Approach to the Diagnosis and Management of Transfusion-Related Acute Lung Injury

What is your approach to the diagnosis and management of transfusion-related acute lung injury (TRALI)?

Epidemiology

The blood supply in the United States is safe. Although non-life- threatening adverse events such as allergic and febrile transfusion reactions are encountered regularly by clinicians, transfusion-related fatalities are rare. From 2007 through 2011, 212 fatalities following blood collection and transfusion were reported to the FDA.¹  Non-infectious complications pose the greatest mortality risk to the transfused patient with TRALI accounting for 43 percent of deaths and hemolytic transfusion reactions due to ABO (10%) and non-ABO (13%) incompatibility accounting for 23 percent.¹  In comparison, 11 percent of transfusion-related deaths were due to microbial infections. Although usually associated with infusion of blood products containing high volumes of plasma (e.g., freshfrozen plasma and platelets), TRALI has also been linked to red blood cell transfusions. Estimates of the incidence of TRALI may be influenced by factors such as transfusion policy. For example, the incidence fell from 2.57 to 0.81 per 10,000 transfusions concurrent with reduction in the use of plasma from female donors.² 

Clinical Presentation and Diagnosis

The diagnosis of TRALI is made on clinical grounds, and no single laboratory or radiologic test definitively identifies or excludes this entity. We currently use the criteria and case definitions proposed by a Canadian Consensus Conference (Table).³  Thus, TRALI is an acute event presenting during a transfusion or within six hours of its completion. Characteristic signs and symptoms include fever, chills, dypsnea, hypoxemia, hypotension (or possible transient hypertension), and the new onset of bilateral noncardiogenic pulmonary edema (e.g., chest x-ray showing bilateral alveolar and interstitial infiltrates in the absence of cardiomegaly). TRALI is often associated with transient leukopenia or neutropenia. A diagnosis of “Possible TRALI” is made based on the same criteria as TRALI except that an alternative risk factor for acute lung injury is present concurrently (Table).

The differential diagnosis of TRALI includes the following: transfusion-associated circulatory overload (TACO), anaphylaxis, and sepsis.⁴  Distinguishing TACO from TRALI may be challenging because some of the signs and symptoms of the two entities overlap; in addition, the two processes can occur concurrently in a given patient. The key difference between these two conditions is the pathophysiologic origin of the pulmonary edema (i.e., cardiogenic in the case of TACO and non-cardiogenic in the case of TRALI). Thus, clinical improvement after treatment with a diuretic and/or an inotropic agent is characteristic of TACO, but not TRALI. Other findings suggestive of TACO include persistent hypertension, a post-transfusion brain natriuretic peptide (BNP) level of at least 100 pg/mL, and a post-transfusion:pre-transfusion BNP ratio of >1.5.⁵  Although anaphylaxis can present with hypotension, cyanosis, and hypoxia due to bronchospasm and laryngeal edema, the absence of fever and pulmonary edema distinguish this process from TRALI. Although transfusion-induced sepsis, particularly after a platelet transfusion, typically presents with pyrexia and hypotension, respiratory distress is an infrequent complication. Other entities, such as myocardial infarction, pulmonary embolism, and other causes of acute lung injury share clinical features with TRALI and should be considered in the differential diagnosis.

The diagnosis of TRALI is particularly challenging in complex inpatients such as those encountered in the intensive care unit setting, given that such patients often have multiple medical problems and may exhibit some symptoms of TRALI even before transfusion.

Pathophysiology

Although the exact mechanism of TRALI is uncertain, a “two-hit” process has been proposed.^6-8  According to this hypothesis, the first “hit” is induced by an underlying condition, such as trauma or sepsis, which primes granulocytes and/or activates endothelial cells, thereby causing neutrophils to become sequestered in the pulmonary vasculature. The second “hit” results from passive infusion of donor antibodies in the blood product that recognize either human leukocyte antigens (HLA) on recipient endothelial cells or human neutrophil antigens (HNA) on recipient neutrophils. Alternatively (or in addition), infusion of biologic response modifiers (e.g., CD40 ligand) in the plasma portion of the donor product could induce the second hit. Together, these processes induce capillary endothelial damage, resulting in vascular permeability and pulmonary edema.^6-8 

Based on this proposed mechanism, one might hypothesize that the incidence of TRALI would be higher for plasmarich transfusion products and that the incidence would be lower when plasma derived from female donors (who have a higher prevalence of anti-HLA antibodies) is restricted; available data support these two hypotheses.²  In addition, recent studies indicate that circulating platelets are involved in TRALI pathophysiology, suggesting that anti-platelet therapy may be beneficial clinically.^7,9 

Management

The first step in managing any suspected transfusion reaction is to stop the transfusion. Once the patient is stabilized, the episode should be reported to the transfusion medicine service so that a transfusion reaction evaluation can begin. Because hemolytic transfusion reactions are associated with significant morbidity and mortality, the transfusion medicine service will first perform a “clerical check” to ensure that the correct unit was transfused into the correct patient. Next, the ABO type of the patient and the transfused unit will be confirmed, the post-transfusion blood sample will be inspected for visible evidence of hemolysis, and an indirect and direct anti-globulin test will be performed on the post-transfusion sample to determine if circulating and/or red blood cell-bound antibodies are present. Additional laboratory tests to investigate for hemolysis, including a complete blood count, urinalysis, and plasma concentration of bilirubin, lactate dehydrogenase, and haptoglobin, are often needed. To diagnose TRALI, physical exam, chest x-ray, and arterial blood gas studies are recommended. In distinguishing TRALI from TACO, an echocardiogram may be useful in determining whether the observed pulmonary edema is of cardiogenic origin. Other causes of adverse events that share clinical features with TRALI (e.g., sepsis, myocardial infarction, and pulmonary embolus) should be promptly investigated.

Current management of TRALI consists of respiratory and circulatory support based on clinical severity. Oxygen supplementation is required in almost all patients; in severe cases, mechanical ventilation may be necessary. Hypotensive episodes can be treated with pressors. Corticosteroid treatment has not improved outcome.¹⁰ In theory, the noncardiogenic pulmonary edema of TRALI should not respond to diuresis. Most patients improve within two to three days, but those who do not improve over this period typically have a protracted clinical course or a fatal outcome.⁸ 

Patients who have experienced an episode of TRALI are not at greater risk for a second episode, assuming that the initial event was a consequence of infusion of donor antibodies that were present in the transfusion product and that subsequent blood products do not come from the initial donor. However, notification of the transfusion medicine service about a possible TRALI episode has important implications for the donor and the safety of the blood supply. If TRALI is suggested by both clinical presentation and laboratory results (e.g., finding anti-HLA and/or anti-HNA antibodies in the transfused blood product that match the corresponding antigens in the patient), the donor must be evaluated for consideration of their continued eligibility to donate. Indeed, many centers choose to exclude such donors permanently. That the product from a particular donor caused an episode of TRALI may be difficult to prove unequivocally, however, because patients often receive products from multiple donors.

Prevention

Approaches to reducing the risk of TRALI have included avoiding the use of plasma from female donors, using plasma derived only from males or from never-pregnant females, and testing female donors for anti-HLA antibodies.^1,2  Although these measures reduce the incidence, they do not completely eliminate risk because TRALI can be induced by other blood products (e.g., red blood cells, platelet concentrates, cryoprecipitate). In addition to avoiding the use of high-risk blood products, conservative transfusion strategies and interventions that address the “first hit” could also help reduce TRALI incidence. Nonetheless, TRALI continues to be the most common cause of transfusion-related mortality, making rapid recognition and institution of appropriate supportive care imperative.^1,7