rsv review peds pulm 2011

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Pediatric Pulmonology 46:324347 (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 pathogenin 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 trialsand, therefore, not likely to become available in the foreseeable future. Pediatr Pulmonol. 2011;

46:324347. 2010 Wiley-Liss, Inc.

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

pneumonia; wheezing.

Funding source: none reported.

INTRODUCTION AND HISTORICAL PERSPECTIVE

Acute bronchiolitis is the most common lower respira-tory tract illness in infants and young children, and is most

frequently causedby respiratorysyncytialvirus (RSV). The

earliest medical description of acute bronchiolitis was

published by Eberle,1 who described a catarrhal affec-

tion of infants under 1 year with labored breathing, cough,

and wheeze that resembled a violent attack of asthma.

Since that time, much has been discovered about RSVas the

primary etiology of acute bronchiolitis. In the late 1930s

and early 1940s, two epidemics of severe respiratory illness

affected infants in the north central United States. John

Adams issued several reports on the epidemics, describing

the seasonal variability and physical and pathologicalmanifestations of the disease. He was unable to isolate a

bacterial agent as the infecting organism, and so attributed

the illness to a viral infection.2,3

In 1955, investigators working at the Walter Reed

Army Institute of Research isolated a virus from the

nasal secretions of young chimpanzees with sneezing and

mucopurulent rhinorrhea. With this new virus, which they

named chimpanzee coryza agent (CCA), they were able

to reproduce the viral syndrome when they introduced

the agent into other chimpanzees.4 The following year,

Robert J. Chanock isolated CCA from two infants,

one with bronchiolitis and one with pneumonia. This

virus replicated in cell cultures, and produced character-istic multinucleated giant cells within a large syncytium.

Based on these findings, Chanock proposed that CCA be

renamed respiratory syncytial virus.5,6

Chanock continued his study of this disease, and in

the early 1960s published further descriptions of RSV

epidemiology, clinical manifestations, and recurrent

infections.7 9 During this period, he also began develop-

ment of a vaccine against RSV in collaboration with

Robert Parrott.10 Testing of this formalin-inactivated

RSV began in 1966. The vaccine was administered to

Department of Pediatrics and Pediatric Research Institute, West VirginiaUniversity School of Medicine, Morgantown, West Virginia

*Correspondence to: Giovanni Piedimonte, MD, Department of Pediatrics,

West Virginia University School of Medicine, 1 Medical Center Drive,

P.O. Box 9214, Morgantown, WV 26506-9214.

E-mail: [email protected]

Received 29 January 2010; Revised 24 August 2010; Accepted 29 August

2010.

DOI 10.1002/ppul.21377

Published online 23 November 2010 in Wiley Online Library

(wileyonlinelibrary.com).

2010 Wiley-Liss, Inc.


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military-dependent infants and children in Washington,D.C., Colorado, and California. During that years RSVoutbreaks, infants who had received the vaccine developedRSV infections at the same rate as those who had receivedthe placebo. Worse yet, 80% of the infants who receivedthe vaccine required hospitalization for severe bronchio-

litis or pneumonia, compared to only 5% for the placebogroup, and two of the vaccinated infants died. Thisresulted in significant concerns for the safety of sub-sequent RSV vaccine development, and to date no RSVvaccine is available. However, several potential candi-dates are currently in development both at the preclinicaland early clinical stage, including Phase I/IIa clinical trialsof live attenuated intranasal vaccines in healthy infants forthe prevention of lower respiratory tract infections (LRTI)caused by RSValone or in combination with parainfluenzavirus.

RSV research expanded through the 1970s and

continues to date. One of the hurdles has been the lackof a suitable animal model reproducing faithfully theclinical and pathological features of RSV infectionsin humans. The virus produces a clinically identicalsyndrome only in chimpanzees, but their cost is toohigh for ongoing research. Although rodents are notnaturally infected by RSV, rabbits, guinea pigs, rats, andmice have been used by a number of investigators toreproduce specific aspects of the disease. The cotton rat, inparticular, is considered by many investigators a reliablemodel to study viral replication in the respiratory tract,and has played an important role in our evolvingunderstanding of RSV infection and safety testing of

RSV vaccines.11

Over the last several decades, our understanding ofthe pathophysiology of RSV infection has grown,allowing for the development and testing of new therapiesto treat this disease. In particular, the ribosyl purineanalog ribavirin was developed for the therapy of activeRSV infection, while RSV-IVIG aimed at preventionthrough passive immunity; both approaches showedinitial promise with subsequent disappointing results.More recently, a humanized monoclonal antibody,palivizumab, has proven safe and effective in preventingsevere RSV disease in high-risk infants, and is currently

the only specific protective strategy licensed for useagainst this infection. In addition, progressive advancesin the supportive care of RSV infected infants havedramatically 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 containedwithin a bilayer lipid envelope that originates from the

host cell plasma membrane. The nucleocapsid containsthe viral genome, a single, non-segmented strand ofnegative polarity RNA including 10 genes but encoding atotal of 11 proteins because of the two open reading framesof the Matrix-2 (M2) gene. Of these, 8 function asstructural proteins and surface glycoproteins (G), while

the remaining 2 direct viral replication.12

In particular, RSVexpresses two surface glycoproteins:the fusion protein (F) and the attachment G protein.These proteins play an important role in infectivity andpathogenesis, and they are the primary targets for thehosts protective antibodies. The G protein mediatesRSV attachment to the host cell, after which the Fprotein enables fusion of the host and viral plasmamembranes to permit virus passage into the host cell.The RSV F protein also promotes the aggregation ofmultinucleated cells through fusion of their plasmamembranes, producing the syncytia for which the virus

is named

12

and the transmission of the virus from cell tocell. An interesting side note is that these syncytia arerarely seen invivo,but are more often noted invitro inviraldetection studies.

There are two distinct antigenic subgroups of RSV,characterized as A and B.13,14 Within these subgroups,there is further variability, with an overall antigenicrelatedness of about 25%. This is due in large part to the Gprotein, which demonstrates a relatedness of only 1 7%.The F protein demonstrates much lower variability, with50% antigenic relatedness.12 During outbreaks, bothsubtypes are generally present and it remains controversialwhether subtype A is more strongly associated with severe

disease and may more frequently result in the need forintensive care.1519

Section Summary

. RSV is a single-stranded RNA virus of the Para-myxoviridae family whose genome includes 10 genesencoding 11 proteins.

Pediatric Pulmonology

Fig. 1. RSV classification. Taxonomy of the viruses included in

the Paramyxoviridae family, which includes RSV.

RSV Prevention and Therapy 325


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. Two surface proteins, the F protein and attachment Gprotein, are the major viral antigens and play a criticalrole in the virulence of RSV.

. RSV has two distinct antigenic subtypes, A and B,which are usually both present during seasonaloutbreaks.

EPIDEMIOLOGY

Recent estimates from the World Health Organization(WHO) indicate that RSV accounts worldwide for morethan 60% of acute LRTI in children, and more than 80% ininfants


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children who had no LRTI, those with RSV LRTI were3.2 times more likely to have infrequent wheeze and4.3 times more likely to have frequent wheeze by 6 years.This risk then decreased, until it became insignificantby 13 years. As in most similar studies, there was no linkbetween RSV LRTI and atopy.53

Sigurs et al.54 conducted a prospective study to compare47 previously healthy children hospitalized with severeRSV bronchiolitis to 93 matched controls. The authorsfound a 30% cumulative presence of asthma among the

RSV group, compared to 3% in the control group. By age 7years, 23% of the RSV group had physician-diagnosedasthma, compared to 2% of controls. In a multivariateanalysis of the data, the combination of RSV LRTI with afamily history of asthma was associated with the highestrisk. Taken together, these two studies suggest a 30 40%likelihood of recurrent asthma-like episodes after early-life RSV LRTI. Sigurs studies also show increased riskbeyond 13 years of age and propose a link between RSVinfection and development of atopy; these discrepanciesfrom other studies may be related to the different severityof the original infection or to differences in the genetic

background.Unfortunately, epidemiologic studies are not suited to

resolve whether early-life RSV LRTI are truly causal insubsequent asthma, or more simply precipitate wheezingin children already predisposed by their genetic orepigenetic makeup. Only carefully randomized controltrials with specific prophylaxis can conclusively deter-mine if preventing or delaying the first RSV infectionlessens the incidenceand/or severityof asthma later in life.A recent industry-sponsored, prospective, multicentertrial concluded that RSV prophylaxis decreases by80% the relative risk of recurrent wheezing during

preschool years in non-atopic children but does not haveany effect in children without atopic background,55

suggesting that in the absence of genetic predispositionto atopy RSV plays an important causative role in thepathogenesis of recurrent wheezing. However, it is criticalto 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, withyearly outbreaks that vary from year to year anddepend on the geographical area.

. Nearly all children have been infected with RSV atleast once by the time they are 2 years of age, resultingin approximately 24 hospitalizationsper 1,000infantsand 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 forrecurrent wheeze and asthma.

PATHOGENESIS AND PATHOPHYSIOLOGY

Transmission

Transmission of RSV occurs primarily through directcontact of respiratory secretions with subsequent inocu-lation of nasopharyngeal or conjunctival mucus mem-

branes, or by entry of large respiratory droplets into thenose or eyes. Small aerosolized particles seem less likelyto spread the infection.5658 The virus can remain viableon hard surfaces (e.g., countertops) for up to 6 hr, onrubber gloves for 90 min, and on skin for 20 min.59 Thisprolonged survival highlights the need (and effectiveness)for hand washing and contact precautions in limiting thespread of RSV infection. The incubation period rangesfrom 2 to 8 days, and immunocompetent individuals canshed the virus for up to 3 weeks, although on average this islimited to about 8 days. Viral shedding is significantlyprolonged in immunocompromised individuals, and cancontinue for several months.

Replication

Viral replication occurs initially within the nasophar-yngeal epithelium, but then spreads to the bronchiolarepithelium where replication is most efficient60 (Fig. 3).This progression may occur by direct cell to cell trans-mission or by aspiration of upper airway secretions.61,62

Additionally, the virus can spread via the blood stream orthrough infection of inflammatory cells (e.g., monocytes),which may also account for disseminated disease inpatients with immunodeficiency.6367 In most cases,


Fig. 2. RSVasthma link. This graph combines retrospective

data from multiple studies209211suggesting an increasedrisk of

subsequent wheezing in children who have had RSV infection in

early life. Theoverall risk declines with age, but is still significant

several years after the original infection.



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however, the infection remains limited to the respiratorytract.

Viral replication is followed by necrosis of thebronchiolar epithelium with subsequent lymphocyticperibronchiolar infiltration and submucosal edema.Mucus secretions increase in both quantity and viscosity,

and mix with cellular debris. Clearance of this mixtureis compromised by the loss of ciliated epithelium andviscosity of the secretions. The end result is the productionof widespread mucus plugging with increased expiratoryresistance and partial airway obstruction causing airtrapping.68 These factors combine to produce the classicclinical triad of wheezing, atelectasis, and hyperinflation.

Immune Response

Historically, it has been held that the severity of an RSVinfection is related to the intensity of the hosts immune

response. This perception stems largely from the resultsof the 1966 formalin inactivated RSV vaccine clinicaltrial.69,70Postmortemexaminations of the two infants whodied revealed the presence of RSV bronchopneumonia,extreme hyperinflation with pneumothorax, and atypicaleosinophilic pulmonary infiltration. These findings sug-gest that immunopathologic mechanisms play an impor-tant role in severe RSV disease, and studies in animalmodels have indicated amplified Th2 immunity andactivated cytotoxic T cells as the main culprits,71,72

although several aspects of RSV pathophysiology remainhighly controversial.

In particular, considerable discussion has emerged inan effort to understand the mechanisms underlying theenhanced disease seen in the formalin inactivated vaccinetrial. Formalin inactivation has been implicated in that itappears to have amplified the immunogenicity of specificviral antigen, especially the RSV G protein. However, the

inactivation also resulted in an altered ability to induce aprotective neutralizing antibody response. Vaccine recip-ients were therefore primed for an enhanced inflammatoryresponse upon exposure to the wild-type virus.12 Thisnegative outcome impacted dramatically the furtherdevelopment of an inactivated RSV vaccine, essentiallybringing it to a halt.

The hosts immune response is clearly of greatimportance in clearing RSV infection and likely inattenuating its course. RSVinfection induces both cellularand humoral immune activity, and although this responsedoes not result in complete protection against reinfection,

it does seem to decrease the severity of subsequentinfections.44,45 In infants, high titers of maternally derivedRSV-neutralizing antibody in cord sera are associatedwith a much lower risk of hospitalization due to RSVbronchiolitis.73,74 This protection can also be conferred byadministration of exogenous RSV immunoglobulin.75,76

In addition, decreased serum anti-RSV titers havebeen associated with a significant increase in the riskof developing a symptomatic RSV infection.28 Cell-mediated immunity probably plays a role in the control ofactive infection and in viral clearance. This is underscoredby the observation that immunocompromised individuals


Fig. 3. RSV infection of airway epithelial cells. A: Human nasal,tracheal, and bronchial epithelial cells after infection with GFP-

expressing RSV(rgRSV) at 1 MOIfor 48hr. Thebrightfield panels

(left) show the total number of cells. The green fluorescent cells

(center) represent those which are actively infected with RSV.

B: Bronchial epithelial cells are the most susceptible to RSV

infection. Flow cytometric data show the percentage of fluores-cent (infected) cells in each panel compared to the non-infected

control cells (shaded histogram). Data are expressed as the

meanSEM (n4 experiments). ***p


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with deficient cell-mediated immunity suffer more severeand prolonged RSV disease, and also shed the virus muchlonger.34,66,77

A recent study, however, provides an alternativeexplanation for the pathophysiology of severe RSVinfections. In this study, autopsy specimens were collected

from 20 Chilean infants with RSV who died withoutaccess to the benefit of mechanical ventilatory support.78

The authors compared their immune responses to those ofinfants who died from influenza infection and the resultswere surprising, as there was no evidence of an RSV-related enhanced inflammatory response; in particular, atthe time of most severe symptoms, there was no activationof cytotoxic T-cell activity. There was, however, signifi-cant apoptosis-induced sloughing of the airway epithe-lium. The authors interpretation is that severe RSVinfection is a result of insufficient adaptive immunity, withviral clearance largely reliant upon less efficient innate

immunity.

Neuro-Immune Interactions

Recent studies show that early-life RSV infectionpromotes a large increase in the expression of nervegrowth factor (NGF) and its receptors in the developingairways of both animal models79 and humans.80 NGF andother similar neurotrophic proteins control the structuraldevelopment of peripheral afferent and efferent neurons,and exert changes in their functional activity in anumber of ways that collectively define neuronalplasticity.81 Thus, RSV-induced NGF overexpression

can drive short- and long-term changes in the distributionand reactivity of sensory and motor nerves across therespiratory tract, causing non-specific airway hyper-reactivity during and after the infection. Furthermore,RSV infection following chronic exposure to environ-mental pollution produces more severe neurotrophicdysregulation and neurogenic-mediated inflammationcompared to either infection or pollution alone.82

Neurotrophic factors and receptors are also synthesizedin several non-neuronal cell types including epithelial andinflammatory cells (e.g., mast cells and CD4 T cells).8385

This function may target the innervation of specific

tissues, but there is growing evidence that NGF functionsas a potent and eclectic neuro-immunomodulator, whichreleases and is released by a variety of inflammatorymediators. In particular, patients with bronchial asthmaand allergic rhinoconjunctivitis display high serum levelsof NGF, suggesting an important pathogenetic role ofneurotrophins in allergic disorders.86

Studies in animal models indicate that NGF over-expression is critical for neurogenic-mediated mucosaledema and for innate lymphocytic and monocyticresponses in RSV-infected airways,87 suggesting thatneuro-immune interactions driven by neurotrophic path-

ways play an important role in the pathophysiology oflocal and systemic inflammation against viral pathogens.This important inflammatory mechanism is largelyresistant to corticosteroids,88 which provides a plausibleexplanation for the poor therapeutic activity of these drugsin children with virus-induced wheezing.

Mast Cells and Leukotrienes

Studies in animal models indicate that RSV affectsdramatically the number, distribution, and function ofmast cells in the airway mucosa.89 Histopathologicalanalysis with an antibody against tryptase identifiednumerous mast cells in sections from RSV-infected ratlungs, with a $7-fold increase compared to the lungs ofnon-infected controls (Fig. 4). In addition, most of thesemast cells were in close spatial association with nerve

fibers, suggesting functional mast cellnerve interactionssimilar to those previously reported in other organsystems, particularly the skin, central nervous system,and gastrointestinal tract.90

Among the inflammatory mediators released from mastcells, cysteinyl leukotrienes (cysLTs) have been shown tocause airway inflammation and airway smooth musclecontraction during RSV infection, accounting for thewheezing observed in bronchiolitis. Increased LTC4 levelswere observed in nasopharyngeal secretions of childrenduring the acute phase of RSV infection, and theirconcentration correlated with clinical severity, beinghigher in patients with lower respiratory tract involvement

than in children with upper respiratory illness alone.91,92

Another clinical study showed that urinary LTE4 (theterminal product of cysLTs metabolism) is especiallyelevated during RSV bronchiolitis in younger infants(


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Section Summary

. Transmission occurs through inoculation of the naso-pharyngeal or conjunctival mucosa with respiratorysecretions from infected individuals.

. Viral shedding persists for about 8 days, but canbe significantly more prolonged in immunocompro-mised individuals.

. Viral replication begins in the nasal mucosa andspreads downward through the respiratory tract,producing edema and necrosis of the respiratoryepithelium, and resulting in airway obstruction.

. The inflammatory response associated with RSVinfection is extremely complex and involves therelease of multiple cytokines and chemokines fromepithelium and immunocytes, neuro-immune inter-actions, and mast cells degranulation with release ofleukotrienes.

CLINICAL MANIFESTATIONS

RSV infection in children almost always causesclinical manifestations; however, these can vary widelyin severity depending on the patients age, comorbidities,environmental exposures, and history of previous infec-tions.45,9598 Infants typically present with upper respira-tory symptoms, such as congestion and rhinorrhea thatover a period of 2 4 days may progress to involve thelower respiratory tract with cough, wheeze, increasedwork of breathing, and cyanosis.22,45,99 Auscultation is

usually remarkable for diffuse polyphonic wheezing andcoarse rales. Chest radiograph findings frequently includebilateral hyperinflation, patchy atelectasis, and peribron-chial thickening (Fig. 6).

Patients with severe lower respiratory tract involvement

may also have radiologic features more consistent withpneumonia, with areas of interstitial infiltration.100102

The resulting respiratory distress can vary in severityfrom minimal to profound, life-threatening respiratoryfailure.22,99,103 Infants may also develop lethargy, fever,poor feeding, and otitis media. Elderly individuals andthose with cardiopulmonary disease or immunodeficiencyare also at risk for severe lower respiratory tract disease.104

Older children and healthy adults typically manifestsymptoms of the upper respiratory tract, but may also havetracheobronchitis.46

Apnea is a well-known complication of RSV infection

in infants, and on occasion may be severe enough to causedeath.38 The virus was isolated as early as 1956 in infantswith apnea, and the incidence of apnea is as high as 20% ininfants under 6 months of age who require hospitalizationfor RSV infection.105110 Bruhn et al. also noted that thehighest incidence occurs in premature infants and ininfants less than 1 month of age. In most cases, however,apnea is self-limited and does not recur with subsequentinfections.106,111 An interesting observation is that apneais frequently the first clinical manifestation of RSVinfection, and mayoccur regardless of the severity of otherRSV-related symptoms.105 This association has led to the


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 scale40mm. *p


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hypothesis that RSV may be involved in at least somecases of sudden infant death syndrome (SIDS), whichalso shares several epidemiological similarities with theinfection in terms of seasonality and risk factors.

The exact pathophysiology of RSV-related apnea isstill controversial. Studies in animal models suggest thatRSV infection prolongs significantly reflex central apneatriggered by peripheral sensorineural stimulation.112 Thiseffect of RSV on ventilatory control is already significant2 days after intranasal inoculation, when the infection isstill confined to the upper airway, which is consistent with

and explains why apnea is an early or even presentingmanifestation of RSVinfection. In addition, apnea-relatedmortality in murine models is highest early during RSVinfection, suggesting that counterregulatory mechanismsthat facilitate autoresuscitation are activated only laterduring the infection. Specific blockade of the centralGABAA receptors or of the high-affinity substance P(NK1) receptors abolishes the influence of RSV infectionon the apnea triggered by sensorineural stimulation. Thisfinding suggests that substance P released from primarysensory neurons within the nodose ganglia activatessecond-order GABAergic interneurons in the spinal dorsal

horn, which in turn inhibit the function of medullaryinspiratory neurons resulting in apnea.

Section Summary

. Infants with RSV infection typically present withupper respiratory symptoms (congestion, rhinorrhea)that frequently progress to involve the lower respira-tory tract with cough, wheeze, and increased work ofbreathing.

. Chest radiography typically shows hyperinflation,patchy infiltrates, and atelectasis.

. Apnea is frequently the presenting manifestation ofRSV infection, especially in very young infants.

MANAGEMENT

Supportive Care

Most infants with RSV infection have a mild, self-limited illness, and are treated in an outpatient setting.This requires close follow up with attention to respiratorydistress, oxygen requirement, and hydration. Thoseinfants with difficulty feeding, pronounced respiratory


Fig. 5. Leukotriene synthesis in RSV-infected infants. Urinary

excretion of LTE4 (the terminal product of cysLTs metabolism)

is increased in children with RSV bronchiolitis as compared

to controls without respiratory infection. The overproduction of

cysLTs reflected by this marker is more prominent in younger

patients (


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distress, or need for supplemental oxygen requireadmission to the hospital for more aggressive manage-ment and monitoring. Regardless of the setting in whichthe patient is treated, the mainstay of therapy remainssupportive care, which includes respiratory support and

adequate fluid and nutrition management.Children with oxygen saturations92% should receive

warm, humidified oxygen.23 Nasal obstruction is acommon problem, and given that young infants areobligate nose breathers, may result in a significantincrease in respiratory distress. Simple nasal toilet withsaline drops and a suction bulb may improve work ofbreathing. Chest physiotherapy is often administered in aneffort to mobilize secretions and recruit atelectatic lungsegments. However, a recent Cochrane systematic reviewfound no evidence to support its use.113

Infants with hypoxemia refractory to supplemental

oxygen, persistent respiratory distress or progressiverespiratory failure usually require either non-invasivesupport with nasal continuous positive airway pressure orendotracheal intubation. Positive pressure mechanicalventilation has been an important modality in the treat-ment of infants with RSV bronchiolitis since the 1960s,and significantly decreases mortality.114 Ventilatory sup-port may require conventional mechanical ventilation orhigh-frequency oscillation (HFOV); also, infants withsevere disease unresponsive to these modalities maybenefit from extra-corporeal membrane oxygenation(ECMO).

Infants hospitalized with RSV bronchiolitis often havedecreased nutritional intake due to respiratory distress andtachypnea, increased insensible losses, and need forvolume and nutritional support. Continued oral feedingin the presence of significant respiratory distress may putthese patients at increased risk of aspiration. In patients

who are unable to tolerate oral feeds, adequate fluid intakeand nutrition should be maintained by placement of anasogastric or orogastric feeding tube, or with parenteralfluids when enteral nutrition is deemed unsafe.

Section Summary

. Supportive care is the mainstay of therapy for RSVinfection.

. Care is directed at ensuring adequate oxygenation,improving respiratory toilet, and meeting fluid andnutrition needs.

. Severe respiratory failure requires mechanical ven-

tilatory support, and occasionally HFOV or ECMO.

PHARMACOLOGICAL INTERVENTIONS

More than 50 years after the discovery of RSV, anddespite relentless attempts to identify pharmacologicaltherapies to improve the clinical course and outcomes ofthis infection, the most effective therapy remains limitedto the supportive care measures discussed above. Thequest for safe and effective active prophylaxis (vaccines)remains unsuccessful; however, pediatricians practicingduring the past decade have been able to protect at least

the more vulnerable patients with safe and effectivepassive prophylaxis. The following paragraphs reviewtherapeutic agents commonly used in the setting of RSVinfection. We will discuss medications used despite thelack of conclusive efficacy data (bronchodilators, cortico-steroids, antivirals, antibiotics), selected experimentaltherapies that have been tested in humans and hold somepromise for the future (DNAse, hypertonic saline,surfactant, heliox, anti-leukotrienes), and the old andnew strategies for passive prophylaxis (RSV-IVIG,palivizumab, motavizumab). Given that the vast majorityof cases of bronchiolitis in infants are due to RSVinfection,115118 studies discussing viral bronchiolitis in

general are also included. This review does not include thepipeline of antiviral compounds and putative vaccinescurrently being developed, but not likely to becomeavailable for clinical use in the near future.

Bronchodilators

Bronchodilators are frequently used in infants withwheezing due to RSV LRTI; however, their routine useremains controversial and most randomized controlledtrials (RCT) have failed to find objective evidence ofclinical benefit.


Fig. 6. Clinical manifestations of RSV. Chest radiograph

obtained from a child with RSV bronchiolitis showing bilateral

hyperinflation, patchy atelectasis, and peribronchial thickening.

Severe patients may also have features more consistent with

pneumonia, with areas of interstitial infiltration.

332 Wright and Piedimonte


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b-Agonists

A 1997 meta-analysis evaluated several outcomesamong eight clinical trials published between 1987 and1994.119 This review found no improvement in clinicalscore or hospitalization rate associated with the use ofalbuterol. There was a statistically significant, but

clinically insignificant, improvement in oxygen satura-tion, and heart rate. The authors concluded that there isno evidence for the efficacy ofb2-agonist therapy in thetreatment of viral bronchiolitis.

Gadomski and Basale120 revisited this topic in arecently updated Cochrane review of the availableliterature. Twenty-two studies, with a combined total of1,428 infants with bronchiolitis and first wheezingepisode, were evaluated in a meta-analysis to addressspecifically the efficacy of bronchodilators in the manage-ment of bronchiolitis. Measured outcomes includedimprovement in clinical score, oxygenation, hospital

admission, and length of hospital stay (LOS). The authorsfound that there was a minimally significant improvementin clinical scores among infants receiving bronchodilatortherapy over those receiving placebo, and that thisimprovement was not likely to be clinically relevant.Likewise, there was no statistically significant improve-ment in oxygenation, admission rate, or LOS. The authorsconcluded that bronchodilators are not recommended forthe routine management of infants with bronchiolitis andfirst episode of wheezing.

Studies in animal models have suggested that single-isomer preparations like levalbuterol may have a betteranti-inflammatory effect than racemic albuterol in RSV-

infected airways,121 but this has yet to be confirmed inclinical trials. In summary, b-agonists have not beenshown to have consistent benefits in the treatment of RSVbronchiolitis. A carefully monitored trial in individualpatients may be warranted, with discontinuation oftherapy if no objective improvement is noted.

Epinephrine

As with albuterol, there is no strong evidence to supportthe use of epinephrine in the treatment of RSVbronchiolitis; nevertheless, it is frequently used in infants

with RSV. A 2004 Cochrane review evaluated 14 studiespublished between 1998 and 2003.122 This reviewevaluated the efficacy of epinephrine versus albuteroland epinephrine versus placebo in both the inpatient andoutpatient settings. Primary outcomes included clinicalscore, heart rate, respiratory rate, oxygenation, admissionrate, and LOS. The authors concluded that the availabledata does not support the use of epinephrine in theinpatient setting, but that in outpatients epinephrine mayproduce a modest short-term improvement and thereforebe preferable to albuterol or nebulized saline in thetreatment of bronchiolitis.

While evidence-based protocols do not support theroutine use of albuterol or epinephrine, the use ofbronchodilators on a trial basis in select patients isacceptable. If clinical improvement can be documented,then continued use can be recommended. However,treatments should be discontinued if no improvement is

demonstrated, because of the possible side effects (e.g.,tachycardia, tremor, hypokalemia, hyperglycemia). Asepinephrine is typically not prescribed for use at home,albuterol may be a more appropriate choice for outpatientuse.

Anticholinergic Agents

Anticholinergics, such as ipratropium bromide, havenot been found to be effective in the treatment of RSVbronchiolitis. Several studies have evaluated ipratropiumalone and in combination with albuterol. While minorimprovements in oxygenation have been reported, there

is no consistent, significant benefit to the overall clinicalcourse or outcome.123126

Corticosteroids

Systemic Corticosteroids

A number of trials have sought to evaluate the efficacyof systemic corticosteroids in the treatment of bronchio-litis. Patel et al.127 conducted a systematic review of 13trials of corticosteroid therapy in 1,198 children with viralwheezing aged 030 months. This meta-analysis found adecrease in LOS of 0.38 hospital days/patient, whichhowever was not statistically significant. There was no

difference in clinical scores, respiratory rate, or oxygensaturation. For patients treated in the emergency depart-ment or clinic, there was no difference in admission rates.The authors caution that significant heterogeneity ofthe included studies and results make the final analysisdifficult to interpret with confidence, but concluded thatthistherapy lacks any significant clinical benefit comparedto placebo and is not indicated for this patient group.

The findings of this meta-analysis are complemented bymore recent individual studies. Teeratakulpisarn et al.128

evaluated 174 children hospitalized with acute bronchio-litis. The children were randomized to receive 0.6 mg/kg

of intramuscular (IM) dexamethasone or placebo. Theauthors evaluated the length of time to resolution ofrespiratory distress as the primary outcome. The durationof respiratory distress was decreased from 39 hr for theplacebo group to 27.2 hr for the dexamethasone group, adifference of about 12 hr. The duration of oxygen therapywas also reduced by 14.9 hr, and the hospital LOS wasdecreased by 13.4 hr.

In another study, Corneli et al.129 compared oraldexamethasone to placebo to determine whether a singledose of the steroid (1 mg/kg) could reduce the need forhospitalization. Over a 3-year period, the authors enrolled




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600 infants between the ages of 2 and 12 monthspresenting to the emergency department with first timewheezing and a diagnosis of moderate- to severe-bronchiolitis. The primary outcome was hospital admis-sion after 4 hr of emergency department observation.Secondary outcomes included change in a respiratory

assessment score, LOS, later medical visits or hospitaladmissions, and adverse events. The authors found that asingle dose of dexamethasone did not change the rate ofhospital admission or the severity score of bronchiolitisafter 4 hr; they also found no change in secondaryoutcomes. In summary, the current evidence suggests thatsystemic steroids should not be recommended for routineuse in the treatment of bronchiolitis.

Inhaled Corticosteroids

Several studies have evaluated inhaled corticosteroidsin patients with bronchiolitis, again without showing any

significant benefit.

130,131

In a 2007 Cochrane review offive studies with a total of 374 infants, Blom et al.132

evaluated the use of inhaled corticosteroids to preventpost-bronchiolitis wheezing. This analysis found noreduction in wheezing, readmission rate, use of systemiccorticosteroids, or use of bronchodilators.

More recently, Ermers et al.133 conducted a RCT toassess the influence of inhaled beclomethasone dipropi-onate on the occurrence and severity of recurrent wheezefollowing RSV LRTI. They enrolled 243 previouslyhealthy infants who had been admitted to the hospitalfor RSV. The infants were randomized to receivebeclomethasone dipropionate (200mg bid) versus placebo

during the first 3 months after hospitalization. There wasno significant difference in the number of days withwheeze or in the proportion of infants with wheezebetween the two groups.

Combination Therapy

Several studies have evaluated the usefulness ofsteroids given together with nebulized racemic epinephr-ine, with encouraging results. A recent RCT compared 61infants randomized to receive nebulized dexamethasoneor saline; both groups also received nebulized epinephr-ine.134 In this study, no statistically significant difference

was noted in clinical score or oxygen saturation. Therewas, however, a significant reduction in LOS in thedexamethasone group, especially among the subgroup ofprematurely born infants (6.5 vs. 9.1 days).

Plint et al.135 conducted a large, multicenter RCT toassess rates of admission to the hospital after treatmentwith oral dexamethasone and nebulized racemic epi-nephrine. Eight hundred infants presenting to theemergency department with bronchiolitis were random-ized into four groups. The first group received twotreatments with nebulized racemic epinephrine plus sixdoses of oral dexamethasone (1 per day for 6 days);

the second group received nebulized racemic epinephrineplus oral placebo; the third group received nebulizedplacebo plus oral dexamethasone; and the fourth groupreceived both placebos. Among the four groups, onlythose infants who received both therapies were foundto be significantly less likely to require hospitalization

(17.1% for the combination therapy group; 23.7% for theepinephrine group; 25.6% for the dexamethasone group;and 26.4% for the placebo group). Therefore, combinationtherapy with racemic epinephrine and oral dexamethasonemay decrease hospital admissions.

In general, young children without an atopic phenotypethat wheeze in response to viral infections show a poorresponse to corticosteroids, and even children that willultimately develop asthma are usually unresponsive tothis therapy when they develop virus-induced wheezingduring their first years of life. Another area of concernderives from safety considerations. In fact, severe RSV

bronchiolitis typically occurs during the first year of lifeand coincides with a critical phase of rapid lung develop-ment. The safety of the therapeutic use of corticosteroidsduring this window, particularly when inhaled at highdoses and for prolonged periods, is virtually unknown andconsequently these medications have never been approvedby the US Food and Drug Administration (FDA) for use inthe treatment of bronchiolitis or asthma in the first year oflife.

We conclude that whether administered systemically orinhaled, corticosteroids should not be routinely used in thetreatment of bronchiolitis. However, some specific patientpopulations may benefit from a trial of steroid therapy,

particularly patients with family history (parental atopy orasthma) or medical history (atopic eczema) consistentwith atopic predisposition.

Antivirals

The only antiviral agent licensed for the therapy ofsevere RSV infections is ribavirin, a synthetic nucleosideanalog with broad in vitro virustatic activity. Unfortu-nately, several factors make its routine use highlycontroversial: it is expensive, difficult to administer, andpossibly a teratogen. Furthermore, the available studies

are all small, have inconsistent quality, and have producedconflicting results, leading to a progressive decline ofits use.

Early studies were encouraging. Hall et al.136 random-ized 33 infants hospitalized with RSV bronchiolitis tocontinuous aerosolized ribavirin for 36 days versusplacebo. The ribavirin group showed a greater improve-ment in severity score, lower respiratory tract signs,oxygen saturations, and viral shedding compared to theplacebo group. Rodriguez et al.137 also found improvedoxygenation and greater rate of clinical improvement inpatients receiving a short course of ribavirin, without




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Hypertonic Saline

Hypertonic saline nebulization has been shown pre-viously to improve mucociliary clearance in patients withasthma and cystic fibrosis,160,161 and more recently hasgained interest as a potential therapy for infants withbronchiolitis. In a 2008 Cochrane review, Zhang et al.162

reviewed four trials including a total of 254 infants withacute bronchiolitis (189 inpatients and 65 outpatients)who received 3% versus 0.9% saline nebulization with orwithout a bronchodilator. The primary outcomes meas-ured were LOS for the inpatients and rate of hospital-ization for the outpatients. This review concluded thatnebulized hypertonic saline could reduce the LOS ofhospitalized infants by almost 1 day (25.9% reduction)when compared to infants who received placebo. Therewas no improvement in the rate of hospitalization amongoutpatients. Importantly, no adverse events were reportedin any of the trials. Furthermore, when considering the

enormous financial burden that the hospitalization ofinfants with bronchiolitis places on healthcare systemsand parents worldwide, the minimal acquisition costsmake this intervention even more appealing.

Surfactant

Beyond its role of decreasing surface tension in alveoliand bronchioles, thereby improving alveolar and smallairway patency, surfactant has protein components (A andD) that bind viral and bacterial surface markers andfacilitate their immune-mediated elimination.163166 Inaddition, surfactant protein D has been demonstrated topromote alveolar macrophage production of free radi-cals.167 In acute bronchiolitis, there is decreased produc-tion of these surfactant proteins, which return to normallevels with the resolution of the illness.168

Administration of exogenous surfactant to infants withsevere respiratory failure due to bronchiolitis seemspromising, and several small RCTs have been conductedto evaluate this therapy, with encouraging results. A recentmeta-analysis by Ventre et al.169 included three studieswith a total of 79 patients. The authors reported decreasesin the duration of mechanical ventilation and PICU stay.There also seem to be improvements in pulmonary

mechanics and gas exchange. It is important to note thatthe available studies are small and underpowered, and thatadditional, larger studies are required. However, exoge-nous surfactant therapy does appear to hold promise foruse in patients with severe respiratory failure due tobronchiolitis.

Heliox

Barach and Eckman170 first described the use of heliumfor the treatment of upper airway obstruction and asthmain the 1930s. Heliox is a mixture of helium and oxygenin a

70:30 or 80:20 ratio. Its theoretical advantage lies in thefact that it maintains laminar flow and, therefore, lessturbulence through constricted airways than do nitrogenoxygenmixtures.This results in improved ventilation witha reduced work of breathing in patients with lowerrespiratory tract disease. Heliox has been studied in the

treatment of bronchiolitis by several investigators,although most of these studies are quite small.171173

Some of the authors have shown small improvements inclinical scores and decreased tachypnea and work ofbreathing.

Liet et al.174 evaluated rates of positive pressureventilation in patients receiving heliox therapy versusstandard nitrogenoxygen air and found no differencebetween the two groups. When heliox therapy wasevaluated in intubated children with bronchiolitis, Grosset al.175 found no improvement in ventilation or oxygen-ation, regardless of the ratio of helium to oxygen

employed (50:50, 60:40, or 70:30).Heliox equipment is bulky and cumbersome, and it canbe problematic to administer. Furthermore, given thatit is most effective at high helium to oxygen ratios, itis minimally effective in patients with significant oxygenrequirements. In summary, the current evidence support-ing heliox use for bronchiolitis is sparse, underpowered,and conflicting, and therefore larger RCTs are requiredbefore it can be recommended for routine use.

Anti-Leukotrienes

As discussed above, strong experimental evidence in

animal models and a number of clinical studies indicatethat cysLTs are released during RSV infection andcontribute to airway inflammation and hyperreactivity.Therefore, it would make sense if leukotriene antagonistswould have therapeutic activity in the setting of acutebronchiolitis, and possibly prevent or reduce the recur-rence of wheezing episodes post-bronchiolitis. The firstpilot trial testing this hypothesis was conducted inDenmark by Bisgaard et al.94 One hundred thirty childrenhospitalized with acute RSV bronchiolitis were random-ized into a double-blind, placebo-controlled trial of thecysLT1 receptor antagonist montelukast given for 28 days

starting within 7 days of symptom debut. Children onmontelukast had significantly more symptom-free dayscompared with children on placebo (22% vs. 4%); inparticular, daytime cough was significantly reduced onactive treatment and exacerbations were delayed.

This study generated a lot of interest and hope in the useof leukotriene modifiers in RSV bronchiolitis despite itsseveral limitations, especially the small sample size andwide age range (3- to 36-month old). To address the latter,the author conducted a post hoc analysis of the same datarevealing that the effect of montelukast was larger in theyounger children compared with the older children,176




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which was consistent with previously reported data on theage-dependency of cysLTs production.93 To address theissue of statistical power, a larger multi-center double-blind study of 979 children 324 months old with RSVbronchiolitis was completed recently.177 This time, nosignificant differences were seen between montelukast and

placebo in symptom-free days. However, post hoc analysislimited to the 523 patients with persistent symptomsshowed more symptom-free days in the montelukastgroup. Therefore, additional studies are necessary todefine conclusively the role of leukotriene modifiers inthe management of patients with more persistent ormore severe respiratory symptoms following RSV infec-tion. Furthermore, it would be important to comparethe effect of anti-leukotriene therapy during the infectionwith its prophylactic use starting before the RSV season,and also assess its effect on the incidence of post-RSVasthma.

Section Summary

. b-Agonists do not provide consistent benefit in thetreatment of RSV infection; however, a brief trialwith objective evaluation of the response may bewarranted.

. Epinephrine does not provide consistent benefit inthe inpatient setting, and although it may produce amodest improvement in the outpatient setting, it is notrecommended for use at home.

. Neither systemic nor inhaled corticosteroids haveshown consistent benefit in the treatment of RSV

disease, and therefore they are not recommended forroutine use.. Ribavirin is not recommended for routine treatment

of RSV infection, but may be considered in selectimmunocompromised individuals.

. Antibiotics are recommended only in the presence ofspecific evidence of coexistent bacterial infection.

. DNAse does not provide consistent benefit in thetreatment of RSV infection.

. Hypertonic saline has been demonstrated to reduceLOS by up to 25% and may provide significant benefitto infants with RSV bronchiolitis.

. Surfactant and Heliox may provide benefit in the

treatment of RSV infection, but the available data isnot conclusive.

. Anti-leukotrienes have shown some clinical benefit inthe treatment of RSVinfection, but the evidence for oragainst their use is not definitive.

PREVENTION

In the non-clinical setting, several measures haveproven effective in limiting the likelihood of RSVinfection. Hand washing is perhaps the most effectiveway to prevent the spread of RSV. Specific recommenda-

tions to caregivers of high-risk infants also include theavoidance of tobacco smoke and restriction of day careduring RSV season. In addition, there is good evidence tosupport the recommendation of breast feeding at riskinfants, given the transfer of maternal immunoglobulin.178

Hand washing in the clinical setting is invaluable

in preventing the nosocomial spread of RSV.178

The useof gloves and gowns can also aid in limiting trans-mission179183; the use of masks is more controversial, asRSV is mostly transmitted by direct contact with infectedsecretions and rarely by aerosolization. Rapid testing ofsuspected patients allows for identification and isolationof those known with RSV-related disease, furtherdecreasing their exposure to non-infected patients.184

Immunoprophylaxis

To date, two products have been developed for clinicaluse: RSV-IVIG, a hyperimmune polyclonal globulin, andpalivizumab, a humanized monoclonal antibody. Motavi-zumab is a second-generation humanized monoclonalantibody not yet available on the market.

Respiratory Syncytial Virus Immunoglobulin (RSV-IVIG)

RSV-IVIG is a pooled polyclonal human immunoglo-bulin purified from donors with high-RSV-neutralizingantibody titers, to be administered by monthly intravenousinfusion during RSV season.185 A significant decrease inRSV-related hospitalizations and LOS was seen whenRSV-IVIG was administered to high-risk infants withprematurity or chronic lung disease. However, it was also

associated with an increase in surgical morbidity andmortality among infants with CHD, and so it was neverlicensed for use in these patients.75,186,187 As RSV-IVIGcould interfere with the immune response to live virusvaccines, it was necessary to delay immunization with themeasles/mumps/rubella (MMR) vaccine until 9 monthsfollowing the last dose of RSV-IVIG.

The major disadvantages of RSV-IVIG included theneed for repeated venous access and a long intravenousinfusion (46 hr), with the consequent need of medicalsupervision in a hospital setting. Thevolume administeredwas considerable using the recommended dose of 15 ml/

kg, with the significant risk offluid overload to intrinsi-cally fluid sensitive infants and frequent need for diuretictherapy. There was also a potential for transfer of blood-borne pathogens and the supply of eligible donors was notdependable. Another practical disadvantage was the highcombined costs deriving from acquisition and supervisedadministration of the immunoglobulin.188

Palivizumab

Given the disadvantages of RSV-IVIG in the treatmentof RSV infection, research focused on the development ofmonoclonal antibody therapies. There are several advan-




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tages to monoclonals: they are less likely to exert animmunosuppressive effect in children,189 and carryessentially no risk of transmitting blood-borne infectionsor other plasma-associated adverse effects190; containhigher titers of neutralizing antibody, and therefore can beprepared in smaller volumes suitable for IM administra-

tion in outpatient or home settings; eliminate the risk offluid overload and need for diuretic rescue.

Palivizumab is a humanizedmonoclonal IgG1 antibodyproduced by recombinant DNA technology, one of thevery first successful therapies of this kind that pioneeredthe large and expanding field of biologicals. With thistechnology, murine-derived sequences complimentary tothe A antigenic site of the RSV F protein are grafted into ahuman IgG frame (Fig. 7); the result is an antibody thatbeing >95% human is minimally immunogenic and hasbroadly reactive activity toward both subtypes of RSV.191

The effectiveness of palivizumab lies not in preventing

infection of the upper respiratory tract, but in limitingdownward spread.192 In addition, studies in animal modelshave suggested that, by preventing alterations in thedevelopment of small airway neural networks caused byRSV in infancy,79,80,193,194 palivizumab might preventsubsequent peripheral airway reactivity and recurrentwheezing195,196 as well as central ventilatory complica-tions like apnea.112

In 1998, a Phase I/IImulticenter, double-blind, placebo-controlled study was published, defining the safety andpharmacokinetics of palivizumab.191 Sixty-two infantswere enrolled, including infants


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be substantially higher than that estimated from RCTs,but these data are difficult to interpret because of lackof controls.

Palivizumab is administered monthly during RSVseason as an IM dose of 15 mg/kg. The AAP recommendsthat RSV prophylaxis be considered in the followinggroups199:

1. Infants with chronic lung disease who are youngerthan 24 months of age and have received medicaltherapy for BPD within 6 months of the onset of RSVseason may benefit from monthly dosing beginningin the 1st month of RSV season for a total of fivedoses.

2. Infants born before 28 weeks of gestation may benefitfrom monthly dosing beginning in the 1st month ofRSV season for a total offive doses.

3. Infants born between 29 and 32 weeks gestation andwho are lessthan 6 monthsof age at the onset of RSVseason may benefit from monthly dosing beginning

in the 1st month of RSV season for a total of fivedoses.

4. Infants born between 32 and 35 weeks gestation whoare younger than 3 months of age at the onset of RSVseason or who are born during RSV season and whoattend day care or have a sibling aged


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injection was 37mg/ml and more than 40% of patientswere below 30mg/ml. Subsequently, the mean troughlevel increased after each monthly injection becauseof progressive accumulation. This pharmacokineticdata explain why almost half of all breakthrough RSVhospitalizations in palivizumab-treated patients occur

after the first injection, and more than 70% after thefirst two. Another issue is that, at the recommendeddosage, palivizumab levels in the nasal mucosa are notprotective, and therefore palivizumab does not preventRSV infection, but rather reduces its spread to the lowerairways.

Palivizumab shortcomings could be fixed with a morepotent antibody. This led to the development of motavi-zumab, a second-generation IgG1 monoclonal antibodywith increased anti-RSV activity. In vitro studies ofpalivizumab variants identified a clearly superior anti-body, A4b4, with 44-fold greater activity against RSV

than palivizumab.

204

Subsequent in vivo studies, however,were disappointing, as the new antibody had only atwofold increase in potency when administered prophy-lactically to cotton rats.205 Further analysis revealed thatthe diminished activity was the result of broad tissuebinding which decreased lung bioavailability. Theincreased tissue binding was attributed to three aminoacid residues that were altered from palivizumab.Reversion of these back to the original amino acidsrestored lung bioavailability and produced the final formof motavizumab.205

While the structure of motavizumab differs frompalivizumab by only 13 amino acids, it has a 70-fold

higher affinity for the RSV F protein, and at equivalentconcentrations yields up to a 100-fold greater activityagainst RSV.206 In addition, motavizumab inhibits RSVreplication in the upper respiratory tract of cotton rats,whereas palivizumab does not.206 Finally, motavizumab isfully humanized, whereas the palivizumab antibody framestill contains a few murine-derived sequences.

A Phase I/II open-label, dose-escalation trial wasconducted to evaluate safety and pharmacokineticsof monthly IM injections in infants.207 The study includedpreterm infants (3235 weeks gestation) who were


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CONCLUSIONS

RSV is the most frequent cause of bronchiolitis andpneumonia in infants and young children, and a source ofsignificant morbidity, mortality, and financial burdenworldwide. It is an RNA virus of the Paramyxoviridaefamily whose two surface G proteins are the majorantigens and are critical for virulence. The two antigenicvariants, A and B, are usually both present during theseasonal outbreaks, which vary from year to year anddepend on the geographical area. Nearly all children havebeen infected with this virus at least once by the time theyare 2 years of age, resulting in about 24 hospitalizationsper 1,000 infants and up to 1 million deaths worldwideeach year. Previous infections do not convey persistentimmunity, and reinfection is common.

Transmission occurs through inoculation of the naso-pharyngeal or conjunctival mucosa with respiratorysecretions from infected individuals. Viral shedding

persists for approximately 1 week, but can be significantlymore prolonged in immunocompromised individuals.Viral replication begins in the nasal mucosa and spreadsdownward through the respiratory tract, producing edemaand necrosis of the respiratory epithelium, and resultingin airflow obstruction. The inflammatory response asso-ciated with this infection is extremely complex andinvolves the release of multiple cytokines and chemokinesfrom epithelium and infiltrating immunocytes, localneuro-immune interactions, and mast cells degranulationwith variable release of leukotrienes.

Infants with RSVinfection typically present with upper

respiratory symptoms that frequently progress to involvethe lower respiratory tract with cough, wheeze, andincreased work of breathing. Chest radiographs typicallyshow hyperinflation, patchy infiltrates, and atelectasis.Apnea is frequently the presenting manifestation, espe-cially in young infants. Supportive care is the mainstayof therapy for RSV disease and is directed at ensuringadequate oxygenation, improving respiratory toilet, andmeeting fluid and nutrition requirements. Severe respira-tory failure requires mechanical ventilatory support, andoccasionally HFOV or ECMO.

Adrenergic a- and b-agonists do not provide consistentbenefit in the treatment of RSV disease, although a brief

trial with objective evaluation of the response may bewarranted. Neither systemic nor inhaled corticosteroidshave been shown to provide clear advantages in thetreatment of RSV disease, and therefore their use is notrecommended. The antiviral drug ribavirin is also notrecommended for routine treatment of RSV infection,but may be considered in select immunocompromisedindividuals. Antibiotics are recommended only in thepresence of specific evidence of coexistent bacterialinfection. Nebulized treatments with hypertonic salinehave been shown to reduceLOS and may offer an effective

low-cost option to improve mucociliary clearance in thesepatients, whereas very expensive mucolytic therapy withDNAse has not provided consistent results. Exogenoussurfactant, Heliox, and leukotriene modifiers may alsoprovide some clinical benefit, but the evidence for oragainst their use is not definitive.

Hand washing and isolation are highly effective inpreventing the spread of RSV infection. The humanizedmonoclonal antibody palivizumab is a safe and effectiveoption for passive RSV prophylaxis, butits use is currentlylimited to infants at high risk for severe disease due to thehigh costs. Motavizumab is a next-generation humanizedmonoclonal antibody with improved activity against RSVcurrently undergoing FDA evaluation for licensing in theUS. The hope for the future is active prophylaxis of allinfants with a safe and effective RSV vaccine, which notonly would protect against the most common respiratorydisease of childhood, but may also prevent frequent long-

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