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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorsSteven Kleinman, MDDaryl J Kor, MD

Section EditorsArthur J Silvergleid, MDScott Manaker, MD, PhD

Deputy EditorJennifer S Tirnauer, MD

Transfusion­related acute lung injury (TRALI)

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Dec 15, 2014.

INTRODUCTION — Transfusion­related acute lung injury (TRALI) is a rare but potentially fatal complicationof blood product transfusion. TRALI has been defined by both a National Heart, Lung, and Blood Institute(NHLBI) working group as well as a Canadian Consensus Conference, as new acute lung injury (ALI)/acuterespiratory distress syndrome (ARDS) occurring during or within six hours after blood product administration(table 1) [1,2]. When a clear temporal relationship to an alternative risk factor for ALI/ARDS coexists, aformal diagnosis of TRALI cannot be made. In these circumstances, the diagnostic terminology to be used is"possible TRALI."

Prior to the institution of TRALI risk mitigation strategies, plasma components and apheresis plateletconcentrates conferred the highest risk of TRALI per component. Currently, due to transfusion of a muchlarger number of red cell units compared with plasma and platelets, the largest number of TRALI­relateddeaths in the United States and other developed countries occur with red blood cell transfusion [3]. (See'Prevention' below.)

The epidemiology, pathogenesis, risk factors, clinical features, management, and prevention strategies forTRALI are presented here. General issues related to blood transfusion, other reactions to transfusiontherapies, and general issues related to acute lung injury are discussed separately.

EPIDEMIOLOGY — Historical estimates suggest that TRALI occurs at a rate of approximately 0.04 to 0.1percent of transfused patients or in approximately 1 in 5000 transfused blood components [4­7]. However,the true incidence of TRALI is not known, largely due to poor syndrome recognition, the reliance on passivereporting rather than active surveillance strategies, and the inclusion of cases that did not meet the NHLBI orCanadian Consensus Conference definitions of TRALI in some reports [3,8­11]. Additionally, due to thecontribution of specific recipient risk factors, TRALI incidence is also likely to depend on the population ofinterest. As an example, estimates suggest that the rate of TRALI in critically ill populations may reach 5 to 8percent [12,13]. (See 'Recipient risk factors' below.)

Importantly, the incidence of TRALI has decreased dramatically following the institution of TRALI mitigationstrategies for transfused plasma and platelet components that were instituted in the mid to late 2000s. (See'Prevention' below.)

As an illustration of this, TRALI cases were identified using a prospective systematic method at a rate of0.0081 percent (ie, 1 in 12,345) in the year 2009 [14,15]. This was substantially lower than the incidence rateof 0.0257 percent (ie, 1 in 3891) in the year 2006, determined with the same case detection strategies[14,15]. Even though case surveillance in this study was active and prospective, under­reporting still mayhave occurred, as has been the case with other published estimates [6].

TRALI is the leading cause of transfusion­related mortality in the United States [3]. Historical estimates forTRALI–associated mortality have ranged from 5 to 8 percent [16]. However, evidence from large

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(See "Immunologic blood transfusion reactions".)(See "Transfusion reactions caused by chemical and physical agents".)(See "Noncardiogenic pulmonary edema".)(See "Acute respiratory distress syndrome: Clinical features and diagnosis in adults".)(See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology inadults".)

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hemovigilance networks suggests higher mortality rates in the range of 13 to 21 percent [8,17­19]. Notsurprisingly, the mortality rate for TRALI/possible TRALI in critically ill populations appears substantiallyhigher, in the range of 35 to 58 percent [12,13].

RISK FACTORS — Specific risk factors for TRALI can be divided conceptually into recipient risk factors andblood component risk factors.

Recipient risk factors — TRALI has been reported to occur in essentially all age groups and equally in bothsexes [20­22]. The presence of an underlying condition such as recent surgery, cytokine treatment, massiveblood transfusion, and active infection have been implicated in some, but not all, studies [4,17,18,21,23­28].The critically ill appear to be at highest risk for TRALI [12,13,29].

Studies evaluating TRALI risk factors are limited by a relatively small number of TRALI cases available foranalysis and the use of varied diagnostic criteria. The following studies are illustrative of the available data:

A multicenter prospective cohort investigation using active surveillance strategies for TRALI detectionidentified recipient risk factors for TRALI in 89 cases compared with 164 matched transfused controls [15].The following pre­transfusion TRALI risk factors were identified:

In a nested case­control study evaluating patients in an intensive care unit (ICU) for more than 48 hours, riskfactors for TRALI/possible TRALI included emergency cardiac surgery, hematologic malignancy, massivetransfusion, sepsis, mechanical ventilation, and a high Acute Physiology and Chronic Health Evaluation II(APACHE II) score [12]. In another study evaluating critically ill patients in a medical ICU, sepsis, liverdisease, and a history of alcohol abuse were more common in transfusion recipients who developedTRALI/possible TRALI than in transfused controls without respiratory compromise [13]. A Medicare databasereview (over 11 million patients, 2556 with a TRALI diagnosis code) identified modestly higher rates ofTRALI in recipients of platelet or plasma­containing products rather than red blood cells; females versusmales; whites versus non­whites; and individuals with postinflammatory pulmonary fibrosis, smoking, orother medical illnesses in the prior six months [28].

Blood component risk factors — Virtually all blood components have been associated with TRALI. Thisincludes transfused whole blood derived platelets, cryoprecipitate [4], and granulocytes [30], as well asintravenous immunoglobulin preparations [31­33], and allogeneic stem cells [2,16,23,34].

Liver transplantation surgeryChronic alcohol abuseShockHigher peak airway pressure while being mechanically ventilatedCurrent smokingHigher interleukin (IL)­8 levelsPositive fluid balance

Donor gender and high­plasma­volume blood components — Though TRALI has been associatedwith virtually all blood products, high­plasma­volume components such as plasma, apheresis plateletconcentrates, and whole blood have been consistently shown to carry the greatest risk per componentor per transfusion episode [8,11,18,35]. The volume of plasma passively infused that results in TRALIis unknown, but may be as small as 10 to 20 mL [36]. Further studies have demonstrated a role forfemale sex and increased parity of the donor in the risk for TRALI [15,37­39]. The role of these factorswas illustrated in a multicenter prospective cohort investigation utilizing active TRALI surveillancestrategies, which identified the following donor/blood component risk factors for TRALI [15]:

Plasma or whole blood from female donors•

Increased volume of highly reactive transfused anti­human leukocyte antigen (HLA) Class IIantibody with specificity for a cognate recipient HLA antigen (ie, antibodies for which the recipienthad the corresponding HLA antigen)

•

Increased volume of transfused anti­human neutrophil antigen (HNA) antibody [15]•

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PATHOGENESIS — The generally accepted theory for TRALI pathogenesis is that it occurs via a two­hitmechanism [4,45,46].

Clinical observations supporting the two­hit theory come from retrospective studies demonstrating that mosttransfused blood products containing HLA antibody do not cause TRALI, even if a cognate recipient antigenis present [53]. In retrospective studies, TRALI was detected in only 2.9 percent of individuals who receivedblood products from donors previously implicated in causing TRALI [40,53­56].

In one case of fatal TRALI, the implicated donor was a multiparous female who had made 290 previousplasma apheresis donations [9]. Of 36 patients who had received her plasma in the prior two years, 15experienced transfusion reactions with pulmonary symptoms, and 21 (58 percent) did not, again highlightingthat factors from the transfusion alone are insufficient to cause TRALI. In this case, the donor had antibodiesagainst a leukocyte antigen (HNA­3a) present in more than 95 percent of the general population that hasbeen associated with severe often fatal TRALI cases [57]. In another case, TRALI occurred in a recipient ofa single lung transplant only in the transplanted lung, and one of the blood products the donor receivedcontained anti­HLA Class I antibodies that matched an HLA antigen present only in the transplanted lung[58].

The proportion of TRALI caused by antibodies versus BRMs remains undetermined and is likely to vary bythe type of component transfused, with antibody­mediated mechanisms explaining the majority of the casesdue to plasma, and non­immune BRMs responsible for most cases from red blood cell transfusion[18,59,60]. The widely stated statistic that 80 to 85 percent of TRALI cases are due to the antibody­mediatedmechanism is likely influenced by publication bias [61]. Of note, a case series comparing BRM­mediatedTRALI with antibody­mediated TRALI suggests that BRM­mediated TRALI is a less severe condition [46].

A second model related to the two­hit theory is the threshold model. This model agrees that two hits areusually necessary for TRALI, but allows for the possibility that in some cases the second hit is so strong that

The presence of non­cognate anti­HLA Class II antibodies, weaker cognate anti­HLA Class IIantibodies, or any anti­HLA Class I antibody were not associated with TRALI in this study.However, other case reports suggest that anti­HLA Class I antibodies can cause TRALI [8,40].

Red blood cell storage duration — Although a longer duration of red blood cell storage has beensuggested to increase the risk of TRALI, two randomized clinical trials and two large observationalstudies have not confirmed this association [15,41­44]. In aggregate, the available evidence suggeststhat the duration of red blood cell storage is not a major risk factor in the development and/or severityof TRALI.

Neutrophil sequestration and priming – The first hit involves neutrophil sequestration and priming inthe lung microvasculature, due to recipient factors such as endothelial injury. Priming refers to shiftingof neutrophils to a state where they will respond to an otherwise innocuous or weak signal [47].Endothelial cells are thought to be responsible for both the neutrophil sequestration (through adhesionmolecules) and priming (through cytokine release). Generally these events are coupled and exist priorto the transfusion, although there may be circumstances in which they can occur as a result of thetransfusion. (See 'Recipient risk factors' above.)

Neutrophil activation – The second hit is activation of recipient neutrophils by a factor in the bloodproduct. Activation is associated with the release from neutrophils of cytokines, reactive oxygenspecies, oxidases, and proteases that damage the pulmonary capillary endothelium. This damagecauses inflammatory (non­hydrostatic) pulmonary edema. Transfused factors responsible for hostneutrophil activation can include antibodies in the blood component directed against recipient antigens,or soluble factors such as bioactive lipids that can activate neutrophils. Donor anti­leukocyte antibodiescan bind to antigens on recipient neutrophils or possibly to other cells such as monocytes or pulmonaryendothelial cells; this is referred to by some authors as immune TRALI [48­52]. Bioactive lipids andother soluble factors in the transfused blood component can act as biological response modifiers(BRMs); TRALI resulting from these non­antibody BRMs is sometimes referred to as non­immuneTRALI [46]. (See 'Blood component risk factors' above.)

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an initial priming event is not required [46,62,63]. This theory explains TRALI cases that have occurred inotherwise healthy individuals who have received fresh frozen plasma (FFP) as a treatment for reversingwarfarin anticoagulation.

Several observations support the role of neutrophils as the major effector cells in TRALI. Neutrophilactivation occurs in animal models of TRALI [64­69]. Transient neutropenia indicative of pulmonarysequestration has been seen in patients in the early phase of TRALI, whereas TRALI is rarely seen inneutropenic patients [40,70­74]. In an autopsy case, postmortem examination within two hours of TRALIonset revealed aggregates of neutrophils within the pulmonary capillaries associated with inflammatoryedema and endothelial injury [75].

Multiple mechanisms of neutrophil activation in TRALI have been proposed. As an example, antibodies tohuman leukocyte antigen (HLA) Class I and human neutrophil antigens (HNA) may bind to recipientneutrophils and trigger their activation [62,63,76,77]. It has been known for years that female donors, due toexposure to fetal alloantigens during pregnancy, have a much higher prevalence of anti­HLA antibodies thando male donors [78,79]. While anti­HNA antibodies account for only a small percentage of TRALI cases frommost countries (<5 percent), in Germany these constitute a higher percentage (28 percent in one series)[19]. Antibodies directed against the HNA 3a antigen have been associated with a substantial number ofsevere or fatal TRALI cases [80,81].

TRALI can also be associated with donor antibodies directed against HLA Class II, which is primarilyexpressed on antigen­presenting cells [47,63]. These antibodies may bind to HLA Class II antigens onmonocytes, causing release of cytokines that in turn activate primed neutrophils [77,82­84].

When the second hit for neutrophil activation is a biological response modifier (BRM) rather than anantibody, the BRM is believed to activate neutrophils directly. Most of the work implicating these substanceshas come from in vitro and animal studies, and has implicated lysophosphatidylcholines (from white bloodcells and platelets), neutral lipids (from the breakdown of red cell membranes), and soluble CD40 ligand(which accumulates in stored platelet concentrates) in neutrophil activation [4,24,45,67,68,85­87].

CLINICAL PRESENTATION — The characteristic clinical presentation of TRALI is the sudden onset ofhypoxemic respiratory insufficiency during or shortly after the transfusion of a blood product (table 1) [1,2].Symptoms may be delayed as long as six hours, but usually begin within one to two hours of initiating theblood component infusion [1,23]. Indeed, the majority of cases occur within minutes of initiating a transfusion[4]. A number of additional signs and symptoms associated with noncardiogenic pulmonary edema andinflammation have been reported [1,18,23,73,74,88,89]. As an example, in a retrospective study of 49 TRALIcases, the most common signs and symptoms and their approximate frequencies were as follows [18]:

Other reports have also noted tachypnea, tachycardia, and elevated peak and plateau airway pressures inintubated patients. An acute, transient drop in the peripheral neutrophil count (consistent with sequestrationof large numbers of neutrophils in the lungs) has also been reported.

DIAGNOSIS — TRALI should be considered whenever a patient develops hypoxemic respiratoryinsufficiency during or shortly after transfusion of any blood product [1]. TRALI is a clinical diagnosis madeusing the criteria outlined by the NHLBI’s working group on TRALI as well as the Canadian ConsensusConference on TRALI (table 1) [1,2]. These criteria require the presence of new ALI/ARDS occurring duringor within six hours after blood product administration, documented by hypoxemia and an abnormal chestradiograph. Hypoxemia is documented when oxygen saturation is ≤90 percent on room air or the PaO2/FIO2

Hypoxemia: in an intubated patient this could manifest as a change in oxygenation or increasedoxygen requirements (100 percent, by definition)

Pulmonary infiltrates on chest radiography (100 percent, by definition; the cardiac silhouette isclassically normal)

If previously intubated, pink frothy airway secretions from the endotracheal tube (56 percent)Fever (33 percent)Hypotension (32 percent)Cyanosis (25 percent)

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ratio is <300 mmHg, although other signs of hypoxia can also satisfy this criterion. Frontal chest radiographmust demonstrate bilateral pulmonary infiltrates. (See "Noncardiogenic pulmonary edema", section on'Definition of noncardiogenic pulmonary edema' and "Acute respiratory distress syndrome: Clinical featuresand diagnosis in adults".)

When a clear temporal relationship to an alternative risk factor for ALI/ARDS coexists, a formal diagnosis ofTRALI cannot be made. In these circumstances, "possible TRALI" is the more appropriate diagnosis. Use ofthese separate diagnostic categories (ie, TRALI and possible TRALI) allows for their separate reporting insurveillance systems, which may facilitate differential approaches to donor investigation and management,as well as targeting research programs to either (or both) groups of patients. (See 'Differential diagnosis'below.)

When TRALI is suspected, the treating physician should evaluate the recipient’s vital signs, assess theextent of hypoxemia, and obtain a chest radiograph. Pulse oximetry is often sufficient, but arterial blood gasanalysis may be warranted in more severe cases. Consideration of the likelihood of other potential causesfor the respiratory distress (eg, cardiovascular compromise, anaphylaxis, sepsis, exacerbation of underlyinglung disease or atelectasis) should guide appropriate clinician­initiated laboratory testing. (See 'Differentialdiagnosis' below.)

When a transfusion reaction such as TRALI is suspected, the transfusion should be stopped immediatelyand the case should be promptly reported to the hospital transfusion medicine service/blood bank. Based onthe details of the case, the blood bank will initiate a transfusion reaction workup, which will usually includedrawing a sample from the patient for appropriate laboratory tests. These may include complete blood count,bilirubin, haptoglobin, direct antiglobulin (Coombs) test, brain natriuretic peptide (BNP) or N­terminal (NT)­Pro­BNP, and HLA antigen typing. (See "Natriuretic peptide measurement in heart failure".)

If TRALI is suspected, the blood bank will compile a list of blood products transfused within the previous sixhours and forward this list to the blood supplier. The blood supplier will then follow its procedures to recallthese donors and initiate testing for HLA and possibly HNA antibodies. However, these results will not beavailable for several weeks. Identifying the implicated donor(s) and deferring that individual from future highplasma volume donation requires cooperation between the clinician (to provide accurate clinical information),the hospital transfusion medicine service, and the blood supplier. (See 'Prevention' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of TRALI includes other conditions that canmanifest with respiratory distress following transfusion. This includes other causes of ALI/ARDS as well asother transfusion reactions. These conditions are described in more detail in the following sections.

Possible TRALI — A formal diagnosis of TRALI requires the absence of temporal relationships withadditional risk factors for ALI/ARDS, such as aspiration, pneumonia, toxic inhalation, lung contusion, trauma,burn injury, and pancreatitis. When other criteria for TRALI are met but additional risk factors for ALI/ARDSare also present (table 1), a diagnosis of TRALI cannot be made and the term "possible TRALI" is preferred.This can also be designated as TRALI with ALI risk factors. Although massive transfusion has historicallybeen recognized as a risk factor for ALI/ARDS, a diagnosis of TRALI should be made in this circumstanceprovided that no other ALI/ARDS risk factors were present.

TACO — Transfusion­associated circulatory overload (TACO) is another cause of transfusion­relatedrespiratory insufficiency. Though it is most commonly reported in elderly patients and small children, TACOcan occur in all age ranges. Additional risk factors for TACO include compromised cardiac function, positivefluid balance, and rapid blood product administration. TACO appears to occur more frequently in surgical orintensive care settings, where large fluid volumes and blood are administered. Characteristic features anddifferentiating factors for TRALI versus TACO are shown in the table (table 2) [90]. (See "Transfusionreactions caused by chemical and physical agents", section on 'Transfusional volume overload (TACO)'.)

As a general rule, TRALI is more likely to be associated with fever, hypotension, and exudative pulmonaryinfiltrates, and less likely to respond to diuresis. In contrast, TACO is more likely to be associated withfindings suggesting volume overload (eg, positive fluid balance, elevated jugular venous pressure, elevatedpulmonary artery occlusion pressure) or poor cardiac function (eg, history of congestive heart failure,reduced left ventricular ejection fraction, or diastolic dysfunction). Similarly, elevated systolic blood pressures

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near the time of dyspnea onset, a widened pulmonary vascular pedicle width or increased cardiothoracicratio on chest radiography, and/or increased circulating levels of brain natriuretic peptide (BNP) or N­terminal (NT)­Pro­BNP suggest a diagnosis of TACO rather than TRALI [91­96]. (See "Natriuretic peptidemeasurement in heart failure".)

Differentiating TRALI from TACO can be a significant challenge, particularly as both may coexist [91,97,98].In such cases, pulmonary findings may be due to a combination of hydrostatic (eg, TACO) and non­hydrostatic (eg, TRALI) lung edema. Indeed, studies show that approximately 30 percent of ALI/ARDSpatients have at least mild evidence of left atrial hypertension [99]. In these circumstances, ALI/ARDS isdiagnosed in the presence of fluid overload based on clinical judgment that the degree of fluid overload isnot sufficient to explain the extent of hypoxemia and pulmonary infiltrates. This type of mixed picture may bemore likely to occur in intensive care unit (ICU) patients.

Other causes of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) — ALI/ARDS maybe present prior to the initiation of transfusion therapies or may arise more than six hours after a transfusionepisode. In these cases, ARDS is the more appropriate diagnosis. Of note, a consensus conference hasrecommended eliminating the term ALI, which has historically described lung injury with less severehypoxemia (ie, PaO /FiO <300 but >200). Rather, it is now recommended that such cases be classified as"mild ARDS" [100]. In such cases, it is recognized that the administration of blood products may in factcontribute to ALI/ARDS development even though a formal diagnosis of TRALI cannot be made. (See "Acuterespiratory distress syndrome: Clinical features and diagnosis in adults".)

Other transfusion reactions

TREATMENT

Overview — If TRALI/possible TRALI is suspected, the transfusion should be discontinued immediately.Physicians should alert the blood bank and initiate an evaluation for a transfusion reaction. This is importantfor the protection of future recipients as well as for TRALI laboratory testing and work­up. This initialevaluation is described in more detail above. (See 'Diagnosis' above.)

Management of the patient with TRALI/possible TRALI is supportive, with oxygen supplementation for thecorrection of hypoxemia being the cornerstone of treatment. Non­invasive respiratory support withcontinuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) may be sufficient in

2 2

Hemolytic transfusion reactions – Hemolytic transfusion reactions can cause respiratory distress,but fever and chills tend to predominate in hemolytic transfusion reactions more than in TRALI.Hemolytic reactions are typically due to ABO incompatibility, and pink serum or hemoglobinuria may beseen due to intravascular hemolysis. The direct antiglobulin (Coombs) test will be positive in hemolyticreactions, but not in TRALI. (See "Transfusion­associated immune and non immune­mediatedhemolysis" and "Immunologic blood transfusion reactions", section on 'Acute hemolytic reactions'.)

Anaphylaxis – Anaphylaxis can cause respiratory distress similar to TRALI, but anaphylaxis is moreoften associated with airway signs and symptoms such as stridor, cough, wheezing, nasal congestion,and bronchospasm. Anaphylaxis is also more often associated with a new rash, gastrointestinalsymptoms such as nausea and/or vomiting, and shock. Notably, however, the latter may be seen inTRALI as well. The cause of most transfusion­associated anaphylactic reactions is unknown, but onerecognized etiology is transfusion of IgA­containing products to an IgA deficient recipient who hasantibodies to IgA. (See "Immunologic blood transfusion reactions", section on 'Anaphylactic reactions'and "Anaphylaxis: Rapid recognition and treatment".)

Sepsis – Severe sepsis and septic shock are often associated with respiratory distress, fever, andhypotension. Evidence for an active infectious process (leukocytosis, fever, positive microbiology)suggests the diagnosis of severe sepsis or septic shock rather than TRALI. Transfusion­associatedsepsis is generally associated with the administration of bacterially contaminated platelets. In this case,evaluation of the transfusion by the blood bank will typically identify a contaminating microorganism.(See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Complications ofplatelet transfusion'.)

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less severe cases, but endotracheal intubation with invasive mechanical ventilation is often required [13].The available evidence suggests that most patients who develop either TRALI or possible TRALI will requireventilatory support (approximately 70 to 80 percent) [5,12,13,101].

Ventilation — There have been no prospective clinical investigations on strategies for managingmechanical ventilation in patients with TRALI, and it is generally believed that ventilator management shouldbe guided by the same principles used in patients with other forms of ALI/ARDS [102]. The successfulapplication of more extreme life support interventions, such as extracorporeal membrane oxygenation, hasalso been described in TRALI [103]. (See "Acute respiratory distress syndrome: Supportive care andoxygenation in adults" and "Mechanical ventilation of adults in acute respiratory distress syndrome" and"Extracorporeal membrane oxygenation (ECMO) in adults".)

Hemodynamic support — Patients with TRALI often present with hypovolemia and associated hypotension[104]. The initial goal of hemodynamic management is to ensure adequate end­organ perfusion. This maybe achieved with fluid resuscitation and/or vasoactive support. Caution should be taken with early empiricadministration of diuretic therapy, as it may result in hypotension in those who were initiallyhemodynamically stable [16,105]. However, for patients with sustained hypoxemia and demonstratedhemodynamic stability, administration of diuretic therapy may be a reasonable intervention. (See "Treatmentof severe hypovolemia or hypovolemic shock in adults" and "Evaluation and management of severe sepsisand septic shock in adults", section on 'Interventions to restore perfusion'.)

Steroids — Intravenous corticosteroids have been extensively studied in the setting of ALI/ARDS withmixed results [16,106,107]. In regards to TRALI, there are isolated case reports supporting high­dosecorticosteroids in the treatment of this syndrome [16,108]. However, the efficacy of corticosteroids has notbeen tested in prospective clinical studies, and the limited anecdotal evidence is unconvincing. Thus, we donot recommend the routine use of corticosteroids when TRALI is suspected. Moreover, due to evidencesuggesting harm when initiating corticosteroids late in the course of ALI/ARDS (>14 days after syndromeonset) [16,105,109], we advise against the use of corticosteroid therapy when the lung injury is fullyestablished and has been present for more than two weeks. (See "Acute respiratory distress syndrome:Novel therapies in adults", section on 'Glucocorticoids'.)

Investigational strategies — In addition to the therapies described above, a number of additionalALI/ARDS and, by association, TRALI treatment and prevention strategies have been proposed and areunder various stages of investigation. Examples include HMG­CoA reductase inhibitors (statins) [110],aspirin [110,111], and alternatives to allogeneic blood products (eg, RBC substitutes, prothrombin complexconcentrates, fibrinogen concentrates, and activated factor VII). However, at present, none of thesetherapies has sufficient evidence to justify its use as a routine TRALI prevention or treatment measure.

Additional transfusions — Patients who recover from TRALI do not appear to be at increased risk forrecurrent episodes following transfusions from other donors; however, published experience is limited.Survivors of TRALI can receive additional blood products in the future, and transfusion of needed bloodproducts should not be withheld [16,23]. Importantly, however, individuals should not receive plasma­containing blood products from the implicated donor [112­115].

PROGNOSIS — Initial descriptions detailing the clinical course for TRALI suggested quick resolution ofhypoxemia, generally within 24 to 48 hours of symptom onset [5]. However, the majority of patients whodevelop TRALI will require ICU admission and ventilator support [12,13]. For those requiring mechanicalventilation, these early reports described a mean duration of ventilatory support lasting approximately 40hours [5]. In contrast, subsequent evidence suggests that most cases will require respiratory support for alonger period (eg, approximately 3 to 10 days) [12,13]. These more contemporary data frequently reportcomposite outcomes from cases of TRALI and possible TRALI and limit the study population to the criticallyill. Such cases are likely to represent the more severe end of the clinical spectrum. In contrast, milder casesof TRALI and/or possible TRALI may go undiagnosed or unreported. As such, the clinical presentation, needfor life­support interventions, and outcomes for patients with TRALI and/or possible TRALI remainincompletely defined.

Mortality rates associated with TRALI/possible TRALI have been reported to be as high as 41 to 67 percent

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[7,12,13,101]. Again, however, these more extreme reports generally originate from critically ill studypopulations with TRALI and possible TRALI combined into a single composite outcome. In contrast, lowermortality rates (5 to 10 percent) are typically described for TRALI itself [21,116]. Although limited informationis available, it appears that most survivors will recover to their baseline pulmonary function, and they cansafely receive additional blood products in the future [1,16,23]. (See "Acute respiratory distress syndrome:Supportive care and oxygenation in adults".)

PREVENTION — Following all cases of TRALI and some cases of possible TRALI, the blood bank and theblood collection facility should investigate all of the associated donors for the presence of anti­humanleukocyte antigen (HLA) and possibly anti­human neutrophil antigen (HNA) antibodies [117], with the goal ofidentifying donors who should be deferred from future donations. In reality, the number of donorsinvestigated may be more limited and the laboratory work­up performed by transfusion services may varydepending upon the number of donors in a case; the availability of donor samples; the availability ofneutrophil antibody testing, which is restricted to a few specialty laboratories in the US; and the availability ofa recipient sample for HLA antigen typing [1,118,119]. Some laboratories in Europe also perform leukocytecross­matching as part of the evaluation [117].

A donor who is shown to have leukocyte antibodies that match or are likely to match a recipient’s leukocyteantigens is classified as an implicated donor and is, at minimum, deferred from future plasma apheresis orplatelet apheresis. Furthermore, most blood banks will defer an implicated donor from any type of blooddonation; this is particularly true if the donor has anti­HNA 3a [1].

In addition, several general blood donor management strategies are in use to reduce the incidence of TRALI[1,8,35,118,120­132]:

Deferral of multiparous female donors — It has been well established that donors implicated in TRALIcases are more likely to be female and more likely to be multiparous [15,38,39]. These factors resulted in theimplementation of a new TRALI risk mitigation policies during the mid to late 2000s throughout most ofEurope and the United States, in which transfusable plasma units were predominantly obtained from maledonors, thereby avoiding the transfusion of plasma units from female donors [8,11,123­125,133]. This policyis feasible for plasma transfusion because the number of plasma units derived from whole blood orapheresis collections is in excess of demand. In contrast, this policy is not feasible for apheresis platelettransfusion where restriction of units to male donors would seriously jeopardize the platelet supply.

The importance of these policies is illustrated by a large multicenter study conducted under the auspices ofthe National Heart, Lung, and Blood Institute (NHLBI) Retrovirology and Donor Epidemiology Program II(REDS­II) [131]. This study, known as the Leukocyte Antibody Prevalence Study (LAPS), used modern flowcytometry techniques to assess the prevalence of HLA antibodies in almost 8000 volunteer blood donors.There was a dose­response increase in the frequency of anti­HLA antibodies according to parity, from 1.7percent for never pregnant females to 32.2 percent for four or more pregnancies. Donors who themselveshad received a blood transfusion, males, and never pregnant female donors all showed very low frequencyof anti­HLA antibodies (in the range of 1 to 2 percent) [131,134]. These data suggest that TRALI riskmitigation programs do not need to exclude plasma from never pregnant females or from donors with aprevious transfusion history [125]. Nevertheless, some European countries do not transfuse plasmaobtained from donors who have themselves received a transfusion [123]. These data also have helped toguide policies for HLA antibody testing of selected subpopulations of female plasma and platelet apheresis

Adherence to current guidelines of blood component utilization, especially for plasma, to decreaserecipient exposure to transfused units.

Deferral of donors implicated in a TRALI reaction.For high plasma volume components (eg, FFP, plasma frozen within 24 hours of phlebotomy [FP­24],plasma, cryo­reduced [cryo­poor] plasma, apheresis platelets, buffy coat derived platelet poolsresuspended in plasma from a single donor, and whole blood), selection of donors who are less likelyto be alloimmunized to leukocytes.

Use of pooled solvent detergent plasma as an alternative to FFP.Testing of parous apheresis donors of platelets or plasma for anti­HLA antibodies.

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donors.

The following observations support the effectiveness of sex­based risk reduction policies for reducing TRALIincidence from plasma transfusion:

Use of solvent detergent treated plasma — Another strategy for TRALI risk reduction is to transfuse apooled solvent detergent plasma product (S/D plasma) in place of FFP. An S/D plasma product wasapproved by the United States Food and Drug Administration in 2013, and S/D plasma has been widelyused in many European countries for many years. Notably, observational data from over 10 million S/Dplasma unit transfusions support the conclusion that this product does not cause TRALI [127]. A morecontrolled data set was provided by hemovigilance data collected in France in 2007 and 2008 [35]. Aftertransfusion of 212,000 S/D plasma units, there were no TRALI cases associated solely with S/D plasma. Incontrast, the TRALI incidence rate from FFP transfusion was 1 in 31,000 units. The absence of TRALIfollowing transfusion of S/D plasma has been attributed to the pooling of plasma from many different donors,resulting either in dilution of anti­HLA antibodies or in binding of such antibodies by soluble HLA antigens[126,128]. Notably, studies on 32 batches of SD plasma were unable to detect the presence of HLAantibodies in this product [126]. See Solvent/detergent­treated fresh frozen plasma drug information. (See"Pathogen inactivation of blood products", section on 'Solvent­detergent method'.)

Mitigating TRALI risk from platelets — Some blood centers have implemented a policy of testing selectedpopulations of platelet apheresis donors (eg, previously pregnant females, depending on the number ofpregnancies) for anti­HLA antibodies and then redirecting anti­HLA antibody positive donors away from allhigh­plasma­volume donations, including platelet apheresis [125]. However, this strategy has not beenuniversally adopted, and thus far there are no adequate data to evaluate its effect on TRALI incidence [123].Another strategy considered for apheresis platelets is to resuspend the platelets in platelet additive solution(PAS) [123]. This reduces the plasma volume of the product by two­thirds. However, it is not currently knownwhether TRALI risk from the reduced plasma volume (still approximately 100 mL of plasma) will bedecreased.

Mitigating TRALI risk from RBC — Due to the success of TRALI risk reduction measures for plasma, therelative percentage of TRALI cases from red blood cells (RBC) has increased, such that the majority of

The UK National Blood Service, starting in late 2003, provided 80 to 90 percent of FFP from maledonors. This was associated with a significant decrease in the risk of highly likely/probable TRALI dueto FFP (from 15.5 per million units issued from 1999 to 2004 to 3.2 per million from 2005 to 2006) [8].There were 23 highly likely/probable TRALI cases from all components in 2003, compared with three in2010 [124].

In a four­year nested case­control study conducted from 2006 to 2009 at the University of CaliforniaSan Francisco and Mayo Clinic, TRALI incidence in 2006 (prior to implementation of risk reductionmethods) was 0.0257 percent (1 in 3891); in 2009, after implementation of risk reduction policies forplasma products, TRALI incidence decreased to 0.0081 percent (1 in 12,345) [15].

In the US, annual TRALI fatalities attributed to plasma transfusion and reported to the FDA declinedfrom a peak of 23 cases in 2006 to three cases in 2011 [3]. In the three years prior to introduction of thesex­based TRALI risk reduction policies, plasma accounted for 48 percent of the fatal cases reported toFood and Drug Administration (FDA), compared with 27 percent in the four years following theirimplementation (2008 to 2011). Similarly, cases of suspected TRALI from plasma reported to theAmerican Red Cross National Hemovigilance Program decreased from a rate of approximately 20probable TRALI cases per million plasma components in 2006 to approximately four per million plasmacomponents in 2008. Moreover, in contrast to six TRALI fatalities related to plasma transfusion in 2006,there were none in 2008 [11].

In Germany, antibody­mediated TRALI from FFP transfusion decreased following the implementation ofTRALI risk reduction policies. The rate fell from 12.71 per million units in 2006 to 2007 (pre­implementation of risk reduction policies) to 6.81 per million units in 2008 to 2009, during which therewas partial implementation of risk reduction policies. With full implementation in 2010, no cases werereported [135].

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current TRALI cases are associated with RBC transfusion [126]. TRALI risk reduction measures appear tohave had no effect on the frequency of TRALI cases associated with RBC transfusion [3,126,136].

Data suggest that a non­antibody mediated mechanism, presumably a soluble biologic response modifier,may account for the majority of TRALI cases caused by RBC transfusion [18,59,60]. In one case series,donor antibodies directed against cognate recipient antigens were identified less frequently in TRALI casesinvolving only RBC transfusions (18 percent) than in cases involving FFP (82 percent) [18]. Two subsequentanalyses found that TRALI cases associated with RBC transfusion were not correlated with female or otheralloimmunized donors. In contrast, these studies did associate high­plasma volume blood components fromfemale and alloimmunized plasma donors with risk for TRALI [18,59].

Although RBC mediated TRALI continues to occur, no effective and practical risk reduction measures areavailable, with the exception of conservative RBC transfusion practices.

One retrospective report suggested that leukocyte reduction may have decreased TRALI incidence at asingle institution; however, a randomized clinical trial comparing pre­storage leukocyte reduced RBCtransfusion with standard allogeneic RBC transfusion found no evidence for differing rates of either early orlate ALI/ARDS in transfused trauma patients [137,138]. Furthermore, TRALI has been reported in manycountries that practice universal leukoreduction [123].

Based on the mechanism for red blood cell­induced TRALI, it has been suggested that the use of youngerred blood cells or washed red blood cells would prevent some TRALI cases [123,139]. However, the data onred blood cell age and TRALI are contradictory and unconvincing. Moreover, the only data concerningprevention of TRALI by RBC washing are retrospective and observational. [42­44,68,123]. Furthermore,washing large number of red cell units is not logistically feasible for most institutions.

A novel approach to TRALI mitigation utilizing a prototype prestorage leukoreduction filter has also beendescribed [52]. This filter removes platelets and plasma proteins such as IgG from the filtered units inaddition to leukocytes. An initial evaluation in an animal model system suggested that TRALI incidence fromtransfused RBC units was reduced with this filter. However, much more work is needed before this approachis ready for clinical testing.

SUMMARY AND RECOMMENDATIONS

Transfusion­related acute lung injury (TRALI) is a serious respiratory complication of transfusion. It isthe leading cause of transfusion­related mortality in the United States. (See 'Prognosis' above.)

TRALI can be seen following transfusion of any type of blood component in any patient. Historically, theblood components most likely to cause TRALI were those with a high concentration of donor plasma(due to antibodies to human leukocyte and human neutrophil antigens). Risk mitigation strategies havedramatically reduced the risk of plasma­associated TRALI, and currently the majority of TRALI casesare associated with transfusion of red blood cells (RBC). (See 'Epidemiology' above and 'Prevention'above.)

A "two­hit" hypothesis for the pathogenesis of TRALI holds that recipient neutrophils are primed foractivation by virtue of the patient's underlying clinical condition. The second hit involves activation ofthese neutrophils by pre­formed anti­leukocyte antibodies or biological response modifiers contained inthe transfused product. In rare cases, the transfused product may provide both hits. (See'Pathogenesis' above.)

The characteristic clinical presentation of TRALI is the sudden onset of hypoxemic respiratoryinsufficiency during or shortly after the transfusion of a blood product. Patients with TRALI often havefrothy airway secretions (if intubated), fever, cyanosis, and hypotension. When TRALI is suspected, thetreating physician should evaluate the recipient’s vital signs, assess the extent of hypoxemia, andobtain a chest radiograph. Pulse oximetry is often sufficient, but arterial blood gas analysis may bewarranted in more severe cases. (See 'Clinical presentation' above.)

TRALI is a clinical diagnosis. It should be considered whenever a patient develops hypoxemicrespiratory distress during or within six hours after transfusion of any blood product. The criteria set

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The differential diagnosis of TRALI includes other conditions that can manifest with respiratory distressfollowing transfusion. This includes other causes of ALI/ARDS as well as other transfusion reactions.The distinction between TRALI and TACO is important for proper management (table 2). Since aconfirmed diagnosis of TRALI has implications for blood suppliers, the term "possible TRALI" ispreferred for patients who meet criteria for TRALI, but have additional risk factors for ALI/ARDS. (See'Differential diagnosis' above.)

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GRAPHICS

Diagnostic criteria for transfusion­related acute lung injury(TRALI) and possible TRALI

TRALI Possible TRALI

Acute lung injury(ALI)/acute respiratorydistress syndrome (ARDS)

Acute onset (during orwithin six hours oftransfusion)Hypoxemia*

Bilateral infiltrates onfrontal chest radiographNo evidence of circulatoryoverload/left atrialhypertensionNo pre­existing ALI/ARDSbefore transfusion

Same as for TRALI

ALI/ARDS risk factor attime of transfusion

Must be absent Must be present

The diagnostic criteria for TRALI and possible TRALI share the following features: acute onsetof hypoxemia, bilateral infiltrates on frontal chest radiograph, and absence of circulatoryoverload as the primary etiology of respiratory insufficiency. For a diagnosis of TRALI to bemade, all of these features must be present. In addition, there should be no preexistingALI/ARDS risk factors at the time of transfusion. If ALI/ARDS risk factors are present, thediagnostic terminology "possible TRALI" is appropriate.

PaO2: arterial oxygen tension; FiO2: fraction of inspired oxygen; SpO2: hemoglobin oxygensaturation.* Hypoxemia is defined as PaO2/FiO2 ≤300 or SpO2 <90 percent on room air or other clinicalevidence of hypoxemia. Δ Risk factors for ALI/ARDS include the following: aspiration, toxic inhalation, pneumonia, toxiccontusion, near drowning, shock states, severe sepsis, multiple trauma, burn injury, acutepancreatitis, cardiopulmonary bypass, or drug overdose.

Modified from: Kleinman S, Caulfield T, Chan P, et al. Toward an understanding of transfusion­related acute lung injury: statement of a consensus panel. Transfusion 2004; 44:1774.

Graphic 64212 Version 3.0

Δ

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Helpful features in distinguishing TRALI and TACO

Feature TRALI TACO

Body temperature Fever may be present Unchanged

Blood pressure Hypotension may be present Hypertension may be present

Respiratory symptoms Acute dyspnea Acute dyspnea

Neck veins Unchanged May be distended

Auscultation Rales Rales and S3 may be present

Chest radiograph Diffuse bilateral infiltrates Diffuse bilateral infiltrates

Ejection fraction Normal Decreased

PAOP Most often 18 mmHg or less Greater than 18 mmHg

Pulmonary edema fluid Exudate Transudate

Fluid balance Neutral or negative Positive

Response to diuretics Inconsistent Significant improvement

White cell count Transient leukopenia may bepresent

Unchanged

BNP <250 pg/mL >1200 pg/mL

TRALI: transfusion­related acute lung injury; TACO: transfusion­associated circulatory overload;PAOP: pulmonary artery occlusion pressure; BNP: brain natriuretic peptide.

Modified with permission from: Skeate RC, Eastlund T. Distinguishing between transfusion relatedacute lung injury and transfusion associated circulatory overload. Curr Opin Hematol 2007; 14:682.Copyright © 2007 Lippincott Williams & Wilkins.

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Disclosures: Steven Kleinman, MD Consultant/Advisory Boards: Creative Testing Solutions [blooddonor laboratory testing]; Cerus [pathogen inactivation of blood components (platelet blood system,plasma blood system)]. Daryl J Kor, MD Nothing to disclose. Arthur J Silvergleid, MD Nothing todisclose. Scott Manaker, MD, PhD Consultant/Advisory boards: Expert witness in workers'compensation and in medical negligence matters [General pulmonary and critical care medicine]. EquityOwnership/Stock Options (Spouse): Johnson & Johnson; Pfizer (Numerous medications and devices).Other Financial Interest: Director of ACCP Enterprises, a wholly owned for­profit subsidiary of ACCP[General pulmonary and critical care medicine (Providing pulmonary and critical care medicine educationto non­members of ACCP)]. Jennifer S Tirnauer, MD Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these areaddressed by vetting through a multi­level review process, and through requirements for references to beprovided to support the content. Appropriately referenced content is required of all authors and mustconform to UpToDate standards of evidence.Conflict of interest policy

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