Transfusion-related acute lung injury (TRALI) is a complication of transfusion characterized by the development of noncardiogenic pulmonary edema, typically within 6 h of blood product transfusion. Diagnosis is based on clinical and radiographic findings and temporal association with transfusion . Clinical findings commonly include dyspnea, tachypnea, and hypoxemia, sometimes accompanied by rigors, tachycardia, fever, hypothermia, and hypotension or hypertension . Bilateral interstitial infiltrates are present on chest radiograph but this finding is nonspecific. Management of TRALI is supportive care including supplemental oxygen or mechanical ventilation when necessary .
TRALI may be difficult to distinguish from other acute transfusion reactions with similar presentations including transfusion-associated circulatory overload (TACO), septic transfusion reactions, and anaphylaxis . A recently described predictive model for TRALI was able to differentiate TACO and TRALI based on evidence of systemic inflammation [elevated interleukin (IL)-6 and IL-8] prior to transfusion among patients who developed TRALI [3▪]. This testing is currently only being used for research purposes.
Although our understanding of TRALI has increased significantly over the last several decades, the pathogenesis remains incompletely understood. Although strong cognate antibody alone is enough to cause TRALI, most cases are postulated to occur via a ‘two event’ model . The ‘first’ or priming event is a clinical condition that causes activation of the pulmonary endothelium, leading to the sequestration and priming of neutrophils in the lung. Clinical risk factors that may function as the ‘first event’ include high IL-8 levels, liver surgery, chronic alcohol abuse, shock, high peak airway pressure during mechanical ventilation, current smoking, and positive fluid balance . The ‘second event’ results from the blood product transfusion, which activates the primed neutrophils causing endothelial damage and subsequently TRALI. This can either result from passive transfer of antibodies (immune-mediated) or pro-inflammatory mediators (nonimmune mediated) in the transfused component [6,7][6,7]. Multicausal models, including the threshold model and the sufficient cause model, offer alternative ways to describe the complex interplay of factors, which leads to the development of TRALI in susceptible patients [8 ▪ ,9][8 ▪ ,9].
Antibody-mediated TRALI occurs following passive transfer of human leukocyte antigen (HLA) or human neutrophil antigen (HNA) antibodies present in the plasma fraction of the transfused unit. High-volume plasma containing products from single donors (plasma, whole blood, and apheresis platelets) poses the greatest risk for antibody-mediated TRALI; however, TRALI can also occur in the setting of pooled platelets, red blood cell transfusions, and following infusion of fractionated derivatives [10–12][10–12][10–12]. Strong cognate HLA class II and HNA antibodies appear to confer the greatest risk for TRALI in susceptible patients . Pregnancy is the strongest stimulus for the formation of HLA antibodies and the risk for the development of these antibodies increases with increasing parity [13 ▪▪ ,14][13 ▪▪ ,14].
Nonantibody-mediated TRALI, a less well understood entity, appears to result from the transfusion of soluble mediators that accumulate during product storage including bioactive lipids, cytokines, CD40L, and red cell-derived microparticles [15 ▪▪ ,16][15 ▪▪ ,16]. Research to clarify the pathogenesis of nonantibody-mediated TRALI is ongoing.
TRALI RISK REDUCTION
Over the past 12 years, efforts to mitigate risk have primarily focused on antibody-mediated TRALI. In the United Kingdom, interventions implemented in 2003 include use of only male donors for plasma and plasma used for suspension of buffy coat-derived platelet pools, preferential recruitment of male donors for apheresis platelets, and screening female apheresis platelet donors for HLA/HNA antibodies with retesting after pregnancies . There have been no reported cases of TRALI involving platelets reported to the U.K. hemovigilance system in the past 3 years of published data (2011–2013) .
In the United States, progress towards TRALI risk mitigation of platelets has been slow but steady. In November 2006, the AABB-mandated implementation of interventions to minimize the preparation of high plasma-volume components from donors known to be leukocyte alloimmunized or at increased risk for alloimmunization . Complete implementation of measures relating to plasma and whole blood was required by November 2007 and as soon as possible, but no later than November 2008, for platelet components. The additional time permitted for implementation of platelet risk mitigation was based on concerns regarding impact on platelet supply. It was estimated that the adoption of approaches that eliminated female donors with anti-HLA antibodies might decrease availability of apheresis platelets by as much as 10% . By 2009, 87% of 47 surveyed U.S. blood collection organizations had implemented polices to reduce TRALI risk for apheresis platelets. The most common intervention was increasing collection from male donors (70%) followed by HLA antibody testing in selected donors (43%).
Currently available evidence indicates that these interventions have significantly reduced TRALI risk. After implementation of a male predominant plasma distribution strategy, the American Red Cross observed a significant decrease in the rate of suspected TRALI from 18.6 cases per million plasma units distributed to 4.2 cases per million; half of the remaining TRALI cases were associated with plasma containing HLA or HNA antibodies collected from untested female group AB donors [20▪▪] In a retrospective study of TRALI diagnoses in elderly Medicare beneficiaries from 2007 to 2011, the risk of TRALI associated with platelet transfusions decreased in 2010 and 2011 [21▪]. A recently published meta-analysis summarizes the existing studies to date and also concludes that the implementation of TRALI risk mitigation strategies has reduced TRALI risk [22▪▪].
In spite of this success, TRALI remains the leading cause of transfusion related fatalities reported to the U.S. Food and Drug Administration (FDA) and in the last 5 years of available data (2009–2013) there have been 10 TRALI deaths associated with apheresis platelets and two associated with pooled platelets . Pooled platelets may confer lower risk for TRALI because of the dilution, which results from combining plasma from multiple donors .
In January 2014, the AABB announced more stringent requirements for TRALI risk mitigation to address reported limitations of a male predominant plasma mitigation strategy [20▪▪]. Effective April 1, 2014, all plasma and whole blood for allogeneic transfusion shall be from men, women who have not been pregnant, or women who have tested negative for HLA antibodies since their most recent pregnancy . In an effort the further reduce risk of TRALI from apheresis platelet transfusions, the AABB recently expanded the above requirements to include apheresis platelets with an implementation deadline of October 1, 2016 . Implementation of these measures is estimated to reduce TRALI risk for apheresis platelets from 2.8 : 100 000 to 1 : 100 000 .
Although implementation of HLA antibody testing of female apheresis platelet donors with a history of pregnancy will reduce risk, it may not eliminate TRALI in the setting of apheresis platelet transfusion. HLA antibodies have been identified in 4.3% of male donors without a history of transfusion and 10.6% of female donors without a history of pregnancy or transfusion . In addition, current U.S. risk mitigation requirements do not require screening for HNA antibodies because of a lack of an acceptable screening test [20▪▪]. Current interventions also do not address nonimmune-mediated TRALI.
ADDITIONAL OPTIONS TO FURTHER REDUCE RISK
Currently available options for further TRALI risk reduction in the setting of platelet transfusion include use of platelet additive solutions (PAS), volume reduction, and washing of platelets . Although our current understanding of TRALI provides a theoretical rationale for the effectiveness of each of these strategies, the cost of each must be weighed against the potential benefit. Evidence supporting these approaches is extremely limited and the incremental risk reduction will be challenging to detect once mandated platelet mitigation strategies are widely implemented.
Various PAS formulations are available and are extensively used in Europe; however, use in the United States remains limited as only one solution (Intersol/PAS 3) has obtained FDA approval . This solution replaces approximately 65% of the plasma in an apheresis unit, which increases the amount of plasma available for other uses . Use of PAS decreases the ABO isohemagglutinin titer and this provides a plausible mechanism for antibody-mediated TRALI risk reduction . However, given that red blood cells in additive solution contain less residual plasma than platelets in additive solution and are still associated with antibody-mediated TRALI, the use of PAS is unlikely to entirely eliminate risk of TRALI from apheresis platelets.
Available data suggest that use of PAS is effective in reducing some types of transfusion reactions. In a recent single-center study, PAS platelets were associated with a 46% reduction in allergic transfusion reactions when compared with standard apheresis platelets suspended in plasma [33▪]. These study investigators also observed, however, that PAS platelets were associated with lower corrected count increments (CCI) at 1–4 h post transfusion. In spite of this difference, the mean CCI at 12–24 h was not significantly different. The impact of these observations on clinical risk for bleeding remains unknown.
A recent large multicenter study also observed a reduction in allergic transfusion reactions for PAS apheresis platelets compared with plasma apheresis platelets [34▪▪]. In addition, a significant decrease in febrile nonhemolytic reactions was noted in the PAS platelet group. Although greater than 14 000 platelet transfusions were administered, there were no TRALI cases observed in either study arm. It is important to recognize, however, that this study was not powered to detect differences in TRALI rates. Furthermore, the platelets used in the study were already TRALI mitigated (i.e. collected from males, nulliparous females or parous females negative for HLA antibodies).
Volume reduction and washing of platelet components are other potential strategies to reduce TRALI risk but both approaches involve additional manipulation of the platelet product, increased work-load for the hospital blood bank, and potential for delays in product availability. Washing effectively removes most of the plasma and any soluble mediators that have accumulated during storage but does so at the expense of lower corrected count increments .
Novel methods for TRALI risk reduction are currently under investigation. A technique for prestorage experimental filtration for TRALI risk mitigation of red blood cells has been developed . This filter removes antibodies, lipids, whereas blood cells and platelets and mitigates TRALI in an animal model. Although the current method would only be applicable to red cell products, because of platelet trapping in the filter, modifications may lead to the development of a configuration that could successfully be applied to platelets.
Although recent risk mitigation efforts have significantly decreased risk, TRALI remains the leading cause of transfusion-related fatalities in the United States. Although it is too soon to determine the impact of mandated HLA antibody testing for parous female platelet donors on TRALI incidence, it is clear that this approach has been successful at decreasing TRALI risk for plasma. Additional options such as PAS, volume reduction, and washing are intellectually appealing, but also costly to implement and may result in lower count increments. It also remains to be proven whether any of these approaches really diminish TRALI risk when applied as an adjunct to existing mitigation strategies. As our understanding of the pathogenesis of TRALI continues to expand, additional options for risk mitigation may emerge. Although the bulk of this review has focused on manufacturing-based mitigation strategies, there are also interventions available to clinicians. These include awareness of patient risk factors for TRALI, efforts to address any modifiable risks prior to transfusion, and adherence to a restrictive transfusion policy in stable, nonbleeding patients.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Retrospective single-center study examining rate of adverse events associated with platelets stored in plasma compared to platelets stored in PAS-C. Lower rates of allergic transfusion reactions were observed. This study was not powered to detect differences in TRALI rates.
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A large multicenter study comparing adverse events associated with platelets stored in plasma to platelets stored in PAS-C. This study was not powered to detect differences in TRALI rates and platelets in both study arms were collected using TRALI risk mitigation strategies. Reduced rates of febrile and allergic transfusion reactions were observed in the PAS-C study arm.
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