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Pathogenesisandclinicalfeaturesofbronchopulmonarydysplasia

Author: AnnRStark,MD
SectionEditors: GregoryRedding,MD,RichardMartin,MD
DeputyEditor: MelanieSKim,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Mar21,2016.

INTRODUCTIONBronchopulmonarydysplasia(BPD),alsoknownasneonatalchroniclungdisease(CLD),is
animportantcauseofrespiratoryillnessinpretermnewbornsthatresultsinsignificantmorbidityandmortality.

ThepathogenesisandclinicalfeaturesofBPDarereviewedhere.Management,prognosis,andpotential
strategiestopreventBPDarediscussedseparately.(See"Managementofbronchopulmonarydysplasia"and
"Outcomeofinfantswithbronchopulmonarydysplasia"and"Preventionofbronchopulmonarydysplasia".)

TERMINOLOGYDifferentdegreesofprematurityaredefinedbygestationalage(GA),whichiscalculated
fromthefirstdayofthemother'slastperiod,orbirthweight(BW).Dataonbronchopulmonarydysplasia(BPD)is
oftenbaseduponthefollowingclassificationofpreterminfantswhoarecategorizedbytheirbirthweightas
follows:

Lowbirthweight(LBW)BWlessthan2500g
Verylowbirthweight(VLBW)BWlessthan1500g
Extremelylowbirthweight(ELBW)BWlessthan1000g

Thesetermsareusedthroughoutthisdiscussion.

DEFINITIONThedefinitionofbronchopulmonarydysplasia(BPD)hascontinuedtoevolvesince1967when
Northwayfirstdescribedthedisorder,whichresultedfromeffectsofoxygenandmechanicalventilationin
prematureinfantswithsevererespiratorydistresssyndrome(RDS)[1].Thisisduetochangesinthepopulation
atrisk(ie,moresurvivorsatearliergestationalages)andimprovedneonatalmanagement(ie,surfactant,
antenatalglucocorticoidtherapy,andlessaggressivemechanicalventilation)thathavealteredthepathologyand
clinicalcourseofBPD.(See'Pathology'below.)

Earlierdefinitionsbaseduponoxygenrequirementeitherat28postnataldays[2,3]or36weekspostmenstrual
age(PMA)donotaccountforextremeprematurity(ie,birthweight<1000gorgestationalage<30weeks)and
theseverityofrespiratorydisease[4,5].Thesedefinitionsbecamelessaccurateinpredictingoutcomebecauseof
theincreasingsurvivalrateofextremelylowbirthweight(ELBW)infants,andtheincreasedprevalenceofmilder
formsofBPDduetoimprovedtreatmentofRDS.Asanexample,oxygensupplementationat28daysofagein
ELBWinfantsmaybeduetolungimmaturityandnotBPD.Whereas,anELBWinfantwithmildBPDdisease
whorequiredoxygenwithinthefirst28daysofage,butnotat36weeksPMA,wouldnotbediagnosedashaving
BPDusingthelatterdefinition.Thefailuretoincludegestationalageatbirthordiseaseseverityledtoconcerns
thatthesedefinitionsareinadequate,especiallywhencomparingtheefficacyofdifferenttherapeuticinterventions
and/orlongtermoutcomeofELBWinfantswithBPD.

NICHDcriteriaIn2001,aconsensusconferenceoftheUnitedStatesNationalInstituteofChildHealthand
HumanDevelopment(NICHD)modifiedthepreexistingdefinitionsofoxygenrequirementbyaddingcriteriathat

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includedgestationalage(GA)andseverityofdisease(table1)[6].ThetimingofassessmentisbaseduponGA:

Patientswhoare<32weeksGAareassessedat36weeksPMAorwhendischargedhome,whichever
comesfirst.

Patientswhoare32weeksGAareassessedbetween29to55daysofageorwhendischargedhome,
whichevercomesfirst.

Infantswhorequiresupplementaloxygenforatleast28postnataldaysareclassifiedashavingmild,moderate,
orseverebronchopulmonarydysplasia(BPD),dependingupontheextentofoxygensupplementationandother
respiratorysupport.Tostandardizetheuseofsupplementaloxygen,theNICHDcriteriaalsoproposedthatthe
needforoxygenbeconfirmedbyusingaphysiologictest,althoughaspecifictestwasnotdefined.

AstudyfromtheNICHDNeonatalResearchNetworkreportedthattheNICHDcriteriamoreaccuratelypredicted
pulmonaryandneurodevelopmentaloutcomesat18to22monthscorrectedageinpreterminfants<32weeks
GAwithBPDthanpreviousdefinitions[7].Inparticular,thedefinitionofsupplementaloxygenat36weeksPMA
wouldhavemissedasubstantialnumberofpatientswithmildBPDwhomaybeatriskforpulmonaryand
neurodevelopmentalcomplications.NICHDcriteriamoreaccuratelypredictedwhichpretermsurvivorswould
requirepulmonarymedicationandrehospitalizationforpulmonarydisease.Theincidenceofneurodevelopmental
impairment(ie,lowermentalandpsychomotordevelopmentalindexscores,cerebralpalsy,blindness,hearing
impairment)increasedwiththeseverityofdiseasebasedupontheNICHDcriteria.

PhysiologictestingAsmentionedabove,theNICHDcriteriaalsoproposedthattherequirementof
supplementaloxygenbeconfirmedbyusingaphysiologictest,althoughaspecifictestwasnotdefined.Adoption
ofaBPDdefinitionbaseduponphysiologictestingwouldreducetheeffectofclinicalpracticedifferenceswhen
comparingoutcomeamongcenterscaringforthesepatients.

Oneprospectivemulticenterstudycomparedaphysiologictestbaseduponoxygenadministrationandsaturation
withthestandardclinicaldefinitionofoxygensupplementationat36weeksPMA[8,9].Thephysiologicdefinition
loweredtherateofBPDfrom35percentbasedupontheclinicaldefinitionto25percent,andreducedthe
variationinincidenceamongcenters.However,inanNICHDstudyofoutcomesamong9575verylowbirth
weight(VLBW)infants,useoftheseveritybaseddefinitionclassifiedmoreinfantsashavingBPD(newdefinition,
68percenttraditionaldefinition,42percentandphysiologicdefinition,40percent)[10]Theseresults
demonstratetheimportanceofastandardizeddefinitionofBPDtocompareoutcomes.

HigheraltitudesChangesinaltitudemayimpacttheutilityoftheNICHDconsensusdefinitionbecause
arterialpartialpressureofoxygen(PaO2)andoxygensaturationarelowerathighaltitudes,whichmakesitmore
difficulttocompareratesofBPDusingtheNICHDcriteriabetweencentersathighaltitudeandthoseatsealevel.
However,correctingforbarometricpressure,orusingastandardphysiologicdefinitionforoxygenneedand
adjustmentforeffectofaltitudeallowsforamoreaccuratecomparisonofBPDratesamongcenters[11].This
wasillustratedbythefollowing:

InamulticenterstudyusingtheNICHDcriteria,correctingforbarometricpressurereducedtheinitialhigher
incidenceofBPDincentersathigheraltitudescomparedwiththoseatsealevel[12].

Inasinglecenterstudyconductedat5280feet,mostVLBWinfants,evenifotherwisehealthy,required
supplementaloxygenat36weekspostmenstrualagetomaintaintargetoxygensaturationof85to94
percent[11].However,adjustingforthelocalaltitudeshowedthatafractionalinspiredoxygenconcentration
(FiO2)of0.25at5280feetwasequivalenttoroomair.BPDratesbasedontheNICHDcriteriabeforeand
afteraltitudeadjustmentwere72and27percent.

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EvolvingdefinitionsAlthoughtheNICHDdefinitionsbasedontheneedforsupplementaloxygenatspecific
timepointsmaybeusefulintheneonatalintensivecareunit(NICU),theydonotpredictlongertermrespiratory
outcomes[13].Furthermore,supportforaffectedinfantsmayincluderespiratorysupportwithoutsupplemental
oxygen,sothatoxygenbaseddefinitionsmaybeinappropriate.Futureevolvingdefinitionswilllikelyinclude
biomarkersinadditiontoclinicalcriteria,whichhopefullywillmoreaccuratelypredictlongtermoutcome.

EPIDEMIOLOGYTherateofbronchopulmonarydysplasia(BPD)variesamonginstitutions,whichmayreflect
neonatalriskfactors,carepractices(eg,targetlevelsforacceptableoxygensaturation),anddifferencesinthe
clinicaldefinitionsofBPD[1416].

Infantswithbirthweight(BW)<1250gaccountfor97percentofthecasesofBPD[17].

TheincidenceofBPDincreaseswithdecreasinggestationalage,asillustratedinareportfromtheNICHD
NeonatalResearchNetwork.Inthismulticenterstudyof9575infantsbornbetween2003and2007with
gestationalagesof22to28weeksandbirthweightsof401to1500g,theoverallincidenceofBPDdefinedas
requiringsupplementaloxygenat36weeksPMAwas42percent(rangeamongcenters20to89percent)the
incidenceusingthephysiologicdefinitionwas40percent(range15to82percent)[10].(See'NICHDcriteria'
above.)

Inthiscohort,incidencesforeachgestationalweekwithrangesamongcentersusingthetraditionaldefinitionof
oxygensupplementationwereasfollows:

22weeks:85(0to100)percent
23weeks:73(35to100)percent
24weeks:69(31to100)percent
25weeks:55(20to100)percent
26weeks:44(19to100)percent
27weeks:34(13to76)percent
28weeks:23(9to88)percent

ItisunclearwhetherornottheincidenceofBPDischanging.

IntheabovestudyfromtheNICHDneonatalnetwork,theincidenceofBPDdidnotchangeoverthefive
years[10].However,thenumberofinfantswithsevereBPD(ie,receivingventilatorysupport)decreased.

InaretrospectivemulticenterCanadianstudy,therewasadecreaseinmortalitybetweeninfantsborn
between1996to1997and2006to2007,butacorrespondingincreaseintheincidenceofBPD[18].

Incontrast,astudyusingaUnitedStatesnationaldatabase(NationwideInpatientSample)reporteda
decreaseintherateofBPDof4.3percentperyearforthestudyperiodbetween1993and2006[19].
However,increasesinthecostsandlengthofhospitalizationsforinfantswithBPDwerealsoseen.

PATHOLOGYInsurfactanttreatedextremelylowbirthweight(ELBW)infants,thecharacteristicpathologic
findingofbronchopulmonarydysplasia(BPD)isdisruptionoflungdevelopment,referredtoasthe"new"BPD
[6,20,21].Inthesepatients,decreasedseptationandalveolarhypoplasialeadtofewerandlargeralveoliwitha
reductioninthesurfaceareaavailableforgasexchange.Thereisalsodysregulationofpulmonaryvasculature
development(eg,abnormaldistributionofalveolarcapillaries,andthickeningofthemusclelayerofthe
pulmonaryarteriolesthatresultsinanincreaseinpulmonaryresistance).Incomparisonwith"old"BPD,thereisa
reductionofairwayinjuryandinflammationislessprominent.Thesefindingsaremostprominentinthesmallest,
mostimmatureinfants.

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EarlydisruptionofvasculogenesiscanleadtopulmonaryvasculardiseaseinBPD,resultinginpulmonary
hypertensionandcontributingtomorbidityandmortality[22].Theunderlyingmechanismsthatcontributeto
impairedvasculogenesisareasubjectofongoingresearch.

Thesefindingsareincontrastto"old"BPDseenininfantspriortotheavailabilityofsurfactantreplacement
therapybeforethe1980s.Theprominentpathologicfindingsin"old"BPDwereairwayinjury,inflammation,and
parenchymalfibrosisduetomechanicalventilationandoxygentoxicity(figure1)[6,21].Similarchangesmaybe
seenincertainsurfactanttreatedinfantswhodevelopsevereBPD.Intheseseverelyaffectedinfants,fibrosis,
bronchialsmoothmusclehypertrophy,andinterstitialedema("old"BPD)maybesuperimposedonthe
characteristicreducednumbersofalveoliandcapillaries("new"BPD).Pulmonaryvascularchanges,suchas
abnormalarterialmuscularizationandobliterationofvessels,mayalsooccur.

Lunginjuryalsoisassociatedwithincreasedelastictissueformationandthickeningoftheinterstitium.These
tissuedeformationsmay,inturn,compromiseseptationandcapillarydevelopment.Inoneautopsystudy,the
amountofelastictissue,septalthickness,andalveolarandductdiametersincreasedwiththeseverityofBPD
[23].

PATHOGENESISANDRISKFACTORSTheetiologyofbronchopulmonarydysplasia(BPD)ismultifactorial
andinvolvesexposuretoantenataland/orpostnatalfactors(eg,mechanicalventilation,oxygentoxicity,and
infection),whichdisruptpulmonarydevelopment,andmaycauseinflammationanddamagetothehighly
vulnerableprematurelung[24](figure1).

ThefollowingstudiesillustratetheeffectofthesefactorsupontheriskofdevelopingBPD.

InaprospectivereportfromtheELGAN(ExtremelyLowGestationalAgeNewborns)study,predictivefactors
forBPDincludedlowergestationalageinthisalreadyextremeprematuritycohort,FiO2requirementgreater
than0.25at14daysofage,andmechanicalventilationatoneweekofage[25].

Inastudyof1244verylowbirthweight(VLBW)infantsinNorthCarolina,significantriskfactorsforBPD
weretheneedforventilationat48hoursofage(oddsratio[OR]1.64),nosocomialinfection(OR2.0),and
increasedfluidintakeondaytwo(OR1.06per10mLincrease)[5].Amonginfantsventilatedat48hours,
patentductusarteriosus(PDA)wasassociatedwithincreasedrisk(OR1.9).

Inastudyof119extremelylowbirthweight(ELBW)infantswithmildinitialrespiratorydistresswhorequired
lessthanthreedaysofsupplementaloxygenconcentration>25percentduringthefirstfivepostnataldays,
44(37percent)developedBPD[26].RiskfactorsforBPDincludedlowbirthweight(OR2.9per100g
decrement),PDA(OR6.2),andsepsis(OR4.4).

Individualriskfactorsarediscussedinthefollowingsections.

PrematurityThelungappearstobemostsusceptibletodamageduringthesaccularstageofdevelopment
from23to32weeksgestation[20,27].Atthisstage,theprematurelunghaspoorlydevelopedairwaysupporting
structures,surfactantdeficiency,decreasedcompliance,underdevelopedantioxidantmechanisms,and
inadequatefluidclearance(figure1)[20,28].Theprematurelung'sstructuralandfunctionalimmaturityincreases
theriskofinjuryanddisruptionofnormalpulmonarymicrovascularandalveolardevelopmentfromexternal
antenatalandpostnatalinsults.

Inaddition,fetalgrowthrestrictioninprematureinfants(gestationalagebelow28weeks)appearstobean
independentriskfactorforBPD[29,30].Inacasecontrolstudythatincluded2255infantslessthan33weeks
gestation,infantsbornsmallforgestationalhadmorethantwicetheriskofBPD(OR2.73,95%CI2.113.55)
[31].Growthrestrictionmayhaveasignificantimpactonthevulnerabilityoflunginjuryandvasculogenesis.

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MechanicalventilationInjurycausedbymechanicalventilationprimarilyisduetolargetidalvolumes
(volutrauma)thatoverdistendairwaysandairspaces,ratherthanincreasedairwaypressures[32,33].Becauseof
theevidencethataggressivemechanicalventilationplayedamajorroleinthepathogenesisofBPD,increased
useofnoninvasivesupportandamoreconservativeapproachtowardsmechanicalventilation(ie,avoidanceof
hightidalvolume)hasevolved.ThisapproachisoneofthefactorsthathaveresultedinamilderformofBPD
("new"BPD).Asaresult,significantairwayinjurycharacteristicoftheoldBPDislesscommon,andisonlyseen
ininfantswithsevereBPD.(See'Pathology'aboveand"Mechanicalventilationinneonates"and"Complications
andlongtermpulmonaryoutcomesofbronchopulmonarydysplasia".)

Acutelunginjuryresultsfrominflationsthatareclosetothemaximumlungvolumeofsmallimmaturelungs,and
playsaroleinthechronicchangesresultinginBPD.TheriskofBPDincreaseswithdecreasingarterialcarbon
dioxidetension(PCO2)asameasureofmoreaggressiveventilationthatincludeslargetidalvolumes[2,34,35].

Positivepressureventilationtypicallyinducesbronchiolarlesions[36].Disruptionofairwaysmayoccurearlyin
thecourseoftreatmentandmaybemanifestedbyincreasedpulmonaryresistance[37].Inonestudyof
ventilatedpreterminfantsinthefirstfivedaysafterbirth,meanpulmonaryresistancewassignificantlygreaterin
thosewhosubsequentlydevelopedBPDcomparedwiththosewhodidnot[38].

Inprematurebaboonstreatedwithexogenoussurfactant,prolongedintubationandlowtidalvolumeventilation
forfivedayscomparedwithonedayintubationandweaningtocontinuouspositiveairwaypressure(CPAP)
resultedinpoorerlungmechanicsandrespiratoryfunction(eg,lowerarterialtoalveolaroxygenratio,higher
PaCO2,andpoorerrespiratorydrive),increasedhistopathologicfindingsofcellularbronchiolitisand
peribronchiolaralveolarwallthickening,andincreasedlavagelevelsofcytokines[39].

Anotheranimalstudyhasshownthatevenasmallnumberoflargeinflationssoonafterbirthcanadverselyaffect
surfactantdeficientlungs[40].Inthisstudyofnewbornlambs,onelambofeachoffivepairswasrandomly
assignedtoreceivesixlargemanualinflations("bagging")afterpretermdelivery,andbeforestartingmechanical
ventilationandreceivingartificialsurfactant.Atfourhours,thebaggedanimalscomparedwithcontrolshadlower
inspiratorycapacityandmaximaldeflation,weremoredifficulttoventilate,andhadlesswellexpandedalveoliand
morewidespreadlunginjuryonhistologicexamination.

DifferencesintheuseofmechanicalventilationmayexplainsomeofthevariationamonghospitalsinBPDrates.
Asanexample,useofvolumetargetedventilatorstrategiesinVLBWinfantsprovidesconsistenttidalvolumes
resultinginimprovedrespiratoryoutcomesandothermorbidity.(See"Mechanicalventilationinneonates",
sectionon'Comparisonbetweenpressureandvolumecontrolledventilation'.)

OxygentoxicityHighconcentrationsofinspiredoxygencandamagethelungs,althoughtheexactlevelor
durationofexposurethatisunsafeisnotknown.Cellulardamageiscausedbytheoverproductionofcytotoxic
reactiveoxygenmetabolites(ie,superoxidefreeradical,hydrogenperoxide,hydroxylfreeradical,andsinglet
oxygen),whichoverwhelmtheneonate'simmatureantioxidantsystem.

Preterminfantshaveinadequateantioxidantdefensesbecauseofnutrientdeficiencies(vitaminsAandE,iron,
copper,zinc,andselenium)orimmatureantioxidantenzymesystems(superoxidedismutase,catalase,
glutathioneperoxidase,glutathioneStransferase)[41].Activityofcatalase,glutathioneperoxidase,and
copper/zinc(Cu/Zn)superoxidedismutaseincordbloodarelowerinpretermthanintermnewborns[42].There
isalsoevidenceofgeneticvariationinantioxidantdefenses.Thiswasillustratedbyastudythatshowedinfants
withthelessefficientisoformofglutathioneStransferaseP1weremoresusceptibletooxygentoxicity
predisposingthemtoBPD[43].

Althoughantioxidantmechanismsareimmature,thereissomeupregulationofthisdefensesysteminpreterm
infantswithBPD.Inastudyof44preterminfants(gestationalagefrom25to30weeks),Cu/Znsuperoxide

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dismutaselevels,followedsequentiallyfrombirthtothefirstweekofage,weregreaterininfantswhodeveloped
BPDcomparedwiththosewithoutBPDbydaysixofage[44].

InfectionBothpostnatalandantenatalinfectionsareassociatedwithBPD.

PostnatalSepsisisassociatedwithanincreasedriskofBPD.Thiswasillustratedinanobservationalstudy
fromasingleAustraliantertiarycenterof798preterminfants(meangestationalage[GA]27.4weeks)born
between1992and2004thatreportedneonatalsepsisincreasedtheriskofBPD(OR2.71,95%CI1.644.51)
[45].InfantswithcandidemiahadthehighestriskofdevelopingBPD(OR8.68,95%CI1.6545.63).

TherateofBPDincreaseswhensepsisispresentinconjunctionwithasymptomaticpatentductusarteriosus
(PDA).Inaseriesof119ELBWinfantswhohadmildornoinitialrespiratorydistresssyndrome,theriskof
developingBPDwassignificantlyhigherwithbothsepsisandPDA(OR48.3)comparedwithPDAalone(odds
ratio6.2)orsepsisalone(OR4.4)[26].

ChorioamnionitisAntenatalinfectionhasbeensuggestedasariskfactorindevelopmentofBPD[4648].
Thehypothesiswasbasedonthefindingofincreasedconcentrationofproinflammatorycytokines(interleukin
[IL]6,IL1beta,andIL8)intheamnioticfluidofinfantswhosubsequentlydevelopBPDcomparedwiththose
whodidnot[49].However,itremainsuncertainwhetheraclinicalrelationshipbetweenchorioamnionitisandBPD
exists.

Asystematicreviewoftheliteraturethough2009reportedaweakassociationbetweenchorioamnionitisandBPD
[50].Afteradjustingforconfoundingvariables(eg,gestationalageandbirthweight),exposuretochorioamnionitis
increasedtheriskofBPD(OR1.58,95%CI1.112.24).However,therewassubstantialheterogeneityamongthe
59includedstudieslikelyduetodifferencesinstudydesign,thegestationalageofpatients,therapeutic
interventions(eg,antenatalcorticosteroidadministration),andthedefinitionsofBPDandchorioamnionitis.The
authorsalsoreportedevidenceofpublicationbiasthatsuggestedpotentialoverestimationoftheassociation
betweenchorioamnionitisandBPD.Arepeatanalysisthatadjustedforpublicationbiasdemonstratedno
associationbetweenchorioamnionitisandBPD.

Subsequently,aprospectiveobservationalcohortof301preterminfants32weeksgestationreportedthat
infantsexposedtochorioamnionitiswithafetalinflammatoryresponserespondedlesswelltosurfactant
treatmentthanexposedinfantswithoutaninflammatoryresponseornoexposuretochorioamnionitis[51].The
exposedinfantswithafetalinflammatoryresponsealsohadanincreasedriskofBPD.

Inparticular,infectionwithUreaplasmaurealyticumhasbeenreportedtocauseasustaineddysregulated
inflammatoryresponsethatimpairslungdevelopment,resultinginBPD[52,53].Asystematicreviewofthe
literaturenotedthatinfantswithpulmonarycolonizationwithUreaplasmaweremorelikelytodevelopBPDthan
thosewithoutcolonizationat36weekspostmenstrualage(OR2.22,95%CI1.423.47)orat28daysoflife(OR
3.04,95%CI2.413.83)[54].WhethereradicationofUreaplasmarespiratorycolonizationacquiredinuteroby
preterminfantsreducestheincidenceofBPDrequirestestinginclinicaltrials[55].

Incontrast,aretrospectivestudypublishedin2013ofpreterminfantsbornat<29weeksgestationwithplacental
histologywhowereadmittedtoaneonatalintensivecareunitfrom2000to2006reportedadecreasedriskof
BPD,riskofthecombinedoutcomeofBPDordeath,andevidenceoffetalinflammatoryresponse(FIR)ininfants
withhistologicchorioamnionitis(HC)comparedwithinfantswithoutHC[56].Inthiscohort,therewasalsoatrend
towardsareductionofBPDininfantswithHC,butnoFIRcomparedwithinfantswithoutHC.

InflammationProinflammatoryandchemotacticfactorsarepresentingreaterconcentrationininfantswho
subsequentlydevelopBPDcomparedwiththosewithoutBPD[49,5761].Thepresenceofthesemediatorsis
associatedwithcomplementactivation,increasedvascularpermeability,proteinleakage,andmobilizationof
neutrophilsintotheinterstitialandalveolarcompartments.Releaseofreactiveoxygenradicals,elastase,and
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collagenasebyactivatedneutrophilsresultsinlungdamage[62].Interactionbetweenmacrophagesandother
celltypes(eg,endothelialandepithelialcells)perpetuatestheproductionofproinflammatorymediators,and
sustainsthecycleoflunginjury.Persistenceoffactors(eg,macrophageinflammatoryprotein1andIL8)and
decreasesofcounterregulatorycytokines(eg,IL10,IL17)mayleadtounregulatedandpersistentinflammation
[6].

ThedevelopmentofBPDmaybeginbeforebirthinsomenewbornsthroughintrauterineexposureto
proinflammatorycytokines,possiblyduetochorioamnionitis.However,thisrelationshipremainscontroversial.
(See'Chorioamnionitis'above.)

GeneticsGeneticpredispositionmayinfluencethedevelopmentofBPD.Thiswasillustratedinastudyof
monozygoticanddizygoticprematuretwinswithGA30weeksthatdemonstratedthatthecorrelationof
developingBPD,definedbytheNationalInstituteofChildHealthandHumanDevelopment(NICHD)criteria,was
greaterinmonozygoticcomparedwithdizygoticpairs[63].However,agenomewideassociationstudy(GWAS)
thatincluded899casesofBPDand827controlsdidnotidentifyanysinglenucleotidepolymorphisms(SNPs)
associatedwithBPD[64].TheauthorsconcludethatageneticriskformoderatetosevereBPDisnotlikelytobe
duetoasmallnumberofmajorancestrallyconservedgeneticvariants.Theirnegativefindingsmayhavemissed
ageneticriskduetoothergeneticfactorssuchasepigeneticeffects,copynumbervariations,orjointeffectsof
multipleSNPsorinteractionamongthem.Conflictingresultsfromthetwinstudiesorothercasecontrolstudies
maybeduetodifferencesinthestudypopulations(GWASpopulationwasprimarilyMexicanHispanic)and
eligibilitycriteria.

Inaretrospectivestudyof157preterminfantswhodevelopedrespiratorydistresssyndromerequiring
mechanicalventilation,twospecificsinglenucleotidepolymorphismsofageneencodingforendothelialnitric
oxidesynthase(eNOS)wereindependentpredictorsofanincreasedriskofdevelopingBPD[65].Inanother
studyof751infantsofwhom428developedBPDordied,pathwayanalysisofagenomewideassociationstudy
identifiedinvolvementofseveralknownpathwaysoflungdevelopmentandrepairthatweresignificantforsevere
BPDordeathandindicatedspecificmoleculesthatwereincreasedinpatientswithBPD[66].

Furtherstudiesarerequiredtodeterminewhetherornotthereisageneticpredisposition,andifso,whatarethe
underlyinggeneticfactors.

LatesurfactantdeficiencyDelayedrecoveryorlatedeficiencyofpostnatalsurfactantmayplayaroleinthe
pathogenesisofBPD.Inastudyof68ventilatordependentprematureinfants(gestationalagesbetween23and
30weeks),75percentoftrachealaspiratesexhibitedabnormallylowsurfacetension[67].Inthesesamples,
surfactantproteinsA,B,andCwerereducedby50,80,and72percent,respectively.Inaddition,thereappears
tobeatemporalassociationbetweensampleswithlowsurfacetension,andepisodesofinfectionandrespiratory
deterioration.Theseresultssuggestthatprematureinfantswhorequirecontinuedrespiratorysupporthave
transientsurfactantdysfunctionordeficiency,whichmayaffecttheirclinicalstatus.

Inapilottrialof136prematureinfants(birthweightsbetween600and900g)whorequiredmechanical
ventilationbetweenday3and10ofage,patientswererandomlyassignedtoreceivelowdosesynthetic
surfactant,highdosesyntheticsurfactant,orplaceboevery48hoursuptofivedoseswhiletheyremained
ventilated[68].Althoughtherewasatrendtoloweroxygenrequirementsinthesurfactantgroupscomparedwith
thecontrolgroup,andalowerincidenceofeitherdeathorBPDinthehighdosesurfactantgroupcomparedwith
eitherlowdosesurfactantorplacebogroups,thesedifferencesdidnotreachstatisticalsignificance.

Inasubsequentpilottrial,85ELBWinfantswererandomlyassignedtoreceiveanSPBcontainingsurfactant
plusinhalednitricoxide(iNO)comparedwithiNOalone.ClinicalstatusandrecoveryofSPBfromtracheal
aspiratesweretransientlyimproved.However,theseeffectswanedafteronedayandfavorablepulmonaryeffects
werenotmaintained.Latesurfactantadministrationhadminimalacuteadverseeffects[69].
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OtherpotentialfactorsOtherpotentialpathogeneticcontributorsincludeendostatinandbombesinlike
peptides.

ImpairedangiogenesisThereisincreasingevidencethatsuggeststhegrowthoflungbloodvessels
activelypromotesalveolargrowth.Disruptionofangiogenesishasbeenproposedasamechanismthatimpairs
alveolarization,therebycontributingtothenewformofBPD[70].(See'Pathology'above.)

SupportforthepotentialroleofimpairedangiogenesisinthepathogenesisofBPDincludesthefollowing:

ElevatedendostatinlevelsInonestudy,elevatedcordplasmaendostatinlevels,anantiangiogenicgrowth
factor,wereassociatedwithanincreasedriskofBPDinverylowbirthweightinfants(birthweightlessthan
1500g)[71].

Inastudyofpreterminfantslessthan35weeksgestation,cordbloodlevelofplacentagrowthfactor(PIGF),
butnotvascularendothelialgrowthfactororsolublefmsliketyrosinekinase1,waselevatedininfantswho
subsequentlydevelopedBPD[72].

MotherswithpreeclampsiaObservationalstudieshaveshownthattheriskofBPDistwofoldgreaterin
infantsborntomotherswithpreeclampsiacomparedwiththoseborntomotherswithoutpreeclampsia
[73,74].Thesefindingssuggestfactorsthattriggermaternalendothelialdysfunction(impairedangiogenesis),
resultinginpreeclampsia,aretransferredtoinfants,whichmaycontributetothepathogenesisofBPD.(See
"Preeclampsia:Pathogenesis",sectionon'Systemicendothelialdysfunction'.)

BombesinlikepeptidesInjurymaybemediatedinpartbybombesinlikepeptides(BLP),whichare
derivedfrompulmonaryneuroendocrinecellsandplayanimportantroleinnormallunggrowthandmaturation.In
onestudy,thenumberofBLPpositivecellswasgreaterininfantswhodiedwithBPDthanincontrols[75].Ina
baboonmodel,urineBLPlevelswereincreasedsoonafterbirthinanimalswhodevelopedBPD,and
administrationofantiBLPantibodyattenuatedthedisorder[76].Ininfants28weeksgestationalage,elevated
urineBLPlevelsinthefirstfourdaysafterbirthwereassociatedwithanincreasedriskofBPD[77].

CLINICALFEATURESAsdiscussedabove,bronchopulmonarydysplasia(BPD)isassociatedwithmultiple
riskfactors,includingprematurity,mechanicalventilation,oxygentoxicity,sepsis,andpatentductusarteriosus.It
occursinfrequentlyininfantswithgestationalage(GA)30weeksorbirthweight(BW)morethan1250g[6,17].

Althoughtheneedforoxygensupplementationmaybepresentattwoweeksofage,therelationshipbetween
oxygenneedandsubsequentdevelopmentofBPDisnottotallypredictable.Thiswasillustratedinathe
previouslymentionedELGANstudythatenrolled1340preterminfantslessthan28weeksgestationina
multicenterprospectivestudybetween2002and2004[25].Duringthefirsttwoweeksofpostnatallife,three
clinicalpulmonarycoursesemergedwithdifferingratesofBPD.

About40percenthadpersistentlungdysfunctiondefinedasaconsistentrequirementofFiO2above0.25.
AbouttwothirdsofthesepatientsdevelopedBPD.

About40percenthaddeteriorationoflungdysfunctiondefinedasanincreaseofFiO2above0.25at14days
ofage.AboutonehalfofthesepatientsdevelopedBPD.

About20percenthadnoorminimallungdysfunctiondefinedasnoconsistentneedofFiO2above0.25.Only
17percentofthisgroupdevelopedBPD.

PhysicalexaminationThephysicalexaminationisvariable.Infantsusuallyaretachypneic.Dependingupon
theextentofpulmonaryedemaand/oratelectasis,theymayhavemildtosevereretractions,andscatteredrales
maybeaudible.Intermittentexpiratorywheezingmaybepresentininfantswithairwaynarrowingfromscar
formation,constriction,mucusretention,collapse,and/oredema.
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ChestradiographAsBPDevolves,thechestradiographalsochangesfromclearlungfieldstofindingsthat
includediffusehazinessandacoarseinterstitialpattern,whichreflectatelectasis,inflammation,and/orpulmonary
edema(image1).Lungvolumesarenormalorlow.Withfurtherevolutionofthedisease,theremaybeareasof
atelectasisthatalternatewithareasofgastrapping,relatedtoairwayobstructionfromsecretionsorbronchiolar
injury.

ThechestradiographininfantswhodevelopsevereBPDshowshyperinflation.Streakydensitiesorcysticareas
maybeprominent,correspondingtofibroticchanges(image1).Duringacuteexacerbations,pulmonaryedema
maybeapparent.

CardiopulmonaryfunctionInpatientswithsevereBPD,abnormalitiesofpulmonaryfunctioninclude
decreasedtidalvolume,increasedairwayresistance,anddecreaseddynamiclungcompliancewithincreasing
ventilation/perfusionmismatch.Unevenairwayobstructionleadstogastrappingandhyperinflationwithabnormal
distributionofventilation[78].Bronchomalaciacanresultinairwaycollapseduringexpiration.Severelyaffected
infantshavehypoxemiaandhypercapnia.

Inmanyofthesepatients,pulmonaryvascularresistanceisincreasedbecauseofdisruptionofpulmonary
vasculargrowthand/orreducedcrosssectionalareaofpulmonaryvessels.Inaddition,alveolarhypoxiain
underventilatedareasofthelunginduceslocalvasoconstriction.Thehighmicrovascularpressurepromotes
increasedfluidfiltrationintotheperivascularinterstitium.Elevatedrightatrialpressureinhibitspulmonary
lymphaticdrainage,furtherpromotingpulmonaryedema.

DIAGNOSISThediagnosisofbronchopulmonarydysplasia(BPD)isbasedonfulfillingcriteriabasedona
standardizeddefinitionasdiscussedabove.Inourcenters,weusetheNationalInstituteofChildHealthand
HumanDevelopment(NICHD)definitionbasedontheneedforoxygensupplementation,thegestationalageand
postmenstrualageofthepatient,andseverityofdisease(table1)[6].(See'Definition'above.)

CLINICALCOURSEMostinfantsimprovegraduallyduringthenexttwotofourmonths.Aspulmonaryfunction
improves,theycanbeweanedtocontinuouspositiveairwaypressureorhighflownasalcannula(HFNC),then
supplementaloxygenalone,untiltheycanmaintainadequateoxygenationwhenbreathingroomair.(See
"Oxygenmonitoringandtherapyinthenewborn",sectionon'Postresuscitation'.)

Someinfantsdevelopseverebronchopulmonarydysplasia(BPD)thatleadstoprolongedventilatordependence.
Theclinicalcourseduringthefirstfewweeksafterbirthincludesmarkedinstabilitywithswingsinoxygen
saturationandintermittentepisodesofacutedeteriorationrequiringincreasedventilatorsupport.Themarked
instabilitytypicallyimprovesslowlyafterfourtosixweeks.However,someoftheseinfantsrequireventilator
supportorsupplementaloxygenbeyondsixmonthsofage.

PulmonaryhypertensionPulmonaryarteryhypertension(PAH)isincreasinglyrecognizedasanimportant
complicationassociatedwithBPDandisdiscussedingreaterdetailseparately.(See"Complicationsandlong
termpulmonaryoutcomesofbronchopulmonarydysplasia",sectionon'Pulmonaryarteryhypertension'.)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandare
comfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
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"patientinfo"andthekeyword(s)ofinterest.)

Basicstopics(see"Patienteducation:Bronchopulmonarydysplasia(TheBasics)")

SUMMARYBronchopulmonarydysplasia(BPD)remainsamajorcomplicationofprematurity,resultingin
significantmortalityandmorbidity.(See"Outcomeofinfantswithbronchopulmonarydysplasia".)

ThecurrentdefinitionofBPDisbasedupontheneedforoxygensupplementation,gestationalageofthe
infant,andtheseverityofdisease(table1).(See'Definition'above.)

Infantswithbirthweights(BW)<1250gaccountfor97percentofthecasesofBPD.TheincidenceofBPDin
verylowBWinfants(BWbelow1500g)isabout25percent,althoughratesofBPDvaryamonginstitutions.
TheriskofdevelopingBPDincreaseswithdecreasingbirthweightandgestationalage.(See'Epidemiology'
above.)

Changesinneonatalmanagement(ie,useofsurfactant,antenatalglucocorticoidtherapy,andless
aggressivemechanicalventilation)andincreasedsurvivalofmoreprematureinfantshaveresultedina
differentformofBPD,referredtoas"new"BPD.The"new"BPDischaracterizedbydisruptionoflung
developmentthatresultsinlargealveolianddysregulationofvasculaturedevelopment.Incontrast,the"old"
BPDwascharacterizedbyairwayinjury,inflammation,andparenchymalfibrosis,whichwereprimarilydueto
injuryfrommechanicalventilationandoxygen.(See'Pathology'above.)

TheetiologyofBPDismultifactorialandisduetoexposuretoantenatalandpostnatalfactorsthatcause
arrestofpulmonarydevelopment,andpotentially,inflammationanddamagetothehighlyvulnerable
prematurelung(figure1).Thesefactorsincludemechanicalventilation,oxygentoxicity,infection,
inflammation,andpossiblygeneticpredispositionandlatesurfactantdeficiency.(See'Pathogenesisandrisk
factors'above.)

InfantswhorequireoxygensupplementationaboveaFiO2of25percentattwoweeksofageareat
significantriskfordevelopingBPD.AlthoughthephysicalfindingsofBPDvary,mostaffectedinfantsare
tachypneic.Otherfindingsincluderetractions,rales,andwheezes.(See'Physicalexamination'above.)

ThechestradiographininfantswithBPDchangeswithevolutionofthediseasefromclearlungfieldstoa
diffusehaziness,reflectingatelectasis,inflammation,andpulmonarycongestions/edema,andinsevere
cases,cysticchanges(image1).(See'Chestradiograph'above.)

PatientswithsevereBPDarehypoxemicandhypercapnicbecauseofsignificantcardiopulmonary
abnormalities.Theseincludedecreasedtidalvolume,increasedairwayresistance,decreaseddynamiclung
compliance,unevenairwayobstructionresultingintrappingandhyperinflationwithabnormaldistributionof
ventilation,andincreasedvascularresistance.(See'Cardiopulmonaryfunction'above.)

MostinfantswithBPDimprovegraduallyduringthefirsttwotofourmonths.Thosewithseverediseasemay
haveaprolongedcourseofmechanicalventilation,andmaydeveloppulmonaryhypertensionandcor
pulmonale.(See'Clinicalcourse'aboveand"Complicationsandlongtermpulmonaryoutcomesof
bronchopulmonarydysplasia",sectionon'Pulmonaryarteryhypertension'.)

ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgeJamesAdams,Jr.,MD,who
contributedtoanearlierversionofthistopicreview.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic4987Version21.0

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GRAPHICS

Definitionofbronchopulmonarydysplasia:Diagnosticcriteria

Gestationalage

<32week 32week

Timepoint 36weeksPMAordischargetohome,whichever >28daysbut<56dayspostnatalageordischarge


of comesfirst tohome,whichevercomesfirst
assessment

Treatmentwithoxygen>21percentforatleast28daysplus

MildBPD Breathingroomairat36weeksPMAor Breathingroomairby56dayspostnatalageor


discharge,whichevercomesfirst discharge,whichevercomesfirst

Moderate Need*for<30percentoxygenat36weeksPMA Need*for<30percentoxygenat56dayspostnatal


BPD ordischarge,whichevercomesfirst ageordischarge,whichevercomesfirst

SevereBPD Need*for30percentoxygenand/orpositive Need*for30percentoxygenand/orpositive


pressure(PPVorNCPAP)at36weeksPMAor pressure(PPVorNCPAP)at56dayspostnatalageor
discharge,whichevercomesfirst discharge,whichevercomesfirst

BPD:bronchopulmonarydysplasiaNCPAP:nasalcontinuouspositiveairwaypressurePMA:postmenstrualagePPV:
positivepressureventilation.
*Aphysiologictestconfirmingthattheoxygenrequirementattheassessmenttimepointremainstobedefined.This
assessmentmayincludeapulseoximetrysaturationrange.
BPDusuallydevelopsinneonatesbeingtreatedwithoxygenandpositivepressureventilationforrespiratoryfailure,most
commonlyrespiratorydistresssyndrome.Persistenceofclinicalfeaturesofrespiratorydisease(tachypnea,retractions,
rales)areconsideredcommontothebroaddescriptionofBPDandhavenotbeenincludedinthediagnosticcriteria
describingtheseverityofBPD.Infantstreatedwithoxygen>21percentand/orpositivepressurefornonrespiratorydisease
(eg,centralapneaordiaphragmaticparalysis)donothaveBPDunlesstheyalsodevelopparenchymallungdiseaseand
exhibitclinicalfeaturesofrespiratorydistress.Adayoftreatmentwithoxygen>21percentmeansthattheinfantreceived
oxygen>21percentformorethan12hoursonthatday.Treatmentwithoxygen>21percentand/orpositivepressureat36
weeksPMA,orat56dayspostnatalageordischarge,shouldnotreflectan"acute"event,butshouldratherreflectthe
infant'susualdailytherapyforseveraldaysprecedingandfollowing36weeksPMA,56dayspostnatalage,ordischarge.

Reproducedwithpermissionfrom:JobeAH,BancalariE.Bronchopulmonarydysplasia.AmJRespirCritCareMed2001
163:1723.Copyright2001AmericanThoracicSociety.

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Pathogenesisofbronchopulmonarydysplasia(BPD)

Exposuretoantenatalpulmonaryinsultsduringthesaccularstateoflungdevelopment
resultindevelopmentalarrestordelayinpulmonarymaturation("new"bronchopulmonary
dysplasia[BPD]),whereaspostnatalinsultscausestructuralpulmonaryinjury("old"BPD).

Adaptedfrom:BaraldiE,FilipponeM.Chroniclungdiseaseafterprematurebirth.NEnglJMed
2007357:1946.

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Sequentialchestradiographsofbronchopulmonarydysplasia(BPD)ina
prematureinfant

ImageAisachestradiographtakenafterbirthofaprematureinfantbornat25weeks.Thelungsare
clear.ImageBisachestradiographtakentwoweekslater,whichshowsacoarsenedinterstitialpattern
anddiffusehaziness.ImageCisaradiographthatshowsfurthercoarseningofthelungmarkingsfive
weeksafterbirth.ImageDshowspulmonarycongestionafterclosureofapatentductusarteriosus
(arrowshowsclip).ImageEisamagnificationofimageDandshowscysticchangesinthelungs
(arrows).

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ContributorDisclosures
AnnRStark,MD Nothingtodisclose GregoryRedding,MD Nothingtodisclose RichardMartin,
MD Consultant/AdvisoryBoards:WindtreeTherapeutics[SurfactantInhalationTrial]CareFusioninAutomated
OxygenationControlTrial[STAMINATrial]. MelanieSKim,MD Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.

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