Splitting versus lumping: reconsidering the definition of transfusion‐related acute lung injury

Transfusion-related acute lung injury (TRALI) is a complication of allogeneic blood transfusion manifested by acute lung injury (ALI) within 6 hours of transfusion. Typical symptoms include shortness of breath, fever, and hypotension. TRALI represents an important and relatively common clinical syndrome with the Food and Drug Administration reporting TRALI to be the leading cause of transfusion-related deaths in 2013.1 The first description of noncardiogenic pulmonary edema after an allogeneic blood transfusion was reported in 1951,2, 3 and TRALI was recognized as a distinct clinical entity in the 1980s. The TRALI working group convened by the National Heart, Lung, and Blood Institute (NHLBI) proposed a definition of TRALI based on the American-European Consensus Conference definition of ALI (acute hypoxemia with PaO2/FiO2 ratio of ≤300 mmHg) with bilateral pulmonary infiltrates on chest x-ray without evidence of circulatory overload.4, 5 Risk factors for ALI included septic shock and sepsis, aspiration, multiple transfusions, near drowning, disseminated intravascular coagulation, pulmonary contusion, pneumonia, drug overdose, fractures of long bones, burns, and cardiopulmonary bypass.5 The authors indicated that if the patient had risk factors for ALI in addition to the transfusion, the new ALI could be due to the transfusion, due to the transfusion and another risk factor, or not TRALI at all.5 Similarly, the panel of a consensus conference held in Toronto in 2004 recommended that TRALI be defined as “a new episode of a ALI that occurs during or within 6 hours of a completed transfusion.”6 The panel further suggested that if the event was temporally related to a competing etiology of ALI, it should be considered as possible TRALI (pTRALI).6 The panel acknowledged that TRALI “should be considered a clinical syndrome rather than a disease with a single etiology.”6 TRALI is a complex syndrome and there is much about TRALI that remains unknown or unclear. It is possible that some of this confusion may be contributed to by the fact that TRALI is, by the definition provided, not a single disease but potentially multiple diseases caused by many etiologies, each with different prognoses and mechanisms of prevention. As well, using the definition developed by the Toronto Consensus Conference, the term pTRALI allows for the diagnosis of TRALI in the presence of alternate risk factors for ALI.6 This terminology allows TRALI to be diagnosed in critically ill patients, as there is nothing to suggest that TRALI does not occur in this patient population. However, the use of the term “pTRALI” highlights the uncertainly of the relationship of the ALI to the transfusion. In fact, it is impossible to distinguish pTRALI from ALI due entirely to etiologies other than transfusion if a transfusion has taken place. In this issue, Toy and colleagues7 report on a retrospective case-control analysis of data collected in a prospective observational study of TRALI conducted between 2006 and 2009 that has previously been published. The earlier study by Toy and colleagues identified recipient and blood product factors associated with increased risk of TRALI. The recipient factors included high interleukin-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and a positive intravascular fluid balance.8 Blood product factors associated with TRALI reactions included plasma or whole blood from female donors, greater volume of high-titer human leukocyte antigen (HLA) Class II antibody, and greater volume of anti-human neutrophil antigen (HNA) antibody.8 In the current study published in this issue of TRANSFUSION, the investigators identified cases of pTRALI and transfused controls who did not develop TRALI or pTRALI.7 Cases were considered pTRALI if there was a clear temporal relationship to an alternate risk factor for ALI. Using multivariate models, the authors assessed the association of various possible transfusion and recipient risk factors. The researchers demonstrated that transfusion factors were not significantly associated with pTRALI. Namely, in contrast to TRALI, receipt of plasma from female donors and receipt of a larger number of transfused units were not risk factors for pTRALI. However, recipient factors that were also associated with risk of ALI, such as chronic alcohol abuse, current smoker, shock before transfusion, and positive fluid balance before transfusion, were associated with the development of pTRALI. The authors concluded that recipient factors for acute respiratory distress syndrome (ARDS) rather than transfusion risk factors predominate in pTRALI. They suggest that pTRALI is likely a misnomer and that the term “transfused ARDS” may be a more appropriate designation of cases of ALI that occur during or after transfusion. This distinction would mean that the definition of TRALI would no longer include pTRALI as these cases would now be considered transfused ARDS. The opinion that pTRALI and TRALI represent distinct clinical syndromes is supported by the findings that the occurrence of pTRALI was not related to the HLA antibody status of the donor of the blood product,9 the fact that methods to decrease alloimmunized plasma in blood products have not decreased the incidence of pTRALI,9 and the fact that pTRALI and TRALI have different clinical outcomes.10 These findings and conclusions are interesting and thought-provoking. It is worthwhile noting that the opinion that pTRALI cases are better classified as transfused ARDS than TRALI is contrasted by other authors who have suggested that critically ill patients, presumably those who have other risk factors for ALI and would therefore be diagnosed with pTRALI rather than TRALI, may actually be more susceptible to TRALI.11 In these patients, Bux and Sachs have proposed that the transfusion of mediators with even low neutrophil-priming activity may be sufficient to overcome a threshold to induce a TRALI reaction.11 Thus, the hypothesis of Bux and Sachs indicates that TRALI is an appropriate diagnosis in patients with risk factors for ALI. In addition, the authors' conclusions represent a departure from the generally accepted definition of TRALI. For example, the NHLBI and the Toronto Consensus Conference definitions were both inclusive rather than exclusive with the definitions defining TRALI broadly allowing ALI associated with risk factors other than transfusion to be included.5, 6 The current definition likely includes cases of ALI where the transfusion was not involved in the etiology. However, this potential is balanced against the risk of excluding cases of TRALI simply because an alternate risk factor for ALI is present. The suggestion that the TRALI definition requires revision is not new and has been made by others. For example, Bux has suggested that the clinical significance of “nonimmune” TRALI is still unclear and that it would be reasonable to restrict the diagnosis of TRALI to cases associated with white blood cell antibodies.12 The idea of differentiating immune from nonimmune TRALI has merit because of the difficulty in assessing risk factors for a syndrome that has multiple etiologies. Ideally, the diagnostic criteria should allow for differentiation of the various etiologies of the condition or it must be accepted that the definition will represent a heterogeneous syndrome that may include pathologies with different risk factors, prognoses, and/or methods of prevention. If one recognized TRALI due to different etiologies as distinct entities, it might lead to different approaches to prevention and improved understanding of the true impact of these measures. For example, currently, TRALI prevention measures are all primarily aimed at decreasing the exposure of recipients to blood from alloimmunized donors or decreasing the amount of plasma in the products transfused. However, these measures may not prevent nonimmune TRALI or pTRALI. Therefore, the true effect of these prevention measures on immune TRALI is unknown and likely diluted by the presence of nonimmune and pTRALI included in the definition and, therefore, in the denominator. Further, other measures specifically targeting pTRALI or nonimmune TRALI must be considered to truly decrease the incidence of all types of TRALI. Without question, TRALI is a syndrome with various pathologies and contributing factions. Bux has suggested that TRALI be defined as immune versus nonimmune TRALI based on pathophysiologic mechanisms.12 In this issue of TRANSFUSION, Toy and colleagues7 have presented a compelling case that TRALI and pTRALI should be considered separate entities based on the presence or absence of other temporally associated risk factors for ALI. The fine tuning or “splitting” of the definition of TRALI may provide greater clarity. However, an important consideration is whether sharpening the focus of the TRALI definition will enhance our knowledge of TRALI or will nuances of its complexity be lost. While certain learnings will likely be enhanced by limiting focus and creating multiple separate distinct syndromes, one must pause to consider what understanding will be compromised if shared pathophysiologic mechanisms or outcomes are ignored. If the definition is made too narrow there is a risk that we will potentially miss gaining insight from similar cases. Many more cases will likely remain undiagnosed or unclassified. It is possible that our seemingly simplistic view of TRALI, while allowing bedside diagnosis of the syndrome, has diluted our efforts to truly identify patients at risk and to modify risk factors for the occurrence of TRALI. Making the definition of TRALI cases more specific will have the positive effect of improving our ability to accurately diagnose cases of TRALI. There may be greater clarity when discussing TRALI as an outcome measure in clinical trials. However, by lumping all etiologies of TRALI into one group, we are potentially limiting our ability to deepen our understanding of all cases of TRALI. Clearly, future investigation and thought about the appropriate definition of TRALI is required with consideration of whether “lumping” or “splitting” is the better option. Kathryn E. Webert, MD, MSc, FRCPC1,2 e-mail: [email protected] 1Canadian Blood Services 2Department of Pathology and Molecular Medicine McMaster University Hamilton, ON, Canada The author has disclosed no conflicts of interest.

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