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Understanding the Consequences of Transfusion-Related Acute Lung Injury
Understanding the Consequences of Transfusion-Related Acute Lung Injury* Aryeh Shander, MD, FCCP; and Mark A. Popovsky, MD
Although the blood supply has become safer with regard to transmission of infectious agents, attention should continue to focus on understanding and eliminating the other serious risks associated with transfusion. Transfusion-related acute lung injury (TRALI) is one such risk, only recently becoming recognized as an important and potentially preventable clinical syndrome. Strategies for prevention of TRALI, however, must rely on knowledge regarding its etiology and diagnosis, and significant gaps in our understanding of the syndrome currently exist. This review summarizes what is known and unknown about the incidence, severity, etiology, diagnosis, and prevention of TRALI and the potential consequences of these knowledge gaps. (CHEST 2005; 128:598S– 604S) Key words: diagnosis; etiology; transfusion-related acute lung injury Abbreviations: ALI ⫽ acute lung injury; FDA ⫽ Food and Drug Administration; FFP ⫽ fresh-frozen plasma; HLA ⫽ human leukocyte antigen; HNA ⫽ human neutrophil antigen; IL ⫽ interleukin; IVIG ⫽ IV immune globulin; TRALI ⫽ transfusion-related acute lung injury; WB-PLT ⫽ whole blood-derived platelet Learning Objectives: 1. To review the incidence and current theories regarding the pathogenesis of transfusionrelated acute lung injury. 2. To understand the rationale and consequences of donor deferrals as a means to prevent transfusion-related acute lung injury.
acute lung injury (TRALI) is a T ransfusion-related well-characterized and serious adverse consequence of blood product transfusion.1 The reported incidence of TRALI indicates it is rare, although its overall occurrence is almost certainly more common than the oft-quoted estimate of one case in 5,000 U of blood transfused,2 and it is among the two leading causes of death resulting from transfusion.3 Cases of TRALI have gone unrecognized or misdiagnosed, since the symptoms can be confused with other transfusion-related events such as anaphylaxis, hemolysis, or circulatory overload, or with non-transfu*From the Department of Anesthesiology and Critical Care Medicine (Dr. Shander), Englewood Hospital and Medical Center, Englewood, NJ; and Haemonetics Corporation (Dr. Popovsky), Braintree, MA. This publication was supported by an educational grant from Ortho Biotech Products, L.P. The following authors have disclosed financial relationships with a commercial party. Grant information and company names appear as pprovided by the author: Aryeh Shander, MD, FCCP: Ortho Biotech - Speaker bureau. The following authors have indicated to the ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in their article: Mark A. Popovsky, MD. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Aryeh Shander, MD, FCCP, Chief, Department of Anesthesiology and Critical Care Medicine, Medical Director, New Jersey Institute for the Advancement of Bloodless Medicine and Surgery, Englewood Hospital and Medical Center, 350 Engle St, Englewood, NJ 07631; e-mail: [email protected] 598S
sion-related comorbidities such as cardiac failure.4,5 Suspected cases of TRALI may be insufficiently investigated,6 and mild or moderate cases may not be investigated or reported at all. Virtually all blood products have been implicated, and controversies exist as to whether the etiology of TRALI is mediated by antibodies, lipids, or a combination of both.7 Donor as well as recipient factors have been implicated in the pathogenesis of TRALI, but the relative importance of each is unknown. This lack of knowledge thwarts the clinician’s ability to identify cases and to manage patients with TRALI who require further blood product support. Strategies to prevent TRALI through blood screening and/or donor deferral could be better formulated if the syndrome were more clearly understood. The rationale and consequences of donor restrictions or lack thereof have been deliberated by regulatory bodies over the last several years and, recently, at a consensus conference in Canada. Following a brief review of the syndrome, its incidence, and the blood products implicated, this article will focus on major areas of medical and scientific dissent concerning the etiology, diagnosis, and prevention of TRALI. The TRALI Syndrome: Definition, Incidence, and Severity TRALI can be defined as an uncommon complication of allogeneic blood transfusion typically man-
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
ifested by bilateral pulmonary edema, dyspnea, hypoxemia, fever, and hypotension in the presence of normal cardiac function.2,4 The time frame of symptom onset helps to identify the syndrome, as symptoms occur during or shortly after transfusion, usually within 1 to 2 h, but always within 6 h. Details about the pathophysiologic mechanisms of TRALI have been reviewed by others.8,9 Its clinical presentation is identical to ARDS,2,10 with at least two important exceptions. First, mortality resulting from TRALI is often approximated at 5 to 10%,2,9,11 occasionally higher (50%),12 but mostly well below the 40 to 70% mortality estimates associated with ARDS.13 Second, in contrast to ARDS, in which lung injury can be irreversible, TRALI is generally transient, with Po2 levels returning to pretransfusion levels within 48 to 96 h.1 The often quoted incidence rate of TRALI is 0.02%/U averaged over all blood products, or 0.16% per patient transfused.2 Because TRALI has previously been underrecognized and underreported, its actual incidence is unknown.1,4 Most types of blood products have been implicated as having caused TRALI. Among cellular products, random donor (0.2%) or whole blood-derived platelet (WB-PLT) transfusions (0.3%) are the most frequently named (Table 1). TRALI occurs after administration of one case in approximately 4,000 U of packed RBCs, ie, approximately one tenth as often as with platelet transfusions. The first case of TRALI after infusion of allogeneic bone marrow cells in a patient with acute lymphoblastic leukemia has recently been doc-
umented.14 Fresh-frozen plasma (FFP) has the lowest rate of reported TRALI events per unit transfused (0.005 to 0.013%), so it seems paradoxical that blood products containing as little as 10 to 60 mL of plasma have the capacity to induce a pulmonary reaction.1 Plasma derivatives manufactured from pooled donors (eg, albumin, clotting factor concentrates) have largely not been implicated, with the exception of a few case reports of TRALI after infusions of cryoprecipitate and IV immune globulin (IVIG).15,16 With regard to its severity, most patients experiencing TRALI have a good prognosis, especially when pulmonary infiltrates and hypoxemia resolve quickly.9 In the opinion of some investigators,4 the severity of the pulmonary reaction in TRALI can be determined by the degree of fluid exudation. In a randomized crossover trial of plasma transfusion from never-pregnant/never-transfused donors (control subjects) vs multiparous (three or more live births) donors (experimental), an acute decrease in the Pao2/fraction of inspired oxygen ratio was seen following experimental but not after control transfusion. This led the authors17 to speculate that some impairment of lung function is induced by plasma from multiparous donors, although it may be subclinical in most cases. Although mortality and morbidity resulting from TRALI are known to be lower than ARDS, TRALI has the potential to be severe, as illustrated by several examples from the medical literature. A report12 from one hospital indicated that TRALI was the most common serious adverse effect of blood transfusion; 10 of the 11 cases reported
Table 1—Incidence/Prevalence of TRALI With Various Blood Transfusion Products Product Type All components All cellular components Packed RBCs Plasma (FFP) From multiparous donors From a single donor implicated in a TRALI fatality Platelets (random donor) Whole blood-derived platelets Apheresis platelets Platelet concentrates and/or RBCs Preuniversal leukodepletion Intermediate leukodepletion* After universal leukodepletion IVIG Cryoprecipitate Allogeneic bone marrow stem cells Granulocytes
Reported Occurrence 1 1 1 1 1 1 1 1 1
in in in in in in in in in
Source 10
1,323 U 5,408 U 1,120 U 2,000 U 4,410 U 19,411 U 7,900 U 200 U 3 patients exposed
Silliman et al, 2003 Popovsky and Moore,2 1985 Silliman et al,10 2003 Silliman et al,18 1997 Silliman et al,10 2003 Silliman et al,10 2003 Wallis et al,12 2003 Palfi et al,17 2001 Kopko et al,4 2002
1 in 317 U 1 in 432 U 1 in 1,224 U
Clarke et al,21 1994 Silliman et al,10 2003 Silliman et al,10 2003
Approximately 1 in 4 patients with transfusion reaction Approximately 1 in 11 patients with transfusion reaction Approximately 1 in 32 patients with transfusion reaction Single case report Single case report Single case report 2 case reports
Yazer et al,20 2004 Yazer et al,20 2004 Yazer et al,20 2004 Rizk et al,15 2001 Reese et al,16 1975 Urahama et al,14 2003 O’Connor et al,22 1998; Sachs and Bux,19 2003
*After universal leukodepletion of platelet concentrates but before universal depletion of RBCs. www.chestjournal.org
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required mechanical ventilatory support and five persons died. Wallis et al12 even postulated that the transfusion-related syndrome may involve damage to extrapulmonary vasculature in addition to the wellrecognized pulmonary insult. In another report from Davoren and colleagues,23 death occurred within 24 h after the onset of respiratory symptoms in two patients who acquired ARDS and hypotension followed by fulminant pulmonary edema necessitating mechanical ventilation. Since patients who receive transfusions tend to be quite ill, even if TRALI alone is benign it has the potential to exacerbate any comorbidities. For example, development of ARDS with a high degree of fatality was noted in a heavily transfused population after liver transplantation.24 In another study,25 the number of blood products transfused was an important predicting factor for ARDS development following cardiac surgery. Finally, incorrect diagnosis of unsuspected TRALI and inappropriate management with ultrafiltration in a patient with end-stage renal disease may have worsened her condition.26 The relative contribution of TRALI— or of its improper management—to worsening outcomes in other severe illnesses should be systematically investigated. Etiology of TRALI As summarized in Table 1, TRALI results mainly from administration of platelets, but RBCs, granulocytes, plasma, cryoprecipitate, IVIG, and bone marrow stem cells have also been implicated. Studies9,27 on the immunologic side effects of blood transfusions are scarce, and many aspects of TRALI etiology are poorly understood or controversial. Animal models suggest that lung injury results from two independent events, neutrophil priming and activation, mediated by separate agents.28 The hypothesis of TRALI pathogenesis involves two “hits,” one derived from stored blood (donor factors), and the other from the clinical condition of the patient (recipient factors),28 but the order of the hits, the precise donor-recipient factors, or their relative importance have not been clearly established. Subsequent to its inception, the hypothesized mechanism evolved to include transfusion with a blood component containing either antibodies to WBC and/or lipid-priming agents.29 Antibodies Antibodies are the major postulated donor factors in the pathogenesis of TRALI and are believed to be the source in 90% of TRALI cases.26 In one of the first reports2 describing the TRALI syndrome, antigranulocyte antibodies were implicated in the donor 600S
plasma of 89% of 36 cases; anti-human leukocyte antigen (HLA) class I antibodies were detected in 72%. Another study4,30 evaluating the risk of receiving blood components in renal transplant recipients found that 22% of blood components tested contained HLA alloantibodies, including both anti-HLA class I and anti-HLA class II types. In an investigation23 of two fatal TRALI cases, granulocyte antibodies with weak specificity were detected using flow cytometry; and using a granulocyte agglutination test, strong antibodies specific for human neutrophil antigen (HNA)-3a (5b) were identified from two separate donors. Testing donors for HLA class II antibodies as well as HLA class I and granulocyte antibodies has been recommended to be part of any investigation of suspected TRALI.31 The prevalence of HLA sensitization correlated strongly with the number of pregnancies in a study of 332 women with a history of ⬎ 9,000 plateletpheresis donations.32 For this reason, multiparous female donors (two or more pregnancies) of plasma-rich blood components are believed to harbor an increased potential for inducing TRALI in those who receive blood products.23,32 Granulocyte antibodies with strong HNA-3a (5b) reactivity but no HLA antibodies were implicated in a TRALI case following infusion of single donor platelets from a multiparous female donor.33 A similar, strong pattern of granulocyte 5b antigen positivity was present in the multiparous donor who triggered a look-back investigation by Kopko and colleagues4 subsequent to a TRALI death. Popovsky and Davenport34 noted that in up to 15% of cases, neither anti-HLA nor antigranulocyte antibodies can be found in the donor or the recipient. In the randomized crossover study17 of transfusion with plasma from multiparous donors vs neverpregnant/never-transfused donors described above, one case of typical TRALI was noted following transfusion from the multiparous donor who was IgG granulocyte antibody positive; however, the compatibility test result between donor plasma and recipient granulocytes was negative. At least one report35 suggests that antimonocyte antibodies also contribute to the development of TRALI, and anti-IgA antibodies may also be involved.36 Antibodies and their link to TRALI are incompletely understood at present. Perhaps the most compelling argument against a strict antibody hypothesis underlying TRALI etiology is the poor correlation of TRALI frequency with the amount of plasma in the transfused product.37 The screening of all donors for all specific antibodies with the intent of eliminating them from the donor pool to prevent TRALI may be a costly, premature, and ultimately futile undertaking.
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
Lipids and Cytokines With Polymorphonuclear Lymphocyte-Priming Capability
establish a definitive link between these cytokines and the etiology of TRALI.
As noted above, not all studies implicate antibodies as the sole underlying cause of TRALI. Silliman and colleagues18 studied 10 patients with TRALI and 10 patients who had febrile or urticarial transfusion reactions but no lung involvement (control subjects). The patients with TRALI all had underlying clinical factors: infection, cytokine administration, recent surgery, or massive transfusion, compared with only 2 of 10 control patients who had such factors. None of the donors had significant titers of HLA or HLA-DR antibodies, and only 50% had weak positivity for granulocyte antibodies. These authors18 were the first to hypothesize that two events might be required to precipitate TRALI, one of which involves polymorphonuclear lymphocyte-priming activity. This priming activity, hypothesized to be the result of predisposing factors (recent surgery, infection or inflammation, massive transfusion, cytokine therapy) was noted to be a necessary but not sufficient component to induce TRALI. Lipids comprised of lysophosphatidylcholine moieties present in stored blood were implicated as the second insult, although leukoagglutinins and/or cytokines were also acknowledged as possible secondary contributors. Infusion of older platelets emerged as a significant risk factor in a more recent investigation conducted by Silliman et al.10 In the prospective portion of that study, the amount of lipid-priming activity (neutral lipids and lysophosphatidylcholine) was higher in implicated WB-PLT units compared to control units. Some believe that this lipid-priming activity may be an even more important etiologic factor than antileukocyte antibodies. Win and colleagues,38 investigating a case of recurrent TRALI in a single patient, also noted that biologically active lipids accumulate during storage of RBCs and platelets and may have been a predisposing factor in the second episode, together with the patient’s underlying pulmonary condition (ie, recovering from lung injury). The first episode was believed to be due to the action of HLA-A2 and granulocyte-specific IgM antibodies. Among inflammatory mediators, an in vitro investigation39 of three cytokines (tumor necrosis factor-␣, interferon-␥, and interleukin [IL]-18) after an anti-major histocompatibility class II DR monoclonal antibody challenge suggested that these cytokines may contribute to inflammatory reactions in the lungs. Involvement of polymorphonuclear lymphocytes in IgE-mediated immune reactions was also cited. In another study,10 IL-6 and IL-8 levels were found to be elevated in WB-PLT units after 5 days of storage, but data were not convincing enough to
Postulated Recipient Factors
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In addition to donor factors, a recipient of blood products may be predisposed to sustain a severe pulmonary reaction. Contributing to lung injury in approximately 5 to 20% of cases is the presence of antibodies in recipient serum.2,19 Anti-HLA-A2 antibodies were identified in a patient with acute myeloblastic leukemia who had an episode of TRALI following each of two granulocyte infusions.19 Santamaria et al40 described a case of TRALI following RBC transfusion associated with an antigranulocyte antibody with NA1 specificity in the patient’s serum. In addition to a recipient’s immunologic status, one of the etiologic factors for TRALI in the “twohit” hypothesis involves the clinical condition of the patient. Silliman et al10 conducted a nested casecontrol study to investigate which preexisting conditions or factors correlated with TRALI risk. Patients with hematologic malignancies and cardiac disease were at significantly higher risk for TRALI, whereas age, ABO compatibility of recipient and donor blood groups, history of prior transfusions, and number of previous transfusion reactions were not predictive. Prior vascular surgery or hemodialysis may have been the sensitizing event in a case report of TRALI described by Guglin et al26 in a patient with endstage renal failure. Finally, little is known about the impact of concurrent treatment of comorbid disease on the development of TRALI. The first reported case of immunotherapy leading to TRALI occurred in a patient who received high-dose IL-2 as treatment for metastatic renal cell carcinoma, in which IL-2 was speculated to have been the first insult and transfusion of platelet concentrate the second.41 These reports underscore the fact that identifying patients at risk for TRALI is still challenging. Diagnosis of TRALI An appropriate diagnosis of TRALI is the key to treatment and may prevent additional reactions, not only in the same patient (who may be susceptible and receive a subsequent transfusion), but quite possibly in other patients who receive blood from a high-risk donor.42 In the look-back investigation requested by the US Food and Drug Administration (FDA) to investigate a transfusion-related fatality, Kopko et al4 found that TRALI is considerably underdiagnosed, primarily due to superimposed illnesses. The clinical presentation of dyspnea, hypoxemia, hypotension, fever, bilateral pulmonary infiltrates, and normal cardiac function2,33 can easily be CHEST / 128 / 5 / NOVEMBER, 2005 SUPPLEMENT
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mistaken for other clinical conditions.42 Both TRALI and transfusion-associated circulatory overload present with dyspnea, but other signs and symptoms aid the proper diagnosis.5 A notable example is acute pulmonary edema following blood transfusion in a dialysis-dependent patient, which does not always signify fluid overload. Nephrologists were cautioned to be aware of the alternative diagnosis of TRALI to facilitate a proper diagnosis and appropriate management.26 Because the diagnosis of TRALI has typically required a serologic confirmation, it has been suggested that the high numbers of TRALI cases associated with antibodies may just reflect a reporting bias.9 Nevertheless, in addition to a clinical diagnosis, a comprehensive laboratory and serologic workup of any suspected case of TRALI is advisable. Table 2 summarizes the tests that should be considered, keeping in mind that no consensus or algorithm is yet available. It is unclear whether crossmatching procedures should be universally implemented prior to transfusion in an attempt to avert lung injury induced by antibodies in the serum of the recipient.19 Testing for selected cytokines or lipids is probably not currently warranted, but because cytokines and lipids that accumulate in stored blood products are under suspicion,28 the age of blood product transfused should be documented and included in any TRALI case report. Management of TRALI The mainstay of TRALI management involves hemodynamic and ventilatory support,9 and Nouraei et al43 has pointed out the potential utility of extracorporeal oxygenation for short durations in severe cases. Other, less well-documented and unproven
Table 2—Laboratory Investigation and Documentation of Suspected TRALI Episode* General ABO typing CBC count Direct antiglobulin test Blood cultures to rule out infection Biologic response modifiers (cytokines: IL-6, IL-8, others)? Plasma lipids? Cross-match? Antibodies (previously implicated in parenthesis) Anti-HLA class I (A2, A9, B13, B27) Anti-HLA class II (DR3/5/6 CRG, DR1, DR4)† Antigranulocyte (anti-HNA1, anti-HNA2, anti-HNA3a, ⫺ 5b, anti-HNB1, anti-HNB2, ⫺9a) Antimonocyte (HLA-II) Anti-IgA (not specified) *Information compiled from previously published data.6,9,12,28,36 †CRG ⫽ cross-reactive group (includes DR17). 602S
therapies (eg, corticosteroids, prostaglandin E1) were noted in the comprehensive review of Webert and Blajchman.9 Although diuretics have been used, they are said to have no role in TRALI treatment.44 As in the case of the patient with TRALI and renal failure treated with ultrafiltration,26 an incorrect diagnoses may lead to inappropriate management. Thus, attention to underlying disorders and the potential for condition/syndrome interactions is of paramount importance. Scant information exists about management of future transfusions in patients with documented TRALI. Blood products from the same donor should clearly be avoided, but little else can be recommended with certainty. In one case report38 of a patient with recurrent TRALI, the sera from donors implicated in the second episode contained no granulocyte- or lymphocyte-specific antibodies, and forward and reverse cross-matching with recipient sera were negative. These observations cast doubt on whether TRALI can be effectively prevented even if the laborious task of cross-matching is dutifully performed. Prevention of TRALI Largely responsible for defining the syndrome in 1985, Popovsky and Moore2 stressed the importance of awareness in medical practice and urged blood banks to identify donors whose plasma is linked to TRALI cases in order to prevent recurrence. Whether donor deferral is a worthwhile strategy to prevent TRALI is a topic of debate. Wallis et al12 suggested that multiparous women should be excluded from donation of plasma-rich components, since many of the cases of TRALI observed in their institution were traceable to HLA class I or class II antibodies. In contrast, despite an observed correlation of pregnancies with HLA-sensitization and the acknowledgment that multiparous women donors add risk, Densmore et al32 argued that exclusion of multiparous plateletpheresis donors would eliminate one third of the female donor pool and was not justified. These differences of opinion are reflective of the discrepant regulatory approaches currently employed around the world. For example, Austria requires their hospitals to report each presumed TRALI case; once confirmed, donors are deferred from subsequent donations (personal communication; A. Hofmann; April 19, 2004). A spokesperson for America’s Blood Centers indicated that the United Kingdom has opted to make FFP only from male donors, but no individual State in the United States has taken any action to limit the impact of TRALI since blood safety and efficacy are regulated by the FDA (personal communication; S. Pavlovsky;
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
April 20, 2004). In 2001, a memo issued by the American Association of Blood Banks stated there was general agreement that blood from a donor implicated in TRALI should never again be transfused to the same patient, although the American Association of Blood Banks acknowledged that the issue of permanent deferrals of implicated donors was less clear.45 The FDA has not yet mandated donor deferrals, but representatives from US and Canadian blood collection agencies, regulatory bodies, and research sponsors met in Canada in April 2004 to further discuss the topic. Leukoreduction is yet another preventative measure that has been investigated and discrepant results found. In one study,20 TRALI reactions were significantly reduced by prestorage WBC reduction. In another study,10 prestorage WBC reduction was ineffective in inhibiting TRALI. Leukoreduction is currently mandated in Canada46 and throughout most of Europe but not in the United States, where its merits are still being debated.47 Patient screening and history as well as performing a cross-match procedure may or may not be helpful in preventing TRALI. Examples may be found in which TRALI occurred despite negative cross-match results.38 Sachs and Bux19 noted that additional data are required to determine whether cross-matching granulocyte transfusions as a regular practice would be of benefit. In the future, molecular biological techniques such as identifying platelet alloantigens and their underlying nucleic acid polymorphisms on platelet glycoprotein genes48 might help to advance the field. Prompt investigations of TRALI episodes would help facilitate appropriate management of implicated donations and donors in order to minimize the future occurrences. Clinicians play a vital role in reporting TRALI cases, and the role of hospital blood banks in collecting appropriate samples is likewise critical. Fung and colleagues49 urged hospital blood banks to retain transfused donated units for at least 24 h after transfusion to expedite TRALI investigations. Due to the highly technical nature of the investigation, these investigators suggested using specialized neutrophil testing services.
New Working Definition of TRALI Recently, a Canadian-sponsored international consensus conference dealt with a number of issues related to TRALI. From this meeting, a new working definition of TRALI emerged: in patients with no acute lung injury (ALI) prior to transfusion, the diagnosis of TRALI is made for the following: (1) new ALI characterized by acute onset, hypoxemia, www.chestjournal.org
bilateral lung infiltrations on the chest radiograph, and no evidence of circulatory overload; (2) occurrence during transfusion or within 6 h of completion; and (3) no other risk factor for ALI. A complete report relating to this and other topics discussed during the Canadian TRALI consensus conference is pending.
Conclusions/Recommendations There is a clinical need for additional basic and clinical research to improve our understanding, diagnosis, reporting, and management of TRALI. On the basis of this research, better strategies might be designed and implemented to ensure that the patients who receive transfusions are not at risk to experience this potentially fatal complication. Without a clearer understanding of the etiology of TRALI, restrictions on donors may either be inappropriately or prematurely enforced.
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acute lung injury (TRALI) following allogeneic stem cell transplant for acute myeloid leukemia. Am J Hematol 2004; 75:48 –51 Popovsky MA, Davenport RD. Transfusion-related acute lung injury: femme fatale? Transfusion 2001; 41:312–315 Kopko PM, Paglieroni TG, Popovsky MA, et al. TRALI: correlation of antigen-antibody and monocyte activation in donor-recipient pairs. Transfusion 2003; 43:177–184 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; 27:96 – 100 Boshkov LK. Transfusion-associated acute lung injury (TRALI): an evolving understanding of the role of antileukocyte antibodies. Vox Sang 2002; 83(suppl 1):299 –303 Win N, Montgomery J, Sage D, et al. Recurrent transfusionrelated acute lung injury. Transfusion 2001; 41:1421–1425 Nishimura M, Mitsunaga S, Ishikawa Y, et al. Possible mechanisms underlying development of transfusion-related acute lung injury: roles of anti-major histocompatibility complex class II DR antibody. Transfus Med 2003; 13:141–147 Santamaria A, Moya F, Martinez C, et al. Transfusion-related acute lung injury associated with an NA1-specific antigranulocyte antibody. Haematologica 1998; 83:951–952 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; 29:25–27 Janatpour K, Holland PV. Noninfectious serious hazards of transfusion. Curr Hematol Rep 2002; 1:149 –155 Nouraei SM, Wallis JP, Bolton D, et al. Management of transfusion-related acute lung injury with extracorporeal cardiopulmonary support in a four-year-old child. Br J Anaesth 2003; 91:292–294 Levy GJ, Shabot MM, Hart ME, et al. Transfusion-associated noncardiogenic pulmonary edema: report of a case and a warning regarding treatment. Transfusion 1986; 26:278 –281 Statement of the American Association of Blood Banks before the Blood Products Advisory Committee, June 14, 2001. Transfusion-related acute lung injury (TRALI). Available at: www.aabb.org/pressroom/press releases/ prbpac061501.htm. Accessed September 13, 2004 Hebert PC, Fergusson D, Blajchman MA, et al. Clinical outcomes following institution of the Canadian Universal Leukoreduction Program for Red Blood Cell Transfusions. JAMA 2003; 289:1941–1949 Corwin HL, AuBuchon JP. Is leukoreduction of blood components for everyone? JAMA 2003; 289:1993–1955 McFarland JG. Platelet and neutrophil alloantigen genotyping in clinical practice. Transfus Clin Biol 1998; 5:13–21 Fung YL, Goodison KA, Wong JK, et al. Investigating transfusion-related acute lung injury (TRALI). Intern Med J 2003; 33:286 –290
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
Although the blood supply has become safer with regard to transmission of infectious agents, attention should continue to focus on understanding and eliminating the other serious risks associated with transfusion. Transfusion-related acute lung injury (TRALI) is one such risk, only recently becoming recognized as an important and potentially preventable clinical syndrome. Strategies for prevention of TRALI, however, must rely on knowledge regarding its etiology and diagnosis, and significant gaps in our understanding of the syndrome currently exist. This review summarizes what is known and unknown about the incidence, severity, etiology, diagnosis, and prevention of TRALI and the potential consequences of these knowledge gaps. (CHEST 2005; 128:598S– 604S) Key words: diagnosis; etiology; transfusion-related acute lung injury Abbreviations: ALI ⫽ acute lung injury; FDA ⫽ Food and Drug Administration; FFP ⫽ fresh-frozen plasma; HLA ⫽ human leukocyte antigen; HNA ⫽ human neutrophil antigen; IL ⫽ interleukin; IVIG ⫽ IV immune globulin; TRALI ⫽ transfusion-related acute lung injury; WB-PLT ⫽ whole blood-derived platelet Learning Objectives: 1. To review the incidence and current theories regarding the pathogenesis of transfusionrelated acute lung injury. 2. To understand the rationale and consequences of donor deferrals as a means to prevent transfusion-related acute lung injury.
acute lung injury (TRALI) is a T ransfusion-related well-characterized and serious adverse consequence of blood product transfusion.1 The reported incidence of TRALI indicates it is rare, although its overall occurrence is almost certainly more common than the oft-quoted estimate of one case in 5,000 U of blood transfused,2 and it is among the two leading causes of death resulting from transfusion.3 Cases of TRALI have gone unrecognized or misdiagnosed, since the symptoms can be confused with other transfusion-related events such as anaphylaxis, hemolysis, or circulatory overload, or with non-transfu*From the Department of Anesthesiology and Critical Care Medicine (Dr. Shander), Englewood Hospital and Medical Center, Englewood, NJ; and Haemonetics Corporation (Dr. Popovsky), Braintree, MA. This publication was supported by an educational grant from Ortho Biotech Products, L.P. The following authors have disclosed financial relationships with a commercial party. Grant information and company names appear as pprovided by the author: Aryeh Shander, MD, FCCP: Ortho Biotech - Speaker bureau. The following authors have indicated to the ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in their article: Mark A. Popovsky, MD. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Aryeh Shander, MD, FCCP, Chief, Department of Anesthesiology and Critical Care Medicine, Medical Director, New Jersey Institute for the Advancement of Bloodless Medicine and Surgery, Englewood Hospital and Medical Center, 350 Engle St, Englewood, NJ 07631; e-mail: [email protected] 598S
sion-related comorbidities such as cardiac failure.4,5 Suspected cases of TRALI may be insufficiently investigated,6 and mild or moderate cases may not be investigated or reported at all. Virtually all blood products have been implicated, and controversies exist as to whether the etiology of TRALI is mediated by antibodies, lipids, or a combination of both.7 Donor as well as recipient factors have been implicated in the pathogenesis of TRALI, but the relative importance of each is unknown. This lack of knowledge thwarts the clinician’s ability to identify cases and to manage patients with TRALI who require further blood product support. Strategies to prevent TRALI through blood screening and/or donor deferral could be better formulated if the syndrome were more clearly understood. The rationale and consequences of donor restrictions or lack thereof have been deliberated by regulatory bodies over the last several years and, recently, at a consensus conference in Canada. Following a brief review of the syndrome, its incidence, and the blood products implicated, this article will focus on major areas of medical and scientific dissent concerning the etiology, diagnosis, and prevention of TRALI. The TRALI Syndrome: Definition, Incidence, and Severity TRALI can be defined as an uncommon complication of allogeneic blood transfusion typically man-
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
ifested by bilateral pulmonary edema, dyspnea, hypoxemia, fever, and hypotension in the presence of normal cardiac function.2,4 The time frame of symptom onset helps to identify the syndrome, as symptoms occur during or shortly after transfusion, usually within 1 to 2 h, but always within 6 h. Details about the pathophysiologic mechanisms of TRALI have been reviewed by others.8,9 Its clinical presentation is identical to ARDS,2,10 with at least two important exceptions. First, mortality resulting from TRALI is often approximated at 5 to 10%,2,9,11 occasionally higher (50%),12 but mostly well below the 40 to 70% mortality estimates associated with ARDS.13 Second, in contrast to ARDS, in which lung injury can be irreversible, TRALI is generally transient, with Po2 levels returning to pretransfusion levels within 48 to 96 h.1 The often quoted incidence rate of TRALI is 0.02%/U averaged over all blood products, or 0.16% per patient transfused.2 Because TRALI has previously been underrecognized and underreported, its actual incidence is unknown.1,4 Most types of blood products have been implicated as having caused TRALI. Among cellular products, random donor (0.2%) or whole blood-derived platelet (WB-PLT) transfusions (0.3%) are the most frequently named (Table 1). TRALI occurs after administration of one case in approximately 4,000 U of packed RBCs, ie, approximately one tenth as often as with platelet transfusions. The first case of TRALI after infusion of allogeneic bone marrow cells in a patient with acute lymphoblastic leukemia has recently been doc-
umented.14 Fresh-frozen plasma (FFP) has the lowest rate of reported TRALI events per unit transfused (0.005 to 0.013%), so it seems paradoxical that blood products containing as little as 10 to 60 mL of plasma have the capacity to induce a pulmonary reaction.1 Plasma derivatives manufactured from pooled donors (eg, albumin, clotting factor concentrates) have largely not been implicated, with the exception of a few case reports of TRALI after infusions of cryoprecipitate and IV immune globulin (IVIG).15,16 With regard to its severity, most patients experiencing TRALI have a good prognosis, especially when pulmonary infiltrates and hypoxemia resolve quickly.9 In the opinion of some investigators,4 the severity of the pulmonary reaction in TRALI can be determined by the degree of fluid exudation. In a randomized crossover trial of plasma transfusion from never-pregnant/never-transfused donors (control subjects) vs multiparous (three or more live births) donors (experimental), an acute decrease in the Pao2/fraction of inspired oxygen ratio was seen following experimental but not after control transfusion. This led the authors17 to speculate that some impairment of lung function is induced by plasma from multiparous donors, although it may be subclinical in most cases. Although mortality and morbidity resulting from TRALI are known to be lower than ARDS, TRALI has the potential to be severe, as illustrated by several examples from the medical literature. A report12 from one hospital indicated that TRALI was the most common serious adverse effect of blood transfusion; 10 of the 11 cases reported
Table 1—Incidence/Prevalence of TRALI With Various Blood Transfusion Products Product Type All components All cellular components Packed RBCs Plasma (FFP) From multiparous donors From a single donor implicated in a TRALI fatality Platelets (random donor) Whole blood-derived platelets Apheresis platelets Platelet concentrates and/or RBCs Preuniversal leukodepletion Intermediate leukodepletion* After universal leukodepletion IVIG Cryoprecipitate Allogeneic bone marrow stem cells Granulocytes
Reported Occurrence 1 1 1 1 1 1 1 1 1
in in in in in in in in in
Source 10
1,323 U 5,408 U 1,120 U 2,000 U 4,410 U 19,411 U 7,900 U 200 U 3 patients exposed
Silliman et al, 2003 Popovsky and Moore,2 1985 Silliman et al,10 2003 Silliman et al,18 1997 Silliman et al,10 2003 Silliman et al,10 2003 Wallis et al,12 2003 Palfi et al,17 2001 Kopko et al,4 2002
1 in 317 U 1 in 432 U 1 in 1,224 U
Clarke et al,21 1994 Silliman et al,10 2003 Silliman et al,10 2003
Approximately 1 in 4 patients with transfusion reaction Approximately 1 in 11 patients with transfusion reaction Approximately 1 in 32 patients with transfusion reaction Single case report Single case report Single case report 2 case reports
Yazer et al,20 2004 Yazer et al,20 2004 Yazer et al,20 2004 Rizk et al,15 2001 Reese et al,16 1975 Urahama et al,14 2003 O’Connor et al,22 1998; Sachs and Bux,19 2003
*After universal leukodepletion of platelet concentrates but before universal depletion of RBCs. www.chestjournal.org
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required mechanical ventilatory support and five persons died. Wallis et al12 even postulated that the transfusion-related syndrome may involve damage to extrapulmonary vasculature in addition to the wellrecognized pulmonary insult. In another report from Davoren and colleagues,23 death occurred within 24 h after the onset of respiratory symptoms in two patients who acquired ARDS and hypotension followed by fulminant pulmonary edema necessitating mechanical ventilation. Since patients who receive transfusions tend to be quite ill, even if TRALI alone is benign it has the potential to exacerbate any comorbidities. For example, development of ARDS with a high degree of fatality was noted in a heavily transfused population after liver transplantation.24 In another study,25 the number of blood products transfused was an important predicting factor for ARDS development following cardiac surgery. Finally, incorrect diagnosis of unsuspected TRALI and inappropriate management with ultrafiltration in a patient with end-stage renal disease may have worsened her condition.26 The relative contribution of TRALI— or of its improper management—to worsening outcomes in other severe illnesses should be systematically investigated. Etiology of TRALI As summarized in Table 1, TRALI results mainly from administration of platelets, but RBCs, granulocytes, plasma, cryoprecipitate, IVIG, and bone marrow stem cells have also been implicated. Studies9,27 on the immunologic side effects of blood transfusions are scarce, and many aspects of TRALI etiology are poorly understood or controversial. Animal models suggest that lung injury results from two independent events, neutrophil priming and activation, mediated by separate agents.28 The hypothesis of TRALI pathogenesis involves two “hits,” one derived from stored blood (donor factors), and the other from the clinical condition of the patient (recipient factors),28 but the order of the hits, the precise donor-recipient factors, or their relative importance have not been clearly established. Subsequent to its inception, the hypothesized mechanism evolved to include transfusion with a blood component containing either antibodies to WBC and/or lipid-priming agents.29 Antibodies Antibodies are the major postulated donor factors in the pathogenesis of TRALI and are believed to be the source in 90% of TRALI cases.26 In one of the first reports2 describing the TRALI syndrome, antigranulocyte antibodies were implicated in the donor 600S
plasma of 89% of 36 cases; anti-human leukocyte antigen (HLA) class I antibodies were detected in 72%. Another study4,30 evaluating the risk of receiving blood components in renal transplant recipients found that 22% of blood components tested contained HLA alloantibodies, including both anti-HLA class I and anti-HLA class II types. In an investigation23 of two fatal TRALI cases, granulocyte antibodies with weak specificity were detected using flow cytometry; and using a granulocyte agglutination test, strong antibodies specific for human neutrophil antigen (HNA)-3a (5b) were identified from two separate donors. Testing donors for HLA class II antibodies as well as HLA class I and granulocyte antibodies has been recommended to be part of any investigation of suspected TRALI.31 The prevalence of HLA sensitization correlated strongly with the number of pregnancies in a study of 332 women with a history of ⬎ 9,000 plateletpheresis donations.32 For this reason, multiparous female donors (two or more pregnancies) of plasma-rich blood components are believed to harbor an increased potential for inducing TRALI in those who receive blood products.23,32 Granulocyte antibodies with strong HNA-3a (5b) reactivity but no HLA antibodies were implicated in a TRALI case following infusion of single donor platelets from a multiparous female donor.33 A similar, strong pattern of granulocyte 5b antigen positivity was present in the multiparous donor who triggered a look-back investigation by Kopko and colleagues4 subsequent to a TRALI death. Popovsky and Davenport34 noted that in up to 15% of cases, neither anti-HLA nor antigranulocyte antibodies can be found in the donor or the recipient. In the randomized crossover study17 of transfusion with plasma from multiparous donors vs neverpregnant/never-transfused donors described above, one case of typical TRALI was noted following transfusion from the multiparous donor who was IgG granulocyte antibody positive; however, the compatibility test result between donor plasma and recipient granulocytes was negative. At least one report35 suggests that antimonocyte antibodies also contribute to the development of TRALI, and anti-IgA antibodies may also be involved.36 Antibodies and their link to TRALI are incompletely understood at present. Perhaps the most compelling argument against a strict antibody hypothesis underlying TRALI etiology is the poor correlation of TRALI frequency with the amount of plasma in the transfused product.37 The screening of all donors for all specific antibodies with the intent of eliminating them from the donor pool to prevent TRALI may be a costly, premature, and ultimately futile undertaking.
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
Lipids and Cytokines With Polymorphonuclear Lymphocyte-Priming Capability
establish a definitive link between these cytokines and the etiology of TRALI.
As noted above, not all studies implicate antibodies as the sole underlying cause of TRALI. Silliman and colleagues18 studied 10 patients with TRALI and 10 patients who had febrile or urticarial transfusion reactions but no lung involvement (control subjects). The patients with TRALI all had underlying clinical factors: infection, cytokine administration, recent surgery, or massive transfusion, compared with only 2 of 10 control patients who had such factors. None of the donors had significant titers of HLA or HLA-DR antibodies, and only 50% had weak positivity for granulocyte antibodies. These authors18 were the first to hypothesize that two events might be required to precipitate TRALI, one of which involves polymorphonuclear lymphocyte-priming activity. This priming activity, hypothesized to be the result of predisposing factors (recent surgery, infection or inflammation, massive transfusion, cytokine therapy) was noted to be a necessary but not sufficient component to induce TRALI. Lipids comprised of lysophosphatidylcholine moieties present in stored blood were implicated as the second insult, although leukoagglutinins and/or cytokines were also acknowledged as possible secondary contributors. Infusion of older platelets emerged as a significant risk factor in a more recent investigation conducted by Silliman et al.10 In the prospective portion of that study, the amount of lipid-priming activity (neutral lipids and lysophosphatidylcholine) was higher in implicated WB-PLT units compared to control units. Some believe that this lipid-priming activity may be an even more important etiologic factor than antileukocyte antibodies. Win and colleagues,38 investigating a case of recurrent TRALI in a single patient, also noted that biologically active lipids accumulate during storage of RBCs and platelets and may have been a predisposing factor in the second episode, together with the patient’s underlying pulmonary condition (ie, recovering from lung injury). The first episode was believed to be due to the action of HLA-A2 and granulocyte-specific IgM antibodies. Among inflammatory mediators, an in vitro investigation39 of three cytokines (tumor necrosis factor-␣, interferon-␥, and interleukin [IL]-18) after an anti-major histocompatibility class II DR monoclonal antibody challenge suggested that these cytokines may contribute to inflammatory reactions in the lungs. Involvement of polymorphonuclear lymphocytes in IgE-mediated immune reactions was also cited. In another study,10 IL-6 and IL-8 levels were found to be elevated in WB-PLT units after 5 days of storage, but data were not convincing enough to
Postulated Recipient Factors
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In addition to donor factors, a recipient of blood products may be predisposed to sustain a severe pulmonary reaction. Contributing to lung injury in approximately 5 to 20% of cases is the presence of antibodies in recipient serum.2,19 Anti-HLA-A2 antibodies were identified in a patient with acute myeloblastic leukemia who had an episode of TRALI following each of two granulocyte infusions.19 Santamaria et al40 described a case of TRALI following RBC transfusion associated with an antigranulocyte antibody with NA1 specificity in the patient’s serum. In addition to a recipient’s immunologic status, one of the etiologic factors for TRALI in the “twohit” hypothesis involves the clinical condition of the patient. Silliman et al10 conducted a nested casecontrol study to investigate which preexisting conditions or factors correlated with TRALI risk. Patients with hematologic malignancies and cardiac disease were at significantly higher risk for TRALI, whereas age, ABO compatibility of recipient and donor blood groups, history of prior transfusions, and number of previous transfusion reactions were not predictive. Prior vascular surgery or hemodialysis may have been the sensitizing event in a case report of TRALI described by Guglin et al26 in a patient with endstage renal failure. Finally, little is known about the impact of concurrent treatment of comorbid disease on the development of TRALI. The first reported case of immunotherapy leading to TRALI occurred in a patient who received high-dose IL-2 as treatment for metastatic renal cell carcinoma, in which IL-2 was speculated to have been the first insult and transfusion of platelet concentrate the second.41 These reports underscore the fact that identifying patients at risk for TRALI is still challenging. Diagnosis of TRALI An appropriate diagnosis of TRALI is the key to treatment and may prevent additional reactions, not only in the same patient (who may be susceptible and receive a subsequent transfusion), but quite possibly in other patients who receive blood from a high-risk donor.42 In the look-back investigation requested by the US Food and Drug Administration (FDA) to investigate a transfusion-related fatality, Kopko et al4 found that TRALI is considerably underdiagnosed, primarily due to superimposed illnesses. The clinical presentation of dyspnea, hypoxemia, hypotension, fever, bilateral pulmonary infiltrates, and normal cardiac function2,33 can easily be CHEST / 128 / 5 / NOVEMBER, 2005 SUPPLEMENT
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mistaken for other clinical conditions.42 Both TRALI and transfusion-associated circulatory overload present with dyspnea, but other signs and symptoms aid the proper diagnosis.5 A notable example is acute pulmonary edema following blood transfusion in a dialysis-dependent patient, which does not always signify fluid overload. Nephrologists were cautioned to be aware of the alternative diagnosis of TRALI to facilitate a proper diagnosis and appropriate management.26 Because the diagnosis of TRALI has typically required a serologic confirmation, it has been suggested that the high numbers of TRALI cases associated with antibodies may just reflect a reporting bias.9 Nevertheless, in addition to a clinical diagnosis, a comprehensive laboratory and serologic workup of any suspected case of TRALI is advisable. Table 2 summarizes the tests that should be considered, keeping in mind that no consensus or algorithm is yet available. It is unclear whether crossmatching procedures should be universally implemented prior to transfusion in an attempt to avert lung injury induced by antibodies in the serum of the recipient.19 Testing for selected cytokines or lipids is probably not currently warranted, but because cytokines and lipids that accumulate in stored blood products are under suspicion,28 the age of blood product transfused should be documented and included in any TRALI case report. Management of TRALI The mainstay of TRALI management involves hemodynamic and ventilatory support,9 and Nouraei et al43 has pointed out the potential utility of extracorporeal oxygenation for short durations in severe cases. Other, less well-documented and unproven
Table 2—Laboratory Investigation and Documentation of Suspected TRALI Episode* General ABO typing CBC count Direct antiglobulin test Blood cultures to rule out infection Biologic response modifiers (cytokines: IL-6, IL-8, others)? Plasma lipids? Cross-match? Antibodies (previously implicated in parenthesis) Anti-HLA class I (A2, A9, B13, B27) Anti-HLA class II (DR3/5/6 CRG, DR1, DR4)† Antigranulocyte (anti-HNA1, anti-HNA2, anti-HNA3a, ⫺ 5b, anti-HNB1, anti-HNB2, ⫺9a) Antimonocyte (HLA-II) Anti-IgA (not specified) *Information compiled from previously published data.6,9,12,28,36 †CRG ⫽ cross-reactive group (includes DR17). 602S
therapies (eg, corticosteroids, prostaglandin E1) were noted in the comprehensive review of Webert and Blajchman.9 Although diuretics have been used, they are said to have no role in TRALI treatment.44 As in the case of the patient with TRALI and renal failure treated with ultrafiltration,26 an incorrect diagnoses may lead to inappropriate management. Thus, attention to underlying disorders and the potential for condition/syndrome interactions is of paramount importance. Scant information exists about management of future transfusions in patients with documented TRALI. Blood products from the same donor should clearly be avoided, but little else can be recommended with certainty. In one case report38 of a patient with recurrent TRALI, the sera from donors implicated in the second episode contained no granulocyte- or lymphocyte-specific antibodies, and forward and reverse cross-matching with recipient sera were negative. These observations cast doubt on whether TRALI can be effectively prevented even if the laborious task of cross-matching is dutifully performed. Prevention of TRALI Largely responsible for defining the syndrome in 1985, Popovsky and Moore2 stressed the importance of awareness in medical practice and urged blood banks to identify donors whose plasma is linked to TRALI cases in order to prevent recurrence. Whether donor deferral is a worthwhile strategy to prevent TRALI is a topic of debate. Wallis et al12 suggested that multiparous women should be excluded from donation of plasma-rich components, since many of the cases of TRALI observed in their institution were traceable to HLA class I or class II antibodies. In contrast, despite an observed correlation of pregnancies with HLA-sensitization and the acknowledgment that multiparous women donors add risk, Densmore et al32 argued that exclusion of multiparous plateletpheresis donors would eliminate one third of the female donor pool and was not justified. These differences of opinion are reflective of the discrepant regulatory approaches currently employed around the world. For example, Austria requires their hospitals to report each presumed TRALI case; once confirmed, donors are deferred from subsequent donations (personal communication; A. Hofmann; April 19, 2004). A spokesperson for America’s Blood Centers indicated that the United Kingdom has opted to make FFP only from male donors, but no individual State in the United States has taken any action to limit the impact of TRALI since blood safety and efficacy are regulated by the FDA (personal communication; S. Pavlovsky;
Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management
April 20, 2004). In 2001, a memo issued by the American Association of Blood Banks stated there was general agreement that blood from a donor implicated in TRALI should never again be transfused to the same patient, although the American Association of Blood Banks acknowledged that the issue of permanent deferrals of implicated donors was less clear.45 The FDA has not yet mandated donor deferrals, but representatives from US and Canadian blood collection agencies, regulatory bodies, and research sponsors met in Canada in April 2004 to further discuss the topic. Leukoreduction is yet another preventative measure that has been investigated and discrepant results found. In one study,20 TRALI reactions were significantly reduced by prestorage WBC reduction. In another study,10 prestorage WBC reduction was ineffective in inhibiting TRALI. Leukoreduction is currently mandated in Canada46 and throughout most of Europe but not in the United States, where its merits are still being debated.47 Patient screening and history as well as performing a cross-match procedure may or may not be helpful in preventing TRALI. Examples may be found in which TRALI occurred despite negative cross-match results.38 Sachs and Bux19 noted that additional data are required to determine whether cross-matching granulocyte transfusions as a regular practice would be of benefit. In the future, molecular biological techniques such as identifying platelet alloantigens and their underlying nucleic acid polymorphisms on platelet glycoprotein genes48 might help to advance the field. Prompt investigations of TRALI episodes would help facilitate appropriate management of implicated donations and donors in order to minimize the future occurrences. Clinicians play a vital role in reporting TRALI cases, and the role of hospital blood banks in collecting appropriate samples is likewise critical. Fung and colleagues49 urged hospital blood banks to retain transfused donated units for at least 24 h after transfusion to expedite TRALI investigations. Due to the highly technical nature of the investigation, these investigators suggested using specialized neutrophil testing services.
New Working Definition of TRALI Recently, a Canadian-sponsored international consensus conference dealt with a number of issues related to TRALI. From this meeting, a new working definition of TRALI emerged: in patients with no acute lung injury (ALI) prior to transfusion, the diagnosis of TRALI is made for the following: (1) new ALI characterized by acute onset, hypoxemia, www.chestjournal.org
bilateral lung infiltrations on the chest radiograph, and no evidence of circulatory overload; (2) occurrence during transfusion or within 6 h of completion; and (3) no other risk factor for ALI. A complete report relating to this and other topics discussed during the Canadian TRALI consensus conference is pending.
Conclusions/Recommendations There is a clinical need for additional basic and clinical research to improve our understanding, diagnosis, reporting, and management of TRALI. On the basis of this research, better strategies might be designed and implemented to ensure that the patients who receive transfusions are not at risk to experience this potentially fatal complication. Without a clearer understanding of the etiology of TRALI, restrictions on donors may either be inappropriately or prematurely enforced.
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Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management