You are on page 1of 24

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

ß 2010 Wiley-Liss, Inc.


RSV Prevention and Therapy 325

military-dependent infants and children in Washington, host cell plasma membrane. The nucleocapsid contains
D.C., Colorado, and California. During that year’s RSV the viral genome, a single, non-segmented strand of
outbreaks, infants who had received the vaccine developed negative polarity RNA including 10 genes but encoding a
RSV infections at the same rate as those who had received total of 11 proteins because of the two open reading frames
the placebo. Worse yet, 80% of the infants who received of the Matrix-2 (M2) gene. Of these, 8 function as
the vaccine required hospitalization for severe bronchio- structural proteins and surface glycoproteins (G), while
litis or pneumonia, compared to only 5% for the placebo the remaining 2 direct viral replication.12
group, and two of the vaccinated infants died. This In particular, RSVexpresses two surface glycoproteins:
resulted in significant concerns for the safety of sub- the fusion protein (F) and the attachment G protein.
sequent RSV vaccine development, and to date no RSV These proteins play an important role in infectivity and
vaccine is available. However, several potential candi- pathogenesis, and they are the primary targets for the
dates are currently in development both at the preclinical host’s protective antibodies. The G protein mediates
and early clinical stage, including Phase I/IIa clinical trials RSV attachment to the host cell, after which the F
of live attenuated intranasal vaccines in healthy infants for protein enables fusion of the host and viral plasma
the prevention of lower respiratory tract infections (LRTI) membranes to permit virus passage into the host cell.
caused by RSValone or in combination with parainfluenza The RSV F protein also promotes the aggregation of
virus. multinucleated cells through fusion of their plasma
RSV research expanded through the 1970s and membranes, producing the syncytia for which the virus
continues to date. One of the hurdles has been the lack is named12 and the transmission of the virus from cell to
of a suitable animal model reproducing faithfully the cell. An interesting side note is that these syncytia are
clinical and pathological features of RSV infections rarely seen in vivo, but are more often noted in vitro in viral
in humans. The virus produces a clinically identical detection studies.
syndrome only in chimpanzees, but their cost is too There are two distinct antigenic subgroups of RSV,
high for ongoing research. Although rodents are not characterized as A and B.13,14 Within these subgroups,
naturally infected by RSV, rabbits, guinea pigs, rats, and there is further variability, with an overall antigenic
mice have been used by a number of investigators to relatedness of about 25%. This is due in large part to the G
reproduce specific aspects of the disease. The cotton rat, in protein, which demonstrates a relatedness of only 1–7%.
particular, is considered by many investigators a reliable The F protein demonstrates much lower variability, with
model to study viral replication in the respiratory tract, 50% antigenic relatedness.12 During outbreaks, both
and has played an important role in our evolving subtypes are generally present and it remains controversial
understanding of RSV infection and safety testing of whether subtype A is more strongly associated with severe
RSV vaccines.11 disease and may more frequently result in the need for
Over the last several decades, our understanding of intensive care.15–19
the pathophysiology of RSV infection has grown,
allowing for the development and testing of new therapies Section Summary
to treat this disease. In particular, the ribosyl purine
analog ribavirin was developed for the therapy of active
. RSV is a single-stranded RNA virus of the Para-
RSV infection, while RSV-IVIG aimed at prevention
myxoviridae family whose genome includes 10 genes
through passive immunity; both approaches showed
encoding 11 proteins.
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 Fig. 1. RSV classification. Taxonomy of the viruses included in
within a bilayer lipid envelope that originates from the the Paramyxoviridae family, which includes RSV.

Pediatric Pulmonology
326 Wright and Piedimonte

. Two surface proteins, the F protein and attachment G of breastfeeding, and any immunodeficiency.28–34 The
protein, are the major viral antigens and play a critical role of environmental tobacco smoke exposure remains
role in the virulence of RSV. controversial despite numerous publications have explored
. RSV has two distinct antigenic subtypes, A and B, its interactions with RSV.35
which are usually both present during seasonal Worldwide, RSV results in more than 1 million
outbreaks. 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
EPIDEMIOLOGY
1985 to 390 deaths in 1999.39,40 The financial burden
Recent estimates from the World Health Organization remains very high, with the estimated annual cost of
(WHO) indicate that RSV accounts worldwide for more hospitalization for infants with bronchiolitis exceeding
than 60% of acute LRTI in children, and more than 80% in $700 million.41 Furthermore, infants are not the only
infants <1 year of age. Therefore, RSV is by far the most population at risk for severe disease, as RSV has
frequent cause of pediatric bronchiolitis and pneumonia.20 historically been an underappreciated cause of severe
Seasonal outbreaks occur each year during the LRTI in immunocompromised adults and the elderly.38,42
winter months throughout the world, although onset, A recent prospective study in adults reported that the
peak, and duration of the season vary from one year to average annual incidence of RSV in adult populations is
the next and are difficult to predict. In the United States 5.5%, about twice that of influenza. In healthy adults, the
and throughout the northern hemisphere, the annual incidence is 3–7%, while in the high-risk group incidence
epidemics usually begin in November, peak in January increases to as high as 10%.43 In addition, RSV may
or February and end in May. Regional variability is account for up to 25% of the wintertime mortality
significant,21 with the sub-tropical areas like Florida attributed previously to influenza.38
showing an endemic pattern and less predictable epidemic Previous infection with RSV does not convey persistent
peaks. Throughout the southern hemisphere, the seasonal immunity even in the presence of significant antibody
outbreaks also occur during the winter months, May titers, although higher titers may attenuate the course
through September. of the disease.28,44 Reinfection is common, can recur in
Virtually all children have been infected with RSV by the same RSV season, and occurs across all age groups.
the age of 2 years, and nearly half of those will experience The first and second episodes of infection typically occur
two infections.22 Of those infants that are infected, 40% in the first 2 years of life, and these tend to be the most
will develop a LRTI.23 It is estimated that each year, as severe.22 Most subsequent infections occur in the upper
many as 126,000 infants (24.3 per 1,000) are hospitalized respiratory tract and run a milder course, although the
in the US due to bronchiolitis, with 2–5% of these illness may still progress to a LRTI with more severe
requiring mechanical ventilation.24 While this represents symptoms.45,46
a large burden, the numbers outside of the US are
staggering. Worldwide, as many as 1/200 infants are
Chronic Sequelae
hospitalized annually for treatment of LRTI, with a
mortality rate as high as 5%.25 The link between RSV infection and the development
RSV infection produces significant morbidity and of asthma has long been debated. There is certainly an
mortality, especially in premature–born infants (<35 weeks increased risk of subsequent wheezing in children who
gestational age) and in infants with chronic lung disease have had RSV infection in early life47–52 (Fig. 2), but the
[e.g., bronchopulmonary dysplasia (BPD) or cystic question remains as to whether RSV is a risk factor, or
fibrosis] or hemodynamically significant congenital heart rather a marker of predisposition to asthma.
disease (CHD).26 Peak incidence of severe illness is Two prospective epidemiologic studies support the
between 2 and 3 months of age, corresponding to the argument that RSV LRTI is indeed an independent risk
postnatal nadir of protective maternal immunoglobulin factor for recurrent wheeze and asthma. In an effort to
passed through the placenta during the last trimester of determine the relationship between RSV LRTI in children
pregnancy.27 As premature–born infants miss the window under 3 years and the development of wheeze and atopy by
for placental IgG transfer in part or completely, they are age 13, Stein et al.53 conducted a prospective study on a
born with minimal or no humoral protection against the subset of the children enrolled in the Tucson Children’s
infection, hence the increased risk for severe disease and Respiratory Study. Questionnaires were completed by the
hospitalization, which is further increased by the develop- parents at age 6, 8, 11, and 13 years. Eight hundred eighty-
ment of chronic lung disease or other conditions limiting eight children were enrolled, and of these 519 had at least
pulmonary functional reserve. Additional risk factors one LRTI; 472 were tested for respiratory viruses, and 207
for severe disease include male sex, crowding, lack of those tested were RSV positive. When compared to
Pediatric Pulmonology
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
Fig. 2. RSV–asthma link. This graph combines retrospective
depend on the geographical area.
data from multiple studies209–211 suggesting an increased risk of . Nearly all children have been infected with RSV at
subsequent wheezing in children who have had RSV infection in least once by the time they are 2 years of age, resulting
early life. The overall risk declines with age, but is still significant in approximately 24 hospitalizations per 1,000 infants
several years after the original infection. 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
children who had no LRTI, those with RSV LRTI were
recurrent wheeze and asthma.
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
PATHOGENESIS AND PATHOPHYSIOLOGY
by 13 years. As in most similar studies, there was no link
between RSV LRTI and atopy.53 Transmission
Sigurs et al.54 conducted a prospective study to compare
Transmission of RSV occurs primarily through direct
47 previously healthy children hospitalized with severe
contact of respiratory secretions with subsequent inocu-
RSV bronchiolitis to 93 matched controls. The authors
lation of nasopharyngeal or conjunctival mucus mem-
found a 30% cumulative presence of asthma among the
branes, or by entry of large respiratory droplets into the
RSV group, compared to 3% in the control group. By age 7
nose or eyes. Small aerosolized particles seem less likely
years, 23% of the RSV group had physician-diagnosed
to spread the infection.56–58 The virus can remain viable
asthma, compared to 2% of controls. In a multivariate
on hard surfaces (e.g., countertops) for up to 6 hr, on
analysis of the data, the combination of RSV LRTI with a
rubber gloves for 90 min, and on skin for 20 min.59 This
family history of asthma was associated with the highest
prolonged survival highlights the need (and effectiveness)
risk. Taken together, these two studies suggest a 30–40%
for hand washing and contact precautions in limiting the
likelihood of recurrent asthma-like episodes after early-
spread of RSV infection. The incubation period ranges
life RSV LRTI. Sigurs’ studies also show increased risk
from 2 to 8 days, and immunocompetent individuals can
beyond 13 years of age and propose a link between RSV
shed the virus for up to 3 weeks, although on average this is
infection and development of atopy; these discrepancies
limited to about 8 days. Viral shedding is significantly
from other studies may be related to the different severity
prolonged in immunocompromised individuals, and can
of the original infection or to differences in the genetic
continue for several months.
background.
Unfortunately, epidemiologic studies are not suited to
Replication
resolve whether early-life RSV LRTI are truly causal in
subsequent asthma, or more simply precipitate wheezing Viral replication occurs initially within the nasophar-
in children already predisposed by their genetic or yngeal epithelium, but then spreads to the bronchiolar
epigenetic makeup. Only carefully randomized control epithelium where replication is most efficient60 (Fig. 3).
trials with specific prophylaxis can conclusively deter- This progression may occur by direct cell to cell trans-
mine if preventing or delaying the first RSV infection mission or by aspiration of upper airway secretions.61,62
lessens the incidence and/or severity of asthma later in life. Additionally, the virus can spread via the blood stream or
A recent industry-sponsored, prospective, multicenter through infection of inflammatory cells (e.g., monocytes),
trial concluded that RSV prophylaxis decreases by which may also account for disseminated disease in
80% the relative risk of recurrent wheezing during 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, infection. Flow cytometric data show the percentage of fluores-
tracheal, and bronchial epithelial cells after infection with GFP- cent (infected) cells in each panel compared to the non-infected
expressing RSV (rgRSV) at 1 MOI for 48 hr. The bright field panels control cells (shaded histogram). Data are expressed as the
(left) show the total number of cells. The green fluorescent cells mean  SEM (n ¼ 4 experiments). ***p < 0.001 compared to nasal
(center) represent those which are actively infected with RSV. or tracheal cells.
B: Bronchial epithelial cells are the most susceptible to RSV

however, the infection remains limited to the respiratory In particular, considerable discussion has emerged in
tract. an effort to understand the mechanisms underlying the
Viral replication is followed by necrosis of the enhanced disease seen in the formalin inactivated vaccine
bronchiolar epithelium with subsequent lymphocytic trial. Formalin inactivation has been implicated in that it
peribronchiolar infiltration and submucosal edema. appears to have amplified the immunogenicity of specific
Mucus secretions increase in both quantity and viscosity, viral antigen, especially the RSV G protein. However, the
and mix with cellular debris. Clearance of this mixture inactivation also resulted in an altered ability to induce a
is compromised by the loss of ciliated epithelium and protective neutralizing antibody response. Vaccine recip-
viscosity of the secretions. The end result is the production ients were therefore primed for an enhanced inflammatory
of widespread mucus plugging with increased expiratory response upon exposure to the wild-type virus.12 This
resistance and partial airway obstruction causing air negative outcome impacted dramatically the further
trapping.68 These factors combine to produce the classic development of an inactivated RSV vaccine, essentially
clinical triad of wheezing, atelectasis, and hyperinflation. bringing it to a halt.
The host’s immune response is clearly of great
importance in clearing RSV infection and likely in
Immune Response
attenuating its course. RSV infection induces both cellular
Historically, it has been held that the severity of an RSV and humoral immune activity, and although this response
infection is related to the intensity of the host’s immune does not result in complete protection against reinfection,
response. This perception stems largely from the results it does seem to decrease the severity of subsequent
of the 1966 formalin inactivated RSV vaccine clinical infections.44,45 In infants, high titers of maternally derived
trial.69,70 Postmortem examinations of the two infants who RSV-neutralizing antibody in cord sera are associated
died revealed the presence of RSV bronchopneumonia, with a much lower risk of hospitalization due to RSV
extreme hyperinflation with pneumothorax, and atypical bronchiolitis.73,74 This protection can also be conferred by
eosinophilic pulmonary infiltration. These findings sug- administration of exogenous RSV immunoglobulin.75,76
gest that immunopathologic mechanisms play an impor- In addition, decreased serum anti-RSV titers have
tant role in severe RSV disease, and studies in animal been associated with a significant increase in the risk
models have indicated amplified Th2 immunity and of developing a symptomatic RSV infection.28 Cell-
activated cytotoxic T cells as the main culprits,71,72 mediated immunity probably plays a role in the control of
although several aspects of RSV pathophysiology remain active infection and in viral clearance. This is underscored
highly controversial. by the observation that immunocompromised individuals
Pediatric Pulmonology
RSV Prevention and Therapy 329

with deficient cell-mediated immunity suffer more severe ways play an important role in the pathophysiology of
and prolonged RSV disease, and also shed the virus much local and systemic inflammation against viral pathogens.
longer.34,66,77 This important inflammatory mechanism is largely
A recent study, however, provides an alternative resistant to corticosteroids,88 which provides a plausible
explanation for the pathophysiology of severe RSV explanation for the poor therapeutic activity of these drugs
infections. In this study, autopsy specimens were collected in children with virus-induced wheezing.
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
Mast Cells and Leukotrienes
infants who died from influenza infection and the results
were surprising, as there was no evidence of an RSV- Studies in animal models indicate that RSV affects
related enhanced inflammatory response; in particular, at dramatically the number, distribution, and function of
the time of most severe symptoms, there was no activation mast cells in the airway mucosa.89 Histopathological
of cytotoxic T-cell activity. There was, however, signifi- analysis with an antibody against tryptase identified
cant apoptosis-induced sloughing of the airway epithe- numerous mast cells in sections from RSV-infected rat
lium. The authors’ interpretation is that severe RSV lungs, with a 7-fold increase compared to the lungs of
infection is a result of insufficient adaptive immunity, with non-infected controls (Fig. 4). In addition, most of these
viral clearance largely reliant upon less efficient innate mast cells were in close spatial association with nerve
immunity. fibers, suggesting functional mast cell–nerve interactions
similar to those previously reported in other organ
systems, particularly the skin, central nervous system,
Neuro-Immune Interactions
and gastrointestinal tract.90
Recent studies show that early-life RSV infection Among the inflammatory mediators released from mast
promotes a large increase in the expression of nerve cells, cysteinyl leukotrienes (cysLTs) have been shown to
growth factor (NGF) and its receptors in the developing cause airway inflammation and airway smooth muscle
airways of both animal models79 and humans.80 NGF and contraction during RSV infection, accounting for the
other similar neurotrophic proteins control the structural wheezing observed in bronchiolitis. Increased LTC4 levels
development of peripheral afferent and efferent neurons, were observed in nasopharyngeal secretions of children
and exert changes in their functional activity in a during the acute phase of RSV infection, and their
number of ways that collectively define ‘‘neuronal concentration correlated with clinical severity, being
plasticity.’’81 Thus, RSV-induced NGF overexpression higher in patients with lower respiratory tract involvement
can drive short- and long-term changes in the distribution than in children with upper respiratory illness alone.91,92
and reactivity of sensory and motor nerves across the Another clinical study showed that urinary LTE4 (the
respiratory tract, causing non-specific airway hyper- terminal product of cysLTs metabolism) is especially
reactivity during and after the infection. Furthermore, elevated during RSV bronchiolitis in younger infants
RSV infection following chronic exposure to environ- (<6 months of age) with an atopic/asthmatic background
mental pollution produces more severe neurotrophic (Fig. 5).93 As cysLTs are known to play critical roles in
dysregulation and neurogenic-mediated inflammation the pathophysiology of asthma, they could also represent
compared to either infection or pollution alone.82 an important component in the link between RSV and
Neurotrophic factors and receptors are also synthesized asthma.
in several non-neuronal cell types including epithelial and Time course analysis of infected lung tissues indicated
inflammatory cells (e.g., mast cells and CD4þ T cells).83–85 that the effect of RSVon leukotriene synthesis is transient;
This function may target the innervation of specific levels are maximal by 3–5 days post-infection and return
tissues, but there is growing evidence that NGF functions to baseline by 30 days.89 These findings collectively
as a potent and eclectic neuro-immunomodulator, which suggest that the acute inflammatory response of airways
releases and is released by a variety of inflammatory infected by RSV in early life involves the release of cysLTs
mediators. In particular, patients with bronchial asthma and activation of the cysLT1 receptor, as manifested by
and allergic rhinoconjunctivitis display high serum levels the anti-inflammatory effect of the receptor antagonist
of NGF, suggesting an important pathogenetic role of montelukast in animal models89 and in human studies.94
neurotrophins in allergic disorders.86 Following the early phase of the viral respiratory
Studies in animal models indicate that NGF over- infection, leukotriene production and release rapidly
expression is critical for neurogenic-mediated mucosal return to baseline levels, but can be reactivated when air-
edema and for innate lymphocytic and monocytic borne irritants (e.g., tobacco smoke) stimulate nociceptive
responses in RSV-infected airways,87 suggesting that nerve fibers connected to the numerous mast cells still
neuro-immune interactions driven by neurotrophic path- 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


coarse rales. Chest radiograph findings frequently include
. Transmission occurs through inoculation of the naso-
bilateral hyperinflation, patchy atelectasis, and peribron-
pharyngeal or conjunctival mucosa with respiratory
chial thickening (Fig. 6).
secretions from infected individuals.
Patients with severe lower respiratory tract involvement
. Viral shedding persists for about 8 days, but can
may also have radiologic features more consistent with
be significantly more prolonged in immunocompro-
pneumonia, with areas of interstitial infiltration.100–102
mised individuals.
The resulting respiratory distress can vary in severity
. Viral replication begins in the nasal mucosa and
from minimal to profound, life-threatening respiratory
spreads downward through the respiratory tract,
failure.22,99,103 Infants may also develop lethargy, fever,
producing edema and necrosis of the respiratory
poor feeding, and otitis media. Elderly individuals and
epithelium, and resulting in airway obstruction.
those with cardiopulmonary disease or immunodeficiency
. The inflammatory response associated with RSV
are also at risk for severe lower respiratory tract disease.104
infection is extremely complex and involves the
Older children and healthy adults typically manifest
release of multiple cytokines and chemokines from
symptoms of the upper respiratory tract, but may also have
epithelium and immunocytes, neuro-immune inter-
tracheobronchitis.46
actions, and mast cells degranulation with release of
Apnea is a well-known complication of RSV infection
leukotrienes.
in infants, and on occasion may be severe enough to cause
death.38 The virus was isolated as early as 1956 in infants
CLINICAL MANIFESTATIONS
with apnea, and the incidence of apnea is as high as 20% in
RSV infection in children almost always causes infants under 6 months of age who require hospitalization
clinical manifestations; however, these can vary widely for RSV infection.105–110 Bruhn et al. also noted that the
in severity depending on the patient’s age, comorbidities, highest incidence occurs in premature infants and in
environmental exposures, and history of previous infec- infants less than 1 month of age. In most cases, however,
tions.45,95–98 Infants typically present with upper respira- apnea is self-limited and does not recur with subsequent
tory symptoms, such as congestion and rhinorrhea that infections.106,111 An interesting observation is that apnea
over a period of 2–4 days may progress to involve the is frequently the first clinical manifestation of RSV
lower respiratory tract with cough, wheeze, increased infection, and may occur regardless of the severity of other
work of breathing, and cyanosis.22,45,99 Auscultation is RSV-related symptoms.105 This association has led to the
Pediatric Pulmonology
RSV Prevention and Therapy 331

Fig. 5. Leukotriene synthesis in RSV-infected infants. Urinary tivity seems to amplify the effect of the virus, as higher LTE4
excretion of LTE4 (the terminal product of cysLTs metabolism) concentrations were found in infants with a medical history
is increased in children with RSV bronchiolitis as compared of eczema or dry cough and/or a family history of asthma.
to controls without respiratory infection. The overproduction of Age or atopy per se did not affect leukotriene synthesis in
cysLTs reflected by this marker is more prominent in younger the absence of infection. *p < 0.05, **p < 0.01, ***p < 0.001 ¼
patients (<6 months of age) infected with this virus. Also, an significantly different from age-matched controls without respi-
intrinsic predisposition to develop atopy or airway hyperreac- ratory infection.

hypothesis that RSV may be involved in at least some horn, which in turn inhibit the function of medullary
cases of sudden infant death syndrome (SIDS), which inspiratory neurons resulting in apnea.
also shares several epidemiological similarities with the
infection in terms of seasonality and risk factors. Section Summary
The exact pathophysiology of RSV-related apnea is
. Infants with RSV infection typically present with
still controversial. Studies in animal models suggest that
upper respiratory symptoms (congestion, rhinorrhea)
RSV infection prolongs significantly reflex central apnea
that frequently progress to involve the lower respira-
triggered by peripheral sensorineural stimulation.112 This
tory tract with cough, wheeze, and increased work of
effect of RSV on ventilatory control is already significant
breathing.
2 days after intranasal inoculation, when the infection is
. Chest radiography typically shows hyperinflation,
still confined to the upper airway, which is consistent with
patchy infiltrates, and atelectasis.
and explains why apnea is an early or even presenting
. Apnea is frequently the presenting manifestation of
manifestation of RSV infection. In addition, apnea-related
RSV infection, especially in very young infants.
mortality in murine models is highest early during RSV
infection, suggesting that counterregulatory mechanisms
that facilitate autoresuscitation are activated only later MANAGEMENT
during the infection. Specific blockade of the central
Supportive Care
GABAA receptors or of the high-affinity substance P
(NK1) receptors abolishes the influence of RSV infection Most infants with RSV infection have a mild, self-
on the apnea triggered by sensorineural stimulation. This limited illness, and are treated in an outpatient setting.
finding suggests that substance P released from primary This requires close follow up with attention to respiratory
sensory neurons within the nodose ganglia activates distress, oxygen requirement, and hydration. Those
second-order GABAergic interneurons in the spinal dorsal 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
RSV Prevention and Therapy 333

b-Agonists While evidence-based protocols do not support the


A 1997 meta-analysis evaluated several outcomes routine use of albuterol or epinephrine, the use of
among eight clinical trials published between 1987 and bronchodilators on a trial basis in select patients is
1994.119 This review found no improvement in clinical acceptable. If clinical improvement can be documented,
score or hospitalization rate associated with the use of then continued use can be recommended. However,
albuterol. There was a statistically significant, but treatments should be discontinued if no improvement is
clinically insignificant, improvement in oxygen satura- demonstrated, because of the possible side effects (e.g.,
tion, and heart rate. The authors concluded that there is tachycardia, tremor, hypokalemia, hyperglycemia). As
no evidence for the efficacy of b2-agonist therapy in the epinephrine is typically not prescribed for use at home,
treatment of viral bronchiolitis. albuterol may be a more appropriate choice for outpatient
Gadomski and Basale120 revisited this topic in a use.
recently updated Cochrane review of the available
literature. Twenty-two studies, with a combined total of Anticholinergic Agents
1,428 infants with bronchiolitis and first wheezing Anticholinergics, such as ipratropium bromide, have
episode, were evaluated in a meta-analysis to address not been found to be effective in the treatment of RSV
specifically the efficacy of bronchodilators in the manage- bronchiolitis. Several studies have evaluated ipratropium
ment of bronchiolitis. Measured outcomes included alone and in combination with albuterol. While minor
improvement in clinical score, oxygenation, hospital improvements in oxygenation have been reported, there
admission, and length of hospital stay (LOS). The authors is no consistent, significant benefit to the overall clinical
found that there was a minimally significant improvement course or outcome.123–126
in clinical scores among infants receiving bronchodilator
therapy over those receiving placebo, and that this
Corticosteroids
improvement was not likely to be clinically relevant.
Likewise, there was no statistically significant improve- Systemic Corticosteroids
ment in oxygenation, admission rate, or LOS. The authors A number of trials have sought to evaluate the efficacy
concluded that bronchodilators are not recommended for of systemic corticosteroids in the treatment of bronchio-
the routine management of infants with bronchiolitis and litis. Patel et al.127 conducted a systematic review of 13
first episode of wheezing. trials of corticosteroid therapy in 1,198 children with viral
Studies in animal models have suggested that single- wheezing aged 0–30 months. This meta-analysis found a
isomer preparations like levalbuterol may have a better decrease in LOS of 0.38 hospital days/patient, which
anti-inflammatory effect than racemic albuterol in RSV- however was not statistically significant. There was no
infected airways,121 but this has yet to be confirmed in difference in clinical scores, respiratory rate, or oxygen
clinical trials. In summary, b-agonists have not been saturation. For patients treated in the emergency depart-
shown to have consistent benefits in the treatment of RSV ment or clinic, there was no difference in admission rates.
bronchiolitis. A carefully monitored trial in individual The authors caution that significant heterogeneity of
patients may be warranted, with discontinuation of the included studies and results make the final analysis
therapy if no objective improvement is noted. 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.
Epinephrine The findings of this meta-analysis are complemented by
As with albuterol, there is no strong evidence to support more recent individual studies. Teeratakulpisarn et al.128
the use of epinephrine in the treatment of RSV evaluated 174 children hospitalized with acute bronchio-
bronchiolitis; nevertheless, it is frequently used in infants litis. The children were randomized to receive 0.6 mg/kg
with RSV. A 2004 Cochrane review evaluated 14 studies of intramuscular (IM) dexamethasone or placebo. The
published between 1998 and 2003.122 This review authors evaluated the length of time to resolution of
evaluated the efficacy of epinephrine versus albuterol respiratory distress as the primary outcome. The duration
and epinephrine versus placebo in both the inpatient and of respiratory distress was decreased from 39 hr for the
outpatient settings. Primary outcomes included clinical placebo group to 27.2 hr for the dexamethasone group, a
score, heart rate, respiratory rate, oxygenation, admission difference of about 12 hr. The duration of oxygen therapy
rate, and LOS. The authors concluded that the available was also reduced by 14.9 hr, and the hospital LOS was
data does not support the use of epinephrine in the decreased by 13.4 hr.
inpatient setting, but that in outpatients epinephrine may In another study, Corneli et al.129 compared oral
produce a modest short-term improvement and therefore dexamethasone to placebo to determine whether a single
be preferable to albuterol or nebulized saline in the dose of the steroid (1 mg/kg) could reduce the need for
treatment of bronchiolitis. 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 the second group received nebulized racemic epinephrine
presenting to the emergency department with first time plus oral placebo; the third group received nebulized
wheezing and a diagnosis of moderate- to severe- placebo plus oral dexamethasone; and the fourth group
bronchiolitis. The primary outcome was hospital admis- received both placebos. Among the four groups, only
sion after 4 hr of emergency department observation. those infants who received both therapies were found
Secondary outcomes included change in a respiratory to be significantly less likely to require hospitalization
assessment score, LOS, later medical visits or hospital (17.1% for the combination therapy group; 23.7% for the
admissions, and adverse events. The authors found that a epinephrine group; 25.6% for the dexamethasone group;
single dose of dexamethasone did not change the rate of and 26.4% for the placebo group). Therefore, combination
hospital admission or the severity score of bronchiolitis therapy with racemic epinephrine and oral dexamethasone
after 4 hr; they also found no change in secondary may decrease hospital admissions.
outcomes. In summary, the current evidence suggests that In general, young children without an atopic phenotype
systemic steroids should not be recommended for routine that wheeze in response to viral infections show a poor
use in the treatment of bronchiolitis. response to corticosteroids, and even children that will
ultimately develop asthma are usually unresponsive to
Inhaled Corticosteroids this therapy when they develop virus-induced wheezing
Several studies have evaluated inhaled corticosteroids during their first years of life. Another area of concern
in patients with bronchiolitis, again without showing any derives from safety considerations. In fact, severe RSV
significant benefit.130,131 In a 2007 Cochrane review of bronchiolitis typically occurs during the first year of life
five studies with a total of 374 infants, Blom et al.132 and coincides with a critical phase of rapid lung develop-
evaluated the use of inhaled corticosteroids to prevent ment. The safety of the therapeutic use of corticosteroids
post-bronchiolitis wheezing. This analysis found no during this window, particularly when inhaled at high
reduction in wheezing, readmission rate, use of systemic doses and for prolonged periods, is virtually unknown and
corticosteroids, or use of bronchodilators. consequently these medications have never been approved
More recently, Ermers et al.133 conducted a RCT to by the US Food and Drug Administration (FDA) for use in
assess the influence of inhaled beclomethasone dipropi- the treatment of bronchiolitis or asthma in the first year of
onate on the occurrence and severity of recurrent wheeze life.
following RSV LRTI. They enrolled 243 previously We conclude that whether administered systemically or
healthy infants who had been admitted to the hospital inhaled, corticosteroids should not be routinely used in the
for RSV. The infants were randomized to receive treatment of bronchiolitis. However, some specific patient
beclomethasone dipropionate (200 mg bid) versus placebo populations may benefit from a trial of steroid therapy,
during the first 3 months after hospitalization. There was particularly patients with family history (parental atopy or
no significant difference in the number of days with asthma) or medical history (atopic eczema) consistent
wheeze or in the proportion of infants with wheeze with atopic predisposition.
between the two groups.
Antivirals
Combination Therapy
Several studies have evaluated the usefulness of The only antiviral agent licensed for the therapy of
steroids given together with nebulized racemic epinephr- severe RSV infections is ribavirin, a synthetic nucleoside
ine, with encouraging results. A recent RCT compared 61 analog with broad in vitro virustatic activity. Unfortu-
infants randomized to receive nebulized dexamethasone nately, several factors make its routine use highly
or saline; both groups also received nebulized epinephr- controversial: it is expensive, difficult to administer, and
ine.134 In this study, no statistically significant difference possibly a teratogen. Furthermore, the available studies
was noted in clinical score or oxygen saturation. There are all small, have inconsistent quality, and have produced
was, however, a significant reduction in LOS in the conflicting results, leading to a progressive decline of
dexamethasone group, especially among the subgroup of its use.
prematurely born infants (6.5 vs. 9.1 days). Early studies were encouraging. Hall et al.136 random-
Plint et al.135 conducted a large, multicenter RCT to ized 33 infants hospitalized with RSV bronchiolitis to
assess rates of admission to the hospital after treatment continuous aerosolized ribavirin for 3–6 days versus
with oral dexamethasone and nebulized racemic epi- placebo. The ribavirin group showed a greater improve-
nephrine. Eight hundred infants presenting to the ment in severity score, lower respiratory tract signs,
emergency department with bronchiolitis were random- oxygen saturations, and viral shedding compared to the
ized into four groups. The first group received two placebo group. Rodriguez et al.137 also found improved
treatments with nebulized racemic epinephrine plus six oxygenation and greater rate of clinical improvement in
doses of oral dexamethasone (1 per day for 6 days); patients receiving a short course of ribavirin, without
Pediatric Pulmonology
RSV Prevention and Therapy 335
138 146
evidence of adverse effects. Smith et al. conducted a differentiate viral from bacterial infections. In fact,
double-blind, placebo-controlled trial of continuously the risk of bacterial superinfection in infants with
aerosolized ribavirin in 28 mechanically ventilated infants bronchiolitis and fever is quite low (0.2%), even when
with RSV infection, using nebulized sterile water as a body temperature is >398C.147,148 However, for intubated
control. This study reported a significant reduction in infants with severe bronchiolitis, the rate of secondary
oxygen use and in the length of mechanical ventilation bacterial infection is much higher, and may be as high as
and hospitalization, especially among infants with no 26%.149,150
underlying illness. When a secondary bacterial infection is diagnosed, the
A subsequent, well-designed study evaluated ribavirin most common sites are the urinary tract and the middle
against nebulized saline in 42 mechanically ventilated ear.151,152 In particular, infants with secondary infections
patients with RSV bronchiolitis and respiratory failure.139 are more likely to have a urinary tract infection than
The authors found no significant improvement in the bacteremia or meningitis (12% vs. 0.43%).153 Acute otitis
length of oxygen therapy, aerosol therapy, mechanical media is also seen as a complication of RSV infection
ventilation, PICU stay, or hospital stay. These findings (57–67%), but its presence does not seem to influence the
were supported by a similar study performed by Meert severity of fever, respiratory distress or the overall clinical
et al.140 Taber et al.141 evaluated 26 infants randomized to course of the disease.154 In one series, evaluation of
receive ribavirin or placebo and found no difference in the middle ear aspirates in children with bronchiolitis
rate of viral clearance between the two groups. In a longer revealed RSV in 17 (71%) of 24 patients.152 In addition,
outcome study, Everard et al.142 followed patients treated all patients with acute otitis media had bacterial pathogens
with ribavirin for RSV bronchiolitis over a 1-year period isolated, the most common being Streptococcus pneumo-
and was unable to demonstrate any short-term improve- niae, Haemophilus influenzae, and Moraxella catarrhalis.
ment in the clinical course or long-term reduction in the If present, otitis media should be managed according to
use of inhaled bronchodilators or steroids. In 2007, Ventre current AAP recommendations.23,155
and Randolph143 reviewed 12 trials published between Several prospective RCTs have evaluated the clinical
1983 and 1999 finding only small and not statistically outcomes of infants who received antibiotics for the
significant improvements in mortality, length of mechan- management of bronchiolitis. As early as 1966, a double-
ical ventilation, LOS, or clinical status. blind RCT failed to demonstrate a benefit to treating
Although ribavirin effectively inhibits RSV replication bronchiolitis with antibiotics.156 Friis et al.157 evaluated
in vitro, its lack of efficacy in vivo is not surprising 136 children between the ages of 1 month and 6 years and
because the first clinical symptoms (coryza) usually found no difference in the course of the acute illness, fever
appear towards the end of the exponential viral replication relapse, or pulmonary complications in those patients with
in the lungs, which is followed by rapid decline of bronchiolitis who received antibiotics when compared to
virus titers. Thus, by the time the classical signs of those who did not.
bronchiolitis are diagnosed, little virus remains in the We conclude that antibiotics should be used in patients
lungs while the immunoinflammatory response of the with bronchiolitis only when specific evidence of coex-
host dominates the pathophysiology. Hence, the thera- istent bacterial infection is present, and confirmed
peutic use of a virustatic agent like ribavirin requires bacterial infections should be managed no differently
immediate intervention at the clinical onset, which is than in the absence of bronchiolitis.
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
Recombinant Human Deoxyribonuclease
the current recommendation is that ribavirin should not
(DNAse)
be used routinely to treat children with bronchiolitis. It
should, however, be used either alone or in combination Given that neutrophils are prominent in the early
with anti-RSV antibodies to treat RSV infections in select immune response to RSV infection, and the free DNA
immunocompromised hosts who can continue to shed deriving from their lysis is often found in the
virus for several months.23 thickened secretions of RSV LRTI, it seems reasonable
that mucolytic therapy with DNAse should be beneficial.
However, a recent multicenter, randomized, placebo-
Antibiotics
controlled trial evaluated the efficacy of DNAse in 225
It is not uncommon for infants with bronchiolitis to hospitalized, oxygen-dependent infants,158 finding no
receive antibiotic therapy. It is estimated that antibiotics demonstrable benefit. Nasr et al.159 reported that DNAse
are used in 34–99% cases of uncomplicated bronchioli- could be used to improve the chest radiologic findings of
tis.144,145 This therapy is frequently started because the infants with RSV; however, again there was no associated
patient is febrile, but fever per se cannot reliably clinical improvement.
Pediatric Pulmonology
336 Wright and Piedimonte

Hypertonic Saline 70:30 or 80:20 ratio. Its theoretical advantage lies in the
fact that it maintains laminar flow and, therefore, less
Hypertonic saline nebulization has been shown pre-
turbulence through constricted airways than do nitrogen–
viously to improve mucociliary clearance in patients with
oxygen mixtures. This results in improved ventilation with
asthma and cystic fibrosis,160,161 and more recently has
a reduced work of breathing in patients with lower
gained interest as a potential therapy for infants with
respiratory tract disease. Heliox has been studied in the
bronchiolitis. In a 2008 Cochrane review, Zhang et al.162
treatment of bronchiolitis by several investigators,
reviewed four trials including a total of 254 infants with
although most of these studies are quite small.171–173
acute bronchiolitis (189 inpatients and 65 outpatients)
Some of the authors have shown small improvements in
who received 3% versus 0.9% saline nebulization with or
clinical scores and decreased tachypnea and work of
without a bronchodilator. The primary outcomes meas-
breathing.
ured were LOS for the inpatients and rate of hospital-
Liet et al.174 evaluated rates of positive pressure
ization for the outpatients. This review concluded that
ventilation in patients receiving heliox therapy versus
nebulized hypertonic saline could reduce the LOS of
standard nitrogen–oxygen air and found no difference
hospitalized infants by almost 1 day (25.9% reduction)
between the two groups. When heliox therapy was
when compared to infants who received placebo. There
evaluated in intubated children with bronchiolitis, Gross
was no improvement in the rate of hospitalization among
et al.175 found no improvement in ventilation or oxygen-
outpatients. Importantly, no adverse events were reported
ation, regardless of the ratio of helium to oxygen
in any of the trials. Furthermore, when considering the
employed (50:50, 60:40, or 70:30).
enormous financial burden that the hospitalization of
Heliox equipment is bulky and cumbersome, and it can
infants with bronchiolitis places on healthcare systems
be problematic to administer. Furthermore, given that
and parents worldwide, the minimal acquisition costs
it is most effective at high helium to oxygen ratios, it
make this intervention even more appealing.
is minimally effective in patients with significant oxygen
requirements. In summary, the current evidence support-
Surfactant ing heliox use for bronchiolitis is sparse, underpowered,
Beyond its role of decreasing surface tension in alveoli and conflicting, and therefore larger RCTs are required
and bronchioles, thereby improving alveolar and small before it can be recommended for routine use.
airway patency, surfactant has protein components (A and
D) that bind viral and bacterial surface markers and Anti-Leukotrienes
facilitate their immune-mediated elimination.163–166 In
addition, surfactant protein D has been demonstrated to As discussed above, strong experimental evidence in
promote alveolar macrophage production of free radi- animal models and a number of clinical studies indicate
cals.167 In acute bronchiolitis, there is decreased produc- that cysLTs are released during RSV infection and
tion of these surfactant proteins, which return to normal contribute to airway inflammation and hyperreactivity.
levels with the resolution of the illness.168 Therefore, it would make sense if leukotriene antagonists
Administration of exogenous surfactant to infants with would have therapeutic activity in the setting of acute
severe respiratory failure due to bronchiolitis seems bronchiolitis, and possibly prevent or reduce the recur-
promising, and several small RCTs have been conducted rence of wheezing episodes post-bronchiolitis. The first
to evaluate this therapy, with encouraging results. A recent pilot trial testing this hypothesis was conducted in
meta-analysis by Ventre et al.169 included three studies Denmark by Bisgaard et al.94 One hundred thirty children
with a total of 79 patients. The authors reported decreases hospitalized with acute RSV bronchiolitis were random-
in the duration of mechanical ventilation and PICU stay. ized into a double-blind, placebo-controlled trial of the
There also seem to be improvements in pulmonary cysLT1 receptor antagonist montelukast given for 28 days
mechanics and gas exchange. It is important to note that starting within 7 days of symptom debut. Children on
the available studies are small and underpowered, and that montelukast had significantly more symptom-free days
additional, larger studies are required. However, exoge- compared with children on placebo (22% vs. 4%); in
nous surfactant therapy does appear to hold promise for particular, daytime cough was significantly reduced on
use in patients with severe respiratory failure due to active treatment and exacerbations were delayed.
bronchiolitis. 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
Heliox
wide age range (3- to 36-month old). To address the latter,
Barach and Eckman170 first described the use of helium the author conducted a post hoc analysis of the same data
for the treatment of upper airway obstruction and asthma revealing that the effect of montelukast was larger in the
in the 1930s. Heliox is a mixture of helium and oxygen in a younger children compared with the older children,176
Pediatric Pulmonology
RSV Prevention and Therapy 337

which was consistent with previously reported data on the tions to caregivers of high-risk infants also include the
age-dependency of cysLTs production.93 To address the avoidance of tobacco smoke and restriction of day care
issue of statistical power, a larger multi-center double- during RSV season. In addition, there is good evidence to
blind study of 979 children 3–24 months old with RSV support the recommendation of breast feeding at risk
bronchiolitis was completed recently.177 This time, no infants, given the transfer of maternal immunoglobulin.178
significant differences were seen between montelukast and Hand washing in the clinical setting is invaluable
placebo in symptom-free days. However, post hoc analysis in preventing the nosocomial spread of RSV.178 The use
limited to the 523 patients with persistent symptoms of gloves and gowns can also aid in limiting trans-
showed more symptom-free days in the montelukast mission179–183; the use of masks is more controversial, as
group. Therefore, additional studies are necessary to RSV is mostly transmitted by direct contact with infected
define conclusively the role of leukotriene modifiers in secretions and rarely by aerosolization. Rapid testing of
the management of patients with more persistent or suspected patients allows for identification and isolation
more severe respiratory symptoms following RSV infec- of those known with RSV-related disease, further
tion. Furthermore, it would be important to compare decreasing their exposure to non-infected patients.184
the effect of anti-leukotriene therapy during the infection
with its prophylactic use starting before the RSV season, Immunoprophylaxis
and also assess its effect on the incidence of post-RSV
asthma. To date, two products have been developed for clinical
use: RSV-IVIG, a hyperimmune polyclonal globulin, and
Section Summary palivizumab, a humanized monoclonal antibody. Motavi-
zumab is a second-generation humanized monoclonal
. b-Agonists do not provide consistent benefit in the antibody not yet available on the market.
treatment of RSV infection; however, a brief trial
with objective evaluation of the response may be Respiratory Syncytial Virus Immunoglobulin (RSV-IVIG)
warranted. RSV-IVIG is a pooled polyclonal human immunoglo-
. Epinephrine does not provide consistent benefit in bulin purified from donors with high-RSV-neutralizing
the inpatient setting, and although it may produce a antibody titers, to be administered by monthly intravenous
modest improvement in the outpatient setting, it is not infusion during RSV season.185 A significant decrease in
recommended for use at home. RSV-related hospitalizations and LOS was seen when
. Neither systemic nor inhaled corticosteroids have RSV-IVIG was administered to high-risk infants with
shown consistent benefit in the treatment of RSV prematurity or chronic lung disease. However, it was also
disease, and therefore they are not recommended for associated with an increase in surgical morbidity and
routine use. mortality among infants with CHD, and so it was never
. Ribavirin is not recommended for routine treatment licensed for use in these patients.75,186,187 As RSV-IVIG
of RSV infection, but may be considered in select could interfere with the immune response to live virus
immunocompromised individuals. vaccines, it was necessary to delay immunization with the
. Antibiotics are recommended only in the presence of measles/mumps/rubella (MMR) vaccine until 9 months
specific evidence of coexistent bacterial infection. following the last dose of RSV-IVIG.
. DNAse does not provide consistent benefit in the The major disadvantages of RSV-IVIG included the
treatment of RSV infection. need for repeated venous access and a long intravenous
. Hypertonic saline has been demonstrated to reduce infusion (4–6 hr), with the consequent need of medical
LOS by up to 25% and may provide significant benefit supervision in a hospital setting. The volume administered
to infants with RSV bronchiolitis. was considerable using the recommended dose of 15 ml/
. Surfactant and Heliox may provide benefit in the kg, with the significant risk of fluid overload to intrinsi-
treatment of RSV infection, but the available data is cally fluid sensitive infants and frequent need for diuretic
not conclusive. therapy. There was also a potential for transfer of blood-
. Anti-leukotrienes have shown some clinical benefit in borne pathogens and the supply of eligible donors was not
the treatment of RSV infection, but the evidence for or dependable. Another practical disadvantage was the high
against their use is not definitive. combined costs deriving from acquisition and supervised
administration of the immunoglobulin.188
PREVENTION
In the non-clinical setting, several measures have Palivizumab
proven effective in limiting the likelihood of RSV Given the disadvantages of RSV-IVIG in the treatment
infection. Hand washing is perhaps the most effective of RSV infection, research focused on the development of
way to prevent the spread of RSV. Specific recommenda- monoclonal antibody therapies. There are several advan-
Pediatric Pulmonology
338 Wright and Piedimonte

tages to monoclonals: they are less likely to exert an <24 months of age with a history of BPD. The infants
immunosuppressive effect in children,189 and carry were randomized to receive monthly IV infusions of 3, 10,
essentially no risk of transmitting blood-borne infections or 15 mg/kg palivizumab versus normal saline placebo.
or other plasma-associated adverse effects190; contain The study drug was well-tolerated and produced no anti-
higher titers of neutralizing antibody, and therefore can be palivizumab response. The authors concluded that optimal
prepared in smaller volumes suitable for IM administra- serum concentrations were achieved with the 15 mg/kg
tion in outpatient or home settings; eliminate the risk of dose and that the mean half-life of approximately 20 days
fluid overload and need for diuretic rescue. supported a monthly dosing schedule.
Palivizumab is a humanized monoclonal IgG1 antibody The IMpact-RSV pivotal trial enrolled 1,502 infants
produced by recombinant DNA technology, one of the under 35 weeks gestational age and/or with chronic lung
very first successful therapies of this kind that pioneered disease.197 The infants were randomized to receive
the large and expanding field of biologicals. With this palivizumab 15 mg/kg IM, or placebo, monthly during
technology, murine-derived sequences complimentary to the RSV season. In those infants that received palivizu-
the A antigenic site of the RSV F protein are grafted into a mab, there was a 55% decrease in hospitalization rate and
human IgG frame (Fig. 7); the result is an antibody that LOS was reduced from 62.6 days per 100 children to
being >95% human is minimally immunogenic and has 36.4 days per 100 children. Illness severity score, need for
broadly reactive activity toward both subtypes of RSV.191 intensive care and oxygen requirement were also reduced.
The effectiveness of palivizumab lies not in preventing There was no difference in the need for mechanical
infection of the upper respiratory tract, but in limiting ventilation.
downward spread.192 In addition, studies in animal models Another multicenter clinical trial of palivizumab for
have suggested that, by preventing alterations in the prophylaxis in 1,287 infants with significant CHD showed
development of small airway neural networks caused by a 45% relative reduction in hospitalization in this
RSV in infancy,79,80,193,194 palivizumab might prevent population when compared to placebo.198 Acyanotic
subsequent peripheral airway reactivity and recurrent patients had a 58% reduction in hospitalization and
wheezing195,196 as well as central ventilatory complica- cyanotic patients had a 29% reduction. Therefore, combin-
tions like apnea.112 ing the data from these RCTs, palivizumab protects quite
In 1998, a Phase I/II multicenter, double-blind, placebo- well preterm infants without BPD, and somewhat well
controlled study was published, defining the safety and infants with acyanotic CHD, whereas the protective effect
pharmacokinetics of palivizumab.191 Sixty-two infants for infants with BPD or cyanotic CHD is limited (Fig. 8).
were enrolled, including infants <6 months of age with a It should also be noted that most post-marketing data
history of <35 weeks premature delivery or infants 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
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.
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
Palivizumab is generally well tolerated. The most
CHD, whereas the protective effect for infants with BPD or commonly reported adverse events are upper respiratory
cyanotic CHD is limited. It should also be noted that most post- tract infection, otitis media, fever, rhinitis, rash, diarrhea,
marketing data suggest that the protection provided by palivi- cough, vomiting, gastroenteritis, and wheezing.200–202
zumab may be substantially higher than that estimated from Severe hypersensitivity can occur, but the incidence is
RTCs, but these data are difficult to interpret because of lack of
controls.
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
be substantially higher than that estimated from RCTs, LRTI in preterm infants, might decrease later recurrent
but these data are difficult to interpret because of lack wheezing.203 A cohort of 191 preterm infants who had
of controls. received palivizumab and were not hospitalized for RSV
Palivizumab is administered monthly during RSV was compared to 230 preterm infants who never received
season as an IM dose of 15 mg/kg. The AAP recommends palivizumab (76 who were hospitalized for RSV and 154
that RSV prophylaxis be considered in the following who were not). These infants were prospectively followed
groups199: for 24 months beginning at a mean age of 19 months.
The incidences of recurrent wheezing and physician-
1. Infants with chronic lung disease who are younger diagnosed recurrent wheezing were approximately 50%
than 24 months of age and have received medical lower in the palivizumab-treated subjects compared with
therapy for BPD within 6 months of the onset of RSV all untreated subjects and with the 154 patients in the
season may benefit from monthly dosing beginning subgroup not hospitalized for RSV LRTI, suggesting
in the 1st month of RSV season for a total of five that preventing RSV LRTI with palivizumab may
doses. reduce subsequent recurrent wheezing in premature
2. Infants born before 28 weeks of gestation may benefit infants. This study needs to be independently repeated
from monthly dosing beginning in the 1st month of and confirmed in larger samples including full-term born
RSV season for a total of five doses. infants in double-blind protocols before a formal recom-
3. Infants born between 29 and 32 weeks gestation and mendation can be made concerning large-scale RSV
who are less than 6 months of age at the onset of RSV prophylaxis to reduce the incidence of post-viral wheeze
season may benefit from monthly dosing beginning in childhood.
in the 1st month of RSV season for a total of five
doses. Motavizumab
4. Infants born between 32 and 35 weeks gestation who The most important limitations of palivizumab derive
are younger than 3 months of age at the onset of RSV from its intrinsic potency and recommended dosage. Early
season or who are born during RSV season and who studies in cotton rats indicated that a mean 99% reduction
attend day care or have a sibling aged <5 years may in pulmonary RSV titer requires 25–30 mg/ml serum level
benefit from monthly doses until they reach 3 months of palivizumab, and levels above 40 mg/ml are necessary to
of age. The maximum number of doses for this achieve 99% reduction in all animals. Therefore, in order
category is 3, with many receiving only one or two to provide optimal protection, palivizumab should be
doses. dosed to maintain trough levels 40 mg/ml and above. Data
5. Infants with congenital anomalies of the airway who from the IMpact-RSV trial indicated that using 15 mg/kg
are less than 1-year old may benefit from monthly 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 infants received monthly motavizumab IM injections.
were below 30 mg/ml. Subsequently, the mean trough During the second season, the infants were randomized to
level increased after each monthly injection because receive motavizumab (n ¼ 66) or palivizumab (n ¼ 70).
of progressive accumulation. This pharmacokinetic Serum trough levels were similar for both monoclonals,
data explain why almost half of all breakthrough RSV with a circulation T1/2 of 3–4 weeks. Adverse effects
hospitalizations in palivizumab-treated patients occur included erythema at the injection site (n ¼ 16), hypo-
after the first injection, and more than 70% after the chromic anemia (n ¼ 2), and elevated serum glutamic
first two. Another issue is that, at the recommended oxaloacetic transaminase (n ¼ 1). No serious drug-related
dosage, palivizumab levels in the nasal mucosa are not adverse reactions were reported.
protective, and therefore palivizumab does not prevent A Phase III, multicenter, randomized, double-blind
RSV infection, but rather reduces its spread to the lower trial was conducted to assess the safety and efficacy of
airways. motavizumab as compared to palivizumab.208 Of the
Palivizumab shortcomings could be fixed with a more 6,635 infants enrolled and followed for 150 days, 3,329
potent antibody. This led to the development of motavi- received motavizumab 15 mg/kg IM monthly and 3,326
zumab, a second-generation IgG1 monoclonal antibody received palivizumab 15 mg/kg IM monthly. Motavizu-
with increased anti-RSV activity. In vitro studies of mab was found to be non-inferior, and reduced RSV-
palivizumab variants identified a clearly superior anti- related hospitalizations by 26% over palivizumab. The
body, A4b4, with 44-fold greater activity against RSV rate of RSVattacks for motavizumab was 1.4%, compared
than palivizumab.204 Subsequent in vivo studies, however, to 1.9% for palivizumab and the rate of medically attended
were disappointing, as the new antibody had only a outpatients was reduced by 50% (1.9% for motavizumab
twofold increase in potency when administered prophy- vs. 3.9% for palivizumab).
lactically to cotton rats.205 Further analysis revealed that Due to its higher potency, motavizumab, whose official
the diminished activity was the result of broad tissue trade name will be RezieldTM, holds several promises for
binding which decreased lung bioavailability. The the future. In particular, it should be able to protect the
increased tissue binding was attributed to three amino mucosa of the upper respiratory tract, thereby preventing
acid residues that were altered from palivizumab. the infection rather than limiting its spread to the lower
Reversion of these back to the original amino acids respiratory tract. This property could add important
restored lung bioavailability and produced the final form benefits, such as the prevention of viral otitis media, and
of motavizumab.205 perhaps reduce the frequency and/or severity of post-viral
While the structure of motavizumab differs from wheeze.
palivizumab by only 13 amino acids, it has a 70-fold In June 2010, the Advisory Committee to the US FDA
higher affinity for the RSV F protein, and at equivalent voted not to recommend approval of motavizumab. This
concentrations yields up to a 100-fold greater activity decision was justified primarily with the questionable
against RSV.206 In addition, motavizumab inhibits RSV evidence that motavizumab provides additional benefit in
replication in the upper respiratory tract of cotton rats, comparison to palivizumab and with concerns about the
whereas palivizumab does not.206 Finally, motavizumab is rare (2–3%) but statistically significant increase in serious
fully humanized, whereas the palivizumab antibody frame adverse events involving the skin of infants injected with
still contains a few murine-derived sequences. motavizumab. Thus, although the Advisory Committee
A Phase I/II open-label, dose-escalation trial was recommendation is not final and the manufacturer
conducted to evaluate safety and pharmacokinetics (MedImmune, Inc., Gaithersburg, MD) will continue to
of monthly IM injections in infants.207 The study included work with the FDA and attempt to address the concerns
preterm infants (32–35 weeks gestation) who were outlined above, the future of this new antibody appears
<6 months and infants with BPD who were <2 years. uncertain.
The preterm infants received doses of 3 or 15 mg/kg, while
the BPD infants were all dosed with 15 mg/kg. Infants in
Section Summary
both groups received monthly injections for 2–5 months
and were followed for 150 days. The 15 mg/kg dosing . Hand washing and isolation are highly effective in
produced serum trough levels similar to those of reducing the spread of RSV infection.
palivizumab. . Palivizumab is a humanized monoclonal antibody
These results were confirmed by a recent Phase I/II, recommended for the prophylaxis of infants at high
randomized, double-blind, multicenter center study of risk for severe RSV disease.
motavizumab and palivizumab conducted in the United . Motavizumab is a next-generation humanized mono-
States, Chile, and Brazil.206 One hundred thirty-six high- clonal antibody with improved in vitro activity
risk infants <2 years of age were included and followed against RSV, currently undergoing FDA evaluation
over two consecutive RSV seasons. In the first season, the for licensing in the US.
Pediatric Pulmonology
RSV Prevention and Therapy 341

CONCLUSIONS low-cost option to improve mucociliary clearance in these


patients, whereas very expensive mucolytic therapy with
RSV is the most frequent cause of bronchiolitis and
DNAse has not provided consistent results. Exogenous
pneumonia in infants and young children, and a source of
surfactant, Heliox, and leukotriene modifiers may also
significant morbidity, mortality, and financial burden
provide some clinical benefit, but the evidence for or
worldwide. It is an RNA virus of the Paramyxoviridae
against their use is not definitive.
family whose two surface G proteins are the major
Hand washing and isolation are highly effective in
antigens and are critical for virulence. The two antigenic
preventing the spread of RSV infection. The humanized
variants, A and B, are usually both present during the
monoclonal antibody palivizumab is a safe and effective
seasonal outbreaks, which vary from year to year and
option for passive RSV prophylaxis, but its use is currently
depend on the geographical area. Nearly all children have
limited to infants at high risk for severe disease due to the
been infected with this virus at least once by the time they
high costs. Motavizumab is a next-generation humanized
are 2 years of age, resulting in about 24 hospitalizations
monoclonal antibody with improved activity against RSV
per 1,000 infants and up to 1 million deaths worldwide
currently undergoing FDA evaluation for licensing in the
each year. Previous infections do not convey persistent
US. The hope for the future is active prophylaxis of all
immunity, and reinfection is common.
infants with a safe and effective RSV vaccine, which not
Transmission occurs through inoculation of the naso-
only would protect against the most common respiratory
pharyngeal or conjunctival mucosa with respiratory
disease of childhood, but may also prevent frequent long-
secretions from infected individuals. Viral shedding
term sequelae like post-RSV wheezing and asthma.
persists for approximately 1 week, but can be significantly
more prolonged in immunocompromised individuals. REFERENCES
Viral replication begins in the nasal mucosa and spreads
1. Eberle J. A treatise on the diseases and physical education of
downward through the respiratory tract, producing edema children. Philadelphia: Lippincott, Grambo and Co; 1850. 548 p.
and necrosis of the respiratory epithelium, and resulting 2. Adams JM. Primary virus pneumonitis with cytoplasmic
in airflow obstruction. The inflammatory response asso- inclusion bodies. JAMA 1941;116:925–933.
ciated with this infection is extremely complex and 3. Adams JM, Green RG, Evans CA. Primary viral pneumonitis: a
involves the release of multiple cytokines and chemokines comparative study of two epidemics. J Pediatr 1942;20:405–
420.
from epithelium and infiltrating immunocytes, local 4. Blount RE, Jr., Morris JA, Savage RE. Recovery of cytopatho-
neuro-immune interactions, and mast cells degranulation genic agent from chimpanzees with coryza. Proc Soc Exp Biol
with variable release of leukotrienes. Med 1956;92:544–549.
Infants with RSV infection typically present with upper 5. Chanock R, Roizman B, Myers R. Recovery from infants with
respiratory symptoms that frequently progress to involve respiratory illness of a virus related to chimpanzee coryza agent
(CCA). I. Isolation, properties and characterization. Am J Hyg
the lower respiratory tract with cough, wheeze, and 1957;66:281–290.
increased work of breathing. Chest radiographs typically 6. Chanock R, Finberg L. Recovery from infants with respiratory
show hyperinflation, patchy infiltrates, and atelectasis. illness of a virus related to chimpanzee coryza agent (CCA). II.
Apnea is frequently the presenting manifestation, espe- Epidemiologic aspects of infection in infants and young children.
cially in young infants. Supportive care is the mainstay Am J Hyg 1957;66:291–300.
7. Chanock RM, Kim HW, Vargosko AJ, Deleva A, Johnson KM,
of therapy for RSV disease and is directed at ensuring Cumming C, Parrott RH. Respiratory syncytial virus. I. Virus
adequate oxygenation, improving respiratory toilet, and recovery and other observations during 1960 outbreak of
meeting fluid and nutrition requirements. Severe respira- bronchiolitis, pneumonia, and minor respiratory diseases in
tory failure requires mechanical ventilatory support, and children. JAMA 1961;176:647–653.
occasionally HFOV or ECMO. 8. Parrott RH, Vargosko AJ, Kim HW, Cumming C, Turner H,
Huebner RJ, Chanock RM. Respiratory syncytial virus. II.
Adrenergic a- and b-agonists do not provide consistent Serologic studies over a 34-month period of children with
benefit in the treatment of RSV disease, although a brief bronchiolitis, pneumonia, and minor respiratory diseases. JAMA
trial with objective evaluation of the response may be 1961;176:653–657.
warranted. Neither systemic nor inhaled corticosteroids 9. Johnson KM, Chanock RM, Rifkind D, Kravetz HM, Knight V.
have been shown to provide clear advantages in the Respiratory syncytial virus. IV. Correlation of virus shedding,
serologic response, and illness in adult volunteers. JAMA 1961;
treatment of RSV disease, and therefore their use is not 176:663–667.
recommended. The antiviral drug ribavirin is also not 10. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart
recommended for routine treatment of RSV infection, CE. An epidemiologic study of altered clinical reactivity to
but may be considered in select immunocompromised respiratory syncytial (RS) virus infection in children previously
individuals. Antibiotics are recommended only in the vaccinated with an inactivated RS virus vaccine. Am J Epidemiol
1969;89:405–421.
presence of specific evidence of coexistent bacterial 11. Prince GA, Jenson AB, Horswood RL, Camargo E, Chanock
infection. Nebulized treatments with hypertonic saline RM. The pathogenesis of respiratory syncytial virus infection in
have been shown to reduce LOS and may offer an effective cotton rats. Am J Pathol 1978;93:771–791.

Pediatric Pulmonology
342 Wright and Piedimonte

12. Peters TR, Crowe JE, Jr. Respiratory syncytial virus. In: Long Pediatric Investigators Collaborative Network on Infections
SS, editor. Principles and practice of pediatric infectious in Canada (PICNIC) study of admission and management
diseases, 3rd edition. Philadelphia, PA: Churchill Livingstone; variation in patients hospitalized with respiratory syncytial viral
2008. 1112–1117. lower respiratory tract infection. J Pediatr 1996;129:390–395.
13. Anderson LJ, Hierholzer JC, Tsou C, Hendry RM, Fernie BF, 31. Navas L, Wang E, de Carvalho V, Robinson J. Improved outcome
Stone Y, McIntosh K. Antigenic characterization of respiratory of respiratory syncytial virus infection in a high-risk hospitalized
syncytial virus strains with monoclonal antibodies. J Infect Dis population of Canadian children. Pediatric Investigators Collab-
1985;151:626–633. orative Network on Infections in Canada. J Pediatr 1992;121:
14. Mufson MA, Orvell C, Rafnar B, Norrby E. Two distinct 348–354.
subtypes of human respiratory syncytial virus. J Gen Virol 32. King JC, Jr., Burke AR, Clemens JD, Nair P, Farley JJ, Vink PE,
1985;66:2111–2124. Batlas SR, Rao M, Johnson JP. Respiratory syncytial virus
15. Hall CB, Walsh EE, Schnabel KC, Long CE, McConnochie KM, illnesses in human immunodeficiency virus- and noninfected
Hildreth SW, Anderson LJ. Occurrence of groups A and B of children. Pediatr Infect Dis J 1993;12:733–739.
respiratory syncytial virus over 15 years: associated epidemio- 33. Milner ME, de la Monte SM, Hutchins GM. Fatal respiratory
logic and clinical characteristics in hospitalized and ambulatory syncytial virus infection in severe combined immunodeficiency
children. J Infect Dis 1990;162:1283–1290. syndrome. Am J Dis Child 1985;139:1111–1114.
16. McConnochie KM, Hall CB, Walsh EE, Roghmann KJ. 34. Hall CB, Powell KR, MacDonald NE, Gala CL, Menegus ME,
Variation in severity of respiratory syncytial virus infections Suffin SC, Cohen HJ. Respiratory syncytial viral infection in
with subtype. J Pediatr 1990;117:52–62. children with compromised immune function. N Engl J Med
17. Papadopoulos NG, Gourgiotis D, Javadyan A, Bossios A, Kallergi 1986;315:77–81.
K, Psarras S, Tsolia MN, Kafetzis D. Does respiratory syncytial 35. Simões EA. Maternal smoking, asthma, and bronchiolitis: clear-cut
virus subtype influences the severity of acute bronchiolitis in association or equivocal evidence? Pediatrics 2007;119:1210–
hospitalized infants? Respir Med 2004;98:879–882. 1212.
18. Walsh EE, McConnochie KM, Long CE, Hall CB. Severity of 36. Howard TS, Hoffman LH, Stang PE, Simoes EA. Respiratory
respiratory syncytial virus infection is related to virus strain. J syncytial virus pneumonia in the hospital setting: length of stay,
Infect Dis 1997;175:814–820. charges, and mortality. J Pediatr 2000;137:227–232.
19. Gilca R, De Serres G, Tremblay M, Vachon ML, Leblanc E, 37. Simoes EA. Respiratory syncytial virus and subsequent lower
Bergeron MG, Dery P, Boivin G. Distribution and clinical impact respiratory tract infections in developing countries: a new twist
of human respiratory syncytial virus genotypes in hospitalized to an old virus. J Pediatr 1999;135:657–661.
children over 2 winter seasons. J Infect Dis 2006;193:54–58. 38. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N,
20. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ, Fukuda K. Mortality associated with influenza and
Anderson LJ. Bronchiolitis-associated hospitalizations among respiratory syncytial virus in the United States. JAMA 2003;
US children, 1980–1996. JAMA 1999;282:1440–1446. 289:179–186.
21. Gilchrist S, Torok TJ, Gary HE, Jr., Alexander JP, Anderson LJ. 39. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ.
National surveillance for respiratory syncytial virus, United Bronchiolitis-associated mortality and estimates of respiratory
States, 1985–1990. J Infect Dis 1994;170:986–990. syncytial virus-associated deaths among US children, 1979–
22. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary 1997. J Infect Dis 2001;183:16–22.
infection and reinfection with respiratory syncytial virus. Am J 40. Leader S, Kohlhase K. Recent trends in severe respiratory
Dis Child 1986;140:543–546. syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr
23. Subcommittee on Diagnosis and Management of Bronchiolitis. 2003;143:S127–S132.
Diagnosis and management of bronchiolitis. Pediatrics 2006; 41. Stang P, Brandenburg N, Carter B. The economic burden of
118:1774–1793. respiratory syncytial virus-associated bronchiolitis hospitaliza-
24. Leader S, Kohlhase K. Respiratory syncytial virus-coded tions. Arch Pediatr Adolesc Med 2001;155:95–96.
pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J 42. Falsey AR, Walsh EE. Respiratory syncytial virus infection in
2002;21:629–632. adults. Clin Microbiol Rev 2000;13:371–384.
25. Sung RY, Murray HG, Chan RC, Davies DP, French GL. 43. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE.
Seasonal patterns of respiratory syncytial virus infection in Hong Respiratory syncytial virus infection in elderly and high-risk
Kong: a preliminary report. J Infect Dis 1987;156:527–528. adults. N Engl J Med 2005;352:1749–1759.
26. Venkatesh MP, Weisman LE. Prevention and treatment of 44. Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and
respiratory syncytial virus infection in infants: an update. Expert frequency of reinfection with respiratory syncytial virus. J Infect
Rev Vaccines 2006;5:261–268. Dis 1991;163:693–698.
27. Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. 45. Henderson FW, Collier AM, Clyde WA, Jr., Denny FW.
Development of the immune system in very low birth weight Respiratory-syncytial-virus infections, reinfections and immun-
(less than 1500 g) premature infants: concentrations of plasma ity. A prospective, longitudinal study in young children. N Engl J
immunoglobulins and patterns of infections. Pediatr Res 1986; Med 1979;300:530–534.
20:899–904. 46. Hall CB, Long CE, Schnabel KC. Respiratory syncytial virus
28. Walsh EE, Peterson DR, Falsey AR. Risk factors for severe infections in previously healthy working adults. Clin Infect Dis
respiratory syncytial virus infection in elderly persons. J Infect 2001;33:792–796.
Dis 2004;189:233–238. 47. Sims DG, Downham MA, Gardner PS, Webb JK, Weightman D.
29. Boyce TG, Mellen BG, Mitchel EF, Jr., Wright PF, Griffin MR. Study of 8-year-old children with a history of respiratory
Rates of hospitalization for respiratory syncytial virus infection syncytial virus bronchiolitis in infancy. Br Med J 1978;1:11–14.
among children in Medicaid. J Pediatr 2000;137:865–870. 48. McConnochie KM, Roghmann KJ. Bronchiolitis as a possible
30. Wang EE, Law BJ, Boucher FD, Stephens D, Robinson JL, cause of wheezing in childhood: new evidence. Pediatrics 1984;
Dobson S, Langley JM, McDonald J, MacDonald NE, Mitchell I. 74:1–10.

Pediatric Pulmonology
RSV Prevention and Therapy 343

49. Mok JY, Simpson H. Outcome for acute bronchitis, bronchiolitis, 69. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM,
and pneumonia in infancy. Arch Dis Child 1984;59:306–309. Jensen K, Parrott RH. Respiratory syncytial virus disease in
50. Murray M, Webb MS, O’Callaghan C, Swarbrick AS, Milner infants despite prior administration of antigenic inactivated
AD. Respiratory status and allergy after bronchiolitis. Arch Dis vaccine. Am J Epidemiol 1969;89:422–434.
Child 1992;67:482–487. 70. Chin J, Magoffin RL, Shearer LA, Schieble JH, Lennette EH.
51. Osundwa VM, Dawod ST, Ehlayel M. Recurrent wheezing in Field evaluation of a respiratory syncytial virus vaccine and a
children with respiratory syncytial virus (RSV) bronchiolitis in trivalent parainfluenza virus vaccine in a pediatric population.
Qatar. Eur J Pediatr 1993;152:1001–1003. Am J Epidemiol 1969;89:449–463.
52. Noble V, Murray M, Webb MS, Alexander J, Swarbrick AS, 71. Legg JP, Hussain IR, Warner JA, Johnston SL, Warner JO. Type 1
Milner AD. Respiratory status and allergy nine to 10 years after and type 2 cytokine imbalance in acute respiratory syncytial
acute bronchiolitis. Arch Dis Child 1997;76:315–319. virus bronchiolitis. Am J Respir Crit Care Med 2003;168:633–
53. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, 639.
Taussig LM, Wright AL, Martinez FD. Respiratory syncytial 72. Aung S, Rutigliano JA, Graham BS. Alternative mechanisms of
virus in early life and risk of wheeze and allergy by age 13 years. respiratory syncytial virus clearance in perforin knockout mice
Lancet 1999;354:541–545. lead to enhanced disease. J Virol 2001;75:9918–9924.
54. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respira- 73. Glezen WP, Paredes A, Allison JE, Taber LH, Frank AL. Risk of
tory syncytial virus bronchiolitis in infancy is an important risk respiratory syncytial virus infection for infants from low-income
factor for asthma and allergy at age 7. Am J Respir Crit Care families in relationship to age, sex, ethnic group, and maternal
Med 2000;161:1501–1507. antibody level. J Pediatr 1981;98:708–715.
55. Simões EA, Carbonell-Estrany X, Rieger CH, Mitchell I, 74. Stensballe LG, Ravn H, Kristensen K, Agerskov K, Meakins T,
Fredrick L, Groothuis JR. The effect of respiratory syncytial Aaby P, Simoes EA. Respiratory syncytial virus neutralizing
virus on subsequent recurrent wheezing in atopic and nonatopic antibodies in cord blood, respiratory syncytial virus hospital-
children. J Allergy Clin Immunol 2010;126:256–262. ization, and recurrent wheeze. J Allergy Clin Immunol 2009;
56. Hall CB, Douglas RG, Jr., Geiman JM. Quantitative shedding 123:398–403.
patterns of respiratory syncytial virus in infants. J Infect Dis 75. The PREVENT Study Group. Reduction of respiratory syncytial
1975;132:151–156. virus hospitalization among premature infants and infants with
57. Hall CB, Douglas RG, Jr. Modes of transmission of respiratory bronchopulmonary dysplasia using respiratory syncytial virus
syncytial virus. J Pediatr 1981;99:100–103. immune globulin prophylaxis. Pediatrics 1997;99:93–99.
58. Hall CB, Douglas RG, Jr., Schnabel KC, Geiman JM. Infectivity 76. Committee on Infectious Diseases and Committee of Fetus and
of respiratory syncytial virus by various routes of inoculation. Newborn. Prevention of respiratory syncytial virus infections:
Infect Immune 1981;33:779–783. indications for the use of palivizumab and update on the use of
59. Hall CB, Douglas RG, Jr., Geiman JM. Possible transmission by RSV-IGIV. Pediatrics 1998;102:1211–1216.
fomites of respiratory syncytial virus. J Infect Dis 1980;141:98– 77. Chandwani S, Borkowsky W, Krasinski K, Lawrence R, Welliver
102. R. Respiratory syncytial virus infection in human immunodefi-
60. Othumpangat S, Gibson L, Samsell L, Piedimonte G. NGF is an ciency virus-infected children. J Pediatr 1990;117:251–254.
essential survival factor for bronchial epithelial cells during 78. Welliver TP, Garofalo RP, Hosakote Y, Hintz KH, Avendano L,
respiratory syncytial virus infection. PLoS ONE 2009;4:e6444. Sanchez K, Velozo L, Jafri H, Chavez-Bueno S, Ogra PL,
61. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. McKinney L, Reed JL, Welliver RC, Sr. Severe human lower
The histopathology of fatal untreated human respiratory respiratory tract illness caused by respiratory syncytial virus and
syncytial virus infection. Mod Pathol 2007;20:108–119. influenza virus is characterized by the absence of pulmonary
62. Hoffman SJ, Laham FR, Polack FP. Mechanisms of illness cytotoxic lymphocyte responses. J Infect Dis 2007;195:1126–
during respiratory syncytial virus infection: the lungs, the virus 1136.
and the immune response. Microbes Infect 2004;6:767–772. 79. Hu C, Wedde-Beer K, Auais A, Rodriguez MM, Piedimonte G.
63. Domurat F, Roberts NJ, Jr., Walsh EE, Dagan R. Respiratory Nerve growth factor and nerve growth factor receptors in
syncytial virus infection of human mononuclear leukocytes in respiratory syncytial virus-infected lungs. Am J Physiol Lung
vitro and in vivo. J Infect Dis 1985;152:895–902. Cell Mol Physiol 2002;283:L494–L502.
64. Panuska JR, Hertz MI, Taraf H, Villani A, Cirino NM. 80. Tortorolo L, Langer A, Polidori G, Vento G, Stampachiacchere
Respiratory syncytial virus infection of alveolar macrophages B, Aloe L, Piedimonte G. Neurotrophins overexpression in lower
in adult transplant patients. Am Rev Respir Dis 1992;145:934– airways of infants with respiratory syncytial virus infection. Am
939. J Respir Crit Care Med 2005;172:233–237.
65. Krilov LR, Hendry RM, Godfrey E, McIntosh K. Respiratory 81. Renz H. Neurotrophins in bronchial asthma. Respir Res
virus infection of peripheral blood monocytes: correlation with 2001;2:265–268.
ageing of cells and interferon production in vitro. J Gen Virol 82. Urrego F, Scuri M, Auais A, Mothasham L, Piedimonte G.
1987;68:1749–1753. Combined effects of chronic nicotine and acute virus exposure
66. Englund JA, Sullivan CJ, Jordan MC, Dehner LP, Vercellotti on neurotrophin expression in rat lung. Pediatr Pulmonol 2009;
GM, Balfour HH, Jr. Respiratory syncytial virus infection in 44:1075–1084.
immunocompromised adults. Ann Intern Med 1988;109:203– 83. Leon A, Buriani A, Dal Toso R, Fabris M, Romanello S, Aloe L,
208. Levi-Montalcini R. Mast cells synthesize, store, and release
67. Padman R, Bye MR, Schidlow DV, Zaeri N, Severe RSV nerve growth factor. Proc Nat Acad Sci USA 1994;91:3739–
bronchiolitis in an immunocompromised child. Clin Pediatr 3743.
(Phila) 1985;24:719–721. 84. Nilsson G, Forsberg-Nilsson K, Xiang Z, Hallbook F, Nilsson K,
68. Aherne W, Bird T, Court SD, Gardner PS, McQuillin J. Metcalfe D. Human mast cells express functional TrkA and are a
Pathological changes in virus infections of the lower respiratory source of nerve growth factor. Eur J Immunol 1997;27:2295–
tract in children. J Clin Pathol 1970;23:7–18. 2301.

Pediatric Pulmonology
344 Wright and Piedimonte

85. Ehrhard P, Erb P, Graumann U, Otten U. Expression of nerve 102. Friis B, Eiken M, Hornsleth A, Jensen A. Chest X-ray
growth factor and nerve growth factor receptor tyrosine kinase appearances in pneumonia and bronchiolitis. Correlation to
Trk in activated CD4-positive T-cell clones. Proc Nat Acad Sci virological diagnosis and secretory bacterial findings. Acta
USA 1993;90:10984–10988. Paediatr Scand 1990;79:219–225.
86. Braun A, Lommatzsch M, Lewin GR, Virchow JC, Renz H. 103. Kim HW, Arrobio JO, Brandt CD, Jeffries BC, Pyles G, Reid JL,
Neurotrophins: a link between airway inflammation and airway Chanock RM, Parrott RH. Epidemiology of respiratory syncytial
smooth muscle contractility in asthma. Int Arch Allergy virus infection in Washington, D.C. I. Importance of the virus in
Immunol 1999;118:163–165. different respiratory tract disease syndromes and temporal
87. Auais A, Adkins B, Napchan G, Piedimonte G. Immuno- distribution of infection. Am J Epidemiol 1973;98:216–225.
modulatory effects of sensory nerves during respiratory syncytial 104. Walsh EE, Falsey AR, Hennessey PA. Respiratory syncytial and
virus infection in rats. Am J Physiol Lung Cell Mol Physiol other virus infections in persons with chronic cardiopulmonary
2003;285:L105–L113. disease. Am J Respir Crit Care Med 1999;160:791–795.
88. Mothasham L, Auais A, Piedimonte G. Nerve growth factor 105. Bruhn FW, Mokrohisky ST, McIntosh K. Apnea associated with
mediates steroid-resistant inflammation in respiratory syncytial respiratory syncytial virus infection in young infants. J Pediatr
virus infection. Pediatr Pulmonol 2007;42:496–504. 1977;90:382–386.
89. Wedde-Beer K, Hu C, Rodriguez MM, Piedimonte G. Leuko- 106. Church NR, Anas NG, Hall CB, Brooks JG. Respiratory
trienes mediate neurogenic inflammation in lungs of young rats syncytial virus-related apnea in infants. Demographics and
infected with respiratory syncytial virus. Am J Physiol Lung Cell outcome. Am J Dis Child 1984;138:247–250.
Mol Physiol 2002;282:L1143–L1150. 107. Hall CB, Hall WJ, Speers DM. Clinical and physiological
90. Bauer O, Razin E. Mast cell–nerve interactions. News Physiol manifestations of bronchiolitis and pneumonia. Outcome of
Sci 2000;15:213–218. respiratory syncytial virus. Am J Dis Child 1979;133:798–802.
91. van Schaik SM, Tristram DA, Nagpal IS, Hintz KM, Welliver 108. Anas N, Boettrich C, Hall CB, Brooks JG. The association of
RCI, Welliver RC. Increased production of IFN-gamma and apnea and respiratory syncytial virus infection in infants. J
cysteinyl leukotrienes in virus-induced wheezing. J Allergy Clin Pediatr 1982;101:65–68.
Immunol 1999;103:630–636. 109. Kneyber MC, Brandenburg AH, de Groot R, Joosten KF, Rothbarth
92. Volovitz B, Welliver RC, De Castro G, Krystofik D, Ogra PL. PH, Ott A, Moll HA. Risk factors for respiratory syncytial virus
The release of leukotrienes in the respiratory tract during associated apnoea. Eur J Pediatr 1998;157:331–335.
infection with respiratory syncytial virus: role in obstructive 110. Willwerth BM, Harper MB, Greenes DS. Identifying hospi-
airway disease. Pediatr Res 1988;24:504–507. talized infants who have bronchiolitis and are at high risk for
93. Piedimonte G, Renzetti G, Di Marco A, Auais A, Tripodi S, apnea. Ann Emerg Med 2006;48:441–447.
Colistro F, Villani A, Di Ciommo A, Cutrera R. Leukotriene 111. Rayyan M, Naulaers G, Daniels H, Allegaert K, Debeer A,
synthesis during respiratory syncytial virus bronchiolitis: Devlieger H. Characteristics of respiratory syncytial virus-
influence of age and atopy. Pediatr Pulmonol 2005;40:285–291. related apnoea in three infants. Acta Paediatr 2004;93:847–849.
94. Bisgaard H. A randomized trial of montelukast in respiratory 112. Sabogal C, Auais A, Napchan G, Suguihara C, Bancalari E,
syncytial virus postbronchiolitis. Am J Respir Crit Care Med Piedimonte G. Effect of respiratory syncytial virus on apnea in
2003;167:379–383. weanling rats. Pediatr Res 2005;57:819–825.
95. Hall WJ, Hall CB, Speers DM. Respiratory syncytial virus 113. Perrotta C, Ortiz Z, Roque M. Chest physiotherapy for acute
infection in adults: clinical, virologic, and serial pulmonary bronchiolitis in paediatric patients between 0 and 24 months old.
function studies. Ann Intern Med 1978;88:203–205. Cochrane Database Syst Rev 2007; (1): CD004873.
96. Aujard Y, Fauroux B. Risk factors for severe respiratory 114. Downes JJ, Wood DW, Striker TW, Haddad C. Acute respiratory
syncytial virus infection in infants. Respir Med 2002;96:S9– failure in infants with bronchiolitis. Anesthesiology 1968;29:426–
S14. 434.
97. Welliver RC. Review of epidemiology and clinical risk factors 115. Mansbach JM, McAdam AJ, Clark S, Hain PD, Flood RG,
for severe respiratory syncytial virus (RSV) infection. J Pediatr Acholonu U, Camargo CA, Jr. Prospective multicenter study of
2003;143:S112–S117. the viral etiology of bronchiolitis in the emergency department.
98. Finger R, Anderson LJ, Dicker RC, Harrison B, Doan R, Acad Emerg Med 2008;15:111–118.
Downing A, Corey L. Epidemic infections caused by respiratory 116. Stempel HE, Martin ET, Kuypers J, Englund JA, Zerr DM.
syncytial virus in institutionalized young adults. J Infect Dis Multiple viral respiratory pathogens in children with bronchio-
1987;155:1335–1339. litis. Acta Paediatr 2009;98:123–126.
99. Parrott RH, Kim HW, Arrobio JO, Hodes DS, Murphy BR, 117. Midulla F, Scagnolari C, Bonci E, Pierangeli A, Antonelli G, De
Brandt CD, Camargo E, Chanock RM. Epidemiology of Angelis D, Berardi R, Moretti C. Respiratory syncytial virus,
respiratory syncytial virus infection in Washington, D.C. II. human bocavirus and rhinovirus bronchiolitis in infants. Arch
Infection and disease with respect to age, immunologic status, Dis Child 2010;95:35–41.
race and sex. Am J Epidemiol 1973;98:289–300. 118. Miron D, Srugo I, Kra-Oz Z, Keness Y, Wolf D, Amirav I, Kassis
100. Simpson W, Hacking PM, Court SD, Gardner PS. The I. Sole pathogen in acute bronchiolitis: is there a role for other
radiological findings in respiratory syncytial virus infection in organisms apart from respiratory syncytial virus? Pediatr Infect
children. II. The correlation of radiological categories with Dis J 2010;29:e7–e10.
clinical and virological findings. Pediatr Radiol 1974;2:155– 119. Flores G, Horwitz RI. Efficacy of beta2-agonists in bronchiolitis:
160. a reappraisal and meta-analysis. Pediatrics 1997;100:233–239.
101. Simpson W, Hacking PM, Court SD, Gardner PS. The 120. Gadomski AM, Bhasale AL. Bronchodilators for bronchiolitis.
radiological findings in respiratory syncytial virus infection in Cochrane Database Syst Rev 2006;3: CD001266.
children. Part I. Definitions and interobserver variation in the 121. Auais A, Wedde-Beer K, Piedimonte G. Anti-inflammatory
assessment of abnormalities on the chest X-ray. Pediatr Radiol effect of albuterol enantiomers during respiratory syncytial virus
1974;2:97–100. infection in rats. Pediatr Pulmonol 2005;40:228–234.

Pediatric Pulmonology
RSV Prevention and Therapy 345

122. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. receiving mechanical ventilation for severe respiratory syncytial
Epinephrine for bronchiolitis. Cochrane Database Syst Rev virus infection. N Engl J Med 1991;325:24–29.
2004;(1):CD003123. 139. Guerguerian AM, Gauthier M, Lebel MH, Farrell CA, Lacroix J.
123. Wang EE, Milner R, Allen U, Maj H. Bronchodilators for Ribavirin in ventilated respiratory syncytial virus bronchiolitis.
treatment of mild bronchiolitis: a factorial randomised trial. Arch A randomized, placebo-controlled trial. Am J Respir Crit Care
Dis Child 1992;67:289–293. Med 1999;160:829–834.
124. Schuh S, Johnson D, Canny G, Reisman J, Shields M, Kovesi T, 140. Meert KL, Sarnaik AP, Gelmini MJ, Lieh-Lai MW. Aerosolized
Kerem E, Bentur L, Levison H, Jaffe D. Efficacy of adding ribavirin in mechanically ventilated children with respiratory
nebulized ipratropium bromide to nebulized albuterol therapy in syncytial virus lower respiratory tract disease: a prospective,
acute bronchiolitis. Pediatrics 1992;90:920–923. double-blind, randomized trial. Crit Care Med 1994;22:566–572.
125. Chowdhury D, al Howasi M, Khalil M, al-Frayh AS, Chowdhury 141. Taber LH, Knight V, Gilbert BE, McClung HW, Wilson SZ,
S, Ramia S. The role of bronchodilators in the management of Norton HJ, Thurson JM, Gordon WH, Atmar RL, Schlaudt WR.
bronchiolitis: a clinical trial. Ann Trop Paediatr 1995;15:77–84. Ribavirin aerosol treatment of bronchiolitis associated with
126. Karadag B, Ceran O, Guven G, Dursun E, Ipek IO, Karakoc F, respiratory syncytial virus infection in infants. Pediatrics 1983;
Ersu RH, Bozaykut A, Inan S, Dagli E. Efficacy of salbutamol 72:613–618.
and ipratropium bromide in the management of acute bronchio- 142. Everard ML, Swarbrick A, Rigby AS, Milner AD. The effect of
litis—a clinical trial. Respiration 2008;76:283–287. ribavirin to treat previously healthy infants admitted with acute
127. Patel H, Platt R, Lozano JM, Wang EE. Glucocorticoids for acute bronchiolitis on acute and chronic respiratory morbidity. Respir
viral bronchiolitis in infants and young children. Cochrane Med 2001;95:275–280.
Database Syst Rev 2004; (3): CD004878. 143. Ventre K, Randolph A. Ribavirin for respiratory syncytial virus
128. Teeratakulpisarn J, Limwattananon C, Tanupattarachai S, infection of the lower respiratory tract in infants and young
Limwattananon S, Teeratakulpisarn S, Kosalaraksa P. Efficacy children. Cochrane Database Syst Rev 2007; (1): CD000181.
of dexamethasone injection for acute bronchiolitis in hospi- 144. Kabir ML, Haq N, Hoque M, Ahmed F, Amin R, Hossain A,
talized children: a randomized, double-blind, placebo-controlled Khatoon S, Akhter S, Shilpi T, Haq R, Anisuzzaman S, Khan
trial. Pediatr Pulmonol 2007;42:433–439. MH, Ahamed S, Khashru A. Evaluation of hospitalized infants
129. Corneli HM, Zorc JJ, Majahan P, Shaw KN, Holubkov R, Reeves and young children with bronchiolitis—a multi centre study.
SD, Ruddy RM, Malik B, Nelson KA, Bregstein JS, Brown KM, Mymensingh Med J 2003;12:128–133.
Denenberg MN, Lillis KA, Cimpello LB, Tsung JW, Borgialli 145. Vogel AM, Lennon DR, Harding JE, Pinnock RE, Graham DA,
DA, Baskin MN, Teshome G, Goldstein MA, Monroe D, Dean Grimwood K, Pattemore PK. Variations in bronchiolitis manage-
JM, Kuppermann N. A multicenter, randomized, controlled trial ment between five New Zealand hospitals: can we do better? J
of dexamethasone for bronchiolitis. N Engl J Med 2007;357: Paediatr Child Health 2003;39:40–45.
331–339. 146. Putto A, Ruuskanen O, Meurman O. Fever in respiratory virus
130. Chao LC, Lin YZ, Wu WF, Huang FY. Efficacy of nebulized infections. Am J Dis Child 1986;140:1159–1163.
budesonide in hospitalized infants and children younger than 24 147. Greenes DS, Harper MB. Low risk of bacteremia in febrile
months with bronchiolitis. Acta Paediatr Taiwan 2003;44:332– children with recognizable viral syndromes. Pediatr Infect Dis J
335. 1999;18:258–261.
131. de Blic J. Use of corticoids in acute bronchiolitis in infants. Arch 148. Titus MO, Wright SW. Prevalence of serious bacterial infections
Pediatr 2001;8:49S–54S. in febrile infants with respiratory syncytial virus infection.
132. Blom D, Ermers M, Bont L, van Aalderen WM, van Woensel JB. Pediatrics 2003;112:282–284.
Inhaled corticosteroids during acute bronchiolitis in the pre- 149. Kneyber MC, Blusse van Oud-Alblas H, van Vliet M, Uiterwaal
vention of post-bronchiolitic wheezing. Cochrane Database Syst CS, Kimpen JL, van Vught AJ. Concurrent bacterial infection
Rev 2007; (1): CD004881. and prolonged mechanical ventilation in infants with respiratory
133. Ermers MJ, Rovers MM, van Woensel JB, Kimpen JL, Bont LJ. syncytial virus lower respiratory tract disease. Intensive Care
The effect of high dose inhaled corticosteroids on wheeze in Med 2005;31:680–685.
infants after respiratory syncytial virus infection: randomised 150. Thorburn K, Harigopal S, Reddy V, Taylor N, van Saene HK.
double blind placebo controlled trial. BMJ 2009;338:b897. High incidence of pulmonary bacterial co-infection in children
134. Bentur L, Shoseyov D, Feigenbaum D, Gorichovsky Y, Bibi H. with severe respiratory syncytial virus (RSV) bronchiolitis.
Dexamethasone inhalations in RSV bronchiolitis: a double- Thorax 2006;61:611–615.
blind, placebo-controlled study. Acta Paediatr 2005;94:866– 151. Purcell K, Fergie J. Driscoll Children’s Hospital respiratory
871. syncytial virus database: risk factors, treatment and hospital
135. Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, Brant R, course in 3308 infants and young children, 1991 to 2002. Pediatr
Mitton C, Gouin S, Bhatt M, Joubert G, Black KJ, Turner T, Infect Dis J 2004;23:418–423.
Whitehouse S, Klassen TP. Epinephrine and dexamethasone 152. Andrade MA, Hoberman A, Glustein J, Paradise JL, Wald ER.
in children with bronchiolitis. N Engl J Med 2009;360:2079– Acute otitis media in children with bronchiolitis. Pediatrics
2089. 1998;101:617–619.
136. Hall CB, McBride JT, Walsh EE, Bell DM, Gala CL, Hildreth S, 153. Purcell K, Fergie J. Concurrent serious bacterial infections in
Ten Eyck LG, Hall WJ. Aerosolized ribavirin treatment of 912 infants and children hospitalized for treatment of respiratory
infants with respiratory syncytial viral infection. A randomized syncytial virus lower respiratory tract infection. Pediatr Infect
double-blind study. N Engl J Med 1983;308:1443–1447. Dis J 2004;23:267–269.
137. Rodriguez WJ, Kim HW, Brandt CD, Fink RJ, Getson PR, 154. Shazberg G, Revel-Vilk S, Shoseyov D, Ben-Ami A, Klar A,
Arrobio J, Murphy TM, McCarthy V, Parrott RH. Aerosolized Hurvitz H. The clinical course of bronchiolitis associated with
ribavirin in the treatment of patients with respiratory syncytial acute otitis media. Arch Dis Child 2000;83:317–319.
virus disease. Pediatr Infect Dis J 1987;6:159–163. 155. Subcommittee on Management of Acute Otitis Media.
138. Smith DW, Frankel LR, Mathers LH, Tang AT, Ariagno RL, Diagnosis and management of acute otitis media. Pediatrics
Prober CG. A controlled trial of aerosolized ribavirin in infants 2004;113:1451–1465.

Pediatric Pulmonology
346 Wright and Piedimonte

156. Field CM, Connolly JH, Murtagh G, Slattery CM, Turkington 175. Gross MF, Spear RM, Peterson BM. Helium–oxygen mixture
EE. Antibiotic treatment of epidemic bronchiolitis—a double- does not improve gas exchange in mechanically ventilated
blind trial. Br Med J 1966;1:83–85. children with bronchiolitis. Crit Care 2000;4:188–192.
157. Friis B, Andersen P, Brenoe E, Hornsleth A, Jensen A, Knudsen 176. Bisgaard B. Montelukast in RSV bronchiolitis. Am J Respir Crit
FU, Krasilnikoff PA, Mordhorst CH, Nielsen S, Uldall P. Care Med 2004;169:542–543.
Antibiotic treatment of pneumonia and bronchiolitis. A pro- 177. Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice
spective randomised study. Arch Dis Child 1984;59:1038–1045. M-P, Marchal J-L, Dass SB, Reiss TF, Knorr BA. Study of
158. Boogaard R, Hulsmann AR, van Veen L, Vaessen-Verberne AA, montelukast for the treatment of respiratory symptoms of post-
Yap YN, Sprij AJ, Brinkhorst G, Sibbles B, Hendriks T, Feith SW, respiratory syncytial virus bronchiolitis in children. Am J Respir
Lincke CR, Brandsma AE, Brand PL, Hop WC, de Hoog M, Crit Care Med 2008;178:854–860.
Merkus PJ. Recombinant human deoxyribonuclease in infants with 178. Koetz A, Nilsson P, Linden M, van der Hoek L, Ripa T. Detection
respiratory syncytial virus bronchiolitis. Chest 2007;131:788–795. of human coronavirus NL63, human metapneumovirus and
159. Nasr SZ, Strouse PJ, Soskolne E, Maxvold NJ, Garver KA, respiratory syncytial virus in children with respiratory tract
Rubin BK, Moler FW. Efficacy of recombinant human infections in south-west Sweden. Clin Microbiol Infect 2006;
deoxyribonuclease I in the hospital management of respiratory 12:1089–1096.
syncytial virus bronchiolitis. Chest 2001;120:203–208. 179. Hall CB, Douglas RG, Jr. Nosocomial respiratory syncytial viral
160. Daviskas E, Anderson SD, Gonda I, Eberl S, Meikle S, Seale JP, infections. Should gowns and masks be used? Am J Dis Child
Bautovich G. Inhalation of hypertonic saline aerosol enhances 1981;135:512–515.
mucociliary clearance in asthmatic and healthy subjects. Eur 180. Agah R, Cherry JD, Garakian AJ, Chapin M. Respiratory
Respir J 1996;9:725–732. syncytial virus (RSV) infection rate in personnel caring for
161. Wark P, McDonald VM. Nebulised hypertonic saline for cystic children with RSV infections. Routine isolation procedure vs
fibrosis. Cochrane Database Syst Rev 2009; (2): CD001506. routine procedure supplemented by use of masks and goggles.
162. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Am J Dis Child 1987;141:695–697.
Nebulized hypertonic saline solution for acute bronchiolitis in 181. Thorburn K, Kerr S, Taylor N, van Saene HK. RSV outbreak in a
infants. Cochrane Database Syst Rev 2008; (4): CD006458. paediatric intensive care unit. J Hosp Infect 2004;57:194–201.
163. LeVine AM, Bruno MD, Huelsman KM, Ross GF, Whitsett JA, 182. Gala CL, Hall CB, Schnabel KC, Pincus PH, Blossom P, Hildreth
Korfhagen TR. Surfactant protein A-deficient mice are suscep- SW, Betts RF, Douglas RG, Jr. The use of eye–nose goggles to
tible to group B streptococcal infection. J Immunol 1997;158: control nosocomial respiratory syncytial virus infection. JAMA
4336–4340. 1986;256:2706–2708.
164. Wright JR. Immunomodulatory functions of surfactant. Physiol 183. Leclair JM, Freeman J, Sullivan BF, Crowley CM, Goldmann
Rev 1997;77:931–962. DA. Prevention of nosocomial respiratory syncytial virus
165. Wright JR. Pulmonary surfactant: a front line of lung host infections through compliance with glove and gown isolation
defense. J Clin Invest 2003;111:1453–1455. precautions. N Engl J Med 1987;317:329–334.
166. Wu H, Kuzmenko A, Wan S, Schaffer L, Weiss A, Fisher JH, 184. Krasinski K, LaCouture R, Holzman RS, Waithe E, Bonk S,
Kim KS, McCormack FX. Surfactant proteins A and D inhibit Hanna B. Screening for respiratory syncytial virus and assign-
the growth of Gram-negative bacteria by increasing membrane ment to a cohort at admission to reduce nosocomial transmission.
permeability. J Clin Invest 2003;111:1589–1602. J Pediatr 1990;116:894–898.
167. LeVine AM, Elliott J, Whitsett JA, Srikiatkhachorn A, Crouch E, 185. Committee on Infectious Diseases and Committee on Fetus and
DeSilva N, Korfhagen T. Surfactant protein-d enhances phag- Newborn. Revised indications for the use of palivizumab and
ocytosis and pulmonary clearance of respiratory syncytial virus. respiratory syncytial virus immune globulin intravenous for the
Am J Respir Cell Mol Biol 2004;31:193–199. prevention of respiratory syncytial virus infections. Pediatrics
168. Dargaville PA, South M, McDougall PN. Surfactant abnormal- 2003;112:1442–1446.
ities in infants with severe viral bronchiolitis. Arch Dis Child 186. Groothuis JR, Simoes EA, Levin MJ, Hall CB, Long CE,
1996;75:133–136. Rodriguez WJ, Arrobio J, Meissner HC, Fulton DR, Welliver
169. Ventre K, Haroon M, Davison C. Surfactant therapy for RC. Prophylactic administration of respiratory syncytial virus
bronchiolitis in critically ill infants. Cochrane Database Syst immune globulin to high-risk infants and young children. The
Rev 2006;(3):CD005150. Respiratory Syncytial Virus Immune Globulin Study Group. N
170. Barach AL, Eckman M. The effects of inhalation of helium Engl J Med 1993;329:1524–1530.
mixed with oxygen on the mechanics of respiration. J Clin Invest 187. Simoes EA, Sondheimer HM, Top FH, Jr., Meissner HC,
1936;15:47–61. Welliver RC, Kramer AA, Groothuis JR. Respiratory syncytial
171. Hollman G, Shen G, Zeng L, Yngsdal-Krenz R, Perloff W, virus immune globulin for prophylaxis against respiratory
Zimmerman J, Strauss R. Helium–oxygen improves Clinical syncytial virus disease in infants and children with congenital
Asthma Scores in children with acute bronchiolitis. Crit Care heart disease. The Cardiac Study Group. J Pediatr 1998;133:
Med 1998;26:1731–1736. 492–499.
172. Cambonie G, Milesi C, Fournier-Favre S, Counil F, Jaber S, 188. O’Shea TM, Sevick MA, Givner LB. Costs and benefits of
Picaud JC, Matecki S. Clinical effects of heliox administration respiratory syncytial virus immunoglobulin to prevent hospital-
for acute bronchiolitis in young infants. Chest 2006;129:676– ization for lower respiratory tract illness in very low birth weight
682. infants. Pediatr Infect Dis J 1998;17:587–593.
173. Martinon-Torres F, Rodriguez-Nunez A, Martinon-Sanchez JM. 189. Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS, Wang
Heliox therapy in infants with acute bronchiolitis. Pediatrics SC, Dormitzer M, O’Grady J, Koenig S, Tamura JK, Woods R,
2002;109:68–73. Bansal G, Couchenour D, Tsao E, Hall WC, Young JF.
174. Liet JM, Millotte B, Tucci M, Laflammme S, Hutchison J, Creery Development of a humanized monoclonal antibody (MEDI-
D, Ducruet T, Lacroix J. Noninvasive therapy with helium– 493) with potent in vitro and in vivo activity against respiratory
oxygen for severe bronchiolitis. J Pediatr 2005;147:812–817. syncytial virus. J Infect Dis 1997;176:1215–1224.

Pediatric Pulmonology
RSV Prevention and Therapy 347

190. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis serious respiratory syncytial virus infection. Eur J Clin Microbiol
associated with high-dose intravenous immunoglobulin therapy: Infect Dis 2003;22:414–417.
frequency and risk factors. Ann Intern Med 1994;121:259–262. 202. Lacaze-Masmonteil T, Seidenberg J, Mitchell I, Cossey V, Cihar
191. Subramanian KN, Weisman LE, Rhodes T, Ariagno R, Sanchez M, Csader M, Baarsma R, Valido M, Pollack PF, Groothuis JR.
PJ, Steichen J, Givner LB, Jennings TL, Top FH, Jr., Carlin D, Evaluation of the safety of palivizumab in the second season of
Connor E. Safety, tolerance and pharmacokinetics of a exposure in young children at risk for severe respiratory
humanized monoclonal antibody to respiratory syncytial virus syncytial virus infection. Drug Saf 2003;26:283–291.
in premature infants and infants with bronchopulmonary 203. Simoes EA, Groothuis JR, Carbonell-Estrany X, Rieger CH,
dysplasia. MEDI-493 Study Group. Pediatr Infect Dis J 1998; Mitchell I, Fredrick LM, Kimpen JL. Palivizumab prophylaxis,
17:110–115. respiratory syncytial virus, and subsequent recurrent wheezing. J
192. Cardenas S, Auais A, Piedimonte G. Palivizumab in the Pediatr 2007;151:34–42.
prophylaxis of respiratory syncytial virus infection. Expert Rev 204. Wu H, Pfarr DS, Tang Y, An LL, Patel NK, Watkins JD, Huse
Anti Infect Ther 2005;3:719–726. WD, Kiener PA, Young JF. Ultra-potent antibodies against
193. Piedimonte G, Rodriguez MM, King KA, McLean S, Jiang X. respiratory syncytial virus: effects of binding kinetics and
Respiratory syncytial virus upregulates expression of the binding valence on viral neutralization. J Mol Biol 2005;350:
substance P receptor in rat lungs. Am J Physiol Lung Cell Mol 126–144.
Physiol 1999;277:L831–L840. 205. Wu H, Pfarr DS, Johnson S, Brewah YA, Woods RM, Patel NK,
194. King KA, Hu C, Rodriguez MM, Romaguera R, Jiang X, White WI, Young JF, Kiener PA. Development of motavizumab,
Piedimonte G. Exaggerated neurogenic inflammation and an ultra-potent antibody for the prevention of respiratory
substance P receptor upregulation in RSV-infected weanling syncytial virus infection in the upper and lower respiratory tract.
rats. Am J Respir Cell Mol Biol 2001;24:101–107. J Mol Biol 2007;368:652–665.
195. Piedimonte G, King KA, Holmgren NL, Bertrand PJ, Rodriguez 206. Abarca K, Jung E, Fernandez P, Zhao L, Harris B, Connor EM,
MM, Hirsch RL. A humanized monoclonal antibody against Losonsky GA. Safety, tolerability, pharmacokinetics, and
respiratory syncytial virus (palivizumab) inhibits RSV-induced immunogenicity of motavizumab, a humanized, enhanced-
neurogenic-mediated inflammation in rat airways. Pediatr Res potency monoclonal antibody for the prevention of respiratory
2000;47:351–356. syncytial virus infection in at-risk children. Pediatr Infect Dis J
196. Piedimonte G. Neural mechanisms of respiratory syncytial virus- 2009;28:267–272.
induced inflammation and prevention of respiratory syncytial 207. Losonsky GA, Fernandez P, Abarca K, Jung E, Gerdes J,
virus sequelae. Am J Respir Crit Care Med 2001;163:S18–S21. Hultquist M, Connor E. Phase I/II trial in high risk infants of
197. IMPACT-RSV. Palivizumab, a humanized respiratory syncytial Medi-524, an enhanced potency respiratory syncytial virus
virus monoclonal antibody, reduces hospitalization from respi- specific monoclonal antibody. Pediatric Academic Societies
ratory syncytial virus infection in high-risk infants. The IMpact- Annual Meeting 2005; Abstract 715.
RSV Study Group. Pediatrics 1998;102:531–537. 208. Simoes E, Carbonell Estrany X, Losonsky GA, Hultquist M,
198. Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Harris B, Connor E. Phase III trial of motavizumab, an enhanced
Top FH, Jr., Connor EM, Sondheimer HM. Palivizumab potency respiratory syncytial virus (RSV)-specific monoclonal
prophylaxis reduces hospitalization due to respiratory syncytial antibody for the prevention of serious RSV disease in high risk
virus in young children with hemodynamically significant infants. Pediatric Academic Societies Annual Meeting 2007;
congenital heart disease. J Pediatr 2003;143:532–540. Abstract 8220.9.
199. American Academy of Pediatrics. Respiratory syncytial virus. 209. Hall CB, Hall WJ, Gala CL, MaGill FB, Leddy JP. Long-term
In: Pickering LK, Baker CJ, Kimberlin DW, Long SS editors. prospective study in children after respiratory syncytial virus
Red Book: 2009 Report of the Committee on Infectious infection. J Pediatr 1984;105:358–364.
Diseases. 28th edition. Elk Grove Village, IL: American 210. Henry RL, Hodges IG, Milner AD, Stokes GM. Respiratory
Academy of Pediatrics; 2009. pp. 560–569. problems 2 years after acute bronchiolitis in infancy. Arch Dis
200. Synagis Product Information. MedImmune, Inc, 2009. Available Child 1983;58:713–716.
at: http://www.synagis.com. 211. Webb MS, Henry RL, Milner AD, Stokes GM, Swarbrick AS.
201. Groothuis JR. Safety of palivizumab in preterm infants 29 to 32 Continuing respiratory problems three and a half years after
weeks’ gestational age without chronic lung disease to prevent acute viral bronchiolitis. Arch Dis Child 1985;60:1064–1067.

Pediatric Pulmonology