Viral Bronchiolitis in Children.pdf

7/25/2019 Viral Bronchiolitis in Children.pdf

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T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med374;1 nejm.org January 7, 201662

Review Article

Few diseases have a greater effect on the health of young chil-

dren than viral lower respiratory tract illness. Approximately 800,000 chil-dren in the United States, or approximately 20% of the annual birth cohort,

require outpatient medical attention during the first year of life because of illnesscaused by respiratory syncytial virus (RSV).1Between 2% and 3% of all childrenyounger than 12 months of age are hospitalized with a diagnosis of bronchiolitis,which accounts for between 57,000 and 172,000 hospitalizations annually.1-4Esti-mated nationwide hospital charges for care related to bronchiolitis in childrenyounger than 2 years of age exceeded $1.7 billion in 2009.5Globally, in 2005, RSValone was estimated to cause 66,000 to 199,000 deaths among children youngerthan 5 years of age, with a disproportionate number of these deaths occurring inresource-limited countries.6,7In the United States, by contrast, bronchiolitis due toRSV accounts for fewer than 100 deaths in young children annually.8

This review describes the current understanding of bronchiolitis, including theincreasing number of viruses that are known to cause it, the current understand-ing of its pathogenesis, the importance of environmental and host genetic factors,and the roles of season, race, and sex in bronchiolitis attack rates and subsequentepisodes of wheezing. In addition, guidelines from the American Academy of Pe-diatrics regarding the diagnosis, management, and prevention of bronchiolitis are

summarized.

9,10

Clinical Fe atures

A young child with bronchiolitis typically presents to a health professional duringthe winter months after 2 to 4 days of low-grade fever, nasal congestion, andrhinorrhea with symptoms of lower respiratory tract illness that include cough,tachypnea, and increased respiratory effort as manifested by grunting, nasal flar-ing, and intercostal, subcostal, or supraclavicular retractions.11Inspiratory cracklesand expiratory wheezing may be heard on auscultation. Various definitions ofbronchiolitis have been proposed, but the term is generally applied to a first epi-sode of wheezing in infants younger than 12 months of age. Apnea, especially in

preterm infants in the first 2 months of life, may be an early manifestation ofviral bronchiolitis.12 Reported rates of apnea among infants with bronchiolitisrange from 1 to 24%, reflecting differences in the definitions of bronchiolitis andapnea and the presence of coexisting conditions.

The variable course of bronchiolitis and the inability of medical personnel topredict whether supportive care will be needed often results in hospital admissioneven when symptoms are not severe. A variety of potential clinical markers havebeen proposed for use in identifying infants who are at risk for severe disease.Unfortunately, current scoring systems have low power to predict whether illnesswill progress to severe complications that would necessitate intensive care or me-chanical ventilation.

From Tufts University School of Medi-cine and the Department of Pediatrics,Tufts Medical Center both in Boston.Address reprint requests to Dr. Meissnerat Tufts Medical Center, 800 WashingtonSt., Boston, MA 02111, or at cmeissner@tuftsmedicalcenter .org.

N Engl J Med 2016;374:62-72.

DOI: 10.1056/NEJMra1413456

Copyright 2016 Massachusetts Medical Society.

Julie R. Ingelfinger, M.D., Editor

Viral Bronchiolitis in ChildrenH. Cody Meissner, M.D.

The New England Journal of Medicine

Downloaded from nejm.org by LEONARDO FERNANDEZ on January 10, 2016. For personal use only. No other uses without permission.

Copyright 2016 Massachusetts Medical Society. All rights reserved.


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n engl j med374;1 nejm.org January 7, 2016 63

Viral Bronchiolitis in Children

Viral Causes

The availability of molecular-detection techniqueshas made it possible to identify a diverse groupof viruses that are capable of causing bronchiol-itis (Table 1). Although the reported proportionof hospitalizations that are attributable to eachvirus differs according to the geographic areaand the year, the most common pathogen is RSV,followed by human rhinovirus. RSV accounts for50 to 80% of all hospitalizations for bronchiol-itis during seasonal epidemics in North Amer-ica.1-4Although the clinical features of bronchi-

olitis due to different viruses are generallyindistinguishable, some differences in the sever-ity of disease have been reported. For example,it has been observed that rhinovirus-associatedbronchiolitis may result in a shorter length ofhospitalization than bronchiolitis that is attrib-utable to RSV.13Differences in the response tomedical intervention have not been identifiedconsistently among children with bronchiolitiscaused by different viruses.

The epidemiologic and clinical importance of

coinfection in hospitalized children with bron-

chiolitis is a focus of active research. Rates ofcoinfection vary widely among studies and rangefrom 6% to more than 30%.4,13-15Greater diseaseseverity, defined as a longer length of hospitalstay or more severe hypoxemia, as well as agreater risk of medically attended relapse, havebeen reported among children with coinfec-tion.13,16,17However, other studies have shown nodifference in disease severity or have shown evenless severe disease in children in whom morethan one respiratory virus was isolated. 15,18,19Studies that have used nucleic acid amplification

tests suggest that one or more viral respiratorypathogens can be isolated from the upper respi-ratory tract of as many as 30% of asymptomaticyoung children.20,21 It is not fully understoodwhether the detection of a viral genome inasymptomatic children represents prolongedshedding after an infection has resolved, anincubation period before a pending infection, apersistent, low-grade infection producing smallamounts of virus, or infection by a serotype withlimited ability to cause disease.

Virus TypeApproximate

Frequency Seasonality in North America

%

Respiratory syncytial virus A and B 5080 November through April

Human rhinovirus Groups A, B, and C;>100 serotypes 525 Peak activity in spring and autumn

Parainfluenza virus Type 3 most common, followedby types 1, 2, and 4

525 Type 3 is most prominent duringspring, summer, and fall in odd-

numbered years

Human metapneumovirus Subgroups A and B 510 Late winter and early spring;season typically peaks 12 mo

later than RSV peak

Coronavirus OC43, 229ENL63, and HKU1

510 Winter and spring

Adenovirus >50 serotypes 510 Year-round, although season forcertain serotypes may be more

restricted

Influenza virus A and B 15 November through AprilEnterovirus Echovirus and

coxsackievirus15 Generally June through

October

* Viruses are listed in descending order of frequency as a cause of bronchiolitis. Human bocavirus has been detected asa copathogen in bronchiolitis, but it is isolated infrequently as a single agent in hospitalized children, leading to specu-lation that this virus is more likely to be an innocent bystander than a true pathogen. No evidence has been found for aprimary role of bacteria as a cause of bronchiolitis, although Bordetella pertussis, Chlamydia trachomatis, or Mycoplasmapneumoniaemay be included in the differential diagnosis of a lower respiratory tract infection in a young child. Coinfectionwith viral and bacterial pathogens such as Haemophilusinfluenzaetype b or Streptococcus pneumoniaeis uncommon,mainly because of the widespread use of conjugate polysaccharide vaccines. RSV denotes respiratory syncytial virus.

Table 1.Viruses Detected in Nasopharyngeal Secretions from Hospitalized Children with Bronchiolitis.*





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T h e n e w e n g l a n d j o u r n a l o f medicine

Pathogenesis

The immune response elicited by RSV may beboth protective and pathogenic, and there ap-pear to be functional differences between aninitial infection in a seronegative infant and re-infection in an older child or adult (Fig. 1). RSV

reinfections occur throughout life, despite theinduction of both antibody and T-cell responsesafter a primary infection and the absence of adetectable antigenic change in RSV surface gly-coproteins. How RSV evades or inhibits hostdefenses is not fully understood.22

Results from a controlled clinical trial, con-ducted in the 1960s, of a formalin-inactivatedRSV vaccine showed that a protective immuneresponse did not develop in recipients of the vac-cine.11 Vaccine recipients who subsequently ac-quired natural RSV infection had more severeillness than did control participants. In addition,evidence suggests that both the relative balancebetween type 1 and type 2 helper T cells thatrespond to antigenic stimulation by the virusand the profile of evoked chemokines and cyto-kines determines the extent of RSV disease ex-pression.11On the basis of these observations,most theories regarding the pathogenesis ofbronchiolitis due to RSV implicate an exagger-ated immune response as well as direct cellulardamage from viral replication.22

Although neutralizing antibodies to viral sur-face glycoproteins are important for the preven-tion of RSV infection, T-cellmediated responsesappear to be crucial for viral clearance duringinfection.23,24Postmortem studies of lung tissueobtained from infants who died from RSV infec-tion reveal macrophages and neutrophils and arelative absence of cytotoxic T cells, along withlow concentrations of classic T-lymphocyte

derived cytokines (released by CD4+ and CD8+T cells). These findings are not consistent witha pathologic inflammatory response.25 Rather,

the presence of abundant viral antigen suggestsactive RSV replication and direct virally inducedcytotoxicity.25

At least in infants who have not had a previousinfection, overwhelming RSV disease appears tobe related to the lack of an adaptive cytotoxicT-cell response in the host; the result is depen-dence on the less effective innate immune re-sponse for the termination of viral replication.The fact that a more effective, adaptive cytotoxic

T-cell response does not develop in such in-fants is supported by reports of a direct correla-tion between RSV load, as measured in naso-pharyngeal aspirates obtained from childrenwho have been hospitalized with bronchiolit is,and more severe disease, defined as a higherrisk of apnea, a longer hospital stay, and agreater need for intensive care.26,27However, notall reports are consistent with an associationbetween a high viral load in respiratory secre-tions and greater severity of disease.28-30A rea-

sonable deduction is that direct cytotoxic injuryinduced by the virus and a robust host inflam-matory response both contribute to the patho-genesis of RSV bronchiolitis, although the rela-tive contribution of each remains uncertain.Resolution of this issue will determine whethera potent antiviral agent administered early inthe course of bronchiolitis can reduce the dura-tion and severity of illness without the need forimmune modulation.

Figure 1 (facing page).Pathogenesis of BronchiolitisDue to Respiratory Syncytial Virus (RSV).

Infection is acquired by inoculation of the nasal or con-junctival mucosa with contaminated secretions or by

inhalation of large (>5m in diameter), virus-containing

respiratory droplets within 2 m of an infectious patient.After an incubation period of 4 to 6 days, viral replica-

tion in the nasal epithelium results in congestion, rhi-norrhea, irritability, and poor feeding. Fever occurs in

approximately 50% of infected infants. Once in thelower respiratory tract, the virus infects the ciliated

epithelial cells of the mucosa of the bronchioles andpneumocytes in the alveoli. Two RSV surface glycopro-

teins, F and G, mediate viral attachment to the glyco-calyx of the target cell. Viral attachment initiates a

conformational change in F protein to a postfusionstructure that facilitates fusion of the viral envelope

and the plasma membrane of the host cell, resulting

in viral entry into the cell. Viral replication initiates aninflux of natural killer cells, helper CD4+ and cytotoxic

CD8+ T lymphocytes, and activated granulocytes. Cellu-lar infiltration of the peribronchiolar tissue, edema, in-

creased mucous secretion, sloughing of infected epi-thelial cells, and impaired ciliary beating cause varying

degrees of intraluminal obstruction. During inspiration,negative intrapleural pressure is generated and air flows

past the obstruction. The positive pressure of expirationfurther narrows the airways, producing greater obstruc-

tion, which causes wheezing. Innate and adaptive im-

mune responses are involved in viral clearance, andmost hospitalized children are discharged after 2 to

3 days. Regeneration of the bronchiolar epitheliumbegins within 3 to 4 days after the resolution of symp-

toms. ICU denotes intensive care unit.





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Sloughed cells

Expandedalveoli withtrapped air

Collapsedalveoli

Obstruction

Obstruction

Migrating

white cells andsloughed cells

Edema

Improvement (hospital discharge)

Worsening (ICU)

HEALTHY CHILD

HOSPITALIZED

CHILD

N AS AL T UR BI NA TE L UM EN B RO NC HI OL E L UM EN

BRONCHIOLE

LUMEN

MUCUS

Healthy bronchiole

Abnormal sloughing of epithelial cells

Intraluminal obstruction and air trapping

Air trapping leading to localized atelectasis

Congenital heart disease Chronic lung disease of prematurity History of prematurity Immunodeficiency Low concentration of maternal antibody

Risk factors for severe RSV disease

Clinical Progression of Respiratory Syncytial Virus (RSV) Pathogenesis of RSV

12

3

4

BA

After 46-day incubation period, fever, congestion,rhinorrhea, irritability, and poor feeding develop.

Bronchiolewith narrowedlumen

Epithelial cells

Virus attaches toand infects theepithelial cells

Child inhalesdroplets

Nasopharyngeal cells are sloughedand aspirated, carrying RSV tolower respiratory tract cellsEPITHELIAL CELLS

EPITHELIUM

ALVEOLI

LUNGS

LUNGS

RSV virion

Debris (mucus,sloughed cells,fibrin)

Edema, cellularinfiltrationcompressingbronchiole

Absorption of trapped air in the alveoli distalto the obstruction leads to localized atelectasis

Sloughing of RSV-infected epithelial cells into the lumen acceleratesviral elimination but also contributes to obstruction of the airway

Virus replication results in epithelial-cell sloughing, inflammatorycell infiltration, edema, increased mucous secretion, andimpaired ciliary action

Loss ofintegrityof alveoli

23 days after onset of upper respiratory tract symptoms,approximately one thirdof patients have spread ofinfection to lower respiratory tract (bronchiolitis).

1

2

Cough, tachypnea, wheezing, grunting, nasal flaring, andthoracic retractions may be present. Hyperinflation of thelung develops as air is trapped behind occluded bronchioles.

3

Air trapped in the alveoli is absorbed, resulting in localizedatelectasis distal to obstruction.

4

Increased work of breathing and decline in lung functionoccur owing to mismatching of ventilation and perfusion,resulting in increasing hypoxemia.

5

Bronchiolitis

Spread of infection from nasopharynx to lower respiratory tract





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Risk Factors

Most infants who are hospitalized with RSVbronchiolitis were born at full term with noknown risk factors.1,2 Chronologic age is thesingle most important predictor of the likeli-hood of severe bronchiolitis, given the observa-

tion that approximately two thirds of hospital-izations of infants with RSV infection occur inthe first 5 months of life.1-3Hospitalization ratesthat are attributable to RSV bronchiolitis arehighest between 30 and 90 days after birth, aperiod that corresponds to the declining concen-tration of transplacentally acquired maternalimmunoglobulin.3 Efficient transplacental pas-sage of RSV neutralizing antibody occurs in in-fants who are born at full term.31,32Because mostmaternal immunoglobulin transfer occurs in thethird trimester, preterm infants may miss theperiod of greatest IgG transfer; this fact partlyexplains the higher risk of disease among pre-term infants.

Children with certain coexisting conditions,including prematurity (delivery at


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Lower serum concentrations of maternal RSVantibody (resulting from waning maternal immu-nity from infection during the previous season)may account for the more severe disease that isobserved among infants born early in the RSVseason, as compared with those who are bornlater.39,40These observations raise the possibility

that active maternal vaccination against RSVduring gestation could have a beneficial clinicaleffect on the infant.41

Both environmental and meteorologic factorsinfluence the timing of the respiratory-virusseason by affecting viral stability, patterns of hu-man behavior, and host defenses. Rainy seasonsand cold weather prompt indoor crowding, whichmay facilitate viral transmission, especially inareas with high population density. A complexinteraction has been identified among latitude,temperature, wind, humidity, rainfall, ultravioletB radiation, cloud cover, and RSV activity.42Hu-man susceptibility to viral infections may be al-tered by certain weather-related factors, such asthe inhalation of cold, dry air that desiccatesairway passages and alters ciliary function, orby the inhibition of temperature-dependent anti-viral responses in the host.43,44

Racial and ethnic-group disparities in rates ofhospitalization for bronchiolitis have been as-sessed in several reports. Rates of hospitaliza-tion for RSV infection among Alaska Native

children living in the YukonKuskokwim Deltain southwestern Alaska and in certain indige-nous Canadian populations are reported to befive times as high as the rate among age-matched children in the continental UnitedStates.45,46Navajo and White Mountain Apachechildren younger than 2 years of age who areliving on a reservation have rates of hospitaliza-tion for RSV infection that are up to three timesas high as the overall rate among children young-er than 2 years of age in the United States.45,47Possible explanations for these disparities include

household crowding, indoor air pollution, lackof running water, and a lower threshold for hos-pital admission because of residence in a remotevillage that is distant from health care facilities.Data from several population-based CDC-spon-sored reports indicate no disparity in the rates ofhospitalization for RSV infection between blackchildren and white children.1-3,48 Because of thelimited numbers of studies, reliable estimates forother ethnic and racial groups are not available.

Some studies have indicated that boys may beat greater risk for severe RSV bronchiolitis thangirls; this finding is similar to the sex differenceobserved with other respiratory viral infec-tions.2,3Sex differences in lung and airway devel-opment and genetic factors have been suggestedas explanations of these findings.49

Bronchiolitis a nd Ast hma

Severe bronchiolitis early in life is associatedwith an increased risk of asthma, especially afterrhinovirus or RSV bronchiolitis, and an increasedrisk of asthma may persist into early adult-hood.50-52 An unresolved question is whetherbronchiolitis early in life results in injury thatalters normal lung development and predisposesthe child to subsequent wheezing or whethercertain infants have a preexisting aberration ofthe immune response or of airway function thatpredisposes them to both severe bronchiolitisand recurrent wheezing.53

Some data support the interesting possibilitythat premorbid lung function may be abnormalamong infants who have severe bronchiolitis inthe first year of life.54-57 Pulmonary-functionstudies conducted before discharge from the neo-natal unit and then repeated after each childsfirst RSV season show persistent pulmonaryabnormalities in some infants, regardless of

whether they had bronchiolit is. This findingsuggests that preexisting pulmonary abnormali-ties are separate from bronchiolitis and not acomplication of it.57For example, some infantsmay have narrow airways when they are well; asa result, bronchioles are less likely to remainpatent once they become further narrowed byinfection. Confirmation of this possibility wouldmake it possible to identify infants who wouldbe most likely to benefit from active or passiveprophylaxis.

A genetic predisposition to severe bronchiolitis

early in life and to the subsequent developmentof asthma is supported by reported associationsbetween polymorphisms in genes involved in theinnate immune response and genes mediatingallergic responses, surfactant proteins, and in-flammatory cytokines.58-60 An association be-tween rhinovirus infection early in life and anincreased risk of childhood-onset asthma is as-sociated with genetic variation at the chromo-some 17q21 locus.52The fact that this associa-





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tion was not found to extend to young childrenwith severe RSV infection indicates that there isa complex interaction between genetic and envi-ronmental factors in the development of asthma.Results from a Danish study involving twinssuggested that severe RSV bronchiolitis is anindicator of a genetic predisposition to asthma

and that, in the absence of this predisposition,asthma is less likely to develop even if they hadpreviously had bronchiolitis.61

Whether the prevention of severe RSV bron-chiolitis will reduce the number of episodes ofrecurrent wheezing has been studied, but theanswer remains elusive. A randomized, double-blind, placebo-controlled trial conducted in theNetherlands involving preterm infants born at33 to 35 weeks of gestation addressed the pos-sible benefit of prophylaxis with palivizumab(a humanized anti-RSV antibody) in preventingwheezing during the first year of life.62Recipi-ents of RSV immunoprophylaxis had a signifi-cant relative reduction of 61% in the number ofdays of wheezing; this difference resulted intheir having 2.7 fewer days of wheezing per 100patient-days than did participants who receivedplacebo. Because the viral cause of wheezingepisodes was determined inconsistently and theprimary end point of the study was audiblewheezing as reported by a parent, rather than amedically verified event, the small reduction in

the number of days with wheezing is of uncer-tain clinical significance.A prospective randomized, placebo-controlled

trial with motavizumab (a second-generationmonoclonal antibody with greater potency againstRSV than palivizumab) that involved 2696 healthy,full-term Native American infants showed a sig-nificant between-group difference (in favor ofmotavizumab) in both inpatient and outpatientmedically attended RSV lower tract disease.63However, no reduction in wheezing occurredamong prophylaxis recipients during 3 years of

careful follow-up. This result is consistent withthe concept that prevention of RSV infectionwith immunoprophylaxis does not have a measur-able effect on subsequent episodes of wheezing.

Supportive Management

Despite the high burden of disease due to bron-chiolitis, it has been difficult to define the best

possible care for a young child with this illnessbecause of the lack of curative therapy. Noavailable treatment shortens the course ofbronchiolitis or hastens the resolution of symp-toms. Therapy is supportive, and the vast ma-jority of children with bronchiolitis do well re-gardless of how it is managed. The intensity of

therapy among hospitalized children has beenshown to have little relationship to the severityof illness.64,65

To improve the standardization of the diag-nosis and management of bronchiolitis in chil-dren, the American Academy of Pediatrics pub-lished a clinical practice guideline, which wasbased on a Grading of Recommendations, Assess-ment, Development and Evaluation (GRADE)analysis, to clarify the level of evidence requiredfor diagnosis and to assess the relationship ofbenefit to harm and the strength of recommen-dations regarding various aspects of the diag-nosis, treatment, and prevention of bronchiol-itis.9,10,66The evidence-based guidelines emphasizethat a diagnosis of bronchiolitis should be basedon the history and physical examination andthat radiographic and laboratory studies shouldnot be obtained routinely (Table 2). Short-acting

2-agonists, epinephrine, and systemic glucocor-

ticoids are not recommended for the treatmentof children with bronchiolitis. Clinicians mayelect not to administer supplemental oxygen

when oxyhemoglobin saturation exceeds 90%.Intravenous or nasogastric fluids may be usedfor children with bronchiolitis who cannot main-tain hydration orally. A complete discussionregarding the management of bronchiolitis isavailable in the clinical practice guidelines.9

Immunoprophylaxis

Palivizumab, a humanized mouse IgG1 mono-clonal antibody directed against a conservedepitope on the surface fusion protein of RSV,

was licensed by the Food and Drug Administra-tion in June 1998 for monthly prophylaxis forinfants at high risk for RSV infection.10 Licen-sure was based largely on the results of a ran-domized, double-blind, placebo-controlled trialconducted during the 19961997 RSV season,which showed a reduction of 5.8% in the rate ofhospitalization attributable to RSV among pre-term infants (10.6% in the placebo group vs.





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4.8% in the prophylaxis group, P3days (most hospitalizations are 90% in the absence ofacidosis

Transient episodes of hypoxemia are not associatedwith complications; such episodes occur commonlyin healthy children

Pulse oximetry Not recommended for patients who do notrequire supplemental oxygen or if oxygensaturation is >90%

Oxygen saturation is a poor predictor of respiratorydistress; routine use correlates with prolongedstays in the emergency department and hospital

Chest physiotherapy Not recommended Deep suctioning is associated with a prolonged hospi-tal stay; removal of obstructive secretions by suc-tioning the nasopharynx may provide temporaryrelief

Antimicrobial therapy Not recommended for routine use Risk of serious bacterial infection is low; routinescreening is not warranted, especially amonginfants 30 to 90 days of age

Nutrition and hydration Hospitalization for observation of hydrationand nutritional status may be needed forinfants with respiratory distress

Intravenous or nasogastric hydration may be used

* Adapted from the clinical practice guidelines for the diagnosis and management of bronchiolitis in children 1 through 23 months of age.9

Table 2.American Academy of Pediatrics Guidance for Diagnosis and Management of Bronchiolitis.*





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adequate attenuation of the vaccine strain, sothat symptoms do not develop in the vaccinerecipient, while at the same time maintainingadequate immunogenicity so that immunity isconferred. Subunit vaccines are being exploredand may be appropriate for seropositive patients;concern about possible enhancement of diseasein seronegative vaccine recipients (particularlyseronegative infants) must be resolved, however,

before trials can proceed. A third approach in-volves maternal immunization during pregnancywith use of a nonreplicating vaccine. Resultsfrom a trial with an RSV recombinant fusionprotein nanoparticle vaccine indicate safety andimmunogenicity in women of childbearing age.69If neutralizing antibodies undergo transplacen-tal passage, protection may be provided for theinfant during the first months of life. This ap-

proach would circumvent the need for vaccina-tion in the first weeks of life, when an infantsimmune response is limited.

Until safe and effective vaccines are available,reduction of the burden of disease due to bron-chiolitis will focus on education about the im-portance of decreasing exposure to and trans-mission of respiratory viruses. The applicationof new forms of technology to the development

of vaccines and antiviral therapies such as fusioninhibitors and nucleoside analogues may im-prove the prevention of RSV infection and thetreatment of children with bronchiolitis through-out the world.68,69

No potential conflict of interest relevant to this article wasreported.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

Category Prophylaxis Recommendation Comment

Preterm infants without chronic lung diseaseof prematurity or congenital heartdisease and


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