the late 1930s
and early 1940s, two epidemics of severe respiratory illness
affected infants in the north central United States. John
Adams issued several reports on the epidemics, describing
the seasonal variability and physical and pathological
manifestations of the disease. He was unable to isolate a
bacterial agent as the infecting organism, and so attributed
the illness to a viral infection.2,3
In 1955, investigators working at the Walter Reed
Army Institute of Research isolated a virus from the
nasal secretions of young chimpanzees with sneezing and
mucopurulent rhinorrhea. With this new virus, which they
named chimpanzee coryza agent (CCA), they were able
to reproduce the viral syndrome when they introduced
the agent into other chimpanzees.4 The following year,
Robert J. Chanock isolated CCA from two infants,
one with bronchiolitis and one with pneumonia. This
virus replicated in cell cultures, and produced character-
istic multinucleated giant cells within a large syncytium.
Based on these findings, Chanock proposed that CCA be
renamed ‘‘respiratory syncytial virus.’’5,6
Chanock continued his study of this disease, and in
the early 1960s published further descriptions of RSV
epidemiology, clinical manifestations, and recurrent
infections.7–9 During this period, he also began develop-
ment of a vaccine against RSV in collaboration with
Robert Parrott.10 Testing of this formalin-inactivated
RSV began in 1966. The vaccine was administered to
Department of Pediatrics and Pediatric Research Institute, West Virginia
University School of Medicine, Morgantown, West Virginia
*Correspondence to: Giovanni Piedimonte, MD, Department of Pediatrics,
West Virginia University School of Medicine, 1 Medical Center Drive,
P.O. Box 9214, Morgantown, WV 26506-9214.
E-mail: gpiedimonte@hsc.wvu.edu
Received 29 January 2010; Revised 24 August 2010; Accepted 29 August
2010.
DOI 10.1002/ppul.21377
Published online 23 November 2010 in Wiley Online Library
(wileyonlinelibrary.com).

ß 2010 Wiley-Liss, Inc.


military-dependent infants and children in Washington,
D.C., Colorado, and California. During that year’s RSV
outbreaks, infants who had received the vaccine developed
RSV infections at the same rate as those who had received
the placebo. Worse yet, 80% of the infants who received
the vaccine required hospitalization for severe bronchio-
litis or pneumonia, compared to only 5% for the placebo
group, and two of the vaccinated infants died. This
resulted in significant concerns for the safety of sub-
sequent RSV vaccine development, and to date no RSV
vaccine is available. However, several potential candi-
dates are currently in development both at the preclinical
and early clinical stage, including Phase I/IIa clinical trials
of live attenuated intranasal vaccines in healthy infants for
the prevention of lower respiratory tract infections (LRTI)
caused by RSValone or in combination with parainfluenza
virus.
RSV research expanded through the 1970s and
continues to date. One of the hurdles has been the lack
of a suitable animal model reproducing faithfully the
clinical and pathological features of RSV infections
in humans. The virus produces a clinically identical
syndrome only in chimpanzees, but their cost is too
high for ongoing research. Although rodents are not
naturally infected by RSV, rabbits, guinea pigs, rats, and
mice have been used by a number of investigators to
reproduce specific aspects of the disease. The cotton rat, in
particular, is considered by many investigators a reliable
model to study viral replication in the respiratory tract,
and has played an important role in our evolving
understanding of RSV infection and safety testing of
RSV vaccines.11
Over the last several decades, our understanding of
the pathophysiology of RSV infection has grown,
allowing for the development and testing of new therapies
to treat this disease. In particular, the ribosyl purine
analog ribavirin was developed for the therapy of active
RSV infection, while RSV-IVIG aimed at prevention
through passive immunity; both approaches showed
initial promise with subsequent disappointing results.
More recently, a humanized monoclonal antibody,
palivizumab, has proven safe and effective in preventing
severe RSV disease in high-risk infants, and is currently
the only specific protective strategy licensed for use
against this infection. In addition, progressive advances
in the supportive care of RSV infected infants have
dramatically decreased the associated mortality in devel-
oped countries.
MICROBIOLOGY
Human RSV is a RNA virus of the order Mononegavir-
ales, family Paramyxoviridae, and genus Pneumovirus
(Fig. 1). The virion consists of a nucleocapsid contained
within a bilayer lipid envelope that originates from the
RSV Prevention and Therapy 325
host cell plasma membrane. The nucleocapsid contains
the viral genome, a single, non-segmented strand of
negative polarity RNA including 10 genes but encoding a
total of 11 proteins because of the two open reading frames
of the Matrix-2 (M2) gene. Of these, 8 function as
structural proteins and surface glycoproteins (G), while
the remaining 2 direct viral replication.12
In particular, RSVexpresses two surface glycoproteins:
the fusion protein (F) and the attachment G protein.
These proteins play an important role in infectivity and
pathogenesis, and they are the primary targets for the
host’s protective antibodies. The G protein mediates
RSV attachment to the host cell, after which the F
protein enables fusion of the host and viral plasma
membranes to permit virus passage into the host cell.
The RSV F protein also promotes the aggregation of
multinucleated cells through fusion of their plasma
membranes, producing the syncytia for which the virus
is named12 and the transmission of the virus from cell to
cell. An interesting side note is that these syncytia are
rarely seen in vivo, but are more often noted in vitro in viral
detection studies.
There are two distinct antigenic subgroups of RSV,
characterized as A and B.13,14 Within these subgroups,
there is further variability, with an overall antigenic
relatedness of about 25%. This is due in large part to the G
protein, which demonstrates a relatedness of only 1–7%.
The F protein demonstrates much lower variability, with
50% antigenic relatedness.12 During outbreaks, both
subtypes are generally present and it remains controversial
whether subtype A is more strongly associated with severe
disease and may more frequently result in the need for
intensive care.15–19
Section Summary
. RSV is a single-stranded RNA virus of the Para-
myxoviridae family whose genome includes 10 genes
encoding 11 proteins.
Fig. 1. RSV classification. Taxonomy of the viruses included in
the Paramyxoviridae family, which includes RSV.
Pediatric Pulmonology
326 Wright and Piedimonte
. Two surface proteins, the F protein and attachment G
protein, are the major viral antigens and play a critical
role in the virulence of RSV.
. RSV has two distinct antigenic subtypes, A and B,
which are usually both present during seasonal
outbreaks.
EPIDEMIOLOGY
Recent estimates from the World Health Organization
(WHO) indicate that RSV accounts worldwide for more
than 60% of acute LRTI in children, and more than 80% in
infants <1 year of age. Therefore, RSV is by far the most
frequent cause of pediatric bronchiolitis and pneumonia.20
Seasonal outbreaks occur each year during the
winter months throughout the world, although onset,
peak, and duration of the season vary from one year to
the next and are difficult to predict. In the United States
and throughout the northern hemisphere, the annual
epidemics usually begin in November, peak in January
or February and end in May. Regional variability is
significant,21 with the sub-tropical areas like Florida
showing an endemic pattern and less predictable epidemic
peaks. Throughout the southern hemisphere, the seasonal
outbreaks also occur during the winter months, May
through September.
Virtually all children have been infected with RSV by
the age of 2 years, and nearly half of those will experience
two infections.22 Of those infants that are infected, 40%
will develop a LRTI.23 It is estimated that each year, as
many as 126,000 infants (24.3 per 1,000) are hospitalized
in the US due to bronchiolitis, with 2–5% of these
requiring mechanical ventilation.24 While this represents
a large burden, the numbers outside of the US are
staggering. Worldwide, as many as 1/200 infants are
hospitalized annually for treatment of LRTI, with a
mortality rate as high as 5%.25
RSV infection produces significant morbidity and
mortality, especially in premature–born infants (<35 weeks
gestational age) and in infants with chronic lung disease
[e.g., bronchopulmonary dysplasia (BPD) or cystic
fibrosis] or hemodynamically significant congenital heart
disease (CHD).26 Peak incidence of severe illness is
between 2 and 3 months of age, corresponding to the
postnatal nadir of protective maternal immunoglobulin
passed through the placenta during the last trimester of
pregnancy.27 As premature–born infants miss the window
for placental IgG transfer in part or completely, they are
born with minimal or no humoral protection against the
infection, hence the increased risk for severe disease and
hospitalization, which is further increased by the develop-
ment of chronic lung disease or other conditions limiting
pulmonary functional reserve. Additional risk factors
for severe disease include male sex, crowding, lack
Pediatric Pulmonology
of breastfeeding, and any immunodeficiency.28–34 The
role of environmental tobacco smoke exposure remains
controversial despite numerous publications have explored
its interactions with RSV.35
Worldwide, RSV results in more than 1 million
pediatric deaths per year. For infants under 1 year of
age, this is about 10 times higher than the influenza
mortality rate.36–38 In the United States, however, RSV
associated mortality has declined from 4,500 deaths in
1985 to 390 deaths in 1999.39,40 The financial burden
remains very high, with the estimated annual cost of
hospitalization for infants with bronchiolitis exceeding
$700 million.41 Furthermore, infants are not the only
population at risk for severe disease, as RSV has
historically been an underappreciated cause of severe
LRTI in immunocompromised adults and the elderly.38,42
A recent prospective study in adults reported that the
average annual incidence of RSV in adult populations is
5.5%, about twice that of influenza. In healthy adults, the
incidence is 3–7%, while in the high-risk group incidence
increases to as high as 10%.43 In addition, RSV may
account for up to 25% of the wintertime mortality
attributed previously to influenza.38
Previous infection with RSV does not convey persistent
immunity even in the presence of significant antibody
titers, although higher titers may attenuate the course
of the disease.28,44 Reinfection is common, can recur in
the same RSV season, and occurs across all age groups.
The first and second episodes of infection typically occur
in the first 2 years of life, and these tend to be the most
severe.22 Most subsequent infections occur in the upper
respiratory tract and run a milder course, although the
illness may still progress to a LRTI with more severe
symptoms.45,46
Chronic Sequelae
The link between RSV infection and the development
of asthma has long been debated. There is certainly an
increased risk of subsequent wheezing in children who
have had RSV infection in early life47–52 (Fig. 2), but the
question remains as to whether RSV is a risk factor, or
rather a marker of predisposition to asthma.
Two prospective epidemiologic studies support the
argument that RSV LRTI is indeed an independent risk
factor for recurrent wheeze and asthma. In an effort to
determine the relationship between RSV LRTI in children
under 3 years and the development of wheeze and atopy by
age 13, Stein et al.53 conducted a prospective study on a
subset of the children enrolled in the Tucson Children’s
Respiratory Study. Questionnaires were completed by the
parents at age 6, 8, 11, and 13 years. Eight hundred eighty-
eight children were enrolled, and of these 519 had at least
one LRTI; 472 were tested for respiratory viruses, and 207
of those tested were RSV positive. When compared to

Fig. 2. RSV–asthma link. This graph combines retrospective
data from multiple studies209–211 suggesting an increased risk of
subsequent wheezing in children who have had RSV infection in
early life. The overall risk declines with age, but is still significant
several years after the original infection.
children who had no LRTI, those with RSV LRTI were
3.2 times more likely to have infrequent wheeze and
4.3 times more likely to have frequent wheeze by 6 years.
This risk then decreased, until it became insignificant
by 13 years. As in most similar studies, there was no link
between RSV LRTI and atopy.53
Sigurs et al.54 conducted a prospective study to compare
47 previously healthy children hospitalized with severe
RSV bronchiolitis to 93 matched controls. The authors
found a 30% cumulative presence of asthma among the
RSV group, compared to 3% in the control group. By age 7
years, 23% of the RSV group had physician-diagnosed
asthma, compared to 2% of controls. In a multivariate
analysis of the data, the combination of RSV LRTI with a
family history of asthma was associated with the highest
risk. Taken together, these two studies suggest a 30–40%
likelihood of recurrent asthma-like episodes after early-
life RSV LRTI. Sigurs’ studies also show increased risk
beyond 13 years of age and propose a link between RSV
infection and development of atopy; these discrepancies
from other studies may be related to the different severity
of the original infection or to differences in the genetic
background.
Unfortunately, epidemiologic studies are not suited to
resolve whether early-life RSV LRTI are truly causal in
subsequent asthma, or more simply precipitate wheezing
in children already predisposed by their genetic or
epigenetic makeup. Only carefully randomized control
trials with specific prophylaxis can conclusively deter-
mine if preventing or delaying the first RSV infection
lessens the incidence and/or severity of asthma later in life.
A recent industry-sponsored, prospective, multicenter
trial concluded that RSV prophylaxis decreases by
80% the relative risk of recurrent wheezing during
RSV Prevention and Therapy 327
preschool years in non-atopic children but does not have
any effect in children without atopic background,55
suggesting that in the absence of genetic predisposition
to atopy RSV plays an important causative role in the
pathogenesis of recurrent wheezing. However, it is critical
to point out that this study was not randomized, and was
also limited to prematurely born children.
Section Summary
. RSV is the most frequent cause of bronchiolitis, with
yearly outbreaks that vary from year to year and
depend on the geographical area.
. Nearly all children have been infected with RSV at
least once by the time they are 2 years of age, resulting
in approximately 24 hospitalizations per 1,000 infants
and up to 1 million deaths worldwide each year.
. Previous infection does not convey persistent immun-
ity, and reinfection is common.
. Prospective epidemiologic studies suggest that early-
life RSV LRTI is an independent risk factor for
recurrent wheeze and asthma.
PATHOGENESIS AND PATHOPHYSIOLOGY
Transmission
Transmission of RSV occurs primarily through direct
contact of respiratory secretions with subsequent inocu-
lation of nasopharyngeal or conjunctival mucus mem-
branes, or by entry of large respiratory droplets into the
nose or eyes. Small aerosolized particles seem less likely
to spread the infection.56–58 The virus can remain viable
on hard surfaces (e.g., countertops) for up to 6 hr, on
rubber gloves for 90 min, and on skin for 20 min.59 This
prolonged survival highlights the need (and effectiveness)
for hand washing and contact precautions in limiting the
spread of RSV infection. The incubation period ranges
from 2 to 8 days, and immunocompetent individuals can
shed the virus for up to 3 weeks, although on average this is
limited to about 8 days. Viral shedding is significantly
prolonged in immunocompromised individuals, and can
continue for several months.
Replication
Viral replication occurs initially within the nasophar-
yngeal epithelium, but then spreads to the bronchiolar
epithelium where replication is most efficient60 (Fig. 3).
This progression may occur by direct cell to cell trans-
mission or by aspiration of upper airway secretions.61,62
Additionally, the virus can spread via the blood stream or
through infection of inflammatory cells (e.g., monocytes),
which may also account for disseminated disease in
patients with immunodeficiency.63–67 In most cases,
Pediatric Pulmonology
328 Wright and Piedimonte
Fig. 3. RSV infection of airway epithelial cells. A: Human nasal,
tracheal, and bronchial epithelial cells after infection with GFP-
expressing RSV (rgRSV) at 1 MOI for 48 hr. The bright field panels
(left) show the total number of cells. The green fluorescent cells
(center) represent those which are actively infected with RSV.
B: Bronchial epithelial cells are the most susceptible to RSV
however, the infection remains limited to the respiratory
tract.
Viral replication is followed by necrosis of the
bronchiolar epithelium with subsequent lymphocytic
peribronchiolar infiltration and submucosal edema.
Mucus secretions increase in both quantity and viscosity,
and mix with cellular debris. Clearance of this mixture
is compromised by the loss of ciliated epithelium and
viscosity of the secretions. The end result is the production
of widespread mucus plugging with increased expiratory
resistance and partial airway obstruction causing air
trapping.68 These factors combine to produce the classic
clinical triad of wheezing, atelectasis, and hyperinflation.
Immune Response
Historically, it has been held that the severity of an RSV
infection is related to the intensity of the host’s immune
response. This perception stems largely from the results
of the 1966 formalin inactivated RSV vaccine clinical
trial.69,70 Postmortem examinations of the two infants who
died revealed the presence of RSV bronchopneumonia,
extreme hyperinflation with pneumothorax, and atypical
eosinophilic pulmonary infiltration. These findings sug-
gest that immunopathologic mechanisms play an impor-
tant role in severe RSV disease, and studies in animal
models have indicated amplified Th2 immunity and
activated cytotoxic T cells as the main culprits,71,72
although several aspects of RSV pathophysiology remain
highly controversial.
Pediatric Pulmonology
infection. Flow cytometric data show the percentage of fluores-
cent (infected) cells in each panel compared to the non-infected
control cells (shaded histogram). Data are expressed as the
mean
SEM (n ¼ 4 experiments). ***p < 0.001 compared to nasal
or tracheal cells.
In particular, considerable discussion has emerged in
an effort to understand the mechanisms underlying the
enhanced disease seen in the formalin inactivated vaccine
trial. Formalin inactivation has been implicated in that it
appears to have amplified the immunogenicity of specific
viral antigen, especially the RSV G protein. However, the
inactivation also resulted in an altered ability to induce a
protective neutralizing antibody response. Vaccine recip-
ients were therefore primed for an enhanced inflammatory
response upon exposure to the wild-type virus.12 This
negative outcome impacted dramatically the further
development of an inactivated RSV vaccine, essentially
bringing it to a halt.
The host’s immune response is clearly of great
importance in clearing RSV infection and likely in
attenuating its course. RSV infection induces both cellular
and humoral immune activity, and although this response
does not result in complete protection against reinfection,
it does seem to decrease the severity of subsequent
infections.44,45 In infants, high titers of maternally derived
RSV-neutralizing antibody in cord sera are associated
with a much lower risk of hospitalization due to RSV
bronchiolitis.73,74 This protection can also be conferred by
administration of exogenous RSV immunoglobulin.75,76
In addition, decreased serum anti-RSV titers have
been associated with a significant increase in the risk
of developing a symptomatic RSV infection.28 Cell-
mediated immunity probably plays a role in the control of
active infection and in viral clearance. This is underscored
by the observation that immunocompromised individuals

with deficient cell-mediated immunity suffer more severe
and prolonged RSV disease, and also shed the virus much
longer.34,66,77
A recent study, however, provides an alternative
explanation for the pathophysiology of severe RSV
infections. In this study, autopsy specimens were collected
from 20 Chilean infants with RSV who died without
access to the benefit of mechanical ventilatory support.78
The authors compared their immune responses to those of
infants who died from influenza infection and the results
were surprising, as there was no evidence of an RSV-
related enhanced inflammatory response; in particular, at
the time of most severe symptoms, there was no activation
of cytotoxic T-cell activity. There was, however, signifi-
cant apoptosis-induced sloughing of the airway epithe-
lium. The authors’ interpretation is that severe RSV
infection is a result of insufficient adaptive immunity, with
viral clearance largely reliant upon less efficient innate
immunity.
Neuro-Immune Interactions
Recent studies show that early-life RSV infection
promotes a large increase in the expression of nerve
growth factor (NGF) and its receptors in the developing
airways of both animal models79 and humans.80 NGF and
other similar neurotrophic proteins control the structural
development of peripheral afferent and efferent neurons,
and exert changes in their functional activity in a
number of ways that collectively define ‘‘neuronal
plasticity.’’81 Thus, RSV-induced NGF overexpression
can drive short- and long-term changes in the distribution
and reactivity of sensory and motor nerves across the
respiratory tract, causing non-specific airway hyper-
reactivity during and after the infection. Furthermore,
RSV infection following chronic exposure to environ-
mental pollution produces more severe neurotrophic
dysregulation and neurogenic-mediated inflammation
compared to either infection or pollution alone.82
Neurotrophic factors and receptors are also synthesized
in several non-neuronal cell types including epithelial and
inflammatory cells (e.g., mast cells and CD4þ T cells).83–85
This function may target the innervation of specific
tissues, but there is growing evidence that NGF functions
as a potent and eclectic neuro-immunomodulator, which
releases and is released by a variety of inflammatory
mediators. In particular, patients with bronchial asthma
and allergic rhinoconjunctivitis display high serum levels
of NGF, suggesting an important pathogenetic role of
neurotrophins in allergic disorders.86
Studies in animal models indicate that NGF over-
expression is critical for neurogenic-mediated mucosal
edema and for innate lymphocytic and monocytic
responses in RSV-infected airways,87 suggesting that
neuro-immune interactions driven by neurotrophic path-
RSV Prevention and Therapy 329
ways play an important role in the pathophysiology of
local and systemic inflammation against viral pathogens.
This important inflammatory mechanism is largely
resistant to corticosteroids,88 which provides a plausible
explanation for the poor therapeutic activity of these drugs
in children with virus-induced wheezing.
Mast Cells and Leukotrienes
Studies in animal models indicate that RSV affects
dramatically the number, distribution, and function of
mast cells in the airway mucosa.89 Histopathological
analysis with an antibody against tryptase identified
numerous mast cells in sections from RSV-infected rat
lungs, with a 7-fold increase compared to the lungs of
non-infected controls (Fig. 4). In addition, most of these
mast cells were in close spatial association with nerve
fibers, suggesting functional mast cell–nerve interactions
similar to those previously reported in other organ
systems, particularly the skin, central nervous system,
and gastrointestinal tract.90
Among the inflammatory mediators released from mast
cells, cysteinyl leukotrienes (cysLTs) have been shown to
cause airway inflammation and airway smooth muscle
contraction during RSV infection, accounting for the
wheezing observed in bronchiolitis. Increased LTC4 levels
were observed in nasopharyngeal secretions of children
during the acute phase of RSV infection, and their
concentration correlated with clinical severity, being
higher in patients with lower respiratory tract involvement
than in children with upper respiratory illness alone.91,92
Another clinical study showed that urinary LTE4 (the
terminal product of cysLTs metabolism) is especially
elevated during RSV bronchiolitis in younger infants
(<6 months of age) with an atopic/asthmatic background
(Fig. 5).93 As cysLTs are known to play critical roles in
the pathophysiology of asthma, they could also represent
an important component in the link between RSV and
asthma.
Time course analysis of infected lung tissues indicated
that the effect of RSVon leukotriene synthesis is transient;
levels are maximal by 3–5 days post-infection and return
to baseline by 30 days.89 These findings collectively
suggest that the acute inflammatory response of airways
infected by RSV in early life involves the release of cysLTs
and activation of the cysLT1 receptor, as manifested by
the anti-inflammatory effect of the receptor antagonist
montelukast in animal models89 and in human studies.94
Following the early phase of the viral respiratory
infection, leukotriene production and release rapidly
return to baseline levels, but can be reactivated when air-
borne irritants (e.g., tobacco smoke) stimulate nociceptive
nerve fibers connected to the numerous mast cells still
present in the lung tissues.
Pediatric Pulmonology
330 Wright and Piedimonte

Fig. 4. Mast cells in RSV infected lungs. Lung sections from weanling rats killed 5 days after the
intranasal inoculation of virus-free medium (A) or RSV suspension (B). Mast cells were identified
by immunohistochemistry using a monoclonal antibody specific for tryptase. An average
sevenfold increase in mast cell density was found in the lung sections from RSV-infected rats
compared with pathogen-free controls (right). Internal scale ¼ 40 mm. *p < 0.05 ¼ significantly
different from pathogen-free rats.

Section Summary usually remarkable for diffuse polyphonic wheezing and

. Transmission occurs through inoculation of the naso-
pharyngeal or conjunctival mucosa with respiratory
secretions from infected individuals.
. Viral shedding persists for about 8 days, but can
be significantly more prolonged in immunocompro-
mised individuals.
. Viral replication begins in the nasal mucosa and
spreads downward through the respiratory tract,
producing edema and necrosis of the respiratory
epithelium, and resulting in airway obstruction.
. The inflammatory response associated with RSV
infection is extremely complex and involves the
release of multiple cytokines and chemokines from
epithelium and immunocytes, neuro-immune inter-
actions, and mast cells degranulation with release of
leukotrienes.
CLINICAL MANIFESTATIONS
RSV infection in children almost always causes
clinical manifestations; however, these can vary widely
in severity depending on the patient’s age, comorbidities,
environmental exposures, and history of previous infec-
tions.45,95–98 Infants typically present with upper respira-
tory symptoms, such as congestion and rhinorrhea that
over a period of 2–4 days may progress to involve the
lower respiratory tract with cough, wheeze, increased
work of breathing, and cyanosis.22,45,99 Auscultation is
Pediatric Pulmonology
coarse rales. Chest radiograph findings frequently include
bilateral hyperinflation, patchy atelectasis, and peribron-
chial thickening (Fig. 6).
Patients with severe lower respiratory tract involvement
may also have radiologic features more consistent with
pneumonia, with areas of interstitial infiltration.100–102
The resulting respiratory distress can vary in severity
from minimal to profound, life-threatening respiratory
failure.22,99,103 Infants may also develop lethargy, fever,
poor feeding, and otitis media. Elderly individuals and
those with cardiopulmonary disease or immunodeficiency
are also at risk for severe lower respiratory tract disease.104
Older children and healthy adults typically manifest
symptoms of the upper respiratory tract, but may also have
tracheobronchitis.46
Apnea is a well-known complication of RSV infection
in infants, and on occasion may be severe enough to cause
death.38 The virus was isolated as early as 1956 in infants
with apnea, and the incidence of apnea is as high as 20% in
infants under 6 months of age who require hospitalization
for RSV infection.105–110 Bruhn et al. also noted that the
highest incidence occurs in premature infants and in
infants less than 1 month of age. In most cases, however,
apnea is self-limited and does not recur with subsequent
infections.106,111 An interesting observation is that apnea
is frequently the first clinical manifestation of RSV
infection, and may occur regardless of the severity of other
RSV-related symptoms.105 This association has led to the

Fig. 5. Leukotriene synthesis in RSV-infected infants. Urinary
excretion of LTE4 (the terminal product of cysLTs metabolism)
is increased in children with RSV bronchiolitis as compared
to controls without respiratory infection. The overproduction of
cysLTs reflected by this marker is more prominent in younger
patients (<6 months of age) infected with this virus. Also, an
intrinsic predisposition to develop atopy or airway hyperreac-
hypothesis that RSV may be involved in at least some
cases of sudden infant death syndrome (SIDS), which
also shares several epidemiological similarities with the
infection in terms of seasonality and risk factors.
The exact pathophysiology of RSV-related apnea is
still controversial. Studies in animal models suggest that
RSV infection prolongs significantly reflex central apnea
triggered by peripheral sensorineural stimulation.112 This
effect of RSV on ventilatory control is already significant
2 days after intranasal inoculation, when the infection is
still confined to the upper airway, which is consistent with
and explains why apnea is an early or even presenting
manifestation of RSV infection. In addition, apnea-related
mortality in murine models is highest early during RSV
infection, suggesting that counterregulatory mechanisms
that facilitate autoresuscitation are activated only later
during the infection. Specific blockade of the central
GABAA receptors or of the high-affinity substance P
(NK1) receptors abolishes the influence of RSV infection
on the apnea triggered by sensorineural stimulation. This
finding suggests that substance P released from primary
sensory neurons within the nodose ganglia activates
second-order GABAergic interneurons in the spinal dorsal
RSV Prevention and Therapy 331
tivity seems to amplify the effect of the virus, as higher LTE4
concentrations were found in infants with a medical history
of eczema or dry cough and/or a family history of asthma.
Age or atopy per se did not affect leukotriene synthesis in
the absence of infection. *p < 0.05, **p < 0.01, ***p < 0.001 ¼
significantly different from age-matched controls without respi-
ratory infection.
horn, which in turn inhibit the function of medullary
inspiratory neurons resulting in apnea.
Section Summary
. Infants with RSV infection typically present with
upper respiratory symptoms (congestion, rhinorrhea)
that frequently progress to involve the lower respira-
tory tract with cough, wheeze, and increased work of
breathing.
. Chest radiography typically shows hyperinflation,
patchy infiltrates, and atelectasis.
. Apnea is frequently the presenting manifestation of
RSV infection, especially in very young infants.
MANAGEMENT
Supportive Care
Most infants with RSV infection have a mild, self-
limited illness, and are treated in an outpatient setting.
This requires close follow up with attention to respiratory
distress, oxygen requirement, and hydration. Those
infants with difficulty feeding, pronounced respiratory
Pediatric Pulmonology
332 Wright and Piedimonte

Infants hospitalized with RSV bronchiolitis often have

decreased nutritional intake due to respiratory distress and
tachypnea, increased insensible losses, and need for
volume and nutritional support. Continued oral feeding
in the presence of significant respiratory distress may put
these patients at increased risk of aspiration. In patients
who are unable to tolerate oral feeds, adequate fluid intake
and nutrition should be maintained by placement of a
nasogastric or orogastric feeding tube, or with parenteral
fluids when enteral nutrition is deemed unsafe.

Section Summary
. Supportive care is the mainstay of therapy for RSV
infection.
. Care is directed at ensuring adequate oxygenation,
improving respiratory toilet, and meeting fluid and
nutrition needs.
. Severe respiratory failure requires mechanical ven-
tilatory support, and occasionally HFOV or ECMO.
Fig. 6. Clinical manifestations of RSV. Chest radiograph
obtained from a child with RSV bronchiolitis showing bilateral PHARMACOLOGICAL INTERVENTIONS
hyperinflation, patchy atelectasis, and peribronchial thickening.
Severe patients may also have features more consistent with More than 50 years after the discovery of RSV, and
pneumonia, with areas of interstitial infiltration. despite relentless attempts to identify pharmacological
therapies to improve the clinical course and outcomes of
this infection, the most effective therapy remains limited
distress, or need for supplemental oxygen require
to the supportive care measures discussed above. The
admission to the hospital for more aggressive manage-
quest for safe and effective active prophylaxis (vaccines)
ment and monitoring. Regardless of the setting in which
remains unsuccessful; however, pediatricians practicing
the patient is treated, the mainstay of therapy remains
during the past decade have been able to protect at least
supportive care, which includes respiratory support and
the more vulnerable patients with safe and effective
adequate fluid and nutrition management.
passive prophylaxis. The following paragraphs review
Children with oxygen saturations 92% should receive
therapeutic agents commonly used in the setting of RSV
warm, humidified oxygen.23 Nasal obstruction is a
infection. We will discuss medications used despite the
common problem, and given that young infants are
lack of conclusive efficacy data (bronchodilators, cortico-
obligate nose breathers, may result in a significant
steroids, antivirals, antibiotics), selected experimental
increase in respiratory distress. Simple nasal toilet with
therapies that have been tested in humans and hold some
saline drops and a suction bulb may improve work of
promise for the future (DNAse, hypertonic saline,
breathing. Chest physiotherapy is often administered in an
surfactant, heliox, anti-leukotrienes), and the old and
effort to mobilize secretions and recruit atelectatic lung
new strategies for passive prophylaxis (RSV-IVIG,
segments. However, a recent Cochrane systematic review
palivizumab, motavizumab). Given that the vast majority
found no evidence to support its use.113
of cases of bronchiolitis in infants are due to RSV
Infants with hypoxemia refractory to supplemental
infection,115–118 studies discussing viral bronchiolitis in
oxygen, persistent respiratory distress or progressive
general are also included. This review does not include the
respiratory failure usually require either non-invasive
pipeline of antiviral compounds and putative vaccines
support with nasal continuous positive airway pressure or
currently being developed, but not likely to become
endotracheal intubation. Positive pressure mechanical
available for clinical use in the near future.
ventilation has been an important modality in the treat-
ment of infants with RSV bronchiolitis since the 1960s,
Bronchodilators
and significantly decreases mortality.114 Ventilatory sup-
port may require conventional mechanical ventilation or Bronchodilators are frequently used in infants with
high-frequency oscillation (HFOV); also, infants with wheezing due to RSV LRTI; however, their routine use
severe disease unresponsive to these modalities may remains controversial and most randomized controlled
benefit from extra-corporeal membrane oxygenation trials (RCT) have failed to find objective evidence of
(ECMO). clinical benefit.
Pediatric Pulmonology

b-Agonists
A 1997 meta-analysis evaluated several outcomes
among eight clinical trials published between 1987 and
1994.119 This review found no improvement in clinical
score or hospitalization rate associated with the use of
albuterol. There was a statistically significant, but
clinically insignificant, improvement in oxygen satura-
tion, and heart rate. The authors concluded that there is
no evidence for the efficacy of b2-agonist therapy in the
treatment of viral bronchiolitis.
Gadomski and Basale120 revisited this topic in a
recently updated Cochrane review of the available
literature. Twenty-two studies, with a combined total of
1,428 infants with bronchiolitis and first wheezing
episode, were evaluated in a meta-analysis to address
specifically the efficacy of bronchodilators in the manage-
ment of bronchiolitis. Measured outcomes included
improvement in clinical score, oxygenation, hospital
admission, and length of hospital stay (LOS). The authors
found that there was a minimally significant improvement
in clinical scores among infants receiving bronchodilator
therapy over those receiving placebo, and that this
improvement was not likely to be clinically relevant.
Likewise, there was no statistically significant improve-
ment in oxygenation, admission rate, or LOS. The authors
concluded that bronchodilators are not recommended for
the routine management of infants with bronchiolitis and
first episode of wheezing.
Studies in animal models have suggested that single-
isomer preparations like levalbuterol may have a better
anti-inflammatory effect than racemic albuterol in RSV-
infected airways,121 but this has yet to be confirmed in
clinical trials. In summary, b-agonists have not been
shown to have consistent benefits in the treatment of RSV
bronchiolitis. A carefully monitored trial in individual
patients may be warranted, with discontinuation of
therapy if no objective improvement is noted.
Epinephrine
As with albuterol, there is no strong evidence to support
the use of epinephrine in the treatment of RSV
bronchiolitis; nevertheless, it is frequently used in infants
with RSV. A 2004 Cochrane review evaluated 14 studies
published between 1998 and 2003.122 This review
evaluated the efficacy of epinephrine versus albuterol
and epinephrine versus placebo in both the inpatient and
outpatient settings. Primary outcomes included clinical
score, heart rate, respiratory rate, oxygenation, admission
rate, and LOS. The authors concluded that the available
data does not support the use of epinephrine in the
inpatient setting, but that in outpatients epinephrine may
produce a modest short-term improvement and therefore
be preferable to albuterol or nebulized saline in the
treatment of bronchiolitis.
RSV Prevention and Therapy 333
While evidence-based protocols do not support the
routine use of albuterol or epinephrine, the use of
bronchodilators on a trial basis in select patients is
acceptable. If clinical improvement can be documented,
then continued use can be recommended. However,
treatments should be discontinued if no improvement is
demonstrated, because of the possible side effects (e.g.,
tachycardia, tremor, hypokalemia, hyperglycemia). As
epinephrine is typically not prescribed for use at home,
albuterol may be a more appropriate choice for outpatient
use.
Anticholinergic Agents
Anticholinergics, such as ipratropium bromide, have
not been found to be effective in the treatment of RSV
bronchiolitis. Several studies have evaluated ipratropium
alone and in combination with albuterol. While minor
improvements in oxygenation have been reported, there
is no consistent, significant benefit to the overall clinical
course or outcome.123–126
Corticosteroids
Systemic Corticosteroids
A number of trials have sought to evaluate the efficacy
of systemic corticosteroids in the treatment of bronchio-
litis. Patel et al.127 conducted a systematic review of 13
trials of corticosteroid therapy in 1,198 children with viral
wheezing aged 0–30 months. This meta-analysis found a
decrease in LOS of 0.38 hospital days/patient, which
however was not statistically significant. There was no
difference in clinical scores, respiratory rate, or oxygen
saturation. For patients treated in the emergency depart-
ment or clinic, there was no difference in admission rates.
The authors caution that significant heterogeneity of
the included studies and results make the final analysis
difficult to interpret with confidence, but concluded that
this therapy lacks any significant clinical benefit compared
to placebo and is not indicated for this patient group.
The findings of this meta-analysis are complemented by
more recent individual studies. Teeratakulpisarn et al.128
evaluated 174 children hospitalized with acute bronchio-
litis. The children were randomized to receive 0.6 mg/kg
of intramuscular (IM) dexamethasone or placebo. The
authors evaluated the length of time to resolution of
respiratory distress as the primary outcome. The duration
of respiratory distress was decreased from 39 hr for the
placebo group to 27.2 hr for the dexamethasone group, a
difference of about 12 hr. The duration of oxygen therapy
was also reduced by 14.9 hr, and the hospital LOS was
decreased by 13.4 hr.
In another study, Corneli et al.129 compared oral
dexamethasone to placebo to determine whether a single
dose of the steroid (1 mg/kg) could reduce the need for
hospitalization. Over a 3-year period, the authors enrolled
Pediatric Pulmonology
334 Wright and Piedimonte
600 infants between the ages of 2 and 12 months
presenting to the emergency department with first time
wheezing and a diagnosis of moderate- to severe-
bronchiolitis. The primary outcome was hospital admis-
sion after 4 hr of emergency department observation.
Secondary outcomes included change in a respiratory
assessment score, LOS, later medical visits or hospital
admissions, and adverse events. The authors found that a
single dose of dexamethasone did not change the rate of
hospital admission or the severity score of bronchiolitis
after 4 hr; they also found no change in secondary
outcomes. In summary, the current evidence suggests that
systemic steroids should not be recommended for routine
use in the treatment of bronchiolitis.
Inhaled Corticosteroids
Several studies have evaluated inhaled corticosteroids
in patients with bronchiolitis, again without showing any
significant benefit.130,131 In a 2007 Cochrane review of
five studies with a total of 374 infants, Blom et al.132
evaluated the use of inhaled corticosteroids to prevent
post-bronchiolitis wheezing. This analysis found no
reduction in wheezing, readmission rate, use of systemic
corticosteroids, or use of bronchodilators.
More recently, Ermers et al.133 conducted a RCT to
assess the influence of inhaled beclomethasone dipropi-
onate on the occurrence and severity of recurrent wheeze
following RSV LRTI. They enrolled 243 previously
healthy infants who had been admitted to the hospital
for RSV. The infants were randomized to receive
beclomethasone dipropionate (200 mg bid) versus placebo
during the first 3 months after hospitalization. There was
no significant difference in the number of days with
wheeze or in the proportion of infants with wheeze
between the two groups.
Combination Therapy
Several studies have evaluated the usefulness of
steroids given together with nebulized racemic epinephr-
ine, with encouraging results. A recent RCT compared 61
infants randomized to receive nebulized dexamethasone
or saline; both groups also received nebulized epinephr-
ine.134 In this study, no statistically significant difference
was noted in clinical score or oxygen saturation. There
was, however, a significant reduction in LOS in the
dexamethasone group, especially among the subgroup of
prematurely born infants (6.5 vs. 9.1 days).
Plint et al.135 conducted a large, multicenter RCT to
assess rates of admission to the hospital after treatment
with oral dexamethasone and nebulized racemic epi-
nephrine. Eight hundred infants presenting to the
emergency department with bronchiolitis were random-
ized into four groups. The first group received two
treatments with nebulized racemic epinephrine plus six
doses of oral dexamethasone (1 per day for 6 days);
Pediatric Pulmonology
the second group received nebulized racemic epinephrine
plus oral placebo; the third group received nebulized
placebo plus oral dexamethasone; and the fourth group
received both placebos. Among the four groups, only
those infants who received both therapies were found
to be significantly less likely to require hospitalization
(17.1% for the combination therapy group; 23.7% for the
epinephrine group; 25.6% for the dexamethasone group;
and 26.4% for the placebo group). Therefore, combination
therapy with racemic epinephrine and oral dexamethasone
may decrease hospital admissions.
In general, young children without an atopic phenotype
that wheeze in response to viral infections show a poor
response to corticosteroids, and even children that will
ultimately develop asthma are usually unresponsive to
this therapy when they develop virus-induced wheezing
during their first years of life. Another area of concern
derives from safety considerations. In fact, severe RSV
bronchiolitis typically occurs during the first year of life
and coincides with a critical phase of rapid lung develop-
ment. The safety of the therapeutic use of corticosteroids
during this window, particularly when inhaled at high
doses and for prolonged periods, is virtually unknown and
consequently these medications have never been approved
by the US Food and Drug Administration (FDA) for use in
the treatment of bronchiolitis or asthma in the first year of
life.
We conclude that whether administered systemically or
inhaled, corticosteroids should not be routinely used in the
treatment of bronchiolitis. However, some specific patient
populations may benefit from a trial of steroid therapy,
particularly patients with family history (parental atopy or
asthma) or medical history (atopic eczema) consistent
with atopic predisposition.
Antivirals
The only antiviral agent licensed for the therapy of
severe RSV infections is ribavirin, a synthetic nucleoside
analog with broad in vitro virustatic activity. Unfortu-
nately, several factors make its routine use highly
controversial: it is expensive, difficult to administer, and
possibly a teratogen. Furthermore, the available studies
are all small, have inconsistent quality, and have produced
conflicting results, leading to a progressive decline of
its use.
Early studies were encouraging. Hall et al.136 random-
ized 33 infants hospitalized with RSV bronchiolitis to
continuous aerosolized ribavirin for 3–6 days versus
placebo. The ribavirin group showed a greater improve-
ment in severity score, lower respiratory tract signs,
oxygen saturations, and viral shedding compared to the
placebo group. Rodriguez et al.137 also found improved
oxygenation and greater rate of clinical improvement in
patients receiving a short course of ribavirin, without

138
evidence of adverse effects. Smith et al. conducted a
double-blind, placebo-controlled trial of continuously
aerosolized ribavirin in 28 mechanically ventilated infants
with RSV infection, using nebulized sterile water as a
control. This study reported a significant reduction in
oxygen use and in the length of mechanical ventilation
and hospitalization, especially among infants with no
underlying illness.
A subsequent, well-designed study evaluated ribavirin
against nebulized saline in 42 mechanically ventilated
patients with RSV bronchiolitis and respiratory failure.139
The authors found no significant improvement in the
length of oxygen therapy, aerosol therapy, mechanical
ventilation, PICU stay, or hospital stay. These findings
were supported by a similar study performed by Meert
et al.140 Taber et al.141 evaluated 26 infants randomized to
receive ribavirin or placebo and found no difference in the
rate of viral clearance between the two groups. In a longer
outcome study, Everard et al.142 followed patients treated
with ribavirin for RSV bronchiolitis over a 1-year period
and was unable to demonstrate any short-term improve-
ment in the clinical course or long-term reduction in the
use of inhaled bronchodilators or steroids. In 2007, Ventre
and Randolph143 reviewed 12 trials published between
1983 and 1999 finding only small and not statistically
significant improvements in mortality, length of mechan-
ical ventilation, LOS, or clinical status.
Although ribavirin effectively inhibits RSV replication
in vitro, its lack of efficacy in vivo is not surprising
because the first clinical symptoms (coryza) usually
appear towards the end of the exponential viral replication
in the lungs, which is followed by rapid decline of
virus titers. Thus, by the time the classical signs of
bronchiolitis are diagnosed, little virus remains in the
lungs while the immunoinflammatory response of the
host dominates the pathophysiology. Hence, the thera-
peutic use of a virustatic agent like ribavirin requires
immediate intervention at the clinical onset, which is
logistically near impossible. In the early 1990s, the AAP
endorsed ribavirin use for severe RSV bronchiolitis in
high-risk patients. This stance has since changed and
the current recommendation is that ribavirin should not
be used routinely to treat children with bronchiolitis. It
should, however, be used either alone or in combination
with anti-RSV antibodies to treat RSV infections in select
immunocompromised hosts who can continue to shed
virus for several months.23
Antibiotics
It is not uncommon for infants with bronchiolitis to
receive antibiotic therapy. It is estimated that antibiotics
are used in 34–99% cases of uncomplicated bronchioli-
tis.144,145 This therapy is frequently started because the
patient is febrile, but fever per se cannot reliably
RSV Prevention and Therapy 335
146
differentiate viral from bacterial infections. In fact,
the risk of bacterial superinfection in infants with
bronchiolitis and fever is quite low (0.2%), even when
body temperature is >398C.147,148 However, for intubated
infants with severe bronchiolitis, the rate of secondary
bacterial infection is much higher, and may be as high as
26%.149,150
When a secondary bacterial infection is diagnosed, the
most common sites are the urinary tract and the middle
ear.151,152 In particular, infants with secondary infections
are more likely to have a urinary tract infection than
bacteremia or meningitis (12% vs. 0.43%).153 Acute otitis
media is also seen as a complication of RSV infection
(57–67%), but its presence does not seem to influence the
severity of fever, respiratory distress or the overall clinical
course of the disease.154 In one series, evaluation of
middle ear aspirates in children with bronchiolitis
revealed RSV in 17 (71%) of 24 patients.152 In addition,
all patients with acute otitis media had bacterial pathogens
isolated, the most common being Streptococcus pneumo-
niae, Haemophilus influenzae, and Moraxella catarrhalis.
If present, otitis media should be managed according to
current AAP recommendations.23,155
Several prospective RCTs have evaluated the clinical
outcomes of infants who received antibiotics for the
management of bronchiolitis. As early as 1966, a double-
blind RCT failed to demonstrate a benefit to treating
bronchiolitis with antibiotics.156 Friis et al.157 evaluated
136 children between the ages of 1 month and 6 years and
found no difference in the course of the acute illness, fever
relapse, or pulmonary complications in those patients with
bronchiolitis who received antibiotics when compared to
those who did not.
We conclude that antibiotics should be used in patients
with bronchiolitis only when specific evidence of coex-
istent bacterial infection is present, and confirmed
bacterial infections should be managed no differently
than in the absence of bronchiolitis.
Recombinant Human Deoxyribonuclease
(DNAse)
Given that neutrophils are prominent in the early
immune response to RSV infection, and the free DNA
deriving from their lysis is often found in the
thickened secretions of RSV LRTI, it seems reasonable
that mucolytic therapy with DNAse should be beneficial.
However, a recent multicenter, randomized, placebo-
controlled trial evaluated the efficacy of DNAse in 225
hospitalized, oxygen-dependent infants,158 finding no
demonstrable benefit. Nasr et al.159 reported that DNAse
could be used to improve the chest radiologic findings of
infants with RSV; however, again there was no associated
clinical improvement.
Pediatric Pulmonology
336 Wright and Piedimonte
Hypertonic Saline
Hypertonic saline nebulization has been shown pre-
viously to improve mucociliary clearance in patients with
asthma and cystic fibrosis,160,161 and more recently has
gained interest as a potential therapy for infants with
bronchiolitis. In a 2008 Cochrane review, Zhang et al.162
reviewed four trials including a total of 254 infants with
acute bronchiolitis (189 inpatients and 65 outpatients)
who received 3% versus 0.9% saline nebulization with or
without a bronchodilator. The primary outcomes meas-
ured were LOS for the inpatients and rate of hospital-
ization for the outpatients. This review concluded that
nebulized hypertonic saline could reduce the LOS of
hospitalized infants by almost 1 day (25.9% reduction)
when compared to infants who received placebo. There
was no improvement in the rate of hospitalization among
outpatients. Importantly, no adverse events were reported
in any of the trials. Furthermore, when considering the
enormous financial burden that the hospitalization of
infants with bronchiolitis places on healthcare systems
and parents worldwide, the minimal acquisition costs
make this intervention even more appealing.
Surfactant
Beyond its role of decreasing surface tension in alveoli
and bronchioles, thereby improving alveolar and small
airway patency, surfactant has protein components (A and
D) that bind viral and bacterial surface markers and
facilitate their immune-mediated elimination.163–166 In
addition, surfactant protein D has been demonstrated to
promote alveolar macrophage production of free radi-
cals.167 In acute bronchiolitis, there is decreased produc-
tion of these surfactant proteins, which return to normal
levels with the resolution of the illness.168
Administration of exogenous surfactant to infants with
severe respiratory failure due to bronchiolitis seems
promising, and several small RCTs have been conducted
to evaluate this therapy, with encouraging results. A recent
meta-analysis by Ventre et al.169 included three studies
with a total of 79 patients. The authors reported decreases
in the duration of mechanical ventilation and PICU stay.
There also seem to be improvements in pulmonary
mechanics and gas exchange. It is important to note that
the available studies are small and underpowered, and that
additional, larger studies are required. However, exoge-
nous surfactant therapy does appear to hold promise for
use in patients with severe respiratory failure due to
bronchiolitis.
Heliox
Barach and Eckman170 first described the use of helium
for the treatment of upper airway obstruction and asthma
in the 1930s. Heliox is a mixture of helium and oxygen in a
Pediatric Pulmonology
70:30 or 80:20 ratio. Its theoretical advantage lies in the
fact that it maintains laminar flow and, therefore, less
turbulence through constricted airways than do nitrogen–
oxygen mixtures. This results in improved ventilation with
a reduced work of breathing in patients with lower
respiratory tract disease. Heliox has been studied in the
treatment of bronchiolitis by several investigators,
although most of these studies are quite small.171–173
Some of the authors have shown small improvements in
clinical scores and decreased tachypnea and work of
breathing.
Liet et al.174 evaluated rates of positive pressure
ventilation in patients receiving heliox therapy versus
standard nitrogen–oxygen air and found no difference
between the two groups. When heliox therapy was
evaluated in intubated children with bronchiolitis, Gross
et al.175 found no improvement in ventilation or oxygen-
ation, regardless of the ratio of helium to oxygen
employed (50:50, 60:40, or 70:30).
Heliox equipment is bulky and cumbersome, and it can
be problematic to administer. Furthermore, given that
it is most effective at high helium to oxygen ratios, it
is minimally effective in patients with significant oxygen
requirements. In summary, the current evidence support-
ing heliox use for bronchiolitis is sparse, underpowered,
and conflicting, and therefore larger RCTs are required
before it can be recommended for routine use.
Anti-Leukotrienes
As discussed above, strong experimental evidence in
animal models and a number of clinical studies indicate
that cysLTs are released during RSV infection and
contribute to airway inflammation and hyperreactivity.
Therefore, it would make sense if leukotriene antagonists
would have therapeutic activity in the setting of acute
bronchiolitis, and possibly prevent or reduce the recur-
rence of wheezing episodes post-bronchiolitis. The first
pilot trial testing this hypothesis was conducted in
Denmark by Bisgaard et al.94 One hundred thirty children
hospitalized with acute RSV bronchiolitis were random-
ized into a double-blind, placebo-controlled trial of the
cysLT1 receptor antagonist montelukast given for 28 days
starting within 7 days of symptom debut. Children on
montelukast had significantly more symptom-free days
compared with children on placebo (22% vs. 4%); in
particular, daytime cough was significantly reduced on
active treatment and exacerbations were delayed.
This study generated a lot of interest and hope in the use
of leukotriene modifiers in RSV bronchiolitis despite its
several limitations, especially the small sample size and
wide age range (3- to 36-month old). To address the latter,
the author conducted a post hoc analysis of the same data
revealing that the effect of montelukast was larger in the
younger children compared with the older children,176

which was consistent with previously reported data on the
age-dependency of cysLTs production.93 To address the
issue of statistical power, a larger multi-center double-
blind study of 979 children 3–24 months old with RSV
bronchiolitis was completed recently.177 This time, no
significant differences were seen between montelukast and
placebo in symptom-free days. However, post hoc analysis
limited to the 523 patients with persistent symptoms
showed more symptom-free days in the montelukast
group. Therefore, additional studies are necessary to
define conclusively the role of leukotriene modifiers in
the management of patients with more persistent or
more severe respiratory symptoms following RSV infec-
tion. Furthermore, it would be important to compare
the effect of anti-leukotriene therapy during the infection
with its prophylactic use starting before the RSV season,
and also assess its effect on the incidence of post-RSV
asthma.
Section Summary
. b-Agonists do not provide consistent benefit in the
treatment of RSV infection; however, a brief trial
with objective evaluation of the response may be
warranted.
. Epinephrine does not provide consistent benefit in
the inpatient setting, and although it may produce a
modest improvement in the outpatient setting, it is not
recommended for use at home.
. Neither systemic nor inhaled corticosteroids have
shown consistent benefit in the treatment of RSV
disease, and therefore they are not recommended for
routine use.
. Ribavirin is not recommended for routine treatment
of RSV infection, but may be considered in select
immunocompromised individuals.
. Antibiotics are recommended only in the presence of
specific evidence of coexistent bacterial infection.
. DNAse does not provide consistent benefit in the
treatment of RSV infection.
. Hypertonic saline has been demonstrated to reduce
LOS by up to 25% and may provide significant benefit
to infants with RSV bronchiolitis.
. Surfactant and Heliox may provide benefit in the
treatment of RSV infection, but the available data is
not conclusive.
. Anti-leukotrienes have shown some clinical benefit in
the treatment of RSV infection, but the evidence for or
against their use is not definitive.
PREVENTION
In the non-clinical setting, several measures have
proven effective in limiting the likelihood of RSV
infection. Hand washing is perhaps the most effective
way to prevent the spread of RSV. Specific recommenda-
RSV Prevention and Therapy 337
tions to caregivers of high-risk infants also include the
avoidance of tobacco smoke and restriction of day care
during RSV season. In addition, there is good evidence to
support the recommendation of breast feeding at risk
infants, given the transfer of maternal immunoglobulin.178
Hand washing in the clinical setting is invaluable
in preventing the nosocomial spread of RSV.178 The use
of gloves and gowns can also aid in limiting trans-
mission179–183; the use of masks is more controversial, as
RSV is mostly transmitted by direct contact with infected
secretions and rarely by aerosolization. Rapid testing of
suspected patients allows for identification and isolation
of those known with RSV-related disease, further
decreasing their exposure to non-infected patients.184
Immunoprophylaxis
To date, two products have been developed for clinical
use: RSV-IVIG, a hyperimmune polyclonal globulin, and
palivizumab, a humanized monoclonal antibody. Motavi-
zumab is a second-generation humanized monoclonal
antibody not yet available on the market.
Respiratory Syncytial Virus Immunoglobulin (RSV-IVIG)
RSV-IVIG is a pooled polyclonal human immunoglo-
bulin purified from donors with high-RSV-neutralizing
antibody titers, to be administered by monthly intravenous
infusion during RSV season.185 A significant decrease in
RSV-related hospitalizations and LOS was seen when
RSV-IVIG was administered to high-risk infants with
prematurity or chronic lung disease. However, it was also
associated with an increase in surgical morbidity and
mortality among infants with CHD, and so it was never
licensed for use in these patients.75,186,187 As RSV-IVIG
could interfere with the immune response to live virus
vaccines, it was necessary to delay immunization with the
measles/mumps/rubella (MMR) vaccine until 9 months
following the last dose of RSV-IVIG.
The major disadvantages of RSV-IVIG included the
need for repeated venous access and a long intravenous
infusion (4–6 hr), with the consequent need of medical
supervision in a hospital setting. The volume administered
was considerable using the recommended dose of 15 ml/
kg, with the significant risk of fluid overload to intrinsi-
cally fluid sensitive infants and frequent need for diuretic
therapy. There was also a potential for transfer of blood-
borne pathogens and the supply of eligible donors was not
dependable. Another practical disadvantage was the high
combined costs deriving from acquisition and supervised
administration of the immunoglobulin.188
Palivizumab
Given the disadvantages of RSV-IVIG in the treatment
of RSV infection, research focused on the development of
monoclonal antibody therapies. There are several advan-
Pediatric Pulmonology
338 Wright and Piedimonte

tages to monoclonals: they are less likely to exert an
immunosuppressive effect in children,189 and carry
essentially no risk of transmitting blood-borne infections
or other plasma-associated adverse effects190; contain
higher titers of neutralizing antibody, and therefore can be
prepared in smaller volumes suitable for IM administra-
tion in outpatient or home settings; eliminate the risk of
fluid overload and need for diuretic rescue.
Palivizumab is a humanized monoclonal IgG1 antibody
produced by recombinant DNA technology, one of the
very first successful therapies of this kind that pioneered
the large and expanding field of biologicals. With this
technology, murine-derived sequences complimentary to
the A antigenic site of the RSV F protein are grafted into a
human IgG frame (Fig. 7); the result is an antibody that
being >95% human is minimally immunogenic and has
broadly reactive activity toward both subtypes of RSV.191
The effectiveness of palivizumab lies not in preventing
infection of the upper respiratory tract, but in limiting
downward spread.192 In addition, studies in animal models
have suggested that, by preventing alterations in the
development of small airway neural networks caused by
RSV in infancy,79,80,193,194 palivizumab might prevent
subsequent peripheral airway reactivity and recurrent
wheezing195,196 as well as central ventilatory complica-
tions like apnea.112
In 1998, a Phase I/II multicenter, double-blind, placebo-
controlled study was published, defining the safety and
pharmacokinetics of palivizumab.191 Sixty-two infants
were enrolled, including infants <6 months of age with a
history of <35 weeks premature delivery or infants
<24 months of age with a history of BPD. The infants
were randomized to receive monthly IV infusions of 3, 10,
or 15 mg/kg palivizumab versus normal saline placebo.
The study drug was well-tolerated and produced no anti-
palivizumab response. The authors concluded that optimal
serum concentrations were achieved with the 15 mg/kg
dose and that the mean half-life of approximately 20 days
supported a monthly dosing schedule.
The IMpact-RSV pivotal trial enrolled 1,502 infants
under 35 weeks gestational age and/or with chronic lung
disease.197 The infants were randomized to receive
palivizumab 15 mg/kg IM, or placebo, monthly during
the RSV season. In those infants that received palivizu-
mab, there was a 55% decrease in hospitalization rate and
LOS was reduced from 62.6 days per 100 children to
36.4 days per 100 children. Illness severity score, need for
intensive care and oxygen requirement were also reduced.
There was no difference in the need for mechanical
ventilation.
Another multicenter clinical trial of palivizumab for
prophylaxis in 1,287 infants with significant CHD showed
a 45% relative reduction in hospitalization in this
population when compared to placebo.198 Acyanotic
patients had a 58% reduction in hospitalization and
cyanotic patients had a 29% reduction. Therefore, combin-
ing the data from these RCTs, palivizumab protects quite
well preterm infants without BPD, and somewhat well
infants with acyanotic CHD, whereas the protective effect
for infants with BPD or cyanotic CHD is limited (Fig. 8).
It should also be noted that most post-marketing data
suggest that the protection provided by palivizumab may

Fig. 7. Humanized monoclonal antibodies. This schematic representation shows that murine-
derived sequences complimentary to the A antigenic site of the RSV F protein are grafted into a
human IgG frame. The result is palivizumab, an antibody that being >95% human is not immuno-
genic and has broadly reactive activity toward both subtypes of RSV. The substitution of 13 amino
acid residues in the complimentarity-defining regions of palivizumab generates the second-
generation antibody motavizumab, which has a 70-fold higher affinity for the RSV F protein.

Pediatric Pulmonology

Fig. 8. Protective effect of palivizumab. Combined data from
RCTs showing that palivizumab protects quite well preterm
infants without BPD, and somewhat well infants with acyanotic
CHD, whereas the protective effect for infants with BPD or
cyanotic CHD is limited. It should also be noted that most post-
marketing data suggest that the protection provided by palivi-
zumab may be substantially higher than that estimated from
RTCs, but these data are difficult to interpret because of lack of
controls.
be substantially higher than that estimated from RCTs,
but these data are difficult to interpret because of lack
of controls.
Palivizumab is administered monthly during RSV
season as an IM dose of 15 mg/kg. The AAP recommends
that RSV prophylaxis be considered in the following
groups199:
1. Infants with chronic lung disease who are younger
than 24 months of age and have received medical
therapy for BPD within 6 months of the onset of RSV
season may benefit from monthly dosing beginning
in the 1st month of RSV season for a total of five
doses.
2. Infants born before 28 weeks of gestation may benefit
from monthly dosing beginning in the 1st month of
RSV season for a total of five doses.
3. Infants born between 29 and 32 weeks gestation and
who are less than 6 months of age at the onset of RSV
season may benefit from monthly dosing beginning
in the 1st month of RSV season for a total of five
doses.
4. Infants born between 32 and 35 weeks gestation who
are younger than 3 months of age at the onset of RSV
season or who are born during RSV season and who
attend day care or have a sibling aged <5 years may
benefit from monthly doses until they reach 3 months
of age. The maximum number of doses for this
category is 3, with many receiving only one or two
doses.
5. Infants with congenital anomalies of the airway who
are less than 1-year old may benefit from monthly
RSV Prevention and Therapy 339
dosing beginning in the 1st month of RSV season for
a total of five doses.
6. Infants with neuromuscular disease who are less than
1-year old may benefit from monthly dosing begin-
ning in the 1st month of RSV season for a total of five
doses.
7. Infants with hemodynamically significant heart
disease who are less than 2 years old may benefit
from monthly dosing beginning in the 1st month of
RSV season for a total of five doses.
8. Infants with severe immunocompromise may benefit
from monthly dosing beginning in the 1st month of
RSV season for a total of five doses.
Palivizumab is generally well tolerated. The most
commonly reported adverse events are upper respiratory
tract infection, otitis media, fever, rhinitis, rash, diarrhea,
cough, vomiting, gastroenteritis, and wheezing.200–202
Severe hypersensitivity can occur, but the incidence is
rare, with less than one anaphylaxis event per 100,000
patients.
A recent industry-sponsored study hypothesized that
palivizumab, by ameliorating or preventing early RSV
LRTI in preterm infants, might decrease later recurrent
wheezing.203 A cohort of 191 preterm infants who had
received palivizumab and were not hospitalized for RSV
was compared to 230 preterm infants who never received
palivizumab (76 who were hospitalized for RSV and 154
who were not). These infants were prospectively followed
for 24 months beginning at a mean age of 19 months.
The incidences of recurrent wheezing and physician-
diagnosed recurrent wheezing were approximately 50%
lower in the palivizumab-treated subjects compared with
all untreated subjects and with the 154 patients in the
subgroup not hospitalized for RSV LRTI, suggesting
that preventing RSV LRTI with palivizumab may
reduce subsequent recurrent wheezing in premature
infants. This study needs to be independently repeated
and confirmed in larger samples including full-term born
infants in double-blind protocols before a formal recom-
mendation can be made concerning large-scale RSV
prophylaxis to reduce the incidence of post-viral wheeze
in childhood.
Motavizumab
The most important limitations of palivizumab derive
from its intrinsic potency and recommended dosage. Early
studies in cotton rats indicated that a mean 99% reduction
in pulmonary RSV titer requires 25–30 mg/ml serum level
of palivizumab, and levels above 40 mg/ml are necessary to
achieve 99% reduction in all animals. Therefore, in order
to provide optimal protection, palivizumab should be
dosed to maintain trough levels 40 mg/ml and above. Data
from the IMpact-RSV trial indicated that using 15 mg/kg
doses, the mean trough concentration after the 1st monthly
Pediatric Pulmonology
340 Wright and Piedimonte
injection was 37 mg/ml and more than 40% of patients
were below 30 mg/ml. Subsequently, the mean trough
level increased after each monthly injection because
of progressive accumulation. This pharmacokinetic
data explain why almost half of all breakthrough RSV
hospitalizations in palivizumab-treated patients occur
after the first injection, and more than 70% after the
first two. Another issue is that, at the recommended
dosage, palivizumab levels in the nasal mucosa are not
protective, and therefore palivizumab does not prevent
RSV infection, but rather reduces its spread to the lower
airways.
Palivizumab shortcomings could be fixed with a more
potent antibody. This led to the development of motavi-
zumab, a second-generation IgG1 monoclonal antibody
with increased anti-RSV activity. In vitro studies of
palivizumab variants identified a clearly superior anti-
body, A4b4, with 44-fold greater activity against RSV
than palivizumab.204 Subsequent in vivo studies, however,
were disappointing, as the new antibody had only a
twofold increase in potency when administered prophy-
lactically to cotton rats.205 Further analysis revealed that
the diminished activity was the result of broad tissue
binding which decreased lung bioavailability. The
increased tissue binding was attributed to three amino
acid residues that were altered from palivizumab.
Reversion of these back to the original amino acids
restored lung bioavailability and produced the final form
of motavizumab.205
While the structure of motavizumab differs from
palivizumab by only 13 amino acids, it has a 70-fold
higher affinity for the RSV F protein, and at equivalent
concentrations yields up to a 100-fold greater activity
against RSV.206 In addition, motavizumab inhibits RSV
replication in the upper respiratory tract of cotton rats,
whereas palivizumab does not.206 Finally, motavizumab is
fully humanized, whereas the palivizumab antibody frame
still contains a few murine-derived sequences.
A Phase I/II open-label, dose-escalation trial was
conducted to evaluate safety and pharmacokinetics
of monthly IM injections in infants.207 The study included
preterm infants (32–35 weeks gestation) who were
<6 months and infants with BPD who were <2 years.
The preterm infants received doses of 3 or 15 mg/kg, while
the BPD infants were all dosed with 15 mg/kg. Infants in
both groups received monthly injections for 2–5 months
and were followed for 150 days. The 15 mg/kg dosing
produced serum trough levels similar to those of
palivizumab.
These results were confirmed by a recent Phase I/II,
randomized, double-blind, multicenter center study of
motavizumab and palivizumab conducted in the United
States, Chile, and Brazil.206 One hundred thirty-six high-
risk infants <2 years of age were included and followed
over two consecutive RSV seasons. In the first season, the
Pediatric Pulmonology
infants received monthly motavizumab IM injections.
During the second season, the infants were randomized to
receive motavizumab (n ¼ 66) or palivizumab (n ¼ 70).
Serum trough levels were similar for both monoclonals,
with a circulation T1/2 of 3–4 weeks. Adverse effects
included erythema at the injection site (n ¼ 16), hypo-
chromic anemia (n ¼ 2), and elevated serum glutamic
oxaloacetic transaminase (n ¼ 1). No serious drug-related
adverse reactions were reported.
A Phase III, multicenter, randomized, double-blind
trial was conducted to assess the safety and efficacy of
motavizumab as compared to palivizumab.208 Of the
6,635 infants enrolled and followed for 150 days, 3,329
received motavizumab 15 mg/kg IM monthly and 3,326
received palivizumab 15 mg/kg IM monthly. Motavizu-
mab was found to be non-inferior, and reduced RSV-
related hospitalizations by 26% over palivizumab. The
rate of RSVattacks for motavizumab was 1.4%, compared
to 1.9% for palivizumab and the rate of medically attended
outpatients was reduced by 50% (1.9% for motavizumab
vs. 3.9% for palivizumab).
Due to its higher potency, motavizumab, whose official
trade name will be RezieldTM, holds several promises for
the future. In particular, it should be able to protect the
mucosa of the upper respiratory tract, thereby preventing
the infection rather than limiting its spread to the lower
respiratory tract. This property could add important
benefits, such as the prevention of viral otitis media, and
perhaps reduce the frequency and/or severity of post-viral
wheeze.
In June 2010, the Advisory Committee to the US FDA
voted not to recommend approval of motavizumab. This
decision was justified primarily with the questionable
evidence that motavizumab provides additional benefit in
comparison to palivizumab and with concerns about the
rare (2–3%) but statistically significant increase in serious
adverse events involving the skin of infants injected with
motavizumab. Thus, although the Advisory Committee
recommendation is not final and the manufacturer
(MedImmune, Inc., Gaithersburg, MD) will continue to
work with the FDA and attempt to address the concerns
outlined above, the future of this new antibody appears
uncertain.
Section Summary
. Hand washing and isolation are highly effective in
reducing the spread of RSV infection.
. Palivizumab is a humanized monoclonal antibody
recommended for the prophylaxis of infants at high
risk for severe RSV disease.
. Motavizumab is a next-generation humanized mono-
clonal antibody with improved in vitro activity
against RSV, currently undergoing FDA evaluation
for licensing in the US.

CONCLUSIONS
RSV is the most frequent cause of bronchiolitis and
pneumonia in infants and young children, and a source of
significant morbidity, mortality, and financial burden
worldwide. It is an RNA virus of the Paramyxoviridae
family whose two surface G proteins are the major
antigens and are critical for virulence. The two antigenic
variants, A and B, are usually both present during the
seasonal outbreaks, which vary from year to year and
depend on the geographical area. Nearly all children have
been infected with this virus at least once by the time they
are 2 years of age, resulting in about 24 hospitalizations
per 1,000 infants and up to 1 million deaths worldwide
each year. Previous infections do not convey persistent
immunity, and reinfection is common.
Transmission occurs through inoculation of the naso-
pharyngeal or conjunctival mucosa with respiratory
secretions from infected individuals. Viral shedding
persists for approximately 1 week, but can be significantly
more prolonged in immunocompromised individuals.
Viral replication begins in the nasal mucosa and spreads
downward through the respiratory tract, producing edema
and necrosis of the respiratory epithelium, and resulting
in airflow obstruction. The inflammatory response asso-
ciated with this infection is extremely complex and
involves the release of multiple cytokines and chemokines
from epithelium and infiltrating immunocytes, local
neuro-immune interactions, and mast cells degranulation
with variable release of leukotrienes.
Infants with RSV infection typically present with upper
respiratory symptoms that frequently progress to involve
the lower respiratory tract with cough, wheeze, and
increased work of breathing. Chest radiographs typically
show hyperinflation, patchy infiltrates, and atelectasis.
Apnea is frequently the presenting manifestation, espe-
cially in young infants. Supportive care is the mainstay
of therapy for RSV disease and is directed at ensuring
adequate oxygenation, improving respiratory toilet, and
meeting fluid and nutrition requirements. Severe respira-
tory failure requires mechanical ventilatory support, and
occasionally HFOV or ECMO.
Adrenergic a- and b-agonists do not provide consistent
benefit in the treatment of RSV disease, although a brief
trial with objective evaluation of the response may be
warranted. Neither systemic nor inhaled corticosteroids
have been shown to provide clear advantages in the
treatment of RSV disease, and therefore their use is not
recommended. The antiviral drug ribavirin is also not
recommended for routine treatment of RSV infection,
but may be considered in select immunocompromised
individuals. Antibiotics are recommended only in the
presence of specific evidence of coexistent bacterial
infection. Nebulized treatments with hypertonic saline
have been shown to reduce LOS and may offer an effective
RSV Prevention and Therapy 341
low-cost option to improve mucociliary clearance in these
patients, whereas very expensive mucolytic therapy with
DNAse has not provided consistent results. Exogenous
surfactant, Heliox, and leukotriene modifiers may also
provide some clinical benefit, but the evidence for or
against their use is not definitive.
Hand washing and isolation are highly effective in
preventing the spread of RSV infection. The humanized
monoclonal antibody palivizumab is a safe and effective
option for passive RSV prophylaxis, but its use is currently
limited to infants at high risk for severe disease due to the
high costs. Motavizumab is a next-generation humanized
monoclonal antibody with improved activity against RSV
currently undergoing FDA evaluation for licensing in the
US. The hope for the future is active prophylaxis of all
infants with a safe and effective RSV vaccine, which not
only would protect against the most common respiratory
disease of childhood, but may also prevent frequent long-
term sequelae like post-RSV wheezing and asthma.
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