Transfusion-related acute lung injury: incidence and risk factors

Since 2003, the FDA has documented that the leading cause of transfusion-related fatality has been transfusion-related acute lung injury (TRALI) ... SkiptoMainContent Advertisement Close ASHClinicalNews ASHNewsDaily ASH-SAP Blood BloodAdvances Hematology TheHematologist International BloodChineseEdition BloodJapaneseEdition BloodItalianEdition BloodLatinAmericaEdition BloodSpanishEdition ASH ASHHome Research Education Advocacy Meetings Publications ASHStore Cart UserToolsDropdown Cart SignIn SearchDropdownMenu headersearch searchinput Searchinputautosuggest filteryoursearch AllContentAllJournalsBlood Search ToggleMenuMenu Issues CurrentIssue AllIssues Firstedition Abstracts 2021AnnualMeeting 2020AnnualMeeting 2020LateBreaking 2019AnnualMeeting 2019LateBreaking AllMeetingAbstracts Collections Collections SpecialCollections Multimedia Alerts AuthorCenter Submit AuthorGuide StyleGuide WhySubmittoBlood? About AboutBlood EditorialBoardandStaff Subscriptions PublicAccess Copyright Alerts BloodClassifieds SkipNavDestination ContentMenu Close Abstract Introduction Methods Results Discussion Acknowledgments Authorship References ArticleNavigation CLINICALTRIALSANDOBSERVATIONS| February16,2012 Transfusion-relatedacutelunginjury:incidenceandriskfactors ClinicalTrials&Observations PearlToy, PearlToy 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar OgnjenGajic, OgnjenGajic 2MayoClinic,Rochester,MN; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar PeterBacchetti, PeterBacchetti 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar MarkR.Looney, MarkR.Looney 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar MichaelA.Gropper, MichaelA.Gropper 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar RolfHubmayr, RolfHubmayr 2MayoClinic,Rochester,MN; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar CliffordA.Lowell, CliffordA.Lowell 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar PhilipJ.Norris, PhilipJ.Norris 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA;3BloodSystemsResearchInstitute,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar EdwardL.Murphy, EdwardL.Murphy 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA;3BloodSystemsResearchInstitute,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar RichardB.Weiskopf, RichardB.Weiskopf 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar GregoryWilson, GregoryWilson 2MayoClinic,Rochester,MN; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar MoniqueKoenigsberg, MoniqueKoenigsberg 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar DeannaLee, DeannaLee 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar RandySchuller, RandySchuller 4AmericanRedCrossNeutrophilReferenceLaboratory,StPaul,MN;and Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar PingWu, PingWu 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar BarbaraGrimes, BarbaraGrimes 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar ManishJ.Gandhi, ManishJ.Gandhi 2MayoClinic,Rochester,MN; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar JeffreyL.Winters, JeffreyL.Winters 2MayoClinic,Rochester,MN; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar DavidMair, DavidMair 4AmericanRedCrossNeutrophilReferenceLaboratory,StPaul,MN;and Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar NoraHirschler, NoraHirschler 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA;5BloodCentersofthePacific,SanFrancisco,CA Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar RosaSanchezRosen, RosaSanchezRosen 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA;3BloodSystemsResearchInstitute,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar MichaelA.Matthay, MichaelA.Matthay 1UniversityofCalifornia–SanFrancisco,SanFrancisco,CA; Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar fortheTRALIStudyGroup fortheTRALIStudyGroup Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar Blood(2012)119(7):1757–1767. https://doi.org/10.1182/blood-2011-08-370932 Articlehistory Submitted: August11,2011 Accepted: November21,2011 FirstEdition: November23,2011 ConnectedContent Arelatedarticlehasbeenpublished: GivingTRALItheone-twopunch Arelatedarticlehasbeenpublished: PlateletsolubleCD40-ligandlevelisassociatedwithtransfusionadversereactionsinamixedthreshold-and-hitmodel Split-Screen ShareIcon Share Twitter LinkedIn ToolsIcon Tools RequestPermissions CiteIcon Cite SearchSite PDF Citation PearlToy,OgnjenGajic,PeterBacchetti,MarkR.Looney,MichaelA.Gropper,RolfHubmayr,CliffordA.Lowell,PhilipJ.Norris,EdwardL.Murphy,RichardB.Weiskopf,GregoryWilson,MoniqueKoenigsberg,DeannaLee,RandySchuller,PingWu,BarbaraGrimes,ManishJ.Gandhi,JeffreyL.Winters,DavidMair,NoraHirschler,RosaSanchezRosen,MichaelA.Matthay,fortheTRALIStudyGroup;Transfusion-relatedacutelunginjury:incidenceandriskfactors.Blood2012;119(7):1757–1767.doi:https://doi.org/10.1182/blood-2011-08-370932 Downloadcitationfile: Ris(Zotero) ReferenceManager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbarsearch SearchDropdownMenu toolbarsearch searchinput Searchinputautosuggest filteryoursearch AllContentAllJournalsBlood Search Abstract Transfusion-relatedacutelunginjury(TRALI)istheleadingcauseoftransfusion-relatedmortality.TodetermineTRALIincidencebyprospective,activesurveillanceandtoidentifyriskfactorsbyacase-controlstudy,2academicmedicalcentersenrolled89casesand164transfusedcontrols.RecipientriskfactorsidentifiedbymultivariateanalysiswerehigherIL-8levels,liversurgery,chronicalcoholabuse,shock,higherpeakairwaypressurewhilebeingmechanicallyventilated,currentsmoking,andpositivefluidbalance.Transfusionriskfactorswerereceiptofplasmaorwholebloodfromfemaledonors(oddsratio=4.5,95%confidenceinterval[CI],1.85-11.2,P=.001),volumeofHLAclassIIantibodywithnormalizedbackgroundratiomorethan27.5(OR=1.92/100mL,95%CI,1.08-3.4,P=.03),andvolumeofanti–humanneutrophilantigenpositivebygranulocyteimmunofluoresencetest(OR=1.71/100mL,95%CI,1.18-2.5,P=.004).Littleornoriskwasassociatedwitholderredbloodcellunits,noncognateorweakcognateclassIIantibody,orclassIantibody.ReducedtransfusionofplasmafromfemaledonorswasconcurrentwithreducedTRALIincidence:2.57(95%CI,1.72-3.86)in2006versus0.81(95%CI,0.44-1.49)in2009per10000transfusedunits(P=.002).TheidentifiedriskfactorsprovidepotentialtargetsforreducingresidualTRALI. Topics: antibodies, humanleukocyteantigens, humanneutrophilantigens, transfusion-relatedacutelunginjury, transfusion, donors Introduction Since2003,theFDAhasdocumentedthattheleadingcauseoftransfusion-relatedfatalityhasbeentransfusion-relatedacutelunginjury(TRALI),1 definedasacutelunginjury(ALI)2 thatdevelopsduringorwithin6hoursaftertransfusionofoneormoreunitsofbloodorbloodcomponents.3,4 IncludedinthisdefinitionarecasesofALIaftermultipletransfusions,awell-knownALIriskfactor.5 Theconditionhasbeenunder-reportedsincethefirstdescriptionin1985byPopovskyandMoore,6 andtheoverallincidencehasbeenreportedonlybypassivesurveillancestudies.Althoughriskfactorshavebeenidentifiedinsubgroups,suchascriticallyillpatients7 andcardiacsurgerypatients,8 riskfactorsinrecipientsandintransfusedbloodproducts(eg,antibody,bioreactivesubstances,olderRBCstorageage9 )havenotbeenidentifiedinthegeneralpopulationoftransfusedpatientsbecauseofthelackofalargeprospective,case-controlledstudy.Thegoalofthisstudywastoprospectivelydetermineincidencebyanactivesurveillancesystem10 implementedat2largeacademiccenters.Duringthecourseofthisstudy,theAmericanAssociationofBloodBanksrecommendedthereductionoftransfusionofplasmaandplateletsfromdonorspotentiallyharboringalloantibodies,11,12 thusmakingitpossibletomeasureanychangeinTRALIincidencethatwasconcurrentwithimplementationofthisrecommendation.TheothergoalofthisstudywastodeterminetransfusionandrecipientriskfactorsbyenrollingconcurrenttransfusedcontrolswithoutTRALI. Methods SeesupplementalMethods(availableontheBloodWebsite;seetheSupplementalMaterialslinkatthetopoftheonlinearticle). Studydesign ActivesurveillanceofTRALIwasconductedat2tertiarycaremedicalcenters:theUniversityofCalifornia–SanFrancisco(UCSF),SanFrancisco,CAandtheMayoClinic,Rochester,MN.EnrollmentbeganonMarch1,2006;thecase-controlstudyendedonAugust31,2009andsurveillanceendedonDecember31,2009.AllRBCandplateletunitstransfusedduringthestudyperiodwereleuko-reduced.Allpatientsolderthan6monthswereprospectivelyevaluatedinrealtimeforhypoxemia(PaO2/FiO2<300mmHg)within12hoursafterissueofanybloodcomponentfromthebloodbank,bycontinuouselectronicsurveillanceofarterialbloodgas(ABG)results,andbloodbankrecordsinthehospitallaboratoryinformationsystem(OztechSystems).10 Giventhe6-hourwindowfortheacuteonsetofTRALIbydefinition,mostcaseswouldhaveanABGresultwithin12hours.CaseswithoutFiO2inABGreportswouldbemissed.Afterreceivinganelectronicalertinrealtime,coordinatorsgatheredandenteredpatientdataintoaWeb-baseddatabase(QuesGenSystems)andsentanelectronicsummary,includinghistory,laboratorydata,chestradiographs,andradiologistreportsofchestradiographs,totheexpertpanelforreview,usuallywithin72hoursofthealert. Reviewerswereblindedtoallinformationregardingtransfusedunits,includingcomponenttype.TRALIwasdiagnosedbyconcurrenceof2expertphysiciansbypredeterminedcriteria(Table1).Atleastmonthly,conferencecallswereconductedwithsiteinvestigatorsandcoordinators,anddisputablecaseswerereviewedbythefullpanelof4expertsbyconferencecall. Table1Expertpanelcriteriaforadjudicationofacuteposttransfusionhypoxemiawithbilateralpulmonaryinfiltrates . TRALI . TACO . TACO/TRALI . TransfusedALI‡ . Other . Bilateralinfiltratesonchestradiographconsistentwithacutepulmonaryedema* Yes Yes Yes Yes No Clinicalevidenceofleftatrialhypertensionastheprincipalexplanationforacutepulmonaryedema† No Yes Indeterminate§ No NA PresenceofmajorALIriskfactor(s)‡ No‖ Yes/No Yes/No Yes NA  . TRALI . TACO . TACO/TRALI . TransfusedALI‡ . Other . Bilateralinfiltratesonchestradiographconsistentwithacutepulmonaryedema* Yes Yes Yes Yes No Clinicalevidenceofleftatrialhypertensionastheprincipalexplanationforacutepulmonaryedema† No Yes Indeterminate§ No NA PresenceofmajorALIriskfactor(s)‡ No‖ Yes/No Yes/No Yes NA NAindicatesnotapplicable.*Atelectasis,pleuraleffusions,chronicinterstitialinfiltrates,oruninterpretablechestx-rays(resultingfrompoorquality)wereconsiderednottobeconsistentwithacutepulmonaryedema.†Asystematicintegratedevaluationofhemodynamicmonitoring(PAOP,CVP),echocardiography(ejectionfraction,E/E′),chestradiographicimaging(vascularpediclewidth,cardiothoracicratio),laboratoryfindings(BNPandNT-ProBNP),andclinicalcourse(rapidwithinhoursresolutionofacuterespiratoryfailureafterpreload/afterloadreductionwouldsuggesthydrostaticTACOratherthanALIpermeabilitypulmonaryedema).‡MajorALIriskfactorsincludedpneumonia,sepsis,aspiration,multiplefractures,andpancreatitis.“TransfusedALI”correspondsto“possibleTRALI”accordingtotheCanadianConsensusConference.3 ToselectclearTRALIcases,these“possibleTRALI”patientswerenotincludedinthisstudy.§Insufficientdatatomakeaccuratedeterminationorbothconditionscoexist.‖Exception:IfapatientwithamajorALIriskfactorwasstable,theriskfactordidnotappeartocauseALI,andALIwasprecipitatedbythetransfusion,thenthepatientwasconsideredtohaveTRALI.ViewLarge Implementationofplasmafrommaledonors(Mayo),andplasmafrommaleandneverpregnantfemaledonors(UCSF)occurredin2007to2008,whereasreductionofplateletsfrompreviouslypregnantfemales(UCSF)andpredominantlymaledonors(Mayo)waspartiallyimplementedin2008.RecipienttracingofcomponentsfromdonorsassociatedwithTRALIcaseswasnotperformed. Becausethestudywasobservationalandtestingwasperformedonresidualclinicallaboratoryspecimens,casesandcontrolswereenrolledwithoutwritteninformedconsent.Theprotocolwasapprovedbytheinstitutionalreviewboardateachinstitution. DefinitionofTRALIcasesandcontrols TRALIwasdefinedasnewALIthatdevelopedduringorwithin6hoursoftransfusionofoneormoreunits,notattributabletoanotherALIriskfactor.4 ThestudywasdesignedtodetectcasesofTRALIthat,bydefinition(PaO2/FiO2<300mmHg),hadsevereenoughhypoxemiathatthepatient'sphysicianonanyservicewouldprobablyobtainABGmeasurement(s)forpatientmanagement.Thestudywasnotdesignedtodetectmildcases13 thatdonotmeetthePaO2/FiO2lessthan300-mmHgcriterionforALI.ToincludepatientswiththehighestlikelihoodofTRALI,weexcludedpatientswhohadanothermajorALIriskfactor(pneumonia,sepsis,aspiration,multiplefractures,andpancreatitis),exceptifthatpatientwasstable,theriskfactordidnotappeartocauseALI,andtheALIwasprecipitatedbytransfusion.“PossibleTRALI”3 caseswithanothermajorALIriskfactorweredesignated“transfusedALI”andnotincludedinthecase-controlstudy. Controlpatientswererandomlyselectedtransfusionrecipientswhohadnopulmonarysignsorsymptomswithin12hoursaftertransfusionofthelastunit.Westratifiedsamplingbynumberofunitstransfused,becausethiswasprobablyastrongriskfactor5 andhavingtoofewcontrolswithlargenumbersofunitstransfusedwouldmakeassessmentofotherriskfactorsmoredifficult.Controlswerestratifiedaccordingtothenumberofunitstransfusedtotherecipient(regardlessofcomponenttype):low(1-2units),medium(3-9units),andhighvolume(≥10units)transfusions. Laboratorytestmethods Caseandcontrolsampleswereperformedinthesamerunstoreducereagentlotvariabilityeffects. RecipientHLAantigentyping LowresolutionclassIHLA-A,B,CwandclassIIHLA-DRB1,DRB3/4/5,DQB1typingwasperformedusingtheLABTypeSSO(OneLambda). AntibodiestoHLA ScreeningforantibodytoHLAclassI(anti–HLA-classI)andantibodytoHLAclassII(anti–HLA-classII)wasperformedusingLABScreenMixedLSM12(OneLambda).Anormalizedbackground(NBG)ratiomorethan2.2wasconsideredapositiveresultandthepositivesampleswerefurthertestedforantibodyspecificityusingtheLABScreenSingle-antigenBeadassay(OneLambda)toidentifyantibodyspecificity.AspecificantibodywasconsideredpositiveiftheMFIwasmorethan300mmHgandstrongiftheMFIwasmorethan2500mmHgforclassI,ormorethan1500mmHgforclassII.14 HLAantibodystrengthwasalsoassessedbytheNBGratioresultofthescreeningtest.15  AntibodytoHNA Screeningforanti–humanneutrophilantigen(HNA)wasperformedusingthegranulocyteagglutinationtest(GAT)andgranulocyteimmunofluorescencetest(GIFT),analyzedbyaflowcytometer(EPICSXL/MCLFlowCytometerBeckmanCoulter).GIFTwasinterpretedaspositiveifcellsfromatleast1paneldonorwereinterpretedaspositive.QuantitativedeterminationofantibodystrengthbytheGIFTwasassessed(seesupplementalMethods). Determininganti-HNAspecificity Anti-HNAspecificitywasdeterminedby2methods:(1)byexaminingthereactivitypatternobtainedfromsamplesinterpretedaspositiveintheGATand/orGIFT(eg,foranti–HNA-3a);and(2)bythemonoclonalantibodyimmobilizationofneutrophilantigensassay,wheremonoclonalantibodieswereusedtocaptureglycoproteinsexpressingHNA-1a,HNA-1b,HNA-1c,HNA-2a,HNA-4a,andHNA-5aalloantigens. Bioreactivesubstances Lysophosphatidylcholineconcentrationsweredeterminedbyliquidchromatography-tandemmassspectrometry.Cytokinelevels,includingvascularendothelialgrowthfactorinplasmaofpatients,anddonorunitsweredeterminedusingLuminexmultiplexbeadassaysasdescribedbythemanufacturer(Bio-Rad).ThelevelsofsolubleCD40ligandandplateletfactor4inplasmasamplesweredeterminedusingstandardplate-boundELISAformatassays.Methodswereusedasdescribedbythemanufacturer(solubleCD40ligandkitfromBenderMedSystems;plateletfactor4kitfromR&DSystems). Todetermineneutrophilprimingactivity,sampleswereexaminedonadual-laserflowcytometer(FACscanFlowCytometer,BDBiosciences)andanalyzedusingFlowJoVersion9.2software(TreeStar).Todetectplasma-inducedCD11b/CD66up-regulation,donorneutrophilswereincubatedwithtestplasmaandthenstainedforCD11b/CD66b:(1)plasmafromtheneutrophildonorincubatedwithhis/herownneutrophils,negativecontrol;(2)donorneutrophilsincubatedwith1nMfMLF/BSA,positivecontrol;(3)donorneutrophilsincubatedwithplasmatestsample,showinglackofreactivity;and(4)donorneutrophilsincubatedwithplasmatestsample,showingsignificantup-regulationofCD11b/CD66b.Numbersineachquadrantdesignatepercentageofpositivecellsbasedonnegativecontrol. Statisticalmethods TRALIincidenceanalysis. StepstoreducetheincidenceofTRALI(TRALImitigation)wereimplementedfrom2007to2008.In2006,neithercenterhadstartedmitigation.In2009,bothsiteshadcompletedmitigation.Incidencesin2006and2009werecompared.Toassesstrend,monthlycountsofTRALIcasesweremodeledbyPoissonregression,controllingforthenumberoftransfusionsineachmonth. Riskfactoranalysis. TRALIoccursinpatientsratherthaninunits;thus,ouranalysestreatedeachpatientasoneobservation.Inkeepingwiththecase-controldesign,theprimaryoutcomewaswhetherthepatientwasaTRALIcaseoracontrol.Regardingpotentialrecipientriskfactors,weanalyzedmeasurementsmadeintherecipientbefore,andnotduring,thetransfusionperiodof6hoursbeforepulmonaryedema,toavoidmeasuringtheeffectsofanyTRALIprodrome. Wedefinedandevaluatedalargenumberofpotentialriskfactors.RecipientfactorsevaluatedwerepotentialorknownriskfactorsforALI.Transfusionfactorsevaluatedweredonorgender,donorpregnancy,componenttype,storageageofRBC,plateletandplasmaunits,patientanddonorABOcompatibility,anti-HNA,anti-HLA,MICAantibody,lysoPC,leukocyteandplateletcytokines,andneutrophilprimingactivity.Thequantityofapotentialtransfusionpredictor(antibodyorbioreactivesubstance)inatransfusedunitwascalculatedbythepredictorstrength/concentrationmultipliedbytheplasmavolumeestimatedforeachpositivecomponent.Allcandidateriskfactorswereevaluatedbylogisticregression.Topermitestimationoftheeffectofnumberofinvolvedunits,theSASSurveyLogisticprocedure16 wasusedforinitialanalyses.Becauseinitialresultsindicatedthatvirtuallyalltheriskofincreasingnumberoftransfusedunitscouldbeexplainedbyothervariablesinmultivariatemodels,simplerstratifiedconditionallogisticregressionmethodsweresubsequentlyusedfortheprimaryresults.Multipleimputationmethods17 wereusedtopreventdeletionofpatientswhenanyoneoftheirunitshadamissingmeasurement,topreservemoreinformationandintroducelessbiasthanalternativemethods. AnalysisofstorageageofRBCunits. WeusedaspredictorsthenumbersofRBCunitsreceivedbyeachpatientthatwereabovecertainunitagecutoffs.Thesecanneverbereducedbyadditionoffresherunits,andtheywerewelldefined(zero)forthosewhodidnotreceiveanyunitsabovethespecifiedunitagecutoff. Multivariatemodelbuilding. WehypothesizedthatthenumberofunitstransfusedmightbeanimportantriskfactorforTRALI.Topreventconfoundingwiththenumberofunitsfromproducingspuriousresultsforotherriskfactors,wecontrolledforthenumberofunitsreceivedduringorwithin6hoursofTRALI(orthecorrespondingartificialTRALItimecreatedforcontrols),whichwecalled“involvedunits,”inallmodelsusedtoinitiallyevaluatepotentialriskfactors.Thus,apatientcharacteristicassociatedwithneedingmanyunitswouldnotappeartoberiskyunlessitalsoincreasedriskbysomeothermechanism.Wealsocontrolledforstudysite(UCSForMayo),asisusualpracticeformultisitestudies.Multivariatemodelswerebuiltstepwise,selectingriskfactorswithsmallPvaluesforadditionand/orfactorsthatnolongerhadsmallPvaluesfordeletionateachstep,takingintoaccountbiologicplausibility. Descriptivedata. Wedonotprovidestatisticalcomparisonsofdescriptivesummaries(Tables2to6)because(1)theydonottakeaccountofthestratifiedsampling,and(2)theywouldreversethecorrectrolesofdependentandindependentvariables.TRALIversuscontrolisthedependentvariableinriskfactoranalyses. Table2DemographiccharacteristicsofTRALIcasesandcontrols . TRALIcases(N=89) . Controlsubjects(N=164) . Ageiny:mean±SD 54±20 56±20.2 Ageiny:median(Q1-Q3) 57(47-66) 59(45-71) Age,y       ≤19 9(10) 9(6)     20-29 4(5) 12(7)     30-39 3(3) 14(9)     40-49 12(14) 14(9)     50-59 21(24) 37(23)     60-69 23(26) 31(19)     ≥70 17(19) 47(29) Sex       Female 45(51) 73(45)     Male 44(49) 91(56) Race       AmericanIndian/Alaska 1(1) 2(1)     Asian 4(5) 10(6)     BlackorAfricanAmerican 4(5) 6(4)     NativeHawaiian/PacificIslander 1(1) 1(1)     Unknownornotreported 16(18) 22(13)     White 63(71) 123(75) Ethnicity       Hispanic 7(8) 11(7)     NotHispanic 70(79) 124(76)     Notreportingethnicity 12(14) 29(18) Hospital       MayoClinic 45(51) 85(52)     UCSF 44(50) 79(48) Transfusionstrata       High(≥10units) 30(34) 48(30)     Medium(3-9units) 32(36) 63(38)     Low(1-2units) 27(30) 53(32) Patientlocationattimeoftransfusion       Floor 14(16) 54(33)     HematologyOncologyfloor 4(5) 20(12)     ICU 27(30) 29(18)     OR/PACU 43(48) 53(32)     Outpatient 1(1) 8(5)  . TRALIcases(N=89) . Controlsubjects(N=164) . Ageiny:mean±SD 54±20 56±20.2 Ageiny:median(Q1-Q3) 57(47-66) 59(45-71) Age,y       ≤19 9(10) 9(6)     20-29 4(5) 12(7)     30-39 3(3) 14(9)     40-49 12(14) 14(9)     50-59 21(24) 37(23)     60-69 23(26) 31(19)     ≥70 17(19) 47(29) Sex       Female 45(51) 73(45)     Male 44(49) 91(56) Race       AmericanIndian/Alaska 1(1) 2(1)     Asian 4(5) 10(6)     BlackorAfricanAmerican 4(5) 6(4)     NativeHawaiian/PacificIslander 1(1) 1(1)     Unknownornotreported 16(18) 22(13)     White 63(71) 123(75) Ethnicity       Hispanic 7(8) 11(7)     NotHispanic 70(79) 124(76)     Notreportingethnicity 12(14) 29(18) Hospital       MayoClinic 45(51) 85(52)     UCSF 44(50) 79(48) Transfusionstrata       High(≥10units) 30(34) 48(30)     Medium(3-9units) 32(36) 63(38)     Low(1-2units) 27(30) 53(32) Patientlocationattimeoftransfusion       Floor 14(16) 54(33)     HematologyOncologyfloor 4(5) 20(12)     ICU 27(30) 29(18)     OR/PACU 43(48) 53(32)     Outpatient 1(1) 8(5) Valuesareno.(%),unlessotherwisespecified.ViewLarge Table3DescriptivedataofcomponentsreceivedbycontrolandTRALIpatients . Unitsreceivedbycontrolpatients(N=164) . UnitsreceivedbyTRALIpatients(N=89) . Totalno.ofunits,mean±SD 6.43±6.1 11±15.1 Totalno.ofunits,median(range) 3(1-37) 4(1-69) No.ofwholebloodunits,mean±SD 0.02±0.22 0.13±0.77 No.ofwholebloodunits,median(range) 0.0(0.0-2) 0.0(0.0-6) No.ofRBCunits,mean±SD 2.52±2.42 3.57±4.87 No.ofRBCunits,median(range) 2(0.0-12) 2(0.0-25) No.ofapheresisplatelets,mean±SD 0.49±0.779 0.91±1.42 No.ofapheresisplatelets,median(range) 0.0(0.0-3) 0.0(0.0-7) No.ofplasmaunits,mean±SD 2.86±4.35 4.69±7.24 No.ofplasmaunits,median(range) 0.0(0.0-21) 2(0.0-40) No.ofcryoprecipitatedoses,mean±SD 0.53±2.42 1.66±4.63 No.ofcryoprecipitatedoses,median(range) 0.0(0.0-20) 0.0(0.0-20) AgeofRBCunits,mean±SD(N) 21.5±11(N=413) 21.8±11.4(N=318) AgeofRBCunits,median(range) 20(3-42) 21(4-42) Ageofplateletunits,mean±SD(N) 4.91±1.11(N=81) 4.99±1.36(N=81) Ageofplateletunits,median(range) 5(2-7) 5(2-7)  . Unitsreceivedbycontrolpatients(N=164) . UnitsreceivedbyTRALIpatients(N=89) . Totalno.ofunits,mean±SD 6.43±6.1 11±15.1 Totalno.ofunits,median(range) 3(1-37) 4(1-69) No.ofwholebloodunits,mean±SD 0.02±0.22 0.13±0.77 No.ofwholebloodunits,median(range) 0.0(0.0-2) 0.0(0.0-6) No.ofRBCunits,mean±SD 2.52±2.42 3.57±4.87 No.ofRBCunits,median(range) 2(0.0-12) 2(0.0-25) No.ofapheresisplatelets,mean±SD 0.49±0.779 0.91±1.42 No.ofapheresisplatelets,median(range) 0.0(0.0-3) 0.0(0.0-7) No.ofplasmaunits,mean±SD 2.86±4.35 4.69±7.24 No.ofplasmaunits,median(range) 0.0(0.0-21) 2(0.0-40) No.ofcryoprecipitatedoses,mean±SD 0.53±2.42 1.66±4.63 No.ofcryoprecipitatedoses,median(range) 0.0(0.0-20) 0.0(0.0-20) AgeofRBCunits,mean±SD(N) 21.5±11(N=413) 21.8±11.4(N=318) AgeofRBCunits,median(range) 20(3-42) 21(4-42) Ageofplateletunits,mean±SD(N) 4.91±1.11(N=81) 4.99±1.36(N=81) Ageofplateletunits,median(range) 5(2-7) 5(2-7) Inmultivariateanalysis,theriskofincreasedno.ofinvolvedunitswasaccountedforbytheantibodyandpatientriskfactorsshowninTable12(“Riskofgreaternumberoftransfusions”).ViewLarge Table4DescriptivedataofantibodiesinunitstransfusedtoTRALIandcontrolpatientsAntibody . Unitsreceivedbycontrolpatients(N=1054) . UnitsbyTRALIpatients(N=976) . Anti-HNA,positivewithatleastonegranulocytepanelcellbyGIFT 6.4%(55/860) 7.8%(56/714) Anti-HNA,withspecificity 1.7%(15/860) 1.7%(12/714) Anti–HLA-classI,cognate(MFI>300) 11.6%(108/930) 12.3%(96/782) Anti–HLA-classII,cognate(MFI>300) 5.8%(54/930) 7.8%(61/782) Antibody . Unitsreceivedbycontrolpatients(N=1054) . UnitsbyTRALIpatients(N=976) . Anti-HNA,positivewithatleastonegranulocytepanelcellbyGIFT 6.4%(55/860) 7.8%(56/714) Anti-HNA,withspecificity 1.7%(15/860) 1.7%(12/714) Anti–HLA-classI,cognate(MFI>300) 11.6%(108/930) 12.3%(96/782) Anti–HLA-classII,cognate(MFI>300) 5.8%(54/930) 7.8%(61/782) In12TRALIunits,therewereantibodiestoHNA-1a,-1b,or-3a.In15controlunits,therewereantibodiestoHNA-1a,-1b,-1c,-2a,-3a,or4a.UsingtheMFIcut-offof>300fordeterminationofanti-HLAspecificity,themostcommoncognateanti–HLA-classIspecificitieswereA2(15TRALIunits,11controlunits)andB7(10TRALIunits,10controlunits).ThemostcommonDQspecificitieswereDQ7(7TRALIunits,13controlunits)andDQ8(9TRALIunits,11controlunits).ThemostcommonDRspecificitywasDR52(9TRALIunits,12controlunits).ViewLarge Table5Descriptivedataoflysophosphatidylcholine(lysoPC)measuredinunitsreceivedbycontrolpatientsandTRALIpatients . Unitsreceivedbycontrolpatients(N=536) . UnitsreceivedbyTRALIpatients(N=419) . LysoPCconcentration,M,mean±SD 128±78.3 142±80.6 LysoPCconcentration,M,median(range) 137(0.2-453) 152(1-367)  . Unitsreceivedbycontrolpatients(N=536) . UnitsreceivedbyTRALIpatients(N=419) . LysoPCconcentration,M,mean±SD 128±78.3 142±80.6 LysoPCconcentration,M,median(range) 137(0.2-453) 152(1-367) LysoPCconcentrationwasthesumoftheconcentrationsofthe16:0and18:0fattyacidmoieties.Inriskfactoranalysis,thesumoflysoPCquantitiesamongallunitsreceivedbyapatientwasastatisticallysignificantriskfactorinunivariateanalysis(Table9)butnotinmultivariateanalysis.ViewLarge Table6DescriptivedataofneutrophilprimingactivityintransfusedunitsCD11borCD66bup-regulation . Unitsreceivedbycontrolpatients(N=532) . UnitsreceivedbyTRALIpatients(N=321) . %cellspositiveforCD11b,mean±SD 9.02±12.7 10.8±14.7 %cellspositiveforCD11b,median(range) 3.8(0.0-78.4) 4.1(0.0-73.7) %cellspositiveforCD11borCD66b,mean±SD 5.94±8.4 5.12±6.36 %cellspositiveforCD11borCD66b,median(range) 2.4(0.0-61.9) 2.8(0.0-49.9) CD11borCD66bup-regulation . Unitsreceivedbycontrolpatients(N=532) . UnitsreceivedbyTRALIpatients(N=321) . %cellspositiveforCD11b,mean±SD 9.02±12.7 10.8±14.7 %cellspositiveforCD11b,median(range) 3.8(0.0-78.4) 4.1(0.0-73.7) %cellspositiveforCD11borCD66b,mean±SD 5.94±8.4 5.12±6.36 %cellspositiveforCD11borCD66b,median(range) 2.4(0.0-61.9) 2.8(0.0-49.9) Inriskfactoranalysis,totalquantitiesofCD11bup-regulation(%positivecells×plasmavolume)inallunitsreceivedbyapatientwereastatisticallysignificantriskfactorinunivariateanalysis(Table9)butnotinmultivariateanalysis.ViewLarge Results Duringtheactivesurveillanceperiodof45months,463207unitsofbloodandbloodcomponentsweretransfusedatthe2centers,and89TRALIcaseswereidentified(Figure1).Seventycasesreceivedoneormorehighplasmavolumebloodproducts.Ofthe89TRALIcases,onlyonehadamajorALIriskfactor(sepsis);thesepticpatientwasstableuntiltransfusionprecipitatedpulmonaryedema.NinehadminorALIriskfactors(4receivingamiodarone,3disseminatedintravascularcoagulation,1afterlungresection,1acutecentralnervoussysteminjury/stroke).Ofthe89TRALIcases,only40(45%)werereportedtothebloodbanksasatransfusionreaction.Fivecaseswereidentifiedaftertransfusionreactionreportsonly,asanABGwasorderedmorethan12hoursafterbloodissueoraFiO2wasnotentered. Figure1ViewlargeDownloadPPTEnrollmentofTRALIcasesandcontrolsat2academiccenters(2006-2009).AllRBCandplateletunits(allcollectedbyapheresis)wereleuko-reduced.Todetermineriskfactors,89TRALIcasesand164controlsthatoccurredduringthecase-controlstudyperiodfromMarch1,2006toAugust31,2009wereincluded.DAHindicatesdiffusealveolarhemorrhage;ILD,interstitiallungdisease;CVP,centralvenouspressure;andTACO,transfusionassociatedcirculatoryoverload.Figure1ViewlargeDownloadPPTEnrollmentofTRALIcasesandcontrolsat2academiccenters(2006-2009).AllRBCandplateletunits(allcollectedbyapheresis)wereleuko-reduced.Todetermineriskfactors,89TRALIcasesand164controlsthatoccurredduringthecase-controlstudyperiodfromMarch1,2006toAugust31,2009wereincluded.DAHindicatesdiffusealveolarhemorrhage;ILD,interstitiallungdisease;CVP,centralvenouspressure;andTACO,transfusionassociatedcirculatoryoverload.Closemodal TRALIincidence TheannualTRALIincidence(March1,2006toDecember31,2009)decreasedfrom2.57(95%confidenceinterval[CI],1.72-3.86)per10000unitstransfused(23cases/89321units)in2006to0.81(95%CI,0.44-1.49)per10000unitstransfused(10cases/123731units)in2009(P=.002;Figure2).Reductionsfrompre-topost-mitigationperiodswerelargeratMayo(P=.014),whereTRALIincidencealsodecreasedinpatientswhoreceivedplasmafromonlymaledonors,associatedwithconcurrentpatientriskfactormitigation.18 Bytrendanalysis,therewasanoverall35%reductionperyear(95%CI,21%-47%,P<.0001 figure2viewlargedownloadppttraliincidencebyyearat2academicmedicalcenters incidencesoftralibytransfusedpatient-days case-controlstudy thedemographiccharacteristics table7allcomponentsreceivedduringorwithin6hoursin89casesoftralicomponents . table8univariatepatientriskfactorsfortrali>9) NA NA 1.17 1.05 1.31 .006     Shockbeforetransfusion 50/184(27.2) 36/69(56.5) 4.3 2.2 8.4 <.001>30cmH2Oifmechanicallyventilated 73/230(31.7) 16/21(69.6) 5.6 2.1 14.9 <.001 .>9) NA NA 1.17 1.05 1.31 .006     Shockbeforetransfusion 50/184(27.2) 36/69(56.5) 4.3 2.2 8.4 <.001>30cmH2Oifmechanicallyventilated 73/230(31.7) 16/21(69.6) 5.6 2.1 14.9 <.001 table9univariatetransfusionriskfactorsfortralitransfusionfactorassessedforeachpatient . table10univariatetransfusionfactors>.05)Transfusionriskfactorassessedforeachpatient . OR . Lower95%CI . Upper95%CI . P . Bloodorbloodcomponentreceived         RBCsfromfemaledonor 0.62 0.35 1.08 .09     RBCsfrompreviouslypregnantfemaledonor 0.79 0.45 1.38 .40 Cytokines:sumofamounts(concentration×volume)inallunitsreceived         IL-6 1.14 0.997 1.30 .06     IL-8 1.26 0.96 1.63 .09     GM-CSF 1.00 0.999 1.00 .52     IFN-γ 1.24 0.99 1.56 .06     TNF-α 1.10 0.96 1.27 .18     SolubleCD40ligand(sCD40L) 1.06 0.97 1.16 .22     Plateletfactor4(PF4) 1.06 0.98 1.14 .14 Neutrophilprimingactivity:sumofamounts(activity×volume)inallunitsreceived         CD11b/CD66bup-regulation 1.00 0.95 1.04 .82 No.ofleuko-reducedRBCunitsreceivedbyeachpatient,byRBCunitstorageage         RBCunitsvsotherunits 1.02 0.90 1.15 .77     No.ofRBCunits>7-day-oldvsotherRBCunits 1.02 0.76 1.37 .88     No.ofRBCunits>14daysvsotherRBCunits 1.03 0.87 1.23 .72     No.ofRBCunits>21-day-oldvsotherRBCunits 1.13 0.95 1.34 .16     No.ofRBCunits>28-day-oldvsotherRBCunits 1.03 0.81 1.31 .79     No.ofRBCunits>35-day-oldvsotherRBCunits 0.99 0.76 1.29 .95     MedianageofallRBCsvsotherRBCunits 1.01 0.99 1.03 .49     MeanageofallRBCunits 1.01 0.99 1.03 .41     MaximumageamongallRBCunits 1.01 0.99 1.03 .26 Apheresisplateletunitstorageage         Platelets>3-day-oldvsotherplatelets 0.67 0.27 1.68 .39     Platelets>4-day-oldvsother 1.24 0.72 2.1 .45     Plateletmedianunitage 1.07 0.96 1.20 .20     Plateletmeanunitage 1.07 0.96 1.2 .22     Plateletmaximumunitage 1.07 0.96 1.2 .20 Transfusionriskfactorassessedforeachpatient . OR . Lower95%CI . Upper95%CI . P . Bloodorbloodcomponentreceived         RBCsfromfemaledonor 0.62 0.35 1.08 .09     RBCsfrompreviouslypregnantfemaledonor 0.79 0.45 1.38 .40 Cytokines:sumofamounts(concentration×volume)inallunitsreceived         IL-6 1.14 0.997 1.30 .06     IL-8 1.26 0.96 1.63 .09     GM-CSF 1.00 0.999 1.00 .52     IFN-γ 1.24 0.99 1.56 .06     TNF-α 1.10 0.96 1.27 .18     SolubleCD40ligand(sCD40L) 1.06 0.97 1.16 .22     Plateletfactor4(PF4) 1.06 0.98 1.14 .14 Neutrophilprimingactivity:sumofamounts(activity×volume)inallunitsreceived         CD11b/CD66bup-regulation 1.00 0.95 1.04 .82 No.ofleuko-reducedRBCunitsreceivedbyeachpatient,byRBCunitstorageage         RBCunitsvsotherunits 1.02 0.90 1.15 .77     No.ofRBCunits>7-day-oldvsotherRBCunits 1.02 0.76 1.37 .88     No.ofRBCunits>14daysvsotherRBCunits 1.03 0.87 1.23 .72     No.ofRBCunits>21-day-oldvsotherRBCunits 1.13 0.95 1.34 .16     No.ofRBCunits>28-day-oldvsotherRBCunits 1.03 0.81 1.31 .79     No.ofRBCunits>35-day-oldvsotherRBCunits 0.99 0.76 1.29 .95     MedianageofallRBCsvsotherRBCunits 1.01 0.99 1.03 .49     MeanageofallRBCunits 1.01 0.99 1.03 .41     MaximumageamongallRBCunits 1.01 0.99 1.03 .26 Apheresisplateletunitstorageage         Platelets>3-day-oldvsotherplatelets 0.67 0.27 1.68 .39     Platelets>4-day-oldvsother 1.24 0.72 2.1 .45     Plateletmedianunitage 1.07 0.96 1.20 .20     Plateletmeanunitage 1.07 0.96 1.2 .22     Plateletmaximumunitage 1.07 0.96 1.2 .20 Thetransfusionunivariateriskfactorsinthistablewerenotstatisticallysignificant.Numbersofpatientswhoreceivedordidnotreceivethistransfusionriskfactorarenotavailablebecausemultipleimputationwasusedforunitswithmissingdata(“Statisticalmethods:riskfactoranalysis”).ViewLarge Table11Receiptofplasmafromfemaledonorscontrolledforrecipientfactors . OR . Lower95%CI . Upper95%CI . P . Transfusionriskfactor         Receiptofanyfemaledonorplasmaorwholeblood 4.5 1.85 11.2 .001 Recipientriskfactors         Chronicalcoholabuse 3.8 1.03 13.8 .045     Fluidbalancebeforetransfusion(incrementperliter) 1.2 1.05 1.3 .006     Peakairwaypressure>30cmH2Owithin12hoursafterintubationbeforetransfusion 2.8 0.89 8.5 .08     Shockbeforetransfusion 2.9 1.32 6.4 .008     Currentsmokervsneverorformersmoker 3.3 1.32 8.2 .01     Liversurgery(transplantation) 3.0 0.78 11.8 .11  . OR . Lower95%CI . Upper95%CI . P . Transfusionriskfactor         Receiptofanyfemaledonorplasmaorwholeblood 4.5 1.85 11.2 .001 Recipientriskfactors         Chronicalcoholabuse 3.8 1.03 13.8 .045     Fluidbalancebeforetransfusion(incrementperliter) 1.2 1.05 1.3 .006     Peakairwaypressure>30cmH2Owithin12hoursafterintubationbeforetransfusion 2.8 0.89 8.5 .08     Shockbeforetransfusion 2.9 1.32 6.4 .008     Currentsmokervsneverorformersmoker 3.3 1.32 8.2 .01     Liversurgery(transplantation) 3.0 0.78 11.8 .11 SeeTable8fornumbersofpatientsforpatientriskfactors.Numbersofpatientswhoreceivedordidnotreceivethistransfusionriskfactorarenotavailablebecausemultipleimputationwasusedforunitswithmissingdata(“Statisticalmethods:riskfactoranalysis”).ViewLarge Table12PrimarymultivariatemodelofTRALIriskfactors:antibodiestransfusedtotherecipientcontrolledforrecipientriskfactors . OR . Lower95%CI . Upper95%CI . P . Transfusionriskfactorsamongalltransfusionstoeachpatient         Totalquantityofcognateanti-HLA-classII(MFI>1500)per10-foldincrease 3.2 1.52 6.7 .002     Totalvolumeofanti-HNApositivebyGIFTamongallunits,per100-mLincrease 1.71 1.18 2.5 .004 Recipientriskfactors         Chronicalcoholabuse 5.9 1.22 28.3 .028     Fluidbalancebeforetransfusion(incrementperliter) 1.15 1.02 1.29 .024     Peakairwaypressure>30cmH2Owithin12hoursafterintubationbeforetransfusion 3.6 1.01 13.1 .048     Shockbeforetransfusion 4.2 1.69 10.6 .002     Currentsmokervsneverorformersmoker 3.4 1.22 9.7 .020     Liversurgery(transplantation) 6.7 1.25 35.7 .027     IL-8concentrationbeforetransfusion,per10-foldincrease 3.0 1.30 6.8 .018  . OR . Lower95%CI . Upper95%CI . P . Transfusionriskfactorsamongalltransfusionstoeachpatient         Totalquantityofcognateanti-HLA-classII(MFI>1500)per10-foldincrease 3.2 1.52 6.7 .002     Totalvolumeofanti-HNApositivebyGIFTamongallunits,per100-mLincrease 1.71 1.18 2.5 .004 Recipientriskfactors         Chronicalcoholabuse 5.9 1.22 28.3 .028     Fluidbalancebeforetransfusion(incrementperliter) 1.15 1.02 1.29 .024     Peakairwaypressure>30cmH2Owithin12hoursafterintubationbeforetransfusion 3.6 1.01 13.1 .048     Shockbeforetransfusion 4.2 1.69 10.6 .002     Currentsmokervsneverorformersmoker 3.4 1.22 9.7 .020     Liversurgery(transplantation) 6.7 1.25 35.7 .027     IL-8concentrationbeforetransfusion,per10-foldincrease 3.0 1.30 6.8 .018 SeeTable8fornumbersofpatientsforpatientriskfactors.Numbersofpatientswhoreceivedordidnotreceivethistransfusionriskfactorarenotavailablebecausemultipleimputationwasusedforunitswithmissingdata(“Statisticalmethods:riskfactoranalysis”).Thepatient'splasmaIL-8levelmeasuredbeforetransfusionwasalsoapredictorofriskinmultivariateanalysis.Becausethisvariablewasmissingfor50patients,reducingthesetofanalyzedpatientstoaccommodatethisvariabledisruptedtheestimatesofotherriskfactors,andsothiswasnotincludedintheprimarymodelbutlistedattheendofthetable.ViewLarge Riskofgreaternumberoftransfusions Initialestimatesshowedthatincreasednumberoftransfusionswereassociatedwithincreasedrisk,withORof4.5(95%CI,2.4-8.4,P<.0001 rbcunitstorageage wefoundevidenceagainstlongerstorageofleuko-reducedrbcunitsbeinganimportantrisk plasmafromfemaledonors plasma>1500)andvolumeofunitsanti-HNApositivebyGIFT(Table12).Whenfemaledonorplasmaandthe2antibodieswereinthesamemodel,femaledonorplasmariskwassmallerandnolongerstatisticallysignificant(OR=2.4,95%CI,0.87-6.9,P=.09). SpecificHLAantibody ConcerningtheimportanceofcognateHLAantibody,totalquantityofcognateanti–HLA-classII(MFI>1500)wasassociatedwithriskinthemultivariateanalysis(Table12).However,foranti–HLA-classII(MFI>1500),totalquantity,strongestMFIinanyunit,andlargestquantityinanyunitwereallcollinearandhighlypredictive(OR=3.2-3.5,P=.0035-.0052),andwhichismostimportantcannotbereliablydeterminedfromourdata.Incontrast,whencontrolledforcognateanti–HLA-classII(MFI>1500),nosubstantialriskwasassociatedwiththequantityofnoncognateanti–HLA-classII(MFI>1500,OR=0.41,95%CI,0.10-1.59,P=.19). RegardingtheimportanceofclassIcognateHLAantibody,nosubstantialriskwasassociatedwiththepresenceofanycognateanti–HLA-classI(MFI>2500,OR=1.12,95%CI,0.20-6.20,P=.90),whencontrolledforcognateanti–HLA-classII(MFI>1500). Withregardtotherelativeimportanceofstrong(MFI>1500)versusweak(MFI300-1500)antibody,nosubstantialriskwasassociatedwiththepresenceofanyweakcognateanti–HLA-classII(MFI300-1500,OR=0.32,95%CI,0.09-1.20,P=.09),whencontrolledforcognateanti–HLA-classII(MFI>1500). RegardingcognateHLAantibodyspecificities(supplementalTable10),nosinglestrongcognateHLAclassIorIIspecificitywasstatisticallysignificantwhenaddedtotheprimarymultivariatemodel(Table12)asananyversusnodichotomouspredictor,althoughmanyweretooraretobeevaluatedindividually. HLAantibodydetectedbyscreeningtest Amongstudyunits,84%(1712of2030)weretestedforHLAantibodybythescreeningtest.Tofacilitateapplyingthefindingstoclinicalpractice,weinvestigatedwhatlevelofantibody(NBGratio)foundbytheanti-HLAdonorscreeningtestwouldposeasignificantlyincreasedriskfortransfusionrecipients.Aftertestingmultipleassaythresholds(inmodelsthatdidnotincludethecognateHLAclassIIvariable),wefoundthatalargervolumeofstronganti–HLA-classII(NBGratio>27.5)increasedrisk(OR=1.92per100mL,95%CI,1.08-3.4,P=.03),athresholdequivalenttogreaterthan5SDsinacohortofnontransfusedmales.15 However,similartothespecificanti-HLAantibodies,thevolumeofweakanti–HLA-classIIpositiveonthescreeningtest(NBGratio,2.2-27.5)wasnotassociatedwithrisk(OR=0.81per100mL,95%CI,0.34-1.93,P=.63),andthevolumeofanti–HLA-classIdidnotappeartoincreaserisk,evenforstrongantibody(NBGratio>59.3,OR=0.98per100mL,95%CI,0.46-2.1,P=.97). HNAantibody Amongstudyunits,78%(1574of2030)weretestedforanti-HNAbyGATandGIFT.PatientswerenottestedforHNAtype,exceptforthe2recipientsofanti–HNA-3a.Bymultivariateanalysis,plasmavolumeofallGIFT-positiveunitsreceivedwasapredictorofrisk(OR=1.71per100mL,95%CI,1.18-2.5,P=.004;Table12).GATwasnotastatisticallysignificantpredictorwhencontrolledforGIFT.Anti-HNAwithdefinedspecificitywasrare(Table4),includinganti–HNA-3a.Ofthe1574testedunits,only2(0.1%)containedanti–HNA-3a:1inanRBCand1inaplasmaunit.ATRALIpatientreceivedthisRBCunitandotherunitsthatcontainedstrongcognateanti–HLA-classII;acontrolpatientreceivedtheplasmaunit.BothrecipientgenotypeswerehomozygousforHNA-3a(courtesyofDrBrianCurtis,BloodCenterWisconsin).GIFTstrengthcouldnotbequantified(seesupplementalDiscussion). Receiptofantibodypredictorsbypatients Amongthe89TRALIpatients,52%receivedoneorbothantibodypredictors(10%receivedcognateanti–HLA-classIIwithMFI>1500,12%receivedanti-HNApositivebyGIFT,and30%receivedboth). Bioreactivesubstances Bioreactivesubstancesweresignificantbyunivariateanalysis(Table9),butwhenaddedtotheprimarymultivariatemodel(Table12),thetotalamountsofMICAantibodyandcandidatebioreactivemoleculeswerenotstatisticallysignificant.Forbioreactivesubstances,halfoftheunitswerenotreturned,andmissingdatarequiredmultipleimputation(“Statisticalmethods”). Patientriskfactors Onunivariateanalysis,weidentifiedpatientriskfactorsthatincreasedtheriskofTRALIorwereprotective(Table8).However,onmultivariateanalysis.theprotectivefactorsdroppedoutofthemodel,leavingindependentpatientriskfactorsofshock,liversurgery(mainlytransplantation),chronicalcoholabuse,positivefluidbalance,peakairwaypressuregreaterthan30cmH2Oifmechanicallyventilatedbeforetransfusion,andcurrentsmoking(Tables11and12).Thepatient'splasmaIL-8levelmeasuredbeforetransfusionwasalsoapredictorofriskbymultivariateanalysis. Discussion ThemajorfindingsofthisfirststudyofTRALIbyactivesurveillanceofthegeneraltransfusionpopulationcanbesummarizedasfollows.First,implementationofapredominantlymaleplasmasupplywasassociatedwithreducedincidenceofTRALIdeterminedbyactivesurveillance,thussupportingtheeffectivenessofthisapproach.Second,2predictivetransfusionriskfactorsidentifiedwerethequantitiesofstrongcognateanti–HLA-classIIandvolumesofanti-HNAinthebloodunits.Nosubstantialriskwasfoundfornoncognateorweakcognateanti–HLA-classII,oranti–HLA-classI.Third,thedatasupportusingacut-offofNBGratiomorethan27.5forscreeningofanti–HLA-classIIinfemaleapheresisplateletdonors.Fourth,thecombinationoftransfusionandpatientriskfactorsappearedtoexplainmostoftheriskofdevelopingTRALIknowntobeassociatedwithmultipletransfusions.5 Fifth,wefoundevidenceagainstlongerRBCstorageagebeinganimportantriskfactor.9  Wefoundthatreceiptofplasma(includingwholeblood)fromfemaledonorsisastrongriskfactor,andreductionofthisriskfactorwasconcurrentwithadecreaseinTRALIincidencefromapproximately1:4000unitstoapproximately1:12000units.Thepremitigationincidenceofapproximately1:4000unitswefoundin2006wasclosetotheapproximately1:5000unitsfoundbyacarefulstudyin1985attheMayoClinicwhereatransfusionteamperformedandmonitoredtransfusions,6 but10-foldhigherthanthe2005premitigationincidenceofapproximately1:40000unitsdistributedfoundbypassivesurveillance(26.3casesin106units).19 Inourstudy,otherfactorsmayhavecontributedtothedecreaseinincidence(eg,institutionalimprovementsincriticalcaredeliverythatreducedpatientriskfactorswefoundthatappeartorenderpatientssusceptibletoTRALI,suchasimprovingtreatmentofsepticshockanddecreasinghighpeakairwaypressure>30cmH20whilebeingmechanicallyventilated).18 DecreasesinTRALIafterconversiontoplasmafrompredominantlymaledonorshavebeenreportedbypassivesurveillancestudiesfromtheUnitedKingdom,20 theFDA,1 andtheAmericanRedCross.21 Nosimilardecreasein“possibleTRALI”incidenceafterimplementationoftheTRALImitigationstrategysuggeststhatplasmafromalloimmunizeddonorsisnotastrongriskfactorin“possibleTRALI.” AlthoughunitstransfusedtoTRALIandcontrolpatientsweresimilarintermsofpercentpositiveforantibody(Table4),TRALIpatientsreceivedmoreunitsofeverycomponent(Table3)andthusprobablyreceivedlargerquantities/volumesofantibody.Multivariateanalysisconfirmedthatantibodystrengthandquantity/volumeareimportant(Table12). RegardingtherelativeimportanceofclassIversusclassIIHLAantibody,wefoundclassIItobemoreimportant.Theassociationofanti–HLA-classIIwithTRALIwasfirstreportedbyKopkoetal.22 Caseserieshavereportedthatcognateanti–HLA-classIIwasthemostfrequentantibodyimplicatedinTRALI.23,24 ThispredominanceoccursdespitethefactthatfrequenciesofclassI(10%)andclassII(12%)antibodiesarecomparableinfemaledonors.25 Thegreaterimportanceofanti–HLA-classIIappearstoalsobetrueinrenaltransplantation.26  Regardinganti–HLA-classI,wefoundevidenceagainstanti–HLA-classIbeinganimportantrisk,evenforstrongcognateantibodywithMFImorethan2500(OR=1.12,95%CI,0.20-6.20,P=.90).Othershavereportedsimilarresults7 andsimilarconclusions.27 AlthoughtheestimatedriskforclassIwasverysmallandnotstatisticallysignificant,wecannotbecertainthatthereisabsolutelynorisk,astheupperconfidenceboundof6.20doesnotprecluderisk.Therearereportsthatcognateanti–HLA-classIcanbeassociatedwithTRALI.23,24,28 However,retrospectivestudieshavefoundthatthisisrare.29,30  RegardingcognateversusnoncognateHLAantibody,wefoundevidenceagainstsubstantialriskfromnoncognateantibody.ThisfindingarguesagainstthehypothesisthatnoncognateHLAantibodyisamarkerforblooddonorswhomakeotherantibodiesthatincreaseTRALIrisk. Volumeofanti-HNApositivebyGIFTwasastrongpredictor(Table12).TheGIFTdetectsantibodiestoHNA,antibodiestounknownHNA,andanti–HLA-classI.Becausewefoundthatanti–HLA-classIdidnotappeartoproducesubstantialrisk,theriskdetectedbytheGIFTisprobablytheresultofanti-HNA.Becausespecificanti-HNAwasrare,wecouldnotexaminethecontributionofanti-HNAspecificities.TheremaybeunidentifiedHNAantigensthatmaybeimportant. The2antibodypredictorsinTable12areapplicabletoallcomponenttypes.Forexample,forthesamecognateanti–HLA-classIIwithMFImorethan1500,theestimatedriskis3.2timesgreaterin200mLofplasma(plasma,apheresisplatelets)thanin20mLofplasma(RBCs,cryoprecipitate)becausetheORis3.2per10-foldincreaseinamounttransfused.Foranti-HNApositivebyGIFT,theestimatedriskis2.6timesgreaterfor200mLthanfor20mLofplasmabecausetheORis1.71per100-mLincrease. WhetherlongerRBCstorageisassociatedwithincreasedriskforlunginjuryandmortalityisconsideredthemostcriticalissuecurrentlyfacingtransfusionmedicine.9 Inthisprospectivecase-controlstudy,wefoundevidenceagainstlongerstorageofleuko-reducedRBCunitsbeinganimportantriskforTRALI. Therisksassociatedwithbioreactivesubstanceswerenotstatisticallysignificantinthemultivariatemodel(Table12),similartotheresultsinastudyofcardiacsurgerypatients.8 Thisresultwassurprising,givenmanypioneeringbasicstudiesbySillimanetalindicatingthatbioreactivesubstancesareimportantinthedevelopmentofTRALI.31-34 However,theCIsoftheoddsratiosinourresultswerewide,andtheupperboundswouldcorrespondtosubstantialrisk.Thus,wecannotconcludethatthesesubstancesdonotcarryrisk.FutureclinicalstudiesshouldtestfortheseimportantpotentialmediatorsinthesettingofongoingTRALImitigation. WhydosomepatientsdevelopTRALIandotherswhoreceivebloodfromthesamedonordonot?Wefoundthatcognateantibodymatters,andpatientswhodevelopedTRALImayhavereceivedcognateantibodyandothersdidnot.However,cognateversusnoncognateantibodyisnottheonlyreason,asseverallook-backstudieshavefoundpatientswhoreceivedcognateantibodybutdidnotdevelopTRALI.29,30,35 Wefound4additionalfactorsthatinfluencewhysomepatientsdevelopTRALIandothersdonot:first,thevolumeofantibodytransfused,second,theHLAclassofthecognateantibody,third,thestrengthofanti–HLA-classII,andfourth,thepresenceorabsenceofpatientfactorsthatincreasetheriskandlowersthethreshold36 forTRALI. ApproximatelyhalfoftheTRALIpatientsreceivedcognateanti–HLA-classII(MFI>1500)oranti-HNA.Someremainingcasesmayhavereceivedtransfusionfactorsforwhichwefoundevidenceagainstsubstantialrisk,buttheupperboundsoftheCIsstillincludedthepossibilityofsomerisk.Somecasesmayhavereceivedothertransfusionfactorswedidnotstudy(supplementalDiscussion).Insomecaseswithpatientriskfactors,itmaybepossiblethattransfusionwascoincidental. Thediversepatient-associatedriskfactorswefoundforTRALIinthisstudyareconsistentwiththeknownunderlyingcomorbiditiesthatpredisposeandlowerthethresholdforALI,thussupportingthevalidityofthisstudy.Shockresultsintissueinjury,37 perhapspredisposingtoTRALIthroughprimingoftherecipient'sneutrophils.Chronicalcoholabuseincreasesrisk,probablybecauseofreducedlevelsoftheantioxidantglutathioneinthelung,38 reducedphagocytosisofapoptoticcells,andtheresultingenhancedpulmonaryinflammatoryresponse.39 PatientswithintravascularvolumeoverloadaremorelikelytomanifestclinicalpulmonaryedemawhenthereisALI.40 PreviousstudieshavedocumentedtheriskfordevelopingALIwithpeakairwaypressuregreaterthan30cmH2041 andcurrentsmoking.42  WefoundhigherIL-8inpatientsbeforetransfusionofinvolvedunitsincreasedrisk.HigherIL-8,amarkerofinflammationandincreasedmortalityrisk,43 mayprimeneutrophilsandthelungendothelium.Acutecontemporaneouseventsthatincreaseinflammationandtissueinjurycouldbe“firsthits”asfirstsuggestedbySillimanetal.31 ExperimentalmodelsofTRALIhaveshownthathostinflammationmaybenecessarytoproduceALIbeforechallengewithcognateantibody.32,44 Inflammation(firsthit)mayup-regulateexpressionofHLAclassIIantigensonactivatedclassicantigen-presentingcells(monocytes,45 macrophages,dendriticcells),activatedneutrophils,46 andactivatedlungendothelialcells,47 andexposuretolargequantitiesofstrongcognateanti–HLA-classIImaythenleadtoALI(secondhit).48  Liversurgery(transplantation)wasapatientriskidentified,evenwhencontrolledforsevereliverdisease,volumeoftransfusions,andalcoholabuse.49,50 Cardiacsurgery8 andspinesurgerywerenotsignificantfactorsinmultivariateanalysis. Theprimarystrengthofthisstudyisthatitisthelargestprospective,case-controlledstudyofTRALIidentifiedbyactivesurveillanceinageneralpopulationoftransfusedpatientsatacademiccenters,andalargenumberofbiologicallyplausibleriskfactorswerestudied.LimitationsincludepossiblemissedTRALIpatientswhohadnoFi02dataavailableoranABGwasobtainedafter12hoursofbloodissue,andnoreportofthereactionwasmadetothebloodbank.ThewideCIsoftheoddsratios,becauseofmissingdata,thedecreaseinTRALIincidence,andpossiblydifferencesinstoragetimesofunitstransfusedtocasesandcontrols,limitedthestrengthofevidencethatthisstudycouldprovide,particularlyfornegativefindings(eg,bioreactivesubstances).Inaddition,wecouldnotassesstheeffectofmeasurestoreducetransfusionofplateletsfromalloimmunizeddonorsbecauseitwaspartiallyimplementedlateinthisstudy. Inconclusion,thisprospectivestudyindicatesthatTRALIincidence,asdeterminedbyactivesurveillance,decreasedafterreductionoftransfusionofplasmafromfemaledonors.ThedecreaseinTRALIincidencewasprobablytheresultinpartofreducedtransfusionofstrongcognateHLAclassIIantibodiesandHNAantibodiestopatientswhoaresusceptibletoALI,althoughdecreasesinpatientriskfactorsprobablyalsoplayedarole.TofurtherreduceTRALIrisk,ourclinicalevidencesupportsconsiderationofscreeningdonorsforstrongHLAclassIIantibodies15 andthedevelopmentofhigh-throughputGIFTmethodstoscreenforantibodiestoknownandunknownhumanneutrophilantigens.Importantly,reductionofmodifiablepatientriskfactorsshouldalsoreducetheriskfordevelopingTRALI.18  Theonlineversionofthisarticlecontainsadatasupplement. Thepublicationcostsofthisarticleweredefrayedinpartbypagechargepayment.Therefore,andsolelytoindicatethisfact,thisarticleisherebymarked“advertisement”inaccordancewith18USCsection1734. Acknowledgments TheauthorsthankCharleneAndersonforpreparationofthemanuscriptandDrBrianCurtisforperformingHNA-3agenotypingofthe2recipientsofanti–HNA-3a. ThisworkwassupportedbytheNationalHeart,Lung,andBloodInstitute(TransfusionMedicineSCCORP50HL081027;P.T.)andClinicalandTranslationalScienceAward(grantUL1RR024131). TheauthorshonortheassistanceandinspirationofthelateDrS.BreanndanMoore,whopassedawayin2009duringthestudyperiod. Authorship Contribution:P.T.,O.G.,E.L.M.,M.A.M.,P.B.,M.R.L.,R.B.W.,R.H.,C.A.L.,andM.A.G.conceivedanddesignedthestudy;G.W.,M.K.,R.S.R.,R.S.,D.L.,andP.W.acquireddata;P.B.,B.G.,P.T.,M.A.M.,M.R.L.,andR.B.W.analyzedandinterpreteddata;P.B.andB.G.performedstatisticalanalysis;P.T.,P.B.,O.G.,E.L.M.,M.A.M.,M.R.L.,R.B.W.,R.H.,andC.A.L.obtainedfunding;G.W.,M.K.,R.S.R.,R.S.,D.L.,andP.W.providedtechnicalormaterialsupport;P.T.supervisedthestudy;O.G.supervisedtheMayoClinicsite;J.L.W.supervisedcollectionofblooddonorsamplesanddataatMayoClinic;N.H.supervisedcollectionofblooddonorsamplesanddataatBloodCentersofthePacific;M.J.G.supervisedthelaboratorytestingforHLAtypingandantibody;P.J.N.superviseddatadownloadofandassistedintheanalysesofHLAantibodyscreeningandsingle-antigenbeadtestresults;D.M.supervisedthetestingforantibodytohumanneutrophilantigens;C.A.L.supervisedlaboratorytestingforcytokinesandneutrophilprimingactivity;andallauthorsdraftedthemanuscriptandcriticallyrevisedthemanuscriptforimportantintellectualcontent. Conflict-of-interestdisclosure:Theauthorsdeclarenocompetingfinancialinterests. Correspondence:PearlToy,DepartmentofLaboratoryMedicine,Box0451,UniversityofCalifornia–SanFrancisco,SanFrancisco,CA94143-0451;e-mail:[email protected]. References 1FatalitiesreportedtoFDAfollowingbloodcollectionandtransfusion:annualsummaryforfiscalyear2009, AnnualSummaries2010AccessedFebruary2,2011 http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm204763.htm2Bernard GR, Artigas A, Brigham KL, etal. TheAmerican-EuropeanConsensusConferenceonARDS:definitions,mechanisms,relevantoutcomes,andclinicaltrialcoordination., AmJRespirCritCareMed, 1994, vol. 149 3(pg. 818-824)GoogleScholarCrossrefSearchADSPubMed 3Kleinman S, Caulfield T, Chan P, etal. Towardanunderstandingoftransfusion-relatedacutelunginjury:statementofaconsensuspanel., Transfusion, 2004, vol. 44 12(pg. 1774-1789)GoogleScholarCrossrefSearchADSPubMed 4Toy P, Popovsky MA, Abraham E, etal. Transfusion-relatedacutelunginjury:defini-ionandreview., CritCareMed, 2005, vol. 33 4(pg. 721-726)GoogleScholarCrossrefSearchADSPubMed 5Fowler AA, Hamman RF, Good JT, etal. Adultrespiratorydistresssyndrome:riskwithcommonpredispositions., AnnInternMed, 1983, vol. 98 5(pg. 593-597)GoogleScholarCrossrefSearchADSPubMed 6Popovsky MA, Moore SB. Diagnosticandpathogeneticconsiderationsintransfusion-relatedacutelunginjury., Transfusion, 1985, vol. 25 6(pg. 573-577)GoogleScholarCrossrefSearchADSPubMed 7Gajic O, Rana R, Winters JL, etal. Transfusion-relatedacutelunginjuryinthecriticallyill:prospectivenestedcase-controlstudy., AmJRespirCritCareMed, 2007, vol. 176 9(pg. 886-891)GoogleScholarCrossrefSearchADSPubMed 8Vlaar AP, Hofstra JJ, Determann RM, etal. Theincidence,riskfactors,andoutcomeoftransfusion-relatedacutelunginjuryinacohortofcardiacsurgerypatients:aprospectivenestedcase-controlstudy., Blood, 2011, vol. 117 16(pg. 4218-4225)GoogleScholarCrossrefSearchADSPubMed 9Ness PM. Doestransfusionofstoredredbloodcellscauseclinicallyimportantadverseeffects?Acriticalquestioninsearchofananswerandaplan., Transfusion, 2011, vol. 51 4(pg. 666-667)GoogleScholarCrossrefSearchADSPubMed 10Finlay HE, Cassorla L, Feiner J, Toy P. Designingandtestingacomputer-basedscreeningsystemfortransfusion-relatedacutelunginjury., AmJClinPathol, 2005, vol. 124 4(pg. 601-609)GoogleScholarCrossrefSearchADSPubMed 11Transfusion-RelatedAcuteLungInjury, AABBAssociationBulletin2006AccessedFebruary2,2011 http://www.aabb.org/Content/Members_Area/Association_Bulletins/ab06-07.htm12ClarificationstorecommendationstoreducetheriskofTRALI, AABBAssociationBulletin2007AccessedFebruary2,2011 http://www.aabb.org/Content/Members_Area/Association_Bulletins/ab07-03.htm13Weiskopf RB, Feiner J, Toy P, etal. Freshandstoredredbloodcelltransfusionequivalentlyinducesubclinicalpulmonarygasexchangedeficitinnormalhumans[publishedonlineaheadofprintJanuary19,2012]., AnesthAnalg doi:10.1213/ANE.06013e318241fcd514Endres RO, Kleinman SH, Carrick DM, etal. Identificationofspecificitiesofantibodiesagainsthumanleukocyteantigensinblooddonors., Transfusion, 2010, vol. 50 8(pg. 1749-1760)GoogleScholarCrossrefSearchADSPubMed 15Carrick DM, Norris PJ, Endres RO, etal. EstablishingassaycutoffsforHLAantibodyscreeningofapheresisdonors., Transfusion, 2011, vol. 51 (pg. 2092-2101)GoogleScholarCrossrefSearchADSPubMed 16TheSURVEYLOGISTICProcedure, SAS/STAT(R)9.2User'sGuide(2nded), 2010AccessedFebruary2,2011 http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.htm#surveylogistic_toc.htm17Schafer JL. Multipleimputation:aprimer., StatMethodsMedRes, 1999, vol. 8 1(pg. 3-15)GoogleScholarCrossrefSearchADSPubMed 18Li G, Malinchoc M, Cartin-Ceba R, etal. Eight-yeartrendofacuterespiratorydistresssyndrome:apopulation-basedstudyinOlmstedCounty,Minnesota., AmJRespirCritCareMed, 2011, vol. 183 1(pg. 59-66)GoogleScholarCrossrefSearchADSPubMed 19Eder A, Herron R, Strupp A, etal. Transfusion-relatedacutelunginjurysurveillance(2003-2005)andthepotentialimpactoftheselectiveuseofplasmafrommaledonorsintheAmericanRedCross., Transfusion, 2007, vol. 47 4(pg. 599-607)GoogleScholarCrossrefSearchADSPubMed 20SHOTAnnualReortsandSummaries(All), SHOT2010AccessedAugust6,2011 http://www.shotuk.org/wp-content/uploads/2011/07/SHOT-2010-Report1.pdf21Eder AF, Herron RM, Strupp A, etal. Effectivereductionoftransfusion-relatedacutelunginjuryriskwithmale-predominantplasmastrategyintheAmericanRedCross(2006-2008)., Transfusion, 2010, vol. 50 8(pg. 1732-1742)GoogleScholarCrossrefSearchADSPubMed 22Kopko PM, Popovsky MA, MacKenzie MR, Paglieroni TG, Muto KN, Holland PV. HLAclassIIantibodiesintransfusion-relatedacutelunginjury., Transfusion, 2001, vol. 41 10(pg. 1244-1248)GoogleScholarCrossrefSearchADSPubMed 23Reil A, Keller-Stanislawski B, Gunay S, Bux J. Specificitiesofleucocytealloantibodiesintransfusion-relatedacutelunginjuryandresultsofleucocyteantibodyscreeningofblooddonors., VoxSang, 2008, vol. 95 4(pg. 313-317)GoogleScholarCrossrefSearchADSPubMed 24Chapman CE, Stainsby D, Jones H, etal. Tenyearsofhemovigilancereportsoftransfusion-relatedacutelunginjuryintheUnitedKingdomandtheimpactofpreferentialuseofmaledonorplasma., Transfusion, 2009, vol. 49 3(pg. 440-452)GoogleScholarCrossrefSearchADSPubMed 25Triulzi DJ, Kleinman S, Kakaiya RM, etal. TheeffectofpreviouspregnancyandtransfusiononHLAalloimmunizationinblooddonors:implicationsforatransfusion-relatedacutelunginjuryriskreductionstrategy., Transfusion, 2009, vol. 49 9(pg. 1825-1835)GoogleScholarCrossrefSearchADSPubMed 26Issa N, Cosio FG, Gloor JM, etal. Transplantglomerulopathy:riskandprognosisrelatedtoanti-humanleukocyteantigenclassIIantibodylevels., Transplantation, 2008, vol. 86 5(pg. 681-685)GoogleScholarCrossrefSearchADSPubMed 27Bierling P, Bux J, Curtis B, etal. RecommendationsoftheISBTWorkingPartyonGranulocyteImmunobiologyforleucocyteantibodyscreeningintheinvestigationandpreventionofantibody-mediatedtransfusion-relatedacutelunginjury., VoxSang, 2009, vol. 96 3(pg. 266-269)GoogleScholarCrossrefSearchADSPubMed 28Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-relatedacutelunginjury(Trali)inapatientwithasinglelungtransplant., BrJHaematol, 2000, vol. 109 3(pg. 674-676)GoogleScholarCrossrefSearchADSPubMed 29Cooling L. Transfusion-relatedacutelunginjury., JAMA, 2002, vol. 288 3(pg. 315-316)GoogleScholarCrossrefSearchADSPubMed 30Toy P, Hollis-Perry KM, Jun J, Nakagawa M. RecipientsofbloodfromadonorwithmultipleHLAantibodies:alookbackstudyoftransfusion-relatedacutelunginjury., Transfusion, 2004, vol. 44 12(pg. 1683-1688)GoogleScholarCrossrefSearchADSPubMed 31Silliman CC, Bjornsen AJ, Wyman TH, etal. Plasmaandlipidsfromstoredplateletscauseacutelunginjuryinananimalmodel., Transfusion, 2003, vol. 43 5(pg. 633-640)GoogleScholarCrossrefSearchADSPubMed 32Kelher MR, Masuno T, Moore EE, etal. PlasmafromstoredpackedredbloodcellsandMHCclassIantibodiescausesacutelunginjuryina2-eventinvivoratmodel., Blood, 2009, vol. 113 9(pg. 2079-2087)GoogleScholarCrossrefSearchADSPubMed 33Silliman CC, Boshkov LK, Mehdizadehkashi Z, etal. Transfusion-relatedacutelunginjury:epidemiologyandaprospectiveanalysisofetiologicfactors., Blood, 2003, vol. 101 2(pg. 454-462)GoogleScholarCrossrefSearchADSPubMed 34Silliman CC, Paterson AJ, Dickey WO, etal. Theassociationofbiologicallyactivelipidswiththedevelopmentoftransfusion-relatedacutelunginjury:aretrospectivestudy., Transfusion, 1997, vol. 37 7(pg. 719-726)GoogleScholarCrossrefSearchADSPubMed 35Muniz M, Sheldon S, Schuller RM, etal. Patient-specifictransfusion-relatedacutelunginjury., VoxSang, 2008, vol. 94 1(pg. 70-73)GoogleScholarPubMed 36Bux J, Sachs UJ. Thepathogenesisoftransfusion-relatedacutelunginjury(TRALI)., BrJHaematol, 2007, vol. 136 6(pg. 788-799)GoogleScholarCrossrefSearchADSPubMed 37Blennerhassett JB. Shocklunganddiffusealveolardamagepathologicalandpathogeneticconsiderations., Pathology, 1985, vol. 17 2(pg. 239-247)GoogleScholarCrossrefSearchADSPubMed 38Moss M, Guidot DM, Wong-Lambertina M, TenHoor T, Perez RL, Brown LA. Theeffectsofchronicalcoholabuseonpulmonaryglutathionehomeostasis., AmJRespirCritCareMed, 2000, vol. 161 2(pg. 414-419)GoogleScholarCrossrefSearchADSPubMed 39Boe DM, Richens TR, Horstmann SA, etal. Acuteandchronicalcoholexposureimpairthephagocytosisofapoptoticcellsandenhancethepulmonaryinflammatoryresponse., AlcoholClinExpRes, 2010, vol. 34 10(pg. 1723-1732)GoogleScholarCrossrefSearchADSPubMed 40Wiedemann HP, Wheeler AP, Bernard GR, etal. Comparisonoftwofluid-managementstrategiesinacutelunginjury., NEnglJMed, 2006, vol. 354 24(pg. 2564-2575)GoogleScholarCrossrefSearchADSPubMed 41Ventilationwithlowertidalvolumesascomparedwithtraditionaltidalvolumesforacutelunginjuryandtheacuterespiratorydistresssyndrome:theAcuteRespiratoryDistressSyndromeNetwork., NEnglJMed, 2000, vol. 342 18(pg. 1301-1308)CrossrefSearchADSPubMed 42Iribarren C, Jacobs DR, Sidney S, Gross MD, Eisner MD. Cigarettesmoking,alcoholconsumption,andriskofARDS:a15-yearcohortstudyinamanagedcaresetting., Chest, 2000, vol. 117 1(pg. 163-168)GoogleScholarCrossrefSearchADSPubMed 43Parsons PE, Eisner MD, Thompson BT, etal. Lowertidalvolumeventilationandplasmacytokinemarkersofinflammationinpatientswithacutelunginjury., CritCareMed, 2005, vol. 33 1(pg. 1-6) discussion230-232GoogleScholarCrossrefSearchADSPubMed 44Looney MR, Nguyen JX, Hu Y, VanZiffle JA, Lowell CA, Matthay MA. Plateletdepletionandaspirintreatmentprotectmiceinatwo-eventmodeloftransfusion-relatedacutelunginjury., JClinInvest, 2009, vol. 119 11(pg. 3450-3461)GoogleScholarPubMed 45Sachs UJ, Wasel W, Bayat B, etal. Mechanismoftransfusion-relatedacutelunginjuryinducedbyHLAclassIIantibodies., Blood, 2011, vol. 117 2(pg. 669-677)GoogleScholarCrossrefSearchADSPubMed 46Gosselin EJ, Wardwell K, Rigby WF, Guyre PM. InductionofMHCclassIIonhumanpolymorphonuclearneutrophilsbygranulocyte/macrophagecolony-stimulatingfactor,IFN-gamma,andIL-3., JImmunol, 1993, vol. 151 3(pg. 1482-1490)GoogleScholarPubMed 47Geppert TD, Lipsky PE. Antigenpresentationbyinterferon-gamma-treatedendothelialcellsandfibroblasts:differentialabilitytofunctionasantigen-presentingcellsdespitecomparableIaexpression., JImmunol, 1985, vol. 135 6(pg. 3750-3762)GoogleScholarPubMed 48Kopko PM, Paglieroni TG, Popovsky MA, Muto KN, MacKenzie MR, Holland PV. TRALI:correlationofantigen-antibodyandmonocyteactivationindonor-recipientpairs., Transfusion, 2003, vol. 43 2(pg. 177-184)GoogleScholarCrossrefSearchADSPubMed 49Yost CS, Matthay MA, Gropper MA. Etiologyofacutepulmonaryedemaduringlivertransplantation:aseriesofcaseswithanalysisoftheedemafluid., Chest, 2001, vol. 119 1(pg. 219-223)GoogleScholarCrossrefSearchADSPubMed 50Benson AB, Burton JR, Austin GL, etal. Differentialeffectsofplasmaandredbloodcelltransfusionsonacutelunginjuryandinfectionriskfollowinglivertransplantation., LiverTranspl, 2011, vol. 17 2(pg. 149-158)GoogleScholarCrossrefSearchADSPubMed  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