Transfusion-related acute lung injury (TRALI) - Canadian ...

Transfusion-related acute lung injury (TRALI) is a rare but serious syndrome characterized by sudden acute respiratory distress following transfusion. Skiptomaincontent Feedback Transfusion Publications Transfusion-relatedacutelunginjury(TRALI) Share Author:AkashGupta,MD,FRCPC;MatthewYan,MD,FRCPC   Introduction Transfusion-relatedacutelunginjury(TRALI)isararebutserioussyndromecharacterizedbysuddenacuterespiratorydistressfollowingtransfusion.Itisdefinedasnew,acuterespiratorydistressduringorwithinsixhoursofbloodcomponent(i.e.,redbloodcells,plasma,platelets)orbloodproduct(i.e.,plasmaproteinproduct)administrationintheabsenceoftemporally-associatedriskfactorsforacuterespiratorydistresssyndrome(ARDS).Allplasma-containingbloodcomponentsandplasmaproteinproductshavebeenimplicatedinTRALI,includingrarereportswithintravenousimmunoglobulin(IVIg)andcryoprecipitate.Despitetheverysmallamountofplasmacontainedinredbloodcells,thiscomponentisassociatedwiththelargestnumberofreportedcasesofTRALI.TRALIisthoughttobecausedbyactivationofrecipientneutrophilsbydonor-derivedantibodiestargetinghumanleukocyteantigens(HLA)orhumanneutrophilantigens(HNA).Non-antibody-mediatedcasesalsooccurandmaybemediatedbybiologicresponsemodifierspresentinthetransfusedbloodcomponentorplasmaproteinproduct,alongwithrecipientfactors. Epidemiology TRALIisrareanditsincidencehasnotbeenwellestablishedduetodifficultyinrecognizingthesyndrome,inconsistentapplicationofstandarddefinitions,andvariabilityinworldwidereportingmechanisms.Historically,thefrequencyofTRALIwasestimatedtooccuratapproximately1in5,000transfusedbloodcomponents.ProspectiveidentificationofcasesinanAmericanstudyplacedtheriskatjustunder1in12,000transfusedunits.1 InCanada,aspertheTransfusionTransmittedInjuriesSurveillanceSystem(TTISS)2011-2015report,TRALIandpossibleTRALI,whenconsideredincombination,arethesecondleadingcauseoftransfusion-relatedmorbidity(22.0%),aftertransfusion-associatedcardiacoverload(TACO,42.6%). Similarly,intheUnitedStates,reactionsreportedasTRALIandpossibleTRALIarethesecondleadingcauseoftransfusion-relatedmortalityat24%,secondbehindTACOat34%.2 Clinicalpresentation SymptomsofTRALItypicallydevelopduringorwithin6hoursofatransfusion.Patientspresentwithrapidonsetofdyspneaandtachypnea,withanSpO2<90%onroomair.Theremaybeassociatedfever,cyanosisandhypotension.Clinicalexaminationmayrevealhypoxicrespiratorydistress,andpulmonarycracklesmaybepresentwithoutsignsofcongestiveheartfailureorvolumeoverload.Ingeneral,however,chestfindingsonauscultationtendtobeminimal.Chestimagingshouldshowclearevidenceofbilateralpulmonaryedemaunassociatedwithheartfailure(non-cardiogenicpulmonaryedema),withbilateralpatchyinfiltrates,whichmayrapidlyprogresstocomplete"whiteout"indistinguishablefromacuterespiratorydistresssyndrome(ARDS).Thereshouldbenoevidenceofleftatrialhypertension(LAH);however,ifLAHispresent,itshouldnotbethemaincontributortothehypoxemia.Physiologicfindingsincludeacutehypoxemiawithnormalcardiacfunctiononechocardiogram.Uptoathirdofpatientsexhibittransientleukopeniaandpatientsmayhavealowlevelofbrainnatriureticpeptide(BNP). Treatmentandclinicalcourse TRALIisassociatedwithhighmorbidityandthemajorityofpatientsrequireventilatorysupport.However,withsupportivecare,thelunginjuryisgenerallytransient,withoxygenlevelsreturningtopre-transfusionlevelswithin48to96hoursandchestX-rayreturningtonormalwithin96hours.However,somepatientsareslowertorecoverandmayremainhypoxicwithpersistentpulmonaryinfiltratesforseveraldaysalthoughpulmonaryfunctioneventuallyreturnstobaselinewithoutapparentsequelae.AswithARDS,thereisnorolefordiureticsorcorticosteroids. Differentialdiagnosis ThedifferentialdiagnosisforhypoxiaaftertransfusionincludesTRALI,TACO,cardiogenicpulmonaryedema,allergicandanaphylactictransfusionreactions,transfusion-associateddyspnea(TAD),andbacteremia/sepsisduetobacterialcontaminationoftransfusedbloodcomponents. TRALImaybedistinguishedfromTACOandcardiogenicpulmonaryedemabytheabsenceofsignsofcirculatoryoverload,suchasanormalcentralvenouspressure(CVP)andnormalpulmonarycapillarywedgepressure(PCWP).ClinicalresponsetodiureticsalsosuggestsadiagnosisofTACOratherthanTRALI.PatientswithTACOwillalsodemonstratebiochemicalevidenceofcardiacoverload,suchasanelevatedBNPorNT-proBNPlevelorapre-/post-transfusionNT-proBNPratiogreaterthan1.5.3 AllergicandanaphylactictransfusionreactionsmaymanifestashypotensionandrespiratorydistressbutaremarkedbylaryngealedemaorbronchospasmwithwheezingandanormalchestX-ray.Anurticarialrashmayalsobepresent.Thesereactionswillrespondquicklytotreatmentwithcorticosteroids,antihistamines,and/ormayrequirevasopressorsandothersupportivecare. TADisanacuterespiratorydistressoccurringwithin24hoursoftransfusionwhichfailstomeetcriteriaforTRALI,TACO,oranaphylactictransfusionreaction. Transfusion-transmittedbacteremiamaypresentwithfeverandrigorswithorwithouthypotensionandculminateinseveresepsiswithassociatedARDS,whichmaybedifficulttodistinguishfromTRALI.Thepresenceofpositivebloodcultureswiththesameorganismculturedfromtheimplicatedbloodproductisausefuldelineatingfinding. Pathophysiology ThemostwidelyacceptedhypothesissuggeststhatTRALIistheresultofatleasttwoindependentclinicalevents.Thefirstrelatestotheclinicalconditionofthepatient(e.g.,activeinfection,historyofcytokineadministration,surgery,severeburninjury)thatcausesactivationofthepulmonaryendothelium.Thisleadstothesequestrationofprimedneutrophilstotheactivatedpulmonaryendothelium.Thesecondeventistheinfusionofeitherdonor-derivedanti-HLAoranti-HNAantibodiesdirectedagainstantigensontheneutrophilsurfaceand/orbiologicalresponsemodifiersthatactivatetheseadherentandfunctionallyhyperactiveneutrophils. Whetheractivatedbyantibodiesorbysomeothermodifier,thisactivationcausesneutrophil-mediatedendothelialdamageandcapillaryleak.Manystudiesintheliteraturesupportthishypothesis,4-7 whichmayexplainhowsomeTRALIreactionsoccurintheabsenceofdonor-derivedanti-HLA/HNAantibodies,orwhyTRALIreactionsdonotoccurinallrecipientsofbloodcomponentsfromdonorswhoareknowntohavetheseantibodies.Thatis,intheabsenceofneutrophilprimingbyrecipientfactors,TRALIwillnotoccurdespitethetransfusionofantibodiesorbiologicresponsemodifiers. Morerecently,athresholdhypothesishasbeenpostulated.Incaseswherethesecondeventissufficientlystrong,TRALImayoccurintheabsenceofthefirstclinicalevent.ThisthresholdmodelcouldexplainwhyTRALImaybeobservedinsometransfusionrecipientswhoarequitewellpriortotransfusionwithoutpredisposingriskfactors. Theactivationofrecipientneutrophilsthroughdonor-derivedanti-HLA/HNAantibodiesisoftenreferredtoasimmuneTRALI.Thetermnon-immuneTRALIisusedtodescribecaseswheresolublebiologicalresponsemodifiersinthetransfusedcomponentsarefelttobethecausativeagentintheabsenceofdonor-derivedantibodies.ItisunknownwhatproportionofTRALIismediatedthroughimmuneornon-immunemechanisms,althoughpublishedliteraturesuggeststhat80–85%ofTRALIcasesareimmuneTRALI. ReportingTRALIevents HealthCanadamandatesthathospitalsidentifyandreportadversetransfusionreactionssuspectedtobeTRALIrelated.Thisreportingmustbecompletedusingastandardprocedureforreportingadversereactions.AguideonhowtoreportadversereactionsanddataoneventsreportedtoCanadianBloodServicesareavailableinAGuidetoReportingAdverseTransfusionReactions. InordertocorrectlyandconsistentlydiagnoseTRALI,thecompletionandsubmissionofCanadianBloodServices’TRALIPatientDataForm,ismandatory.ForfurtherdetailsonsubmittingtheTRALIPatientDataFormandpossiblepatientsamplesforTRALIinvestigation,pleaserefertoCanadianBloodServicescustomerletterCL2021-01.Ingeneral,thefollowingclinicalinformationisrequestedbyCanadianBloodServices: Timingoftransfusionwithrespecttosymptomonset Presenceofotherriskfactorsforacuterespiratorydistresssyndrome(seeTable1) Chestimagingfindings Evidenceofhypoxia:PaO2orSaO2 Clinicalindicatorsofvolumestatussuchasclinicalevaluation,responsetodiuretics(ifgiven),orwhereavailableJVP,PCWP,CVP,echocardiogramreport,BNP,etc. Table1:UpdatedRiskFactorsforAcuteRespiratoryDistressSyndrome(Vlaaretal.2019)8 DirectLungInjury IndirectLungInjury Aspirationofgastriccontents Pneumonia Inhalationinjury Pulmonarycontusion Pulmonaryvasculitis Drowning Non-pulmonarysepsis Majortrauma Severeburns Pancreatitis Noncardiogenicshock Drugoverdose Historically,CanadianBloodServicesdefinedTRALIusingthe2004CanadianConsensusConferencePaneldefinition(Table2).In2012,thedefinitionofARDS(knownastheBerlindefinition)wasrevisedresultinginremovalofthetermacutelunginjury(ALI)amongthecriticalcarecommunityinternationally.Toalignwiththischangeinterminology,Vlaaretal.revisedthedefinitionsofTRALIandpossibleTRALI,includinganewnamingconventionofTRALItype1andTRALItype2(Table3)8  CanadianBloodServicesreportsallreportedcasesofTRALIorpossibleTRALI(orcasesredefinedasTRALItype1ortype2)toHealthCanada,includingcaseswhichfailtomeetthedefinitionbutwhereTRALIcannotbeexcludedduetoincompleteclinicalinformation. BecausethediagnosisofARDScanbedifficult,communicationbetweenthetransfusionservicemedicaldirectorandthepatient’sphysicianiscriticaltodetermine,inparticular,whetherapatienthasevidenceofvolumeoverload.AlthoughARDSandhydrostaticpulmonaryedemamaycoexist,thelatterisamorecommoncomplicationoftransfusionandmustbeexcludedinorderforadiagnosisofTRALItobemade. Table2:2004 CanadianConsensusConferencePanelTRALIandAcuteLungInjury(ALI)definitions9 Term Definition TRALI Acutelunginjury(definedbelow)occurringwithin6 hoursofcompletionoftransfusionofbloodproduct. Nopre-existingacutelunginjury. Noothertemporally-associatedriskfactorsforacutelunginjury(Table1). PossibleTRALI Acutelunginjury(definedbelow)occurringwithin6 hoursoftransfusion. Nopre-existingacutelunginjury. Oneor moretemporally-associatedriskfactorsforacutelunginjury. Acutelunginjury(ALI) Newonset. HypoxemiaSpO2<90%orPa02/Fi02<300mmHgonroomair,orotherclinicalevidenceofhypoxemia. BilateralinfiltratesonfrontalchestX-ray. Table3:  2019UpdatedConsensusRedefinitionofTRALI(Vlaaretal.2019)8 Term Definition TRALItype1 Acuteonset(within6hoursoftransfusion) Hypoxemia(PaO2/FiO2≤300orSpO2<90%onroomair) Clearevidenceofbilateralpulmonaryedemaonimaging(CXR,chestcomputedtomography(CT),orultrasound) Noevidenceofleftatrialhypertension(LAH)or,ifLAHispresent,itisnotthemaincontributortothehypoxemia NotemporalrelationshiptoanalternativeriskfactorforARDS TRALItype2 SameclinicalcriteriaasTRALITypeI(seefirstfourbulletsdefiningTRALItype1above) PresenceofanARDSriskfactorormildARDS(P/F200-300) Previouslystablepulmonarystatusinthe12hourspriortotransfusion Prevention Theroleofhealth-careprofessionals ItisunlikelythatTRALIcaneverbeentirelyprevented,butitsfrequencymaybereducedbythejudicioususeofbloodcomponentsandplasmaproteinproductsonlyforappropriateindications.Hospitalsshouldhaveproceduresinplace(e.g.,bloodutilizationguidelines,bloodconservationprograms)thatminimizeunnecessarytransfusions.Inaddition,hospitalmedicalstaffmustcontinuetohaveahighindexofsuspicioninordertodiagnoseTRALIappropriately.Asnotedabove,allcasesofsuspectedTRALImustbereportedtoCanadianBloodServices(inadditiontotheProvincial/TerritorialSurveillanceofficeaspartoftheTTISSprogram). TheroleofCanadianBloodServices Primaryprevention PrimarypreventionreferstomeasuresforreducingincidenceofTRALIthatarenotassociatedwithaparticularTRALIevent.InaccordancewithAABBrecommendations,10-14CanadianBloodServicesimplementedseveralmeasuresbetween2007and2009toreducethelevelsofdonor-derivedantibodiesinbloodcomponentsandplasmaproteinproductscontaininghighvolumesofplasma.Thesemeasuresareprimarilybasedontheobservationthatfemaleswithahistoryofpregnancyhaveahigherriskofanti-HLAantibodiesthanfemaleswhohaveneverbeenpregnantormales: InOctober2007,CanadianBloodServicesswitchedtousingplasmafrompredominantlymaledonorsforproductionofplasmafortransfusion(frozenplasmaandfreshfrozenplasma),andforproductionofcryosupernatantplasma. InMarch2008,thesemeasureswereexpandedtoincludepredominantlymaleapheresisplasmadonationsforfreshfrozenplasma. InNovember2008,CanadianBloodServicesimplementedthebuffycoatmethodforpooledplateletsproduction.Thismethodallowsresuspensionofplateletpoolsinplasmafrommaledonorsexclusively. InJuly2009,CanadianBloodServicesbegancollectingapheresisplateletsexclusivelyfromfemaleswithoutahistoryofpregnancyandfrommales. Secondaryprevention Recognizingthatdonor-derivedantibodiesmaybeoneofthecausesofTRALI,CanadianBloodServiceshasadoptedastandardized,nationaldonormanagementstrategyaspartofasecondarypreventionmeasure.AnyblooddonorsinvolvedincasesdefinedasTRALI(includingpossibleTRALIorTRALItype2,orcaseswhereTRALIcannotbeexcluded)aredeferredfromfurtherwholebloodorapheresisdonation.Thesedonorsaretestedforanti-HLAantibodiesandatthistimemaybeacceptabletodonatesourceplasmaforfractionationiftheirHLAantibodyresultsarenegative.Donorswithrareredbloodcellphenotypesareanexceptiontothedeferralpolicy:iftheyareinvolvedincasesdefinedasTRALIandhavepositiveHLAantibodyresultstheymaystillbeabletodonatefrozenorwashedredbloodcells.Allotherinvolveddonorsnotmentionedabovewhohavedemonstrableanti-HLAantibody(regardlessofcognateantigenmatch)aredeferredfromalltypesofblooddonation.IncaseswherethecriteriaforTRALIarenotmet,donorsareneithertestednordeferred,butareflaggedwithaspecialcodesothattheycanbeidentifiedandsubsequentlyinvestigatedintheeventthattheyarelaterassociatedwithanotherTRALIsuspectedreaction. TheCanadianBloodServicesTRALIMedicalReviewGroup TheTRALIMedicalReviewGroup(TMRG)wasestablishedatCanadianBloodServicesin2006asanationalresourceteamtoassistCanadianBloodServices’physiciansinthemanagementofdonorsassociatedwithreportedTRALIcases.TMRGmembersindependentlyreviewallcasesofsuspectedTRALIreportedtoCanadianBloodServicesandmeetmonthlytoattainconsensusonwhetherthesecasesmeetthedefinitionforTRALIorpossibleTRALI(orredefinedasTRALItype1orTRALItype2).TheroleoftheTMRGistodeterminedonormanagementinordertoensurethatdonorswhomayrepresentariskforafutureTRALIreactionareremovedfromthedonorpool.TheconsensusrecommendationofTMRGregardingdonormanagementforspecificcasesiscommunicatedtothehospitalviaasummaryreport. TRALIremainsaclinicaldiagnosisandassuchtheTMRGclassificationmaynotalignwiththatofthereportingphysician.ClassificationbytheTMRGshouldnotbeusedtoguideclinicalassessmentnormanagementofpatientssufferingtransfusionreactions. TheroleofTMRGisprimarilytodeterminedonor—notpatient—management. Current(June2021)membersoftheTMRGinclude,Dr.G.Clarke(Edmonton),Dr.J.Hannon(Edmonton),Ms.M.Huang(Toronto),Dr.A.Khandelwal(Toronto),Dr.D.Lane(Winnipeg),Ms.JWong(Winnipeg),Dr.M.Yan(Vancouver)andDr.M.Zeller(Hamilton). Furtherreading Recentarticlesandreviews PolitisC,WiersumJC,RichardsonC,RobillardP,JorgensenJ,RenaudierP,FaberJC,WoodEM.TheInternationalHaemovigilanceNetworkDatabasefortheSurveillanceofAdverseReactionsandEventsinDonorsandRecipientsofBloodComponents:technicalissuesandresults.VoxSang2016;111:409-17. LiebermanL,PetraszkoT,YiQL,HannachB,SkeateR.Transfusion-relatedlunginjuryinchildren:acaseseriesandreviewoftheliterature.Transfusion2014;54:57-64. ToyP,GajicO,BacchettiP,LooneyMR,GropperMA,HubmayrR,LowellCA,NorrisPJ,MurphyEL,WeiskopfRB,WilsonG,KoenigsbergM,LeeD,SchullerR,WuP,GrimesB,GandhiMJ,WintersJL,MairD,HirschlerN,SanchezRosenR,MatthayMA,GroupTS.Transfusion-relatedacutelunginjury:incidenceandriskfactors.Blood2012;119:1757-67. TransfusionTransmittedInjuriesSurveillanceSystem(TTISS).SummaryResultsfor2006-2012. ChapmanCE,StainsbyD,JonesH,LoveE,MasseyE,WinN,NavarreteC,LucasG,SoniN,MorganC,ChooL,CohenH,WilliamsonLM,SeriousHazardsofTransfusionSteeringG.Tenyearsofhemovigilancereportsoftransfusion-relatedacutelunginjuryintheUnitedKingdomandtheimpactofpreferentialuseofmaledonorplasma.Transfusion2009;49:440-52. SillimanCC,McLaughlinNJ.Transfusion-relatedacutelunginjury.BloodRev.2006;20:139-59.   BuxJ.Transfusion-relatedacutelunginjury(TRALI):aseriousadverseeventofbloodtransfusion.VoxSang2005;89:1-10. LooneyMR,GropperMA,MatthayM.Transfusion-relatedacutelunginjury:areview.Chest2004Jul;126(1):249-58. WebertKE,BlajchmanMA.Transfusion-relatedacutelunginjury.TransfusMedRev.2003Oct;17(4):252-62. Definition/consensusarticles KleinmanS,CaulfieldT,ChanP,DavenportR,McFarlandJ,McPhedranS,MeadeM,MorrisonD,PinsentT,RobillardP,SlingerP.TowardanUnderstandingofTransfusion-RelatedAcuteLungInjury:StatementofaConsensusPanel.Transfusion2004;44:1774-89. VlaarAPJ,ToyP,FungM,LooneyMR,JuffermansNP,BuxJ,Bolton-MaggsP,PetersAL,SillimanCC,KorDJ,KleinmanS.AConsensusRedefinitionofTransfusion-RelatedAcuteLungInjury.Transfusion2019;59:2465-76. BuxJ,SachsUJ.Pulmonarytransfusionreactions. TransfusMedHemother.2008;35(5):337-345.doi:10.1159/000151349 ForNurses 1.  KnippenMA.Transfusion-relatedacutelunginjury.AmJNursing.2006;106(6):61-4. SuggestedCitation GuptaA,YanM.Transfusion-relatedacutelunginjury(TRALI)[Internet].Ottawa:CanadianBloodServices;2021[citedYYYYMMDD].Availablefrom:Transfusion-relatedacutelunginjury(TRALI)|ProfessionalEducation(blood.ca) Acknowledgements TheauthorsacknowledgeDr.TanyaPetraszko,MD,FRCPC,astheauthorofthepreviousversionofthispublication. 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