mmm BRIEF Transfusion-Related Acute Lung Injury Report of a Clinical Look-Back Investigation Patricia M. Kopko, MD ‘rol S. Marshall, MD Malcolm R. MacKenzie, MD Paul V. Holland, MD Mark A Popoveky, MD. |RANSFUSION-RELATED ACUTE Jung injury (TRALD is a elini- cal syndrome associated with twansfusion that typically in- cludes dyspnea, hypoxemia, hypoten- sion, bilateral pulmonary edema, and fever. Symptoms may occur during the period between the beginning of trans Tusion and 4 hours afterward. The se- verity of symptoms can range from mild to severe. However, in a large series of TRALL cases, 100% required oxygen support, and 72% also required me- chanical ventilation.* In this same s Hes, symptoms resolved within 96 hours in 80% of patients. The other 20% of patients required longer support, ‘which was associated with persistence of pulmonary infiltrates on chest ra- diograph, Pathophysiology TRALI has been associated with the presence of granulocyte antibod HLA class | anubodies,? HLA class anubodies,” and biologteally active lipids" ia donor plasma, All plasina- containing blood components, snchid- ing ed blood cells, platelets, fesh fro- zen plasma (FEP), and eryoprecipitat have been implicated in TRALL! Infu sion of even small volumes of plasma can trigger the reaction.” Intravenous immunoglobulin prepared froma large pool of plasma has also been re- See also Patient Page. Context Transfusion-related acute lung injury (TRALI) is a syndrome that includes dyspnea, hypotension, bilateral pulmonary edema, and fever. TRALI isthe third lead- ing cause of transfusion-related mortality, but itis probably underdiagnosed and un- derreported. Objective To determine ifblood products from a frequent plasma donor, whose blood product was implicated ina fatal case of TRALI, caused symptoms of TRALI in other Fecipients of her plasma, Design, Setting, and Participants Retrospective chart review (conducted from November 2000 through April 2001) of 50 patients who received blood components, within 2 years (October 1998 through October 2000) from a donor linked toa trans- fusion-related fatality, ‘Main Outcome Measure Occurrence of mild/moderate (dyspnea with fever, chills, hypotension, and/or hypoxemia) or severe (acute pulmonary edema or need for me- chanical ventilation) reaction associated with transfusion. Results Superimposed iliness prevented assessment of TRALI in 14 patients, Of the 36, patient charts that could be reviewed, 7 mild/moderate reactions were reported in 6 pa- tients (16.7%) and @ severe reactions were reported in 8 patients (22.2%). Of patients, who received multiple transfusions from the same donor, 2 experienced 2 reactions: one had 2 mild/maderate reactions and the other had both a mild/moderate and a severe reaction. While 5 of the 7 mild/moderate reactions were reported to the hospital trans- fusion service, only 2 ofthe 8 severe reactions were reported. Only 2 reactions (1 mild/ ‘moderate and 1 severe) were reported to the regional blood collection facilty. Conclusions TRAL! was frequently underdiagnosed and underreported in recipl- ents of blood products from a donor whose blood products may have caused TRALI in several transfusion recipients. Clinical education and awareness of this often- ‘overlooked diagnosis are imperative for appropriate prevention and treatment. JAMA, 20022877968-1971 wera jama com portedto case TRALL"butpooled sol cause TRAL auchan anacaton snot Temtdcorgenteeted plasma hasnot_ been demoted, Lite teknowh e- ScvenivatTRALIdoconotappesrto gun the elle of anbedy be related 9 the volume opin idly svi or eukocyte snug der foc butmaybeconelated withthe de. siy om the seventy or requ) af grec ofhypovemia: Infusion of white TRA! rscuona! Hood elles lone probably ther seipet ito, however, ay not sllicent to induce TRALL” Ap. playavoleiNTRALL A cwenthypou proximately 20% of women who have tataf TRALL has been avancel a Te aprenancesve anisole lorcet Thereore infin ofan pg gage ee bodies alone were Sufficient 10 cause fimerte, Caf ors Kepte, Mckenna, an Hel. THALL, the reaction would bevela. acca la esto ak tively common. Although tseemsnatt- _jflghal): nd Haamorctes Corp ries Mess DE Iwas ht tetas e-payment a Silent mst possess thecoresponding Senators Se a Teukocyte agen foram anubody to Loan au Ga ata 4968 JAMA, Apel 17, 2002Vol 287, No. 15 (Reprinted) (©2002 American Medical Association. AIL rights reservedpossible way of explaining why some re- cipients experience the reaction while thers do not. It has been theorized that a transfusion recipient must fest havea predisposing condition and then receive plasma that contains leukocyte anubody oF biologteally active lipid.* ‘Conditions thought to predispose trans: fusion reeipicnts to develop TRALL in- clude infeetion, eytokine administra tion, recent surgery, and/or transfusion of large volumes of blood prodcs.* Leukocytes coated with antibodies lo- calize to the pulmonary microvascula- ture.” The release ofeytokinesby these antibody-coated leukocytes in the vas- colar space is thought to lead to an in- crease in vascular permeability and ext dation of fluid and protein into the alveolar spaces." The degree of fluid exudation likely determines the sever- ity of the pulmonary reaction and whether oxygen administration oF me- chanical ventilation is required. Clinical Aspects TRALI is fatal in 5% to 10% of eases," and is the third leading cause of trans- Iusion-related mortality."? Unfortu nately, the signs and symptoms assocl- ated with TRALI can easily be attributed to other causes, including fluid o load, pneumonia, and acute respira- tory distress syndrome (ARDS)."" Pul- monary edema, with bilateral “white cout” on chest radiograph (FIGURE), sim larto that seen in ARDS, is generally pres- cent along with fever and hypotension. The key to distinguishing TRALI from other forms of pulmonary edema is ree- cognition that the pulmonary edema is noneardiogenic and that alfected pa- tients do not have volume overload,’ This distinction is important because treating patients with TRALL with ag- gressive diuresis can result in further hy- potension, shock, and death.'*" Treat- ment should consist of maintenance of hemodynamic status and ventilatory as- sistance. An extensive review of TRALI, Including diagnostic eriteria, has re- cently been published! “Although TRALLis often discussed in the transfusion literature, it has re- ceived litle attention among clini- (©2002 American Medical Association, All rights reserved, "TRANSFUSION-RELATED ACUTE LUNG INJURY cians. Therefore, itis likely to be under- recognized asa clinical entity. We report a fatal case of TRALI following an PEP transfusion froma frequent plasima do- nor. Prior transfusions from this fr quent plasma donor had not been 1 ported (o the regional blood center as causing any transfusion reactions. Report of a Case A 54-year-old man was given PEP for reversal of coumadin effect prior to elec- tive knee surgery. Approximately 45 minutes after initiation of the PEP transfusion, the patient experienced res- piratory arrest. He died 6 hours later despite aggressive attempts at cardio pulmonary resuscitation, The blood donor, whose blood com- ponent was implicated in this reac tion, wasa 54-year-old woman who had made 290 previous donations. She had hhad 3 pregnancies, resulting in 2 births and 1 abortion, The donor's plasma was found to be strongly positive for granu- locyte Sb antibody. Although the granu locyte-specific 5b antigen is present in more than 90% of whites," this was the first time this donor was implicated in a case of TRALL, despite more than 15, years of frequent donation. The donor \was permanently deferred from future donations. During the transfusion- related fatality investigation, the Food and Drug Administration (FDA) inves- Ligator requested that we perform a look-back study to determine if previ- ous recipients of this donor's blood components had experienced TRALL or other transfuston reactions, METHODS: All donations made by the implicated donor in the 2 yeats prior to the fatal- lty were investigated. Transfusion ser- vice medical directors at the facilities that transfused the donor's FFP units were asked to perform chart reviews, including review of both physicians’ and nurses’ notes, to determine ifany other recipients had an adverse reaction to this donor's blood components. They were asked to determine and report Af the recipients experienced fever, chills, hypotension, dyspnea, pulmo- Figure, Pontranstuson Chest Radograpy cof Blsteral “White Out” Consistent ‘With Pulmonary Edema nary edema, ARDS, or any other unto- ward event within 6 hours of trans- Iusion, Reactions were classified as either mild/moderate or severe. Mild/ moderate reactions consisted of dys pea with fever, chills, hypotension and/or oxygen desaturation, but with- ‘out documented evidence of acute pul- monary edema or need for mechanical ventilation. Severe reactions were de- Fined as any reaction with clinical or m= diographic evidence of acute pulmo- nary edema and/or need for mechanical ventilation within 6 hours of transfu- sion. Recipients were excluded from the aanalysisif their underlying clinical con- dition prevented the reviewer's ability to determine if a symptomatic reac- lion was related to the transfusion, These preexisting conditions in- cluded pulmonary edema, ARDS, or rapidly deteriorating clinical status re- sultingin efforts of cardiopulmonary re suseitation prior to transfusion of the blood component. RESULTS The donor made 73 donations (72 plas- maphereses and 1 whole blood) in the 2 years prior to her deferral, A total of 54 patients received 63 blood prod- ucts from this donor. The remaining components were either quarantined when the donor was deferred or not transfused for other reasons. Underly- ing illness prevented evaluation for ev dence of TRALI following transfusion (Reprnes) JAMA, spe 17, 2002 Nol 207, No, 15 1968‘TRANSFUSION-RELATED ACUTE LUNG INJURY in 14 patients. Charts were unavail- multiple trinsfusions from thisdonor,2 COMMENT. able for review in 4 patients experienced 2 reactions each: 1 had 2 Our findings suggest that TRALL is fre (Of the 36 patient charts that could be mild/moderate reactions, and the other quently not diagnosed. Lack of recogni- evaluated, 13 (36.1%) indicated trans- had both a mild/moderate and a severe tion of this syndrome can result in in- fusion reaction. The clinical scenarios of reaction. Seven (46.7%) of the 15 reac- appropriate treatment, as well a failure the patients identified as having had ations (5 of 7 mild/moderate, 2 of 8 se- to report the reaction to the transfusion transfusion reaction are presented in the vere) were reported to the hospital's service and the blood collection facil- TABLE. All reactions were temporally as- transfusion service. Only 2 reactions ity. Lack of recognition of TRALL and its sociated with an infusion of FFP. Seven (13.3%) were reported to the blood col- reporting in thisseries of cases led ton mild/moderate reactions were identi-__ lection facility: one was the fatality and merous reactions and, ultimately, a fa- fied in 6 (16.7%) recipients. Severe re- the other was a mild/moderate reaction tality that might have been prevented. actions were reported in 8 (22.2%) re- that occurred while the fatality was un- TRALI should be included in the dif- pients, Ofthe 5 patients who received — der investigation, {al diagnosis of respiratory dis- ‘Table, Ciniea!Scenaror of 15 Tranrfusion Related Ace Lang Injures Among 12 Patents” Severity of TTanstision Tranetion Patint Reason for Gincat Cinical Feacton Faction Diagrocis Transfusion Maniestations Impression Suspected ‘amecerte —Trarbote Pasa exchange Chis, dysonea aon bio easton Yee Trombocyopenic Pstrantusion purpura Croray aay Gamadhreerad — Ola fret Gepne, Thpoatiardiaien — Fesforecion Ye inaes rat facyearda Cirgestve heat Coumadinrerral Fever, dyspnea Daingtacidon Vou avaioad Ye ‘aise ‘achjeaa Fi, trombote Pasmaecharge Ghost pain, igo, 20 Todaro Te itrombocyopenic ‘achypnea, Pstrantusion purpura Fi, trombote Pama echage Gils nasa Thpostianaten Ne dagrase Te itrembocyopenic Nomtng. oxygen purpura ‘Ssaturaion| inera bec, Bales For dyepnes Daingtacidon Tarcudonrehied Yeo ‘aera eu Lrg uy ‘Rehole her deesse Gaskoriesiral Fever paterson, D0-min Fabio reaction Ye tact bleeding depen stanton iawe Tronbaie Pasmaechage Raspraloy tale Tn Cacogare vs Te Trombacyopenic Tachearda, Pstranduson — nonearsogene purpurst ppurnonary edema pulmonary ema alos ‘Cound reveal Dyipres, eapraioy Dung iarsison Ne dagross Te obatucton ‘are Tronbate Pama echarge — Tachyeada, Danguasiaon Aid oratoad Te Trombocyopenic tactypnsa, chest pupurs an purscray sam Camano Bosian _Reuisrespiaioy 17 Tora Te ‘oper des syrdrore —"postrantuion Temaamaty Bod oss Fore, iadyeada, Dag iarsion —FUu-aut beading? Te ‘oper ‘cule espratery ecton ‘oon dies gncrore ‘ema eae, Bad oes Fare cis, Thpostiarsucon — RUB oATBSaS Te ‘adcrnin rach Frpotasion, acto roepratry dsvess Sera ‘ema eae, BaToes Fer sca Dang uactison — Rascionto Taman Ver ‘adcrnin rach Toepralry sess prota rah Syncrore frzen plasma Rresrepiacamet Cournot Pulrenay ecita, Dung tarsson Tartuson-roied Yes ‘eprty an seu Lrg riury 4970 JAMA, Apel 17, 2002Vol 287, No. 15 (Reprinted) (©2002 American Medical Association. AIL rights reserved