TRALI: moving toward prevention

Although transfusion-related acute lung injury (TRALI) has always been a potential complication of blood transfusion (recently briefly reviewed), it was only described and named in the medical literature by Popovsky and colleagues in the early 1980s.1-3 Even after those first descriptions, TRALI did not initially receive much attention, likely because of the overwhelming concern in the 1980s and early 1990s for transfusion-transmitted (TT) human immunodeficiency virus (HIV) and hepatitis C virus (HCV) and, after that, for bacterial contamination. However, over the past decade, TRALI has increasingly gained the attention of the transfusion medicine community and with the decrease in the risk of TT-HIV, HCV, and bacterial contamination, in recent years TRALI has become the leading cause of transfusion-related mortality reported to the US Food and Drug Administration.4 With the first reports of TRALI, the observation that there was an excess number of TRALI cases associated with high-plasma-volume blood components collected from female donors led to the “antibody hypothesis” to explain the pathophysiology of TRALI reactions, that is, that the lung injury is due to a series of events triggered by the interaction of donor (or occasionally recipient) white blood cell (WBC) antibodies with the corresponding recipient (or less often donor) WBC antigen. This hypothesis is now widely accepted as one, and possibly the most common, cause of TRALI. However, WBC antibodies cannot be found in all cases and it is now accepted that other factors can also initiate the cascade of events leading to lung injury (the “neutrophil priming hypothesis”). Bux and Sachs5 have recently proposed a “threshold model” of the pathophysiology of TRALI that incorporates both of the proposed mechanisms together with the role of the pulmonary endothelium and the blood recipient's clinical status. In light of the importance of TRALI as a leading cause of transfusion-related morbidity and mortality, yet the realization that there were still many unanswered questions, in April 2004, Canadian Blood Services and Héma-Québec convened a consensus development conference entitled “Toward an Understanding of TRALI.” The questions posed to the expert panel ranged from the very basic question of how to define TRALI to questions about pathophysiology and recommended areas for research. On a very practical note for blood suppliers, the panel was asked whether there was sufficient evidence at that time to recommend that any laboratory screening tests and/or other deferral measures be implemented to exclude donors to reduce the risk of TRALI. The panel did suggest a definition for TRALI, which has become widely accepted, namely that TRALI be defined as a new episode of acute lung injury (ALI) that occurs during or within 6 hours of transfusion completion, which is not temporally related to a competing etiology for ALI; when ALI is temporally related to both transfusion and another risk factor for ALI, the panel recommended the use of the term “possible TRALI.”6 ALI itself was also explicitly defined and includes the requirement that circulatory overload be excluded; in practice distinguishing circulatory overload from ALI is the most difficult part of applying this definition. The panel specifically emphasized that this definition is based entirely on clinical and radiologic criteria and is not dependent on the results of any laboratory tests or any proposed pathophysiologic mechanism. In answer to the very specific question cited above concerning proactive donor deferrals, the panel did not make a definitive recommendation but considered the possible restriction from donation of donors having or at risk of having WBC antibodies (i.e., primarily females with a history of pregnancy) and concluded that a more detailed assessment of the impact of such a policy on blood availability, donor behavior, and other factors (detailed in Kleinman et al.6) should be undertaken by each blood supplier. The panel also discussed the important role of surveillance or hemovigilance systems for reporting adverse transfusion reactions in determining TRALI incidence and in contributing to our understanding of the pathophysiology of TRALI. The UK hemovigilance system, Serious Hazards of Transfusion (SHOT), initiated in 1996 was one of the first national hemovigilance systems to be established and since its inception has remained among the leading systems worldwide. Already at the time of the Canadian consensus conference, data from SHOT and the UK approach to the evaluation of suspected TRALI cases had convinced the UK National Transfusion Service that procedures to decrease the number of high-plasma-volume components prepared from female donors should lead to a decrease in TRALI reactions. In the UK, plasma not used for transfusion was already being discarded (to decrease the risk of variant Creutzfeldt-Jakob disease transmission), so a policy of using predominantly male plasma could be implemented relatively simply. In addition, in the UK, whole blood platelets (PLTs; which accounted for approximately 60% of the UK PLT supply in 2003) are produced using the buffy coat method, in which PLT pellets with approximately 25 mL of plasma from four donors are resuspended in an additional 200 mL of plasma from one of the donors; thus, it was also possible to assure that the majority of plasma for resuspension of these PLTs would be from male donors. These policies were therefore implemented in the UK in 2003 to 2004. Within just 2½ years from the Canadian consensus conference, data from SHOT as well as other sources, for example, the American Red Cross, convinced the AABB leadership to issue guidance recommending the implementation of interventions to minimize the preparation of high-plasma-volume components from donors known to have or at increased risk of having WBC antibodies.7-9 In this issue of TRANSFUSION, Chapman and colleagues10 report the results of 10 years of hemovigilance reports of TRALI in the UK and the impact of preferential use of male donor plasma. This publication is important for several reasons. It is the first full publication of findings previously only available in abstract form (or on the SHOT website), which nevertheless have contributed significantly to factors influencing blood suppliers worldwide to implement proactive TRALI reduction measures. It also demonstrates the ability of a hemovigilance system, even if voluntary (as was the case for SHOT until 2006), and in spite of its inherent limitations, to provide information that can be used to propose policies to decrease blood transfusion complications and to monitor the effectiveness of the implementation of such policies. As described in this article, between 1996 and 2006, 225 initial reports of suspected TRALI cases were received by SHOT and 195 retained for analysis. Over the course of these 10 years several changes occurred in their approach to the evaluation of these cases including the introduction of a categorization system and expert medical evaluation of cases reported (and likely the quality of clinical information reported by hospital physicians) and several enhancements to the laboratory investigations. (These changes, while beneficial, do make the analysis of the data as reported somewhat difficult for the reader to follow and evaluate.) The system for categorizing reported TRALI cases was introduced in 1999 (5 years before the Canadian consensus conference definition was proposed) and it is important to note that the terms used by SHOT do not have the same definitions as those of the Canadian consensus conference definition. Using the SHOT categorization system, 49 percent of their cases were considered to be highly likely or probable TRALI and 51 percent possible or unlikely TRALI. Of 96 cases that were fully investigated for WBC antibodies, donor antibodies recognizing recipient antigens were found in 73 cases (65%). The results up to 2003 revealed that the TRALI risk per component was 6.9 times higher for fresh-frozen plasma (FFP) and 8.2 times higher for PLTs than for red blood cells (RBCs) and that in donors of implicated FFP/PLTs, WBC antibodies were found 3.6 times more often than by chance (p < 0.0001), with all implicated donors being female. The provision of male plasma was associated with a reduction in total reports of suspected TRALI cases from 36 in 2003 to 23 in each of 2004 and 2005, and 10 in 2006, with the majority of the decrease being due to the decrease in highly likely or probable cases. The risk of highly likely or probable TRALI due to FFP decreased from 15.5 per million units issued during 1999 through 2004 to 3.2 per million during 2005 through 2006 (p = 0.0079) and from 14.0 per million to 5.8 per million for PLTs (p = 0.068). Deaths associated with TRALI reached a peak of nine in 2003 and decreased to one in 2006. These results do indeed confirm the efficacy of a “predominantly male plasma” policy, as recommended by AABB and as now implemented by many blood suppliers, in decreasing the number of TRALI cases and probably also in decreasing the number of deaths due to TRALI. However, there are some aspects of this report that are important to keep in mind when assessing these results. First, while the authors correctly state that the TRALI definition used by SHOT is closely aligned to the Canadian consensus conference definition and does not include a requirement for positive donor or recipient serology, laboratory testing results (and so, a presumed pathophysiologic mechanism) are taken into consideration when categorizing reported TRALI cases as highly likely, probable, possible, or unlikely. SHOT defines positive serology as the presence of donor WBC antibodies that correspond with one or more recipient antigens and/or a positive WBC cross-match between donor and recipient and negative if a full investigation of all potential donors is performed and no such antibodies or incompatibility found. Using this definition for positive/negative serology, TRALI cases reported to SHOT are then categorized as follows: Highly likely: no other cause identified for the symptoms and positive serology. Probable: either positive serology but with other causes for symptoms also present or no other causes present, but with either absent or incomplete serology. Possible: clinical picture compatible with TRALI, no other cause present, but results of patient and donor investigation negative. Unlikely: another cause of symptoms present and results of patient and donor investigation negative. Consequently, a case fulfilling the Canadian consensus conference definition for TRALI would be categorized in the SHOT system as highly likely, probable, or possible depending on the results of the laboratory investigation (positive, incomplete, or negative, respectively) and a case fulfilling the Canadian consensus conference definition for possible TRALI would be categorized as probable if there was positive serology but unlikely if the serology testing was negative; it is not explicitly stated what would be the case with incomplete testing. Unfortunately, then, the reader cannot determine if the TRALI cases categorized in the SHOT system as possible or unlikely represent cases that would not actually meet the Canadian consensus conference definitions for TRALI or possible TRALI (e.g., because of an inability to exclude circulatory overload) or, alternately and importantly, represent true TRALI events caused either by undetectable WBC antibodies or by mechanisms other that those involving WBC antigen–antibody interactions. This, then, limits what might otherwise have been learned from this data about cases with negative serology. In addition, the use of this categorization system makes it very difficult, if not impossible, to compare or combine results from this report with those of others using the Canadian consensus conference definition. Given that TRALI is a rare event, this is unfortunate and is precisely what the consensus conference panel had hoped to avoid in proposing the use of a standardized definition. Second, SHOT results from 2007 have now been published and show an increase in the number of TRALI cases in 2007 over those reported in the SHOT report for 2006 and in this publication.10,11 Specifically, in 2007 there were a total of 24 TRALI cases with 12 being categorized as highly likely or probable and 12 as possible or unlikely. Possible reasons for this observation include the fact that cases are assigned to the year in which they are reported and not necessarily the year in which they occurred, so that some of the 2007 cases would actually have occurred in 2006. Does this change the significance of the findings reported in this month's issue of TRANSFUSION? Probably not—if TRALI cases from 2003 through 2004 (as reported in the current publication) and cases from 2006 through 2007 (current publication plus the 2007 SHOT report) are put together, the results are as follows: in 2003 through 2004 a total of 59 TRALI cases of which 35 are categorized as highly likely or probable and 24 are categorized as possible or unlikely and in 2006 through 2007 a total of 34 cases of which 15 are highly likely or probable and 19 are possible or unlikely. While the difference is not as striking as that when only the 2006 data are considered, there does still appear to be a trend toward a decrease in TRALI cases, specifically in those associated with high-plasma-volume components and positive serology. On the other hand, if the cases categorized as possible and unlikely do in fact fulfill the Canadian consensus conference definition for TRALI and possible TRALI respectively, then it is also important to note that these have not decreased between the two time periods. There also remain a few serology positive cases due to low-plasma-volume components such as RBCs and cryoprecipitate. In summary, even with the addition of the 2007 SHOT information and the limitations resulting from the definition and categorization system used by SHOT, the data reported in this month's issue of TRANSFUSION do provide important evidence that the number of TRALI cases can be decreased through the use of predominantly male donors for the production of high-plasma-volume components. Chapman and her colleagues in the UK Blood Transfusion Service and SHOT program are to be congratulated for their important contribution over the past decade, summarized in their current publication. Hopefully other blood services that have implemented similar TRALI risk reduction measures will also monitor and publish their results.

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