J. Pediatr. (Rio J.) vol.93 número5

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www.jped.com.br

ORIGINAL

ARTICLE

One-year

observational

study

of

palivizumab

prophylaxis

on

infants

at

risk

for

respiratory

syncytial

virus

infection

in

Latin

America

夽

Leandro

Martin

Castillo

a

_,

_Gabriela

_Bugarin

a,∗

,

Juan

Carlos

Arias

b

,

Jairo

Israel

Barajas

Rangel

c

_,

_Maria

_Elina

_Serra

d

_,

_Nestor

_Vain

d,e

a_AbbVie_Inc.,_Buenos_Aires,_Argentina

b_Casa_Madre_Canguro_Alfa_S.A.,_Cali,_Colombia

c_Hospital_General_Regional_de_León,_León,_Guanajuato,_Mexico

d_FUNDASAMIN_Fundación_para_la_Salud_Materno_Infantil,_Buenos_Aires,_Argentina

e_Sanatorio_de_la_Trinidad_Palermo,_Buenos_Aires,_Argentina

Received26July2016;accepted9November2016 Availableonline22February2017

KEYWORDS

Palivizumab; Prophylaxis;

Respiratorysyncytial virus;

Lowerrespiratory tractinfection; LatinAmerica

Abstract

Objective: Thisstudyaimstodescriberealworldpalivizumabuseandeffectivenessinhigh-risk LatinAmericaninfantsandyoungchildren.

Method: Prospective,multicenterobservationalstudywithinfantsatriskforsevereRSV infec-tionwhoreceivedpalivizumabaccordingtoroutineclinicalpractice.Subjectswerefollowed foroneyearwithmonthlyvisitsafterthefirstdoseofpalivizumab.Aninfantwasconsidered adherentifreceivingalltheexpectedinjectionsorfiveorfewerinjectionswithinappropriate inter-doseintervals.Annualincidenceratesandriskfactorsoflowerrespiratorytractinfection (LRTI)hospitalizationweredeterminedthroughPoissonregressionmodels(˛=0.05).

Results: Thestudyenrolled458childrenfromsevencountriesinLatinAmerica,fromFebruary 2011toSeptember2012.Themajority(98%)wereborn<36weeksgestation.Overall,patients received83.7%oftheirexpectedinjectionsand86.7%completedoneyearoffollow-up.Ofthe 61LRTIhospitalizations,12episodeswereduetoRSVinfection.TheRSV-associated hospital-izationratewas 2.9per100patient-years.Bronchopulmonarydysplasiawas identifiedasan

夽

Pleasecitethisarticleas:CastilloLM,BugarinG,AriasJC,RangelJI,SerraME,VainN.One-yearobservationalstudyofpalivizumab prophylaxisoninfantsatriskforrespiratorysyncytialvirusinfectioninLatinAmerica.JPediatr(RioJ).2017;93:467---74.

∗_{Corresponding}_author.

E-mail:gabriela.bugarin@abbvie.com(G.Bugarin).

http://dx.doi.org/10.1016/j.jped.2016.11.006

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independentriskfactorforLRTIhospitalization.Atotalof1165adverseeventswererecorded duringoneyearoffollow-up.Onehundredandtwopatients(22.3%)hadatotalof135serious adverseevents,butnoeventswereconsideredtoberelatedtopalivizumab.

Conclusions: TherateofRSVhospitalizationinhigh-riskinfantsinLatinAmericawaslowand alignedwiththoseobservedinrandomizedcontroltrialsandobservationalstudies.Palivizumab prophylaxisappearedeffectiveandhadagoodsafetyprofileinthispopulation.

PALAVRAS-CHAVE

Palivizumabe; Profilaxia; Vírussincicial respiratório; Infecc¸ãodotrato respiratórioinferior; AméricaLatina

Estudoobservacionaldeumanodaprofilaxiacompalivizumabeemneonatos comriscoparainfecc¸ãoporvírussincicialrespiratórionaAméricaLatina

Resumo

Objetivo: Esteestudo visadescrevero usoeaeficáciado palivizumabenomundo real em neonatosejovenscrianc¸asdealtoriscolatino-americanas.

Método: Estudo observacional prospectivo multicêntrico com neonatos em risco devido a infecçãograveporVSRquereceberampalivizumabedeacordocomapráticaclínicaderotina. Osindivíduosforamacompanhadosporumano,comvisitasmensaisapósaprimeiradosede palivizumabe.Umneonatofoiconsideradoadeptoserecebeutodasasinjeçõesesperadasou ≤5injeçõesnosintervalosentredosesadequados.Astaxasdeincidênciaanuaiseosfatores deriscodeinternaçãoporinfecçãodotratorespiratórioinferior(ITRI)foramdeterminadospor meiodosmodelosderegressãodePoisson(␣=0,05).

Resultados: Oestudoinscreveu458criançasdesetepaísesdaAméricaLatina,defevereirode 2011asetembrode2012.A maioria(98%) nasceucom<36semanas.Emgeral, ospacientes receberam 83,7% de suas injeções esperadas, e 86,7% completaram um ano de acompan-hamento.Das61internaçõesporITRI,12episódiosforamdevidosainfecçãoporVSR.Ataxade internaçãoassociadaaoVSRfoide2,9emcada100pacientes-anos.Adisplasiabroncopulmonar foiidentificadacomoumfatorderiscoindependentedainternaçãoporITRI.Foramregistrados 1165eventosadversosnototalduranteumano deacompanhamento.122pacientes(22,3%) apresentaramumtotalde135eventosadversosgraves,porémnenhumdelesfoiconsiderado relacionadoaopalivizumabe.

Conclusões: A taxadeinternação porVSRem neonatos dealto risconaAmérica Latina foi baixaeemlinhacomasobservadasemensaiosclínicoscontroladosrandomizadoseestudos observacionais.Aprofilaxiacompalivizumabepareceueficazecombomperfildesegurança nessapopulação.

Introduction

Lower respiratory tract infections (LRTIs) are a leading causeof acuteillnesses andmortalityin infants and chil-dren <5 years of age, accounting for approximately 1.4 million deaths in 2010 worldwide.1 _Respiratory _syncytial virus(RSV)isthemostfrequentetiologyofsevere respira-toryillness,suchasbronchiolitisand/orpneumonia.2,3_One meta-analysisestimatedthatatleast33.8millionepisodes ofLRTIand66,000---199,000 deathsinchildren<5yearsof agewerecaused byRSV infectionin 2005.2_Nearly _99%_of RSVdeathsoccurredindevelopingcountries,wherethe inci-denceofRSV-associatedLRTIseemstobemorethantwice thatobservedinindustrializedcountries.2

In Latin America, a recent meta-analysis estimated a 41.5% (95% CI, 32.0---41.4) prevalence of RSV in infants aged0---11 months with LRTI,and that RSV was responsi-ble for 36.5% (95% CI, 28.5---44.9) of hospital admissions

due to LRTIamonginfants aged0---11 months.4 _Moreover, aprospective epidemiologicalcohortofpatients aged<18 yearshospitalizedduetoLRTIsfrom2000to2013inBuenos Airesregistered aRSV associatedfatality rateof1.9% (74 deaths/3888cases).5_Although_these_estimates_may_imply_an urgencyfor health-relatedinterventions,morestudiesare neededtoquantifythediseaseburdenduetoRSVandrisk factorsassociatedtoLRTIhospitalizationsinLatinAmerican countries.2,4

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bronchopulmonary dysplasia (BPD), and hemodynamically significantcongenitalheartdisease(HSCHD).3,8---10_However, therelativeimportanceoftheseriskfactorsmaybe differ-entinLatinAmerica.

Palivizumab(Synagis®_;_AbbVie_Inc,_IL, _USA)_is _a

human-ized monoclonal antibody approved for theprevention of severeRSVdiseaseinprematureinfantsandinyoung chil-dren with BPD or HSCHD.11 _Its _safety _and _efficacy _have been assessed in randomized controlled studies, open-label non-comparative trials, and several observational studies.12 _Lower_rates _of _RSV _{hospitalizations} _and_clinical complicationshavebeenreportedinchildrenwhoreceived palivizumab prophylaxis.8,12,13 _However,_there_is _a_paucity ofdata aboutthe useandeffectivenessof palivizumabin developingcountrieswhereratesofRSVinfectionarehigher, specificallyinLatinAmericancountries.12,14---17

Thisstudyaimstodescribepalivizumabuseinhigh risk-infants,andtoestimatethefrequencyofRSVhospitalization amonginfantsandyoungchildrentreatedwithpalivizumab in Latin American countries, during a one-year period of follow-upafterthefirstdose.

Methods

Studydesign

This was a prospective, observational, multicenter study in a cohort of infants at risk for severe RSV infection whoreceivedpalivizumabduringlocalRSVcirculation and within the terms of marketing authorization with regard to dose, population, and indication. The study was con-ducted at 24 sites across seven Latin American countries (Argentina, Chile, Colombia, Ecuador, Mexico, Peru, and Uruguay).SubjectrecruitmentbeganonFebruary19,2011, andconcludedonSeptember6,2012;eachsubjectwas fol-lowedfor12months,withmonthlyvisitsduringtheperiodof palivizumabadministrationand,afterwards, withmonthly calls.

Eligibilitycriteria

Ateachstudysite,prematureinfants(bornat≤35weeksof gestationalage)oryoungchildrenwithahistoryofBPDor HSCHDwhoreceivedthefirstdoseofpalivizumabwithinthe twoweeksprior tothe inclusioncriteriaassessment were eligibletoparticipateinthestudy.Childrenexcludedfrom receiving palivizumab as per local practice did not enter intothestudy.Theparentsorlegalguardiansoftheinfants andyoungchildrenincluded inthestudyprovidedwritten informedconsentfortheirchild’sparticipation.

Follow-upanddatacollection

Enrolledsubjectswerefollowedfor oneyearafter receiv-ing their first dose of palivizumab. Epidemiological and clinicaldata,informationaboutpatientadherence, hospi-talizations, and safety data were collected ona monthly basisandaccordingtoroutineclinicalpractice,through in-officeevaluationsduringthefirstfourmonths.Afterthefirst

fourmonths,thereweresixand12-month follow-upvisits andfollow-upphonecallsatmonthsfive,seven,eight,nine, 10,and11afterthesubjectwasincludedinthestudy.

Each patient’s medical history and exposure to envi-ronmental risk factors were collected and a physical examination was performed at each in-office study visit. Adverse events and hospitalizations that occurred since the previous visit were also recorded. LRTI was defined as pneumonia, bronchiolitis, or wheezing, according to clinical diagnosis. Nasal and pharyngeal swabs were col-lected for RSV testing only when recommended by local clinical guidelines and/or according to physician/medical decision.

Childrencouldreceive uptofivedosesofpalivizumab, according to the physician’s prescription. Patient adher-encetotreatmentwascalculatedasthereceivednumber of palivizumab doses vs. the expected number of doses. The expectednumberof doses for each patientwas esti-matedbasedonseasonalityandthecurrentguidelinesfor eachcountry. An analysisof inter-dose interval(for cases inwhich the date for every dose wasavailable) was per-formed,andintervalsof30(±5)dayswereconsideredtobe compliant.

Safetyanalysis

AdverseeventswereclassifiedbasedontheMedical Dictio-naryforRegulatoryActivitiesclassificationsystem,version 16.0.Seriousadverse events were definedasany adverse eventthat resulted in death, a life-threateningsituation, inpatienthospitalization,persistentorsignificantdisability orincapacity,orotherclinicallyrelevantevents.

Statisticalanalysis

Aminimumsamplesizeof400patientswasestimatedbased onthepotentialnumberofpatientsreceivingpalivizumab in each country, and to allow an estimate of the pro-portion of LRTIs with a 95% confidence interval (CI) and withinan estimated precisionof 3%.Alldata analysiswas conducted with Stata (StataCorp. 2007. Stata Statistical Software:version10. TX, USA).Frequencies and percent-agesofcategoricalvariables,aswellasmeasuresofcentral positionanddispersionforquantitativevariables,wereused todescribethecharacteristicsofsamplesubjects,theuse ofpalivizumab,andmostcommonadverseevents.The95% CIswereestimatedfortheproportionsorincidenceratesof relevantoutcomes.Generalizedlinearmodelswereusedto estimateannual LRTIhospitalizationrates.Poisson regres-sionmodels wereapplied toidentify risk factorsfor LRTI hospitalizations,and baselinecharacteristics such asage, gender, birth weight, andcomorbidities were included as covariates.

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Results

Samplecharacteristics

Atotalof464infantsandyoungchildrenwereenrolledat 24 sites in seven countries in Latin America, from which six were excluded due to having no additional follow-up visits (n=4), invalid informed consent (n=1), or having receivedpalivizumabinthepreviousseason(n=1).Hence, 458infantsandyoungchildrenwereincludedinthestudy, and397(86.7%)completedoneyearoffollow-up.Amongthe 61infantsandyoungchildrenthatdidnotcomplete follow-up,43(70.5%)werelosttofollow-up,six(9.8%)hadstudy consentwithdrawn,three(4.9%)diedfromnon-respiratory disease-associatedreasons,andnine(29.4%)didnot com-pletethestudyforotherreasons.

Patientdemographicsoftheincludedinfantsandyoung children are shown in Table 1. Fifty-two percent of the patients were male. The mean birth weight was 1345g (standarddeviation[SD],460),andthemediangestational agewas31weeks(range,23---39weeks).Nearlyallofthe patients in the study (98.2%) were premature; 29.2% of patientshadBPDand10.1%hadHSCHD.Furthermore, pre-maturity with BPD and/or HSCHD were seen in 33.4% of patients.

Useandpatientadherencetopalivizumab

Themostfrequentreasonforindicationofpalivizumabwas prematurity(byitselfor inconjunction withother indica-tions)(98.0%).Thetotalnumberofdosesadministeredwas 1744in458patients, correspondingto3.8±1.3dosesper patientonaverage.Overall,patientsreceived83.7%(95%CI, 80.8---86.5)oftheirexpecteddoses,basedonseasonalityand currentguidelinesforeachcountry,and78.4%ofthe1249 inter-dose intervalswere classified asadherent (Table1). The mean time between starting palivizumab prophylaxis anddeveloping an LRTIdue toRSVwas75.7 days,witha medianof44days.

HospitalizationsduetoLRTI

Sixty-one episodes of LRTI that required hospitalization occurredin52children (Table2).Thehospitalizationrate due to LRTI was 14.6 per 100 patient-years (95% CI, 10.5---18.6).RSVinfectionwasconfirmedin12episodesin12 infants,andtheRSV-associatedhospitalizationratewas2.9 per100patient-years(95%CI,1.3---4.5).NoneoftheRSV hos-pitalizationsrequiredrespiratorysupport.Fromthe12cases ofRSV-associatedhospitalizations,allwerepretermbabies andtenhadanotherriskfactor:ninewereBPDpatientsand onewasHSCHD.

Univariate and multivariate analyses were performed for identification of risk factors for LRTI hospitalization (Table3).Intheunivariateanalysis,alowerlevelof mater-naleducationandBPD wereshowntoincreasethe riskof LRTIhospitalizationin a population receiving palivizumab prophylaxis. In the multivariate model analysis, only BPD wasconfirmedasanindependentriskfactor(adjustedIRR, 2.77).

Table1 Demographic,clinical,andtreatment

character-isticsofthestudypopulation(n=458).

Enrollmentcountry,n(%)

Argentina 149(32.5%)

Colombia 147(32.1%)

Mexico 100(21.8%)

Chile 32(7.0%)

Peru 13(2.8%)

Uruguay 10(2.2%)

Ecuador 7(1.5%)

Male,n(%) 239(52.2%)

Age(days)atfirstdose,median (IQR)

55(31---99)

Birthweight(g),mean±SDb _1,344.6_±_460.5 Gestationalage(weeks),median

(IQR)

31(28---32)

Gestationalage(weeks),n(%)

<32weeks 287(62.7%) <29weeks 118(25.8%) 29to<32weeks 169(36.9%) 32---35weeks 163(35.6%) >35weeks 8(1.7%)

Prematurity,n(%) 449(98.0%) Prematurityalone 296(64.6%) Prematurity+BPD 112(24.5%) Prematurity+CHD 24(5.2%) Prematurity+BPD+CHD 17(3.7%) Prematurity+BPDand/orCHD 153(33.4%)

BPD,n(%) 134(29.2%)

CHD,n(%) 46(10.0%)

Mothercompletedprimary school,n(%)

443(96.7%)

Smokingduringpregnancy,n(%) 9(19.7%)

Asthmatic/atopicmother,n(%) 55(12.0%)

Multiplebirth,n(%) 141(30.8%)

Breastfeedingat3monthsold,a_n (%)

222(49.4%)

Otherchildreninhousehold≤6 years,n(%)

160(34.9%)

Exposuretotobaccosmokeat home,n(%)

78(17.0%)

Daycareattendance,n(%) 5(1.1%)

Prenatalmedicalassistance,b_n (%)

386(84.2%)

Neonatalintensivecare hospitalization,n(%)

447(97.5%)

Neonatalassistedventilation,n (%)

257(56.1%)

Adherencetopalivizumab treatment,n(%)

383(83.7%)

Dosesadministeredperpatient,n(%)

Fivedoses 200(43.7%) Fourdoses 66(14.4%) Threedoses 130(28.4%) Twodoses 28(6.1%) Onedose 34(7.4%)

Patientsreceivingexpecteddoses,n(%)

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Table1 (Continued)

Palivizumabprovider(n=1707doses)

Privatehealthinsurance 814(47.7%) Publichealthsystem 669(39.2%) Socialsecurity/mutualaid

society

207(12.1%)

Patientout-of-pocket 17(1.0%)

BPD, bronchopulmonarydysplasia;CHD,congenitalheart dis-ease;IQR,interquartilerange;SD,standarddeviation.

a _{Breastfeeding} _was _reviewed _at ₃ _months _of _age _for ₄₄₉

patients:222infants(49.4%)werebreastfeeding,with49infants (10.9%) receiving breastfeeding exclusively and 173 infants (38.5%)receivingbreastfeedingnon-exclusively.

b _Prenatal_medical_assistance _was_defined _as_having_four _or

moremedicalvisitsduringpregnancy.

Additionalanalyzeswere performedin thesubgroupof 134patientswithBPD;28patientswithBPDhadatotalof32 hospitalizationepisodesrelatedtoLRTI,andnineepisodes were confirmed as associated to RSV infection. The LRTI hospitalizationratewas26.4per100patient-years(95%CI,

17.1---35.8),andtheRSVhospitalizationratewas7.4per100 patient-years(95%CI,2.7---12.1).

Adverseeventsduringtreatmentwithpalivizumab

Atotal of 1165 adverse events were recorded duringone year of follow-up. Onehundred and twopatients (22.3%) hadatotalof135seriousadverseevents.Table4presents thenon-seriousadverseevents(≥5%ofpatients)reportedin thestudy(n=299).Oftheseriousadverseeventsreported, themostcommonevent(≥5%ofpatients)was bronchioli-tis(n=28; 6.1%). Furthermore, 92 seriousadverse events (68.1%)resultedinorprolongedahospitalstay,29(21.4%) were classified by the investigator as clinically relevant, and 11 (8.1%) were life-threatening. Three deaths (2.2%) wererecorded during follow-up and were not considered toberelatedtotreatment withpalivizumabor RSV infec-tion.A totalof six events of injection-sitepain following palivizumabadministrationwerereportedinthreepatients. Therewerenoseriousadverseeventsthatwereconsidered toberelatedtopalivizumab.

Table2 CharacterizationofhospitalizationepisodesduetoLRTI.

LRTIepisodes RSV-relatedLRTIepisodes

Childrenwithatleastonehospitalization,n(%) 52/458(11.4%) 12/458(2.6%) Hospitalizationrate(95%CI)per100patient-years 14.6(10.5---18.6) 2.9(1.3---4.5)

Numberofhospitalizations 61 12

Lengthofstay(days),a_median_(range) ₅_(1---43) ₇_(5---21)

Respiratorysupport,a_n_(%) ₄_(6.5%) ₀

Gestationalage(weeks),a,b_n_(%)

<32weeks 41(67.2%) 6(50.0%)

<29weeks 20(32.8%) 4(33.3%)

30---31weeks 21(34.4%) 2(16.7%)

32---34weeks 20(32.8%) 6(50.0%)

BPD,a_n_(%) ₃₂_(52.4%) ₉_(75.0%)

CHD,a_n_(%) ₇_(11.4%) ₁_(8.3%)

Ageatepisode(days),a_mean_±_SD _236.2_±₁₂₀ _224.5_±_115.1

BPD,bronchopulmonarydysplasia;CHD,congenitalheartdisease;CI,confidenceinterval;LRTI,lowerrespiratorytractinfection;RSV, respiratorysyncytialvirus;SD,standarddeviation.

a _Percentages_were_calculated_by_total_of_{hospitalization}_episodes_due_to_LRTI_(overall_and_{RSV-related).} b _All_patients_with_LRTI_episodes_were_less_than₃₅_weeks_of_gestational_age.

Table3 RiskfactorsforLRTIhospitalizations.

Covariates CrudeIRR(95%CI) p AdjustedIRR(95%CI) p

Femalesex(reference=male) 0.92(0.55---1.53) 0.744 0.92(0.54---1.57) 0.773 Gestationalage(weeks) 0.92(0.84---1.02) 0.112 1.02(0.87---1.21) 0.795 Bronchopulmonarydysplasia(reference=no) 2.77(1.67---4.60) <0.001 2.75(1.53---4.96) 0.001 Congenitalheartdisease(reference=no) 1.15(0.49---2.67) 0.747 0.92(0.38---2.26) 0.864 Smokinga_(reference₌_no) _2.55_{(0.80---8.13)} _0.115 _1.36_{(0.38---4.89)} _0.637

Birthweight(g) 1.00(0.99---1.00) 0.167 0.99(0.99---1.00) 0.643 Adherencetotreatmentb_(percentage) _1.00_{(0.99---1.01)} _0.371 _1.00_{(0.99---1.01)} _0.290

Mothercompletedprimaryschool(reference=yes) 2.11(1.04---4.28) 0.039 1.84(0.85---3.99) 0.123

CI,confidenceinterval;IRR,incidencerateratio;LRTI,lowerrespiratorytractinfection. Boldtextisconsideredsignificant;p<0.05.

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Table 4 Most common serious and non-serious adverse events(≥5%ofsubjects).a

n(%)

Seriousadverseevents Infectionsandinfestations

Bronchiolitis 28(6.1%)

Non-seriousadverseevents Gastrointestinaldisorders

Diarrhea 52(11.4%)

Generaldisorders

Pyrexia 49(10.7%)

Infectionsandinfestations

Bronchiolitis 71(15.5%)

Earinfection 23(5.0%)

Upperrespiratorytractinfection 242(52.8%) Respiratory,thoracic,andmediastinaldisorders

Bronchospasm 73(15.9%)

Skinandsubcutaneoustissuedisorders

Dermatitis 23(5.0%)

Rash 23(5.0%)

MedDRA,MedicalDictionaryforRegulatoryActivities.

a_Subjects _could _have _experienced _more_than _one _adverse

event(MedDRApreferredtermlevel).

Discussion

Palivizumabis approvedfor theprophylaxis of severeRSV disease,withprovenefficacyinreducinghospitalizationsin high-riskinfants.8,13_However,_consistent_prophylaxis_may_be challengingduetoavarietyofmedicalandsocio-economic factorsofthechild.18,19 _This _study_provided_a_prospective descriptionofthe useandeffectivenessof palivizumabin LatinAmericancountries.

The rate of RSV-associated hospitalizations observed in this study (2.9 per 100 patient-years) is low and within the range reported for the palivizumab arm in differentclinical trials (0.0---5.3%).8,13,20 _Furthermore, _the present study’s results are also consistent with those fromotherobservationalstudies(1.3---2.9episodesper100 patient-years).12,21,22 _However,_there_are_few _data _on_RSV hospitalizationratesininfantswithoutpalivizumab prophy-laxisinLatinAmerica.Onestudyfromapublichospitalin Argentinashowedthatinfantswithoutpalivizumab prophy-laxishadRSV-LRTI hospitalizationrates of26% and29% in twohistoricalcohorts.23

Ithasbeen shown thattheRSV hospitalizationrates in patientswithpalivizumab prophylaxis couldbe ashigh as 7.6%in certain circumstances, especially in patients with BPD.13,18,23_In_fact,_in_the_present_study,_a_RSV_{hospitalization} rateof7.4per100patient-years wasobservedinchildren withBPD,afindingthatisalignedwithpreviouslyreported results.18_The_median_time_of_{hospitalization}_due_to_illness causedbyRSVwassevendays,similartotheresultsnoted instudiesfromothercountries22,24_and_to_what_was_found_in thestudybyBaueretal.atasinglecenterinArgentina.23

The incidenceandseverityofRSV infectioninpreterm infants has been associated with several factors, such as presence of siblings at home and attendance at daycare, among others.6,25 _A _prospective _cohort _study _with ₁₅₂

infantshospitalizedforLRTIshowedthatlowbirthweight, loweducationallevelofthemother,andpoorsocioeconomic conditions wererisk factors associatedwithRSV hospital-izationsintermandpreterminfantswithouthemodynamic instability, cardiac conditions, or chronic lung disease in Brazil.26 _In_Argentina,_Bauer_et_al._also_observed_that chil-dren in the household younger than 10 years of age and mothers with incomplete primary school education were associated with an increased risk of RSV hospitalization amongpreterminfants withandwithoutBPD.27 _Moreover, some studieshave shown anincreased riskof LRTIdueto tobaccosmokeexposureathome,althoughfurtherresearch isnecessarytodetermineitsimpactonRSVLRTIseverity.6 Inthepresentstudy,onlyBPDwasidentifiedasan indepen-dentriskfactorforhospitalizationduetoLRTI,whileother factorswerenotassociatedwithanincreasedrisk.

Withregardtosafety,noseriousadverseeventsrelated topalivizumabwerereportedinthepresentstudy.The pat-tern andtypeof adverse events wereconsistent withthe knownsafetyprofileofpalivizumab,whichgenerallyreflects theunderlyingmedicalconditionsofthesepatients.8,12,18,28 Similartoother studies,upperrespiratoryinfectionswere themostfrequentadverseevents,withaproportion compa-rabletothatreportedinaBrazilianstudy(59.4%vs.52.8% inthepresentstudy).29

Thisstudyhadsomelimitations,asisthecasewith obser-vationalstudies.Asthepresentstudydidnothaveacontrol arm,itdoesnotprovideasclearanestimateoftheimpact of palivizumab prophylaxis asdoresults obtainedthrough randomized comparative clinical trials.24 _In _addition, _not allhospitalizationshadadiagnostictestperformedto con-firmiftheepisodewascausedbyRSVinfection.However, becausetestingforRSVdependsonlocalguidelinesandwas notalwaysperformed,theseresultsshouldbeinterpreted withcaution.Thisismainlyduetothevariabilityamongthe participating sitesregarding localguidelinesondiagnostic tests,alimitationthatwasalsopresentinsimilarreal-world studies.21,24,30_Missing_information_may_also_be_a_factor_in_a few cases where the hospitalization occurred at a hospi-talthatwasnotinvolvedinthestudy.Nevertheless,efforts weremadetocollectdataregardingthepresenceofRSVin thesecases.Finally,anotherlimitationwasthatnon-serious adverse events were notclassified bythe investigatorsas relatedorunrelatedtopalivizumab.

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American region, with the advantage of collecting com-pletedemographicandclinicaldatafornearlyallenrolled children,eventhoughothersingle-centerstudiesandwith shorterfollow-uphavebeenconductedinthisregion.

Inconclusion,thehospitalizationrateduetoRSV infec-tion was low in this population and aligned with those observedinseveralrandomizedcontroltrialsand observa-tionalstudies.Basedonthisstudy,palivizumabprophylaxis iseffectiveandhasagoodsafetyprofileinLatinAmerican infantsathighriskofsevereRSVinfection.

Funding

ThisstudywasfundedbyAbbVie,Inc.

Conflicts

of

interest

NVain has received grant/research support, speaker, and consultingfeesfromAbbVie.MESerraisemployeeof FUN-DASAMIN, who was contracted by AbbVie for study data management.AbbVieInc.wasinvolvedinthestudydesign; collection, analysis, and interpretation of data, and the preparationandapprovalofthismanuscript.L.Castilloand G.BugarinareemployeesofAbbVieandmayholdstockor options.

Acknowledgments

TheauthorswanttoexpresstheirgratitudetoDr.Guillermo de Jesus Ruelas Orozco, Dr. Margarita Morales Marquez, Dr.Carolina Salazar, Dr.Adriana Castro, and Mrs.Mariana Jacqueline Martínez Mu˜noz for their collaboration in this study,and toMrs. Milene Fernandes(Eurotrials,Scientific Consultants),whoassistedinwritingthispaper.

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