Transfusion-related acute lung injury Kathryn E. Webert a,c and Morris A. Blajchman a,b,c

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1 Transfusion-related acute lung injury Kathryn E. Webert a,c and Morris A. Blajchman a,b,c Purpose of review Transfusion-related acute lung injury is an uncommon complication of blood transfusion typically manifested by shortness of breath, fever, and hypotension. Transfusion-related acute lung injury is an important cause of transfusion-related morbidity and mortality. Recent findings Much about the pathogenesis, treatment, and prevention of transfusion-related acute lung injury is poorly understood or is controversial. There is increasing recognition that transfusion-related acute lung injury is an important clinical syndrome, causing most transfusion-related deaths. Summary In this report, what is known about transfusion-related acute lung injury is summarized with particular emphasis on recent studies. Some of the areas in which knowledge and/or consensus are currently lacking are identified. Keywords lung injury, pulmonary edema, respiratory distress, transfusion reaction, transfusion-related acute lung injury Curr Opin Hematol 12: ª 2005 Lippincott Williams & Wilkins. McMaster University, a Department of Medicine and b Department of Pathology and Molecular Medicine, c Canadian Blood Services; Hamilton, Ontario, Canada Correspondence to M.A. Blajchman, MD, FRCP(C), Departments of Pathology and Medicine, McMaster University, 1200 Main Street West, HSC 2N34 Hamilton, Ontario Canada, L8N 3Z5 Tel: x76274; fax: ; blajchma@mcmaster.ca Sponsorship: K. Webert is supported by a Fellowship in Transfusion Medicine and Hemostasis from Canadian Blood Services and Novo Nordisk Current Opinion in Hematology 2005, 12: Abbreviations ARDS acute respiratory distress syndrome FFP fresh-frozen plasma HLA human leukocyte antigen NHLBI National Heart, Lung and Blood Institute RBC red blood cell TRALI transfusion-related acute lung injury ª 2005 Lippincott Williams & Wilkins Introduction Transfusion-related acute lung injury (TRALI) is an uncommon complication of blood transfusion. The TRALI syndrome has increasingly been recognized as an important cause of transfusion-associated mortality. However, much about the pathogenesis, treatment and prevention of TRALI is poorly understood and/or controversial. In this report we summarize what is known about TRALI, with an emphasis on recent studies and reports. Definition The need for a common definition of TRALI has been identified as a priority by the TRALI Working Group convened by the US National Heart, Lung and Blood Institute (NHLBI) of the NIH, the Canadian Consensus conference (Towards an Understanding of TRALI), and authors of recent reviews [1,2,3,4,5 7]. A universally accepted case definition is crucial for the collection of accurate and reliable epidemiologic data, the accurate diagnosis of TRALI, and the comparison of TRALI reports between centers and countries. The US NHLBI Working Group definition of TRALI includes new acute lung injury (ALI) that develops with a clear temporal relationship to transfusion, in patients without or with alternate risk factors for ALI [4 ]. The NHLBI group used the definition for ALI developed by the North American-European Consensus Conference on Acute Respiratory Distress Syndrome (ARDS) (Table 1) [8]. Strengths of this definition are that it provides objective criteria for the diagnosis of TRALI and includes consideration of TRALI in patients with risk factors for ARDS [3 ]. However, the definition may miss milder cases of TRALI and cases that begin more than 6 h after transfusion [3 ]. A Canadian consensus conference was held in Toronto, Canada in April 2004 with the goal of providing recommendations about several outstanding issues including the lack of a common definition of TRALI [2,3 ]. After considering information presented by expert panelists and a review of relevant literature, the panel proposed the following TRALI definition: a new episode of ALI that occurs during or within six hours of a completed transfusion which is not temporally related to a competing etiology for ALI (Table 2) [2 ]. For episodes occurring in patients with other risk factors for ALI, the Consensus Panel recommended the use of the term possible TRALI. The diagnosis of TRALI was considered to be a clinical and radiographic diagnosis, not dependent on the results of laboratory testing or any specific pathophysiologic 480

2 Transfusion-related acute lung injury Webert and Blajchman 481 Table 1. Criteria for diagnosing acute lung injury. Acute onset No evidence of circulatory overload Pulmonary artery occlusion pressure: <18 mm Hg when measured; or Lack of clinical evidence of left atrial hypertension. Bilateral infiltrates on frontal chest radiograph Hypoxemia Ratio of PaO 2 /FiO 2 #300 mm Hg regardless of positive end-expiratory pressure level; or Oxygen saturation of #90% on room air Proposed by the North American-European Consensus Conference on Acute Respiratory Distress Syndrome and Modified by the NHLBI TRALI Working Group. Modified from [4,8]. mechanism. This definition is an adapted version of that suggested by the US NHLBI Working Group on TRALI [4 ]. The main differences are that the ALI criteria for hypoxemia were expanded to include other clinical evidence of hypoxemia rather than just pulse oximetry measurements. The term possible TRALI was proposed because of the uncertainty of the relation of ALI to transfusion in instances where other risk factors for ALI might be present. These risk factors include aspiration, pneumonia, toxic inhalation, pulmonary contusion, near drowning, sepsis, shock, multiple trauma, burns, acute pancreatitis, cardiopulmonary bypass, and drug overdose [2 ]. It was acknowledged that this definition of TRALI represented the start to the development of an international consensus definition that would evolve as addition data became available from additional surveillance, epidemiologic studies, pathologic evaluations, and research [2 ]. Epidemiology The incidence of TRALI has been estimated to be between 0.014% and 0.08% per allogeneic blood product Table 2. Canadian Consensus Conference Criteria for TRALI and possible TRALI. Criteria for TRALI ALI Acute onset Hypoxemia In research setting Ratio of PaO 2 /FiO 2 #300; or SpO 2 <90% on room air In a nonresearch setting Ratio of PaO 2 /FiO 2 #300 or SpO 2 <90% on room air; or Other clinical evidence of hypoxemia Bilateral infiltrates on frontal chest radiograph No evidence of left atrial hypertension (i.e. circulatory overload) No preexisting ALI before transfusion During or within 6 hours of transfusion; and No temporal relationship to an alternative risk factor for ALI Criteria for possible TRALI ALI (see above) No preexisting ALI before transfusion During or within 6 hours of transfusion; and A clear temporal relationship to an alternative risk factor for ALI ALI, acute lung injury. Modified from [2 ]. unit transfused or 0.04% and 0.16% per patient transfused [9 13,14 ]. The reported incidence of TRALI is increasing. For example, in the United Kingdom, there were 36 cases of TRALI in 2003, an increase from 26 cases reported in and from an average of 14 cases per year for the years [15 ]. This most likely indicates an increasing awareness of the condition. It is generally agreed that TRALI is still underdiagnosed [6,13,16,17] and that its true prevalence may be higher than current estimates. The risk factors for TRALI are unknown. TRALI has occurred in all age groups and appears to be distributed evenly among males and females [3,12,18 ]. Certain clinical conditions may be associated with an increased risk of TRALI including thrombotic thrombocytopenic purpura, massive transfusion, underlying thrombocytopenia, active infection, organ transplantation, hematologic malignancy, and various cardiac conditions [8,14,19 26,27 ]. Many TRALI cases occur in patients in poor clinical condition at the time of the implicated transfusion [28]; however, TRALI also occurs in healthy subjects [17,29]. Various blood components, including whole blood, red blood cells (RBC), platelets, fresh frozen plasma (FFP), cryoprecipitate, intravenous immunoglobulin, allogeneic bone marrow, autologous RBCs, and granulocyte concentrates have been implicated in TRALI [12,18,30 33,34,35, FFP is the most frequently implicated blood product [18 ]. In most cases, the implicated blood product contains more than 60 ml of plasma [16]. The severity of TRALI appears not to be related to the type of blood product transfused and not dependent on the titer of the antibody in the transfused product [36]. Antibodies against certain granulocyte antigens, such as HNA-3a (5b), may be more prone to cause severe TRALI reactions [37]. TRALI prevalence may be increased with the administration of older units of blood. For example, in a study by Silliman et al., implicated whole blood platelet units were generally older than nonimplicated units [13]. Clinical presentation and laboratory investigations TRALI is clinically indistinguishable from ARDS [11]. The manifestations of TRALI begin within 6 h of transfusion and most cases occur during or within 2 h [9]. The symptoms and signs of TRALI include acute respiratory distress, severe hypoxemia, hypotension, and fever (Table 3). The hypotension is frequently unresponsive to the administration of intravenous fluids [16]. The physical examination is usually consistent with noncardiogenic pulmonary edema. Rales and diminished breath sounds are usually present without evidence of fluid overload (normal jugular venous pressure and/or absent third heart sound). Radiographic investigations usually reveal bilateral pulmonary infiltrates that are both alveolar and interstitial [16].

3 482 Transfusion medicine There may be a discrepancy between the severity of the x-ray findings and the auscultatory findings [9,38]. The presentation of TRALI likely represents a spectrum of severity and there is increasing recognition that milder forms of TRALI do occur such as hypoxia without pulmonary edema [10,16]. Laboratory findings include the presence of leukoagglutinating and/or leukocytotoxic antibodies in the donor, high levels of active lipids, and neutrophil-priming activity in the donor and patient plasma [3 ]. Other findings include leukopenia, neutropenia, monocytopenia, and hypocomplementemia in the recipient [3,39 ]. Pathophysiology The pathologic mechanisms of TRALI have not been clearly elucidated, and both immunologic and nonimmunologic mechanisms have been suggested. It is also possible that the mechanism of TRALI may vary from patient to patient, representing a spectrum including immunologic mechanisms, nonimmunologic mechanisms, or a combination of both. It is likely that biologically active molecules (for example, cytokines and antibodies) that activate leukocytes represent a common pathophysiological mechanism. Immunologic mechanisms Some investigators have postulated that TRALI is an immune-mediated event [10,17,40]. In series of 36 cases of TRALI, 89% of donors had human leukocyte antigen (HLA) or leukoagglutinating alloantibodies with antibody/antigen concordance demonstrated in 59% of cases [9]. The pathogenic alloantibodies are typically of donor origin [17,40] but in less than 10% of cases, the alloantibodies may be of recipient origin [17,41]. Donors most commonly implicated in TRALI are multiparous women because of maternal alloantibody formation following exposure to paternally-derived alloantigens on the fetal white blood cells entering the maternal circulation during pregnancy. Donors who have previously been transfused may also have formed such alloantibodies. Alloantibodies Table 3. Symptoms associated with TRALI. Symptom or sign Dyspnea, respiratory distress Hypoxia Pulmonary edema Fever (1 2 o C increase) Tachycardia Hypotension Cyanosis Hypertension Relative frequency Very common Very common Very common Very common Common Common Common Rare Many previous authors have diagnosed TRALI only when there was evidence of pulmonary edema. However, there has been increasing recognition that TRALI is a syndrome with a wide spectrum of clinical manifestations. Thus, many reports of the frequency of the symptoms and signs of TRALI may be inaccurate due to bias in reporting only cases which involved pulmonary edema. in the infused blood product interact with the recipient s leukocyte antigens which may result in the activation of the complement cascade. Although the initiating antigen antibody interaction is generally thought to involve granulocyte alloantigens, the interaction may also occur between monocytes or endothelial cell alloantigens [10]. The production of activated complement components, such as C5a, possibly results in pulmonary leukostasis and activation of leukocytes [42]. Alternately, antibody antigen complexes may activate neutrophils through one of the Fc receptors (CD16, CD32, CD64). The activation of leukocytes then could result in the production of inflammatory mediators to cause increased vascular permeability, capillary leak, and pulmonary tissue damage [9,41,42]. There is experimental evidence to support this hypothesis. For example, the infusion of leukoagglutinating antibodies in humans has been shown to cause the localization of granulocytes in the pulmonary circulation [44] and, in animal models these alloantibodies have been shown to cause acute pulmonary edema in the presence of a complement source [45]. The alloantibodies usually thought to be responsible for TRALI have been identified as anti-granulocyte, anti- HLA or anti-hla-dr antibodies [9,10,17,22,41,46 54]. Nonetheless, there are some reports of TRALI associated with anti-lymphocyte, anti-monocyte, and anti-immunoglobulin alloantibodies [10,17,36,55 57]. The specific granulocyte alloantigens that have been implicated in TRALI episodes include NA1 (or HNA-1a) [29,58]; NA2 (or HNA-1b) [59]; 5b [60,61]; NB2 [62]; and NB1(or HNA-2a) [42,63]. The ability of transfused HLA alloantibodies to induce TRALI was elegantly illustrated in a case report of a patient who had previously undergone a single lung transplant [64]. The patient developed TRALI after the transfusion of packed red cells, which was subsequently demonstrated to contain antibodies to HLA-B44. The lung injury occurred only in the patient s transplanted lung, which expressed the HLA-B44 antigen, and not in the native lung, which was HLA-B44 negative. Nonimmunologic mechanisms In at least 15% of cases of TRALI, antibodies are not detected in either the recipient or the donor [13,28,65]. Furthermore, in one study, control cases without TRALI were just as likely to have been transfused a blood component from a donor with an anti-leukocyte antibody as had occurred with TRALI patients [13]. In another report of a case series, more than 100 implicated donor plasma samples from whole blood derived platelets and RBC concentrates involved in 28 TRALI cases from Edmonton, Canada were tested [66]. Plasma samples from 24 nonimplicated

4 Transfusion-related acute lung injury Webert and Blajchman 483 donors who had been transfused to five control cases were also tested. Anti-granulocyte and anti-hla class I and class II antibodies did not appear to be the predominant cause of the reactions. Moreover, the frequency of donor antigranulocyte and anti-hla class I antibodies did not differ between TRALI and control patients. These findings support the hypothesis that the pathogenesis of TRALI may be non-antibody-mediated and may be associated with the transfusion of lipids with neutrophil-priming activity [13,28,67 71]. These lipids, lysophosphatidyl cholines, accumulate in cellular blood products with storage [13,72]. Two-event model TRALI is clinically similar to ARDS, and it has been demonstrated in animal models that the development of ARDS requires at least two pulmonary insults [73,74]. Similarly, it has been hypothesized that two events are required to cause TRALI, the first being a predisposing clinical condition, such as surgery, trauma or severe infection, and the second being the transfusion of biologically active lipids, cytokines, or the presence of leukoagglutinating alloantibodies in the blood product transfused [13,14,28,62,72]. The first event results in activation of the pulmonary endothelium, which causes a release of cytokines and an increase in the number of adhesion molecules expressed on endothelial cell surfaces [25]. This hypothesis proposes that this increase in cytokines results in the attraction and priming of neutrophils with their subsequent adherence to the endothelial surface. The second event then results in neutrophil activation and release of substances leading to pulmonary damage as well as capillary leakage [25,74,75]. Diagnosis There is no rapid or conclusive test with which to diagnose TRALI [2 ]. The clinical diagnosis of TRALI should be suspected if a blood product recipient has appropriate clinical findings within 6 h of a transfusion, together with the exclusion of other causes of pulmonary edema. It has been suggested that the determination of brain-derived natriuretic peptide (BNP) levels may help to differentiate TRALI and the volume overload observed in congestive heart failure (CHF) because elevated levels of BNP are highly predictive of CHF [76]. This hypothesis requires confirmation. Treatment The treatment of TRALI is primarily supportive. The patient s hemodynamic status should be maintained. All patients with TRALI require supplemental oxygen and more than 70% of patients will require mechanical ventilation [3,12,70]. Vasopressor medications may be necessary to treat the hypotension. Diuretics should not be used [16]. Treatments with no established benefit include corticosteroids, prostaglandin E 1, anti-endotoxin antibodies, nonsteroidal anti-inflammatory medications; anti-tumor necrosis factor antibodies; pentoxiphylline; and surfactant [17,77]. A recent case report describes the successful use of extracorporeal membrane oxygenation (ECMO) for the treatment of TRALI in a 4-year-old patient undergoing elective cardiac surgery [78]. Thus, ECMO or cardiopulmonary bypass should be considered in the management of severe TRALI. It is important to point out that if TRALI is suspected during the transfusion of a blood product, that transfusion should be immediately discontinued. Prognosis TRALI patients generally improve clinically within 48 to 96 h of onset [12]. In 80% of patients, there is resolution of the pulmonary infiltrates within 1 to 4 days and there are no long-term sequelae [12,30]. TRALI is fatal in 5% to 10% of cases [9,12,17,79]. It is one of the top three causes of transfusion-related mortality [3,23, gov/ohrms/dockets/ac/04/transcripts/ t1.doc]. According to the Food and Drug Administration, TRALI has been suspected or confirmed in more than 10% of fatalities related to transfusion from 1997 to 2000 and more than 13% of the fatalities in 2003 [18 ]. The Serious Hazards of Transfusion (SHOT) Annual Report for 2003 found that TRALI was the second greatest cause in Great Britain of transfusion-related morbidity and mortality second only to ABO incompatibility [23]. Moreover, it was found to be the major cause of transfusion-associated mortality over 6 years [15 ]. In France, TRALI was reported to have been responsible for 25% of transfusion-associated fatalities in 2003 [80]. Testing of donors associated with transfusion-related acute lung injury In cases of suspected TRALI, all allogeneic blood components transfused within 6 h of the reaction should be examined [12]. Samples of donor plasma should be tested for HLA-I and -II and granulocyte antibodies. If an antibody is found, its specificity should be determined and it should be tested for concordance with the recipient s granulocyte or lymphocyte antigens. The diagnosis of TRALI is clearly established if there is concordance. However, even without concordance, the presence of such alloantibodies is considered to be strong presumptive evidence of TRALI [12]. The method of diagnosis described above will result only in the identification of donors with some of the immunologic causes of TRALI, but it will be negative in many cases of TRALI. Ideally, consideration should be given to the investigation of the implicated products for alloantibodies and other granulocyte priming agents. Prevention Because the pathophysiology and etiology of TRALI are currently ill-defined and because of the lack of a rapid specific diagnostic test, clear recommendations for the prevention of TRALI presently do not exist [2,63].

5 484 Transfusion medicine Deferral of implicated donors There is consensus that blood donors who have demonstrable antibodies and who have been implicated in TRALI reactions should be permanently deferred [2,3 ]. Several studies have suggested that donors with an alloantibody who have been implicated in TRALI may represent a future transfusion hazard [22,81,82,83]. Studies have also demonstrated, however, that infusion of blood products containing white blood cell (WBC) antibodies that appeared to have caused TRALI in some patients did not result in TRALI in other recipients [82,83,84]. Therefore, it is acknowledged that this strategy will result in the deferral of some donors with leukocyte antibodies that may not have been causal in the TRALI reaction [2 ]. It is less clear what should be done with donors who are temporally associated with a TRALI episode but without anti-hla or anti-granulocyte antibodies. This is the case in at least 15% of TRALI cases in the literature [13,31,40]. There is no evidence that these antibody-negative donors are associated with increased risk of future episodes of TRALI. The TRALI Consensus Panel has suggested that it would be reasonable for such individuals to continue to donate [2 ]. Deferral of multiparous women Donors implicated in TRALI reactions are often multiparous women [16]. HLA-antibodies have been demonstrated in 19.2% of primiparous women compared with 50% of multiparous women [85,86]. In female blood donors, the frequency of anti-hla antibodies increases with the number of pregnancies, ranging from 7.8% in nulliparous women to 26.3% in women who have had three or more pregnancies [87]. In a study of female platelet donors, 12.9% were positive for either HLA class I or class II antibodies [53]. To investigate the effects of plasma from multiparous donors, Palfi et al. [88] performed a study in which patients in the intensive care unit were randomized to receive one unit of plasma from a multiparous donor and one unit of control plasma. Plasma from multiparous donors was associated with significantly lower oxygen saturations in the recipients. Furthermore, the mean arterial pressure increased after the transfusion of control plasma but did not change after the infusion of multiparous donor plasma. These investigators concluded that plasma from multiparous donors might impair respiratory function in critically ill patients. Further studies are required to evaluate the effects of plasma from multiparous donors in other patient groups. As TRALI is a serious, potentially fatal, condition, this approach may be justified [12]. However, the deferral of multiparous donors would result in a substantial reduction in the donor pool. For example, approximately one third of apheresis donors in a program in the United States would be affected by such a policy [87]. Furthermore, the use of this strategy by America s Blood Centers members and the American Red Cross would result in the loss of donations annually in the United States [ americasblood.org/index.cfm?fuseaction=display.showpage &pageid=294]. Thus, some have argued that it might be reasonable to use a more moderate approach [70,89]. This issue is further complicated by the fact that recent prospective studies have not identified anti-leukocyte antibodies as a major pathogenic mechanism of TRALI [13]. Use of plasma from multiparous women only for fractionation Some investigators have suggested that blood from multiparous donors who have not been screened for WBC alloantibodies should not be used as whole blood, FFP, or single donor apheresis platelets [3,12]. It is generally agreed that such donors could serve as a safe source of plasma for fractionation or washed RBCs [12]. To decrease the risk of TRALI, in 2003, the UK decided to divert plasma from female donors away from FFP production. In England, more that 90% of the FFP available is now derived from male donors [3 ]. The potential efficacy of this initiative in reducing TRALI risk likely will be not be evaluable for several years. Screening of donors for anti-granulocyte and anti-human leukocyte antigen antibodies Some blood banks have used a preventative strategy that involves the screening of all donors for leukocyte antibodies. Those donors that are identified as having leukocyte alloantibodies are excluded from donating, or their blood is only used for blood products that do not contain significant amounts of plasma, or that are fractionated [17]. This approach has been questioned because HLA antibodies, most of which do not cause TRALI reactions [42], are present in many donors. In fact, in a recent study, HLA antibodies were found to be present in 22% of blood components tested [90 ]. Furthermore, this screening method would not prevent cases of TRALI caused by nonimmunologic mechanisms, or those associated with recipient alloantibodies. Use of prestorage leukoreduced red blood cells The use of leukoreduced blood components may result in decreased risk of TRALI [91]. This theory is based on the fact that animal experiments have demonstrated complement activation to have a role in initiating TRALI and that leukoreduction prevents complement-mediated hemolysis in transfused patients with paroxysmal nocturnal hemoglobinuria [45]. Use of younger blood products As biologically active lipids accumulate in blood products with storage, it has been suggested that the administration

6 Transfusion-related acute lung injury Webert and Blajchman 485 of fresh cellular components would reduce the risk of TRALI by preventing exposure of recipient neutrophils to neutrophil-priming agents [3,13,88]. Available data to support this hypothesis are from animal studies. Further study is thus needed before older units of blood components can be clearly implicated in TRALI [70]. Furthermore, a recent study in patients receiving mechanical ventilation found no significant association between the storage age of RBC transfusions and the development of acute lung injury [27 ]. Appropriate utilization of blood products A simple way of decreasing the frequency of TRALI reactions is to ensure that blood products are used only when clinically indicated. Reduction of blood product utilization by using evidence-based criteria for transfusion may be a safe, important, and appropriate strategy to decrease the incidence of TRALI [2,92]. Use of solvent/detergent plasma The use of solvent detergent plasma instead of FFP may decrease the risk of TRALI. It has been hypothesized that the pooling process decreases the titer of responsible antibodies [2,93]. There is currently no clinical evidence to support this approach, however. Moreover, this intervention would probably not prevent cases of TRALI caused by nonimmune mechanisms. Other possible interventions There have been reports of TRALI occurring in children as a result of directed donations from their mothers [94 96 ]. This represents a situation potentially associated with increased risk of TRALI, because mothers may have developed antibodies to antigens on fetal leukocytes during the pregnancy. TRALI should be recognized as a potential, serious consequence of directed maternal blood donation [40]. Conclusion TRALI is a complex clinical syndrome that probably does not represent a single pathogenic entity. The ability to define and accurately diagnose TRALI has been hampered by our poor understanding of the pathophysiologic mechanisms of TRALI. Thus, the recent recognition that TRALI likely is a spectrum of clinical presentations and the creation of a standardized TRALI definition represents significant progress in our understanding of this perplexing syndrome. There are thus still many unanswered questions and controversial issues related to our understanding of TRALI. Many of these issues were addressed by a recent Canadian Consensus Conference [2,3 ]. However, despite the outstanding job that was done by presenters at the conference and by the Consensus Conference Panel, many remain unresolved. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev 2003; 17: Kleinman S, Caulfield T, Chan P, et al. Toward an understanding of transfusionrelated acute lung injury: statement of a consensus panel. Transfusion 2004; 44: This is the statement of the Consensus Panel of the Canadian Consensus Conference Towards an Understanding of TRALI held in Toronto, Canada in April The Consensus Panel discussed important issues including the need for a standardized definition of TRALI. 3 Goldman M, Webert KE, Arnold DM, et al. Proceedings of a consensus conference: towards an understanding of TRALI. Transfus Med Rev 2005; 19: This article reports the proceedings of the Canadian Consensus Conference Towards an Understanding of TRALI held in Toronto, Canada in April 2004, which summarizes the presentations of the invited panel of experts. 4 Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med 2005; 33: This is the statement of the National Heart, Lung and Blood Institute Working Group on TRALI. It presents a discussion of a possible definition of TRALI and the mechanisms of TRALI. 5 Williamson LM. Transfusion hazard reporting: powerful data, but do we know how best to use it? Transfusion 2002; 42: Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc 2005; 80: Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang 2005; 89: Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994; 9: Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985; 25: Kopko PM, Popovsky MA, MacKenzie MR, et al. HLA class II antibodies in transfusion-related acute lung injury. Transfusion 2001; 41: Weber JG, Warner MA, Moore SB. What is the incidence of perioperative transfusion-related acute lung injury? Anesthesiology 1995; 82: Popovsky MA, Chaplin HC Jr, Moore SB. Transfusion-related acute lung injury: a neglected, serious complication of hemotherapy. Transfusion 1992; 32: SillimanCC, Boshkov LK, Mehdizadehkashi Z, et al. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003; 101: Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005; 105: This is a review that summarizes the clinical presentation, treatment, differential diagnosis, epidemiology, pathogenesis and prevention of TRALI. 15 Stainsby D, Williamson L, Jones H, Cohen H.6 Years of shot reporting: its influence on UK blood safety. Transfus Apheresis Sci 2004; 31: This report reviews the data collected during the first 6 years of the Serious Hazards of Transfusion (SHOT) scheme and discusses how the data have provided evidence to support the development of blood safety strategies in the UK. 16 Popovsky MA. Transfusion-related acute lung injury (TRALI). In: Popovsky MA, editor. Transfusion reactions, edn 2. Bethesda, MD: AABB Press; pp Engelfriet CP, Reesink HW, Brand A, et al. Transfusion-related acute lung injury (TRALI). Vox Sang 2001; 81: Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Transfus Med Rev 2004; 18: This article provides a retrospective review of fatalities caused by TRALI over a 5-year period ( ) that were reported to the Center for Biologics Evaluation and Research. 19 Boshkov L, Silliman C, Clarke G, et al. Transfusion related acute lung injury (TRALI) following platelet transfusion: a study of possible etiologic factors. Blood 1995; 86:1403.

7 486 Transfusion medicine 20 Yost CS, Matthay MA, Gropper MA. Etiology of acute pulmonary edema during liver transplantation: a series of cases with analysis of the edema fluid. Chest 2001; 119: Distenfeld A. Transfusion-related acute lung injury. JAMA 2002; 288: Cooling L. Transfusion-related acute lung injury. JAMA 2002; 288: Stainsby D, Cohen H, Jones H, et al. for the SHOT Steering Committee. Serious Hazards of Transfusion (SHOT) Annual Report Serious Hazards of Transfusion Office, Manchester Blood Office, Roffey P, Thangathurai D, Mikhail M, et al. TRALI and massive transfusion. Resuscitation 2003; 58: Silliman CC. Transfusion-related acute lung injury. Transfus Med Rev 1999; 13: Medeiros BC, Kogel KE, Kane MA. Transfusion-related acute lung injury (TRALI) following platelet transfusion in a patient receiving high-dose interleukin-2 for treatment of metastatic renal cell carcinoma. Transfus Apheresis Sci 2003; 29: Gajic O, Rana R, Mendez JL, et al. Acute lung injury after blood transfusion in mechanically ventilated patients. Transfusion 2004; 44: This retrospective cohort study investigated the risk of ALI in 181 mechanically ventilated patients receiving blood transfusions. The authors concluded that thrombocytopenia and transfusion of fresh frozen plasma, but not storage age of red blood cells, were associated with the development of ALI. 28 Silliman CC, Paterson AJ, Dickey WO, et al. The association of biologically active lipids with the development of transfusion-related acute lung injury: a retrospective study. Transfusion 1997; 37: Lucas G, Rogers S, Evans R, et al. Transfusion-related acute lung injury associated with interdonor incompatibility for the neutrophil-specific antigen HNA-1a. Vox Sang 2000; 79: Popovsky MA. Transfusion-related acute lung injury. Transfusion 1995; 35: Popovsky MA. Transfusion-related acute lung injury. Curr Opin Hematol 2000; 7: Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41: Urahama N, Tanosaki R, Masahiro K, et al. TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia. Transfusion 2003; 43: Covin RB, Ambruso DR, England KM, et al. Hypotension and acute pulmonary insufficiency following transfusion of autologous red blood cells during surgery: a case report and review of the literature. Transfus Med 2004; 14: This is an interesting case report of a case of TRALI that occurred after the transfusion of autologous RBCs. 35 Sachs UJ, Bux J. TRALI after the transfusion of cross-match-positive granulocytes. Transfusion 2003; 43: Flesch BK, Neppert J. Transfusion-related acute lung injury caused by human leucocyte antigen class II antibody. Br J Haematol 2002; 116: Davoren A, Curtis BR, Shulman IA, et al. TRALI due to granulocyteagglutinating human neutrophil antigen-3a (5b) alloantibodies in donor plasma: a report of 2 fatalities. Transfusion 2003; 43: Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann Intern Med 1970; 73: Nakagawa M, Toy P. Acute and transient decrease in neutrophil count in transfusion related acute lung injury: cases at one hospital. Transfusion 2004; 44: This report describes two cases of TRALI both associated with a decrease in neutrophil count. This represents a previously unrecognized feature of TRALI and may yield new insights into the pathophysiology of TRALI. 40 Popovsky MA, Davenport RD. Transfusion-related acute lung injury: femme fatale? Transfusion 2001; 41: Bux J, Becker F, Seeger W, et al. Transfusion-related acute lung injury due to HLA-A2-specific antibodies in recipient and NB1-specific antibodies in donor blood. Br J Haematol 1996; 93: Clay ME, Stroncek DF. Granulocyte immunology. In: Anderson KC, Ness PM, editors. Scientific basis of transfusion medicine: implications for clinical practice. Philadelphia: WB Saunders; pp Carilli AD, Ramanamurty MV, Chang YS, et al. Noncardiogenic pulmonary edema following blood transfusion. Chest 1978; 74: McCullough J, Clay M, Hurd D, et al. Effect of leukocyte antibodies and HLA matching on the intravascular recovery, survival, and tissue localization of 111-indium granulocytes. Blood 1986; 67: Seeger W, Schneider U, Kreusler B, et al. Reproduction of transfusion-related acute lung injury in an ex vivo lung model. Blood 1990; 76: Andrews AT, Zmijewski CM, Bowman HS, Reihart JK. Transfusion reaction with pulmonary infiltration associated with HL-A-specific leukocyte antibodies. Am J Clin Pathol 1976; 66: Popovsky MA, Abel MD, Moore SB. Transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 1983; 128: Eastlund T, McGrath PC, Britten A, Propp R. Fatal pulmonary transfusion reaction to plasma containing donor HLA antibody. Vox Sang 1989; 57: Florell SR, Velasco SE, Fine PG. Perioperative recognition, management, and pathologic diagnosis of transfusion-related acute lung injury. Anesthesiology 1994; 81: Virchis AE, Contreras M, Navarrete C, et al. Transfusion-related acute lung injury (TRALI) due to inter-donor incompatibility. Blood 1996; 88: Dry SM, Bechard KM, Milford EL, et al. The pathology of transfusion-related acute lung injury. Am J Clin Pathol 1999; 112: Varela M, Mas A, Nogues N, et al. TRALI associated with HLA class II antibodies. Transfusion 2002; 42: Kao GS, Wood IG, Dorfman DM, et al. Investigations into the role of anti-hla class II antibodies in TRALI. Transfusion 2003; 43: Win N, Brown C, Navarrete C. TRALI associated with HLA class II antibodies. Transfusion 2003; 43: Dooren MC, Ouwehand WH, Verhoeven AJ, et al. Adult respiratory distress syndrome after experimental intravenous gamma-globulin concentrate and monocyte-reactive IgG antibodies. Lancet 1998; 352: Paglieroni TG, Kopko PM, Popovsky MA, et al. Monocyte antibody associated with transfusion related acute lung injury (TRALI). Blood 2001; 98:57A. 57 Saigo K, Sugimoto T, Tone K, et al. Transfusion-related acute lung injury in a patient with acute myelogenous leukaemia having anti-iga2m(1) antibody. J Int Med Res 1999; 27: Santamaria A, Moya F, Martinez C, et al. Transfusion-related acute lung injury associated with an NA1-specific antigranulocyte antibody. Haematologica 1998; 83: Yomtovian R, Kline W, Press C, et al. Severe pulmonary hypersensitivity associated with passive transfusion of a neutrophil-specific antibody. Lancet 1984; 1: Nordhagen R, Conradi M, Dromtorp SM. Pulmonary reaction associated with transfusion of plasma containing anti-5b. Vox Sang 1986; 51: Zupanska B, Uhrynowska M, Konopka L. Transfusion-related acute lung injury due to granulocyte-agglutinating antibody in a patient with paroxysmal nocturnal hemoglobinuria. Transfusion 1999; 39: Van Buren NL, Stroncek DF, Clay ME, et al. Transfusion-related acute lung injury caused by an NB2 granulocyte-specific antibody in a patient with thrombotic thrombocytopenic purpura. Transfusion 1990; 30: Leger R, Palm S, Wulf H, et al. Transfusion-related lung injury with leukopenic reaction caused by fresh frozen plasma containing anti-nb1. Anesthesiology 1999; 91: Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (TRALI) in a patient with a single lung transplant. Br J Haematol 2000; 109: Engelfriet CP, Reesink HW. Transfusion-related acute lung injury (TRALI). Vox Sang 2001; 81: Boshkov L, Mehdizadehkashi Z, Alcorn J, et al. Failure to implicate antigranulocyte or anti-hla class I or class II antibodies as the major pathogenetic mechanism in a series of transfusion associated acute lung injury cases (TRALI) [abstract]. Blood 2001; 98:828a. 67 SillimanCC, Clay KL, Thurman GW, et al. Partial characterization of lipids that develop during the routine storage of blood and prime the neutrophil NADPH oxidase. J Lab Clin Med 1994; 124: Silliman CC, Dickey WO, Paterson AJ, et al. Analysis of the priming activity of lipids generated during routine storage of platelet concentrates. Transfusion 1996; 36: Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 1998; 101:

8 Transfusion-related acute lung injury Webert and Blajchman Lenahan SE, Domen RE, Silliman CC, et al. Transfusion-related acute lung injury secondary to biologically active mediators. Arch Pathol Lab Med 2001; 125: Silliman CC, Thurman GW, Ambruso DR. Stored blood components contain agents that prime the neutrophil NADPH oxidase through the plateletactivating-factor receptor. Vox Sang 1992; 63: Silliman CC, Bjornsen AJ, Wyman TH, et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003; 43: Salzer WL, McCall CE. Primed stimulation of isolated perfused rabbit lung by endotoxin and platelet activating factor induces enhanced production of thromboxane and lung injury. J Clin Invest 1990; 85: Rabinovici R, Esser KM, Lysko PG, et al. Priming by platelet-activating factor of endotoxin-induced lung injury and cardiovascular shock. Circ Res 1991; 69: Downey GP, Doherty DE, Schwab B III, et al. Retention of leukocytes in capillaries: role of cell size and deformability. J Appl Physiol 1990; 69: Burgher AH, Aslan D, Laudi N, Bowman RJ. Use of brain natriuretic peptide to evaluate transfusion-related acute lung injury. Transfusion 2004; 44: Wu TJ, Teng RJ, Tsou Yau KI. Transfusion-related acute lung injury treated with surfactant in a neonate. Eur J Pediatr 1996; 155: Nouraei SM, Wallis JP, Bolton D, Hasan A. Management of transfusionrelated acute lung injury with extracorporeal cardiopulmonary support in a four-year-old child. Br J Anaesth 2003; 91: Wolf CF, Canale VC. Fatal pulmonary hypersensitivity reaction to HL-A incompatible blood transfusion: report of a case and review of the literature. Transfusion 1976; 16: Rebibo D, Hauser L, Slimani A, et al. The French Haemovigilance System: organization and results for Transfus Apheresis Sci 2004; 31: Kopko PM, Marshall CS,MacKenzie MR,et al. Transfusion-related acute lung injury: report of a clinical look-back investigation. JAMA 2002; 287: Nicolle AL, Chapman CE, Carter V, Wallis JP. Transfusion-related acute lung injury caused by two donors with anti-human leucocyte antigen class II antibodies: a look-back investigation. Transfus Med 2004; 14: This is a lookback investigation of two donors implicated in TRALI who were identified as having HLA type II alloantibodies. Eighteen patients were identified as having received a blood component transfusion from one of the two donors. One of the recipients had evidence of a TRALI reaction, previously undiagnosed. 83 Toy P, Hollis-Perry KM, Jun J, Nakagawa M. Recipients of blood from a donor with multiple HLA antibodies: a lookback study of transfusion-related acute lung injury. Transfusion 2004; 44: Win N, Ranasinghe E, Lucas G. Transfusion-related acute lung injury: a 5-year look-back study. Transfus Med 2002; 12: Vives J, Gelabert A, Castillo R. HLA antibodies and period of gestation: decline in frequency of positive sera during last trimester. Tissue Antigens 1976; 7: Morin-Papunen L, Tiilikainen A, Hartikainen-Sorri AL. Maternal HLA immunization during pregnancy: presence of anti HLA antibodies in half of multigravidous women. Med Biol 1984; 62: Densmore TL, Goodnough LT, Ali S, et al. Prevalence of HLA sensitization in female apheresis donors. Transfusion 1999; 39: Palfi M, Berg S, Ernerudh J, Berlin G. A randomized controlled trial of transfusion-related acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion 2001; 41: Kopko PM, Holland PV. Transfusion-related acute lung injury. Br J Haematol 1999; 105: Bray RA, Harris SB, Josephson CD,et al. Unappreciated risk factors for transplant patients: HLA antibodies in blood components. Hum Immunol 2004; 65: This study tested 77 units of FFP, 66 units of cryoprecipitate, 106 units of RBCs, and 59 units of apheresis platelets for class I and class II HLA antibodies. Approximately 22% of blood components tested contained alloantibodies. 91 WinN, Montgomery J,Sage D, et al. Recurrent transfusion-related acute lung injury. Transfusion 2001; 41: Wallis JP, Dzik S. Is fresh frozen plasma overtransfused in the United States? Transfusion 2004; 44: Sinnott P, Bodger S, Gupta A, Brophy M. Presence of HLA antibodies in single-donor-derived fresh frozen plasma compared with pooled, solvent detergent-treated plasma (Octaplas). Eur J Immunogenet 2004; 31: Campbell DA Jr, Swartz RD, Waskerwitz JA, et al. Leukoagglutination with interstitial pulmonary edema. A complication of donor-specific transfusion. Transplantation 1982; 34: Goeken NE, Schulak JA, Nghiem DD, et al. Transfusion reactions in donorspecific blood transfusion patients resulting from transfused maternal antibody. Transplantation 1984; 38: Yang X, Ahmed S, Chandrasekaran V. Transfusion-related acute lung injury resulting from designated blood transfusion between mother and child: a report of two cases. Am J Clin Pathol 2004; 121: This article reports two cases of TRALI resulting from a designated blood transfusion between mother and child. This represents a situation potentially associated with increased risk of TRALI, because mothers may have developed antibodies to antigens on fetal leukocytes during the pregnancy.