refrensi 1

DOI: 10.1542/peds.2009-2092; originally published online January 25, 2010; 2010;125;342Pediatrics

Joseph J. Zorc and Caroline Breese HallBronchiolitis: Recent Evidence on Diagnosis and Management

http://pediatrics.aappublications.org/content/125/2/342.full.html

located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Bronchiolitis: Recent Evidence on Diagnosis andManagement

abstractViral bronchiolitis is a leading cause of acute illness and hospitaliza-tion of young children. Research into the variation in treatment andoutcomes for bronchiolitis across different settings has led toevidence-based clinical practice guidelines. Ongoing investigation con-tinues to expand this body of evidence. Authors of recent surveillancestudies have defined the presence of coinfections withmultiple virusesin some cases of bronchiolitis. Underlying comorbidities and youngage remain the most important predictors for severe bronchiolitis.Pulse oximetry plays an important role in driving use of health careresources. Evidence-based reviews have suggested a limited role fordiagnostic laboratory or radiographic tests in typical cases of bronchi-olitis. Several large, recent trials have revealed a lack of efficacy forroutine use of either bronchodilators or corticosteroids for treatmentof bronchiolitis. Preliminary evidence suggests a potential future rolefor a combination of these therapies and other novel treatments suchas nebulized hypertonic saline. Pediatrics 2010;125:342349

AUTHORS: Joseph J. Zorc, MD, MSCEa,b and CarolineBreese Hall, MDc

aDivision of Emergency Medicine, Department of Pediatrics,Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania;bDepartment of Pediatrics, University of Pennsylvania School ofMedicine, Philadelphia, Pennsylvania; and cDepartments ofPediatrics and Medicine, University of Rochester School ofMedicine and Dentistry, Rochester, New York

KEY WORDSbronchiolitis, respiratory syncytial virus

ABBREVIATIONSRSVrespiratory syncytial virusAAPAmerican Academy of PediatricsHMPVhuman metapneumovirusEDemergency department

www.pediatrics.org/cgi/doi/10.1542/peds.2009-2092

doi:10.1542/peds.2009-2092

Accepted for publication Nov 5, 2009

Address correspondence to Joseph J. Zorc, MD, MSCE, ChildrensHospital of Philadelphia, Division of Emergency Medicine, MainAS01, 34th Street and Civic Center Boulevard, Philadelphia, PA19104-4399. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Hall has received grant supportand consulting fees from MedImmune, Inc; Dr Zorc has indicatedhe has no financial relationships relevant to this article todisclose.

342 ZORC and HALL at Indonesia:AAP Sponsored on July 2, 2012pediatrics.aappublications.orgDownloaded from

http://pediatrics.aappublications.org/

Bronchiolitis is a disorder of the lowerrespiratory tract that occurs mostcommonly in young children and iscaused by infection with seasonal vi-ruses such as respiratory syncytial vi-rus (RSV). Bronchiolitis is the leadingcause of infant hospitalization in theUnited States and has been associatedwith increasing morbidity rates andcost over recent decades.13 Multiplestudies have documented variation indiagnostic testing, treatment, hospital-ization rates, and length of hospitalstay for bronchiolitis, suggesting alack of consensus and an opportunityto improve care for this common dis-order.46 Recognition of this need led toa clinical practice guideline7 publishedby the American Academy of Pediatrics(AAP) and other organizations in 2006based on a review of the scientific evi-dence funded by the Agency for Health-care Research and Quality.8

Bronchiolitis is an active area of re-search, and many important studieshave advanced the understanding ofthis disorder in the past few years. Inthis review we focus on new develop-ments in the scientific evidence thatrelate to the pathophysiology, epidemi-ology, diagnosis, and management ofbronchiolitis. Because the AAP guide-line recently summarized the previousbody of research, we highlight subse-quently available information relevantto those recommendations. The pre-vention and potential long-term effectsof bronchiolitis, although active re-search areas, will not be reviewed.

DEFINITION ANDPATHOPHYSIOLOGY

Although the term bronchiolitis re-fers to inflammation of the bronchi-oles, these findings are rarely ob-served directly but inferred in a youngchild who presents with respiratorydistress in association with signs of aviral infection. Definitions of bronchi-olitis vary andmay account for some of

the variability in the clinical evidencederived from published studies. In theUnited Kingdom, the term tends to beused more specifically. The authors ofUniversity of Nottingham study deriveda consensus definition of a seasonalviral illness characterized by fever, na-sal discharge, and dry, wheezy cough.On examination there are fine inspira-tory crackles and/or high-pitched expi-ratory wheeze.9 In North America,bronchiolitis commonly is appliedmore broadly but is linked to the spe-cific finding of wheeze. The AAP guide-line defined bronchiolitis as a constel-lation of clinical symptoms and signsincluding a viral upper respiratoryprodrome followed by increased respi-ratory effort and wheezing in childrenless than 2 years of age.7 The distinc-tion is important, because recurrentwheezing among older children is of-ten triggered by viruses that are typi-cally limited to the upper respiratorytract, such as rhinoviruses (see dis-cussion below). Researchers have of-ten attempted to focus the populationof children with bronchiolitis by limit-ing inclusion to infants younger than12 months with a first-time episode ofwheezing, although even then hetero-geneity in the population may persist.

Recognizing the pathologic picturethat occurs in the airways of childrenwith bronchiolitis is important in un-derstanding the clinical manifesta-tions and developing rational manage-ment.10 The viral infection occursthrough the upper respiratory tractand spreads lower within a few days,resulting in inflammation of the bron-chiolar epithelium, with peribronchialinfiltration of white blood cell types,mostly mononuclear cells, and edemaof the submucosa and adventitia.Plugs of sloughed, necrotic epitheliumand fibrin in the airways cause partialor total obstruction to airflow. The de-gree of obstruction may vary as theseareas are cleared, resulting in rapidly

changing clinical signs that confoundan accurate assessment of the sever-ity of illness. A ball-valve mechanismcan result in trapping of air distal toobstructed areas, with subsequent ab-sorption, atelectasis, and a mismatchof pulmonary ventilation and perfusionthat may lead to hypoxemia. Atelecta-sis may be accelerated by the lack ofcollateral channels in young childrenand potentially by the administrationof high concentrations of supplemen-tal oxygen, which is absorbed morerapidly than room air. Smooth-muscleconstriction seems to have little role inthe pathologic process, which may ex-plain the limited benefit of bronchodi-lators observed in clinical studies.

The number of viruses recognized tocause bronchiolitis has markedly ex-panded with the availability of sensi-tive diagnostic tests that use mo-lecular amplification techniques. RSVcontinues to account for 50% to 80% ofcases.11 Other causes include the para-influenza viruses, primarily parainflu-enza virus type 3, influenza, and humanmetapneumovirus (HMPV).1214 HMPVhas been estimated to account for 3%to 19% of bronchiolitis cases.15,16 Theclinical courses of RSV and HMPV seemto be similar; most children are in-fected during annual widespread win-tertime epidemics, with a subset devel-oping bronchiolitis.12,17,18

Molecular diagnostic techniques havealso revealed that young children withbronchiolitis and other acute respira-tory illnesses often are infected withmore than 1 virus. Rates of coinfectionhave ranged from 10% to 30% in sam-ples of hospitalized children, mostcommonly with RSV and either HMPVor rhinovirus.19 A recent large pro-spective study of children youngerthan 5 years of age hospitalized withRSV infection revealed a coinfectionrate of 6%.3 Whether concomitant in-fection increases the severity of bron-chiolitis is controversial. A 10-fold in-

STATE-OF-THE-ART REVIEWS

PEDIATRICS Volume 125, Number 2, February 2010 343 at Indonesia:AAP Sponsored on July 2, 2012pediatrics.aappublications.orgDownloaded from


crease in the risk of mechanicalventilation was associated with dualRSV and HMPV infection in 1 smallstudy.20 Other studies, however, haverevealed no increased illness severityassociated with the presence of morethan 1 virus.19,21

The role of rhinoviruses in bronchioli-tis is unclear because of their well-documented role in triggering exacer-bations of wheezing among olderchildren with reactive airway diseaseor asthma.2225 A multicenter emer-gency department (ED)-based study ofchildren younger than 2 years diag-nosed with bronchiolitis revealed thatchildren infected with rhinovirus weremore likely to be black, to have a pre-vious history of wheezing, and to betreated with corticosteroids than in-fants with other viral infections.13

Genomics is an emerging area of re-search for bronchiolitis. Studies haveidentified single-nucleotide polymor-phisms in a number of genes, includ-ing those involved in innate immunity,that are associated with risk for moresevere bronchiolitis.26,27 Other genes,such as the vitamin D receptor gene,have been associated with bronchi-olitis and may link to preliminary ev-idence associating neonatal vitaminD levels with wheezing in youngchildren.28,29

DISEASE COURSE AND PREDICTION

Epidemiologic study results of bron-chiolitis have suggested a high degreeof morbidity but low mortality. Morethan one third of children developbronchiolitis during the first 2 years oflife.7,30 Of these, approximately 1 in 10(3% of all infants in the UnitedStates) will be hospitalized, up fromapproximately 1% in the 1970s.1 Therate of hospitalization retrospectivelyestimated during 19952003 from aTennessee Medicaid population was7.1%, which suggests that higherrates may occur among some groups

of children.31 A recent prospectivepopulation-based study showed thatthe yearly rate from RSV alone for in-fants younger than 6 months of agewas 17 hospitalizations, 55 ED visits,and 132 office visits per 1000 children.3

Although the number of hospitaliza-tions seems to have increased, themortality rate is low; fewer than 400deaths related to RSV occur annual-ly.3,32,33 Most deaths that result frombronchiolitis occur in infants duringthe first 6 months of life; infants withprematurity and underlying cardiopul-monary disease or immunodeficiencyare at higher risk.7,34 Studies of preven-tive immune therapies, such as palivi-zumab, have documented a reductionin RSV hospitalization rates for specifichigh-risk groups, and AAP recommen-dations were updated recently.3537

The potential for disease progressionhas led to research to identify risk fac-tors for severe bronchiolitis. Table 1presents the clinical predictors of hos-pitalization evaluated in several outpa-tient populations.3840 The likelihoodratios demonstrate the limited predic-tive value of individual clinical findingson the physical examination to predictoutcomes, which may be related to thetypical minute-to-minute variability ofthese findings among children withbronchiolitis. When evaluated indepen-dently, other predictors, including at-electasis on chest radiography, havebeen correlated with outcomes insome studies.38 However, a recentstudy showed that chest radiographicabnormalities correlated with overallclinical severity on physical examina-tion, which suggests that the pre-

TABLE 1 Selected Risk Factors for Outcomes of Bronchiolitis in 3 Prospective Studies ofOutpatients

Shaw et al38

(1991)Mansbach et al40

(2008)Voets et al39

(2006)

Outcome Severe diseasea Hospitalization HospitalizationRisk factorsAge

2 mo 4.5/0.783 mo 2.2/0.756 mo 2.2/0.53

Prematurity34 wk 5.4/0.7735 wk 1.5/0.96

Ill appearance 3.2/0.32Oxygen saturation

94% 5.4/0.7795% 16/0.69 5.2/0.37

Respiratory rate45 breaths per min 3.8/0.39At or higher than normal for age (4045breaths per min according to age)

1.3/0.61

70 breaths per min 5.8/0.75Work of breathingAccessory muscle use 2.2/0.42Moderate/severe retractions 3.2/0.76

Chest radiograph resultAtelectasis 10.5/0.81Abnormal 1.2/0.73

Risk factors are presented as positive or negative likelihood ratios (LR/LR). The likelihood ratio can bemultiplied by thepretest odds (ratio of the risk/1-risk) to obtain the posttest odds. For example, with a previous risk of hospitalization of 33%(odds of 0.33/0.66 0.5), a finding with a positive likelihood ratio of 4 increases the odds to 2 (4 0.5), corresponding toa posttest risk of 67% (2/2 1).a Severe disease was defined as unable to maintain alert, active, and well hydrated while taking oral fluids throughout theillness.Adapted with permission from Zorc JJ. Recent Advances in Paediatrics. London, United Kingdom: Royal Society of MedicinePress; 2009:19.



sence of atelectasis adds little to theassessment.41

Pulse oximetry is among the measuresmost strongly correlated with out-comes of bronchiolitis. In a recent mul-ticenter prospective study, a pulseoximetry level of 94% was associ-ated with a more-than-fivefold in-crease in likelihood of hospitalization.40

A cohort study conductedwhenoximetrywasnot in routine use revealed thatmildhypoxemia was correlated with a moresevere course, which likely reflects pul-monary ventilation-to-perfusion mis-match.38 However, arbitrary thresholdsfor oxygen therapy may also influenceoutcomes. A survey of emergency physi-cians revealed that reducing the oxime-try level from 94% to 92% in a clinicalvignette significantly increased the likeli-hood of recommending hospitalization.42

Furthermore, a substantial proportionof infants remain in the hospital to re-ceive oxygen when other abnormalitieshave improved.43 A recent British studyrevealed that the mean lag time for oxy-gen saturation to normalize was 66hours after all other problems had re-solved.44 Continuous oximetry may en-hance this situation, because it will de-tect the characteristic transient dips inoxygenation associated with bronchioli-tis. This evidence further supports theAAP recommendations that oxygen ther-apy be initiated judiciously when oxygensaturation levels fall below 90% and thatthe intensity of monitoring oxygen satu-ration levels be reduced as the infant im-proves.7 Novel approaches, such as theuse of home oxygen therapy, have beenstudied in somepopulations, and furtherresearch on oxygen use in bronchiolitisis needed.45,46

Apnea is a specific and important con-cern in the management of young in-fants with bronchiolitis, especiallythose with RSV. The incidence of thiscomplication may be much lower thanprevious reports have suggested.47,48 Aretrospective study of 691 infants

younger than 6 months of age whowere hospitalized for bronchiolitis re-vealed that apnea occurred in 19(2.7%).49 All of these apneic infantswere identified by risk criteria includ-ing either (1) history of an apneic epi-sode having already occurred or (2)young age, defined as less than 1month for term infants or a postcon-ceptional age of48weeks for prema-ture infants.49

DIAGNOSTIC TESTING

The type and frequency of diagnostictests used for bronchiolitis, such as vi-ral detection and radiographs, varymarkedly among clinicians.5 As statedin the AAP guideline, results ofevidence-based reviews have not sup-ported a role for any diagnostic testsin the management of routine cases ofbronchiolitis.7,50 In addition, studies ofefforts to standardize care have dem-onstrated substantial reductions in di-agnostic testing rates with potentialbenefits on costs and outcomes.51,52 Re-cent evidence further supports a lim-ited role for diagnostic testing in mostcases of bronchiolitis.

Rapid viral antigen tests have variablesensitivity and specificity dependingon the test and when they are usedduring the respiratory season.53 Theirpredictive value is generally good dur-ing the peak viral season but de-creases considerably at times of lowprevalence. Because most viruses thatcause bronchiolitis have similar clini-cal courses, the value of identifying thespecific agent varies according to thesetting. In typical outpatient cases, re-sults would likely have little impact onmanagement. In the hospital setting,however, specific viral testing hasbeen used as part of successfulinterventions to reduce nosocomialinfection.48,49

For the specific clinical scenario of aninfant presenting during the first few

months of life with bronchiolitis andfever, studies have evaluated prospec-tively the ability of a positive viral testto predict a low likelihood for a bacte-rial infection. Authors of 1 study docu-mented a low but not insignificant rateof bacterial infection accompanyingRSV infection, mostly in the urinarytract.54 Low rates of coinfections alsohave been observed in recent studiesonly on the basis of the clinical diagno-sis of bronchiolitis.55 In a prospectivepediatric officebased study of 218 fe-brile infants younger than 3 months ofage with clinically diagnosed bronchi-olitis, no serious bacterial infectionswere identified.56 These findings fur-ther support the idea that, for mostcases of bronchiolitis, the clinical diag-nosis of bronchiolitis is sufficient, andviral testing adds little to routinemanagement.

The use of chest radiography for diag-nosis and management of bronchioli-tis has also varied widely and is notrecommended routinely by the AAP.7 Asubsequent prospective study of chil-dren aged 2 to 23 months who pre-sented to the ED with bronchiolitis fur-ther showed the low yield of routineradiography as well as a potentialdetrimental effect.57 Of 265 childrenwith simple bronchiolitis (definedas coryza, cough, and respiratory dis-tress accompanying a first episode ofwheeze in a child without underlyingillness), routine radiography identifiedfindings inconsistent with bronchioli-tis in only 2 cases, and in neither casedid the findings change acute manage-ment. After reviewing the radiographs,clinicians were more likely to treatwith antibiotics, although the findingsdid not support treatment.

Although the diagnosis of most casesof bronchiolitis is clinically evident anddoes not require diagnostic testing,the differential diagnosis is broad andalways warrants consideration (see




Table 2). This is essential for childrenwith atypical presentations, such asthe absence of viral symptoms, severerespiratory distress, and frequent re-currences. Children with this type ofpresentation may require diagnosticevaluation to rule out another cause.

THERAPYThe role of bronchodilators in thetreatment of bronchiolitis has been thesubject of many studies and systematicevidence-based reviews of the litera-ture.58 Summarizing the results ofthese studies is confounded by the va-riety of therapies and outcome mea-sures, which range from short-termclinical scores obtained soon aftertreatment to broader clinical out-comes such as hospitalization or dura-tion of illness. Even score-based stud-ies are difficult to compare, becausemany of the measures used do nothave established validity or provencorrelation with clinically significantimprovement. Pooling the results ofclinical scores from a large number ofstudies may result in a statisticallysignificant difference of questionableclinical importance.

In a recent Cochrane collaborationsystematic review, studies that dichot-

omized patients into thosewho did anddid not respond to bronchodilatorswere compared (Fig 1).58 Several over-arching principles are demonstratedin Fig 1. First, the results are heteroge-neous, with a minority of studies find-ing improvement. This likely mirrorsthe heterogeneity of the responsesamong individual patients. Second, ahigh rate of improvement among con-trol subjects (43%) exists that may re-sult from the characteristic clinicalvariability observed with bronchiolitisor from a response to other supportivemeasures that could be mistakenly at-tributed to a bronchodilator responsein an uncontrolled setting. The modestdifference in the treatment group

(57%) did not reach statistical signifi-cance in this analysis. The question-able clinical importance of thisresponse is underscored by a meta-analysis of studies that found no effectof bronchodilator administration onhospitalization rates.58 Furthermore,results of a multicenter clinical trial ofepinephrine administration revealedthat epinephrine had no effect on du-ration of hospitalization.59

A 2006 Cochrane systematic review ofstudies that compared bronchodila-tors for themanagement of bronchioli-tis in outpatients suggested a potentialbenefit with epinephrine administra-tion.60 However, several more recentstudies did not support the routine useof epinephrine. A study of 703 childrenwith bronchiolitis in 2 EDs compared 3doses of albuterol with 1 dose of race-mic epinephrine and revealed a smallbenefit that favored albuterol insuccessful discharge.61 A multicenterstudy from the Pediatric EmergencyResearch Canada network enrolled800 healthy infants with a first episodeof bronchiolitis and compared epi-nephrine to placebo as part of a facto-rial design trial with 4 groups that alsoevaluated dexamethasone (see discus-

FIGURE 1Cochrane collaboration systematic review of studies that assessed the difference in rate of improvement after 2-agonist bronchodilators or placeboamong children with bronchiolitis. (Reproduced with permission from Gadomski AM, Bhasale AL. Cochrane Database Syst Rev. 2006;(3):CD001266.)

TABLE 2 Differential Diagnosis for a WheezingInfant

Viral bronchiolitisOther pulmonary infections (eg, pneumonia,Mycoplasma, Chlamydia, tuberculosis)

LaryngotracheomalaciaForeign body, esophageal or aspiratedGastroesophageal refluxCongestive heart failureVascular ringAllergic reactionCystic fibrosisMediastinal massBronchogenic cystTracheoesophageal fistula



sion below).62 Two doses of nebulizedepinephrine did not reduce the num-ber of hospitalizations when com-pared with placebo. Overall, the avail-able current evidence continues tosupport the AAP recommendationagainst the routine use of bronchodila-tors for bronchiolitis.7 A monitoredtrial of a bronchodilator can be consid-ered as an option, but it should be con-tinued only after a documented benefi-cial response (Table 3).

Corticosteroid administration for thetreatment of bronchiolitis also hasbeen controversial. The studies re-viewed in theAAPguideline revealed thatcorticosteroid administration was notassociatedwith significant reductions inclinical scores, hospitalization rates, orlength of hospitalization.7 Several largestudies subsequently expanded thesedata. A multicenter trial from the Pediat-ric Emergency Care Applied ResearchNetwork, which enrolled 600 previouslyhealthy infants with a first episode ofbronchiolitis, showed that a single oraldose of dexamethasone resulted in nosignificant improvement compared withplacebo in the rates of hospitalization orclinical scores.63

The Pediatric Emergency ResearchCanada study, mentioned above, con-

firmed this finding by using a regimenof 6 days of dexamethasone and alsorevealed no improvement in diseasecourse.62 It is interesting to note that inthis factorial design study, the groupof those who received dexamethasonecombined with 2 doses of nebulizedepinephrine had a lower admissionrate over 7 days compared with thosewho were on placebo (17.1% vs 26.4%).The study authors did not anticipatethis potential interaction in the design,and after adjustment for multiple com-parisons the difference did not reachstatistical significance (P .07). Inter-pretation of this result awaits furtherinvestigation before it can be imple-mented in routine practice. Synergybetween adrenergic agents and corti-costeroids has been well described inasthma and has been observed inother small studies of bronchioli-tis.6466 If confirmed, the moderate ef-fect (11 infants needing to be treatedfor 1 not to be admitted) could, never-theless, represent a potentially impor-tant relative reduction in the numberof hospitalizations for this commondisorder. Future studies may evaluatewhether a larger effectmay be presentamong a subgroup of infants and as-sess other dose combinations.

Among other therapies explored forpotential use in bronchiolitis is the leu-kotriene receptor antagonist, monte-lukast, which did not seem beneficialin resolution of symptoms.67,68 Nebu-lized hypertonic saline has been asso-ciated in recent randomized trials andin a Cochrane meta-analysis with im-provement in clinical score and dura-tion of hospitalization.69,70 Other thera-pies such as helium/oxygen, nasalcontinuous positive airway pressure,and surfactant are being assessed foruse in critically ill patients.7173

CONCLUSIONS

Bronchiolitis continues to be an activearea of investigation across the spec-trum from genetic mechanisms topopulation-based research. Surveil-lance studies continue to identify newcauses of bronchiolitis and explore therole of viral coinfections. Research onprediction of the course of illness hasrevealed comorbidities as importantrisk factors and specific physical or di-agnostic test findings as less predic-tive of outcomes for most bronchiolitiscases. The use of pulse oximetry haslikely contributed to longer hospital-izations and greater use of healthcare resources, suggesting that thestandard of care for oxygen therapyrequires better definition. Recentmulticenter research on therapy forbronchiolitis supports previous AAPrecommendations against the routineuse of bronchodilators or corticoste-roids. Further investigation is neededto explore the combination of thesetherapies and other interventions,such as nebulized hypertonic saline.

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TABLE 3 Summary of Recent Evidence for Therapies Used for Bronchiolitis

Therapy Summary Recommendation

Bronchodilators No improvement in duration of illnessor hospitalization58,59

No routine use

May improve short-term clinicalscores in a subset of children58

Use only after proven benefit in a trialof therapy, if chosen as an option

Corticosteroids No improvement in duration of illnessor hospitalization7,63

No routine use

Leukotriene receptorantagonists

No improvement in duration ofillness67,75

Not recommended

Nebulized hypertonicsaline

May reduce length of inpatienthospitalization70

None




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DOI: 10.1542/peds.2009-2092; originally published online January 25, 2010; 2010;125;342Pediatrics

Joseph J. Zorc and Caroline Breese HallBronchiolitis: Recent Evidence on Diagnosis and Management

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