Proposed revised nomenclature for transfusion‐related acute lung injury

A decade ago, definitions of “transfusion?related acute lung injury (TRALI)” and “possible TRALI” were standardized for research and clinical diagnosis. Since then, evidence has confirmed that TRALI is often due to transfusion of white blood cell antibodies to at‐risk patients, and the term “TRALI, antibody mediated” is appropriate for such cases. Other TRALI cases are non–antibody mediated. Because specific, nonantibody transfusion factors have not yet been confirmed to cause TRALI in humans, the general term “TRALI, non–antibody mediated” is appropriate for such cases. In contrast, evidence is against possible TRALI being due to transfusion with the more likely cause of the acute respiratory distress syndrome (ARDS) being the alternative ARDS risk factor present in these patients. We propose to drop the misleading term “possible TRALI” and to rename this category of cases as “transfused ARDS.” These nomenclature updates will more accurately categorize ARDS cases that develop after transfusion.     

Blood donors implicated in transfusion‐related acute lung injury with patient‐specific HLA antibodies are more broadly sensitized to HLA antigens compared to other blood donors

BACKGROUND: The prevalence of HLA antibodies in randomly surveyed blood donors was compared to the prevalence of antibody in donors who were associated with transfusion‐related acute lung injury (TRALI) cases reported to Canadian Blood Services (CBS). STUDY DESIGN AND METHODS: Current operating procedure mandates that the CBS TRALI Medical Review Group (TMRG) refer possible TRALI cases to the (CBS) Platelet Immunology Laboratory for investigation. Donor samples from these TRALI cases were screened for HLA antibodies. In parallel, a survey was conducted to screen serum samples from blood donors who were not associated in TRALI cases. A comparison analysis of HLA antibody profiles in the two groups of donors was performed. RESULTS: We studied 121 TRALI‐associated donors (TDs) who were recalled in a total of 44 cases reported to CBS and classified by TMRG. We also studied 149 survey donors (SDs) who were deferred for donation for varied reasons and consented to participate in a survey for HLA antibody screening. Twenty‐two percent of SDs and 50.4% of TDs tested positive for HLA antibodies. In addition, TDs who were implicated in TRALI demonstrated broader sensitization and higher level of quantitative HLA antibody compared to nonimplicated TDs and SDs. CONCLUSION: Patient‐specific Class I and II HLA antibodies are directly related to the risk of TRALI. Moreover, it supports the concept that HLA antibody strength is directly related to the risk of TRALI when the HLA antibody is patient specific; however, no clear cutoff as defined by mean fluorescence intensity is evident.     

Relationship of donor HLA antibody strength to the development of transfusion‐related acute lung injury

BACKGROUND: Antibodies against the human leukocyte antigen (HLA) in donors' blood are implicated in the development of transfusion‐related acute lung injury (TRALI). Screening of female donors for HLA antibodies has been introduced to prevent TRALI; however, the relationship of HLA antibody strength in the transfused components to the development of TRALI has not been evaluated in detail. STUDY DESIGN AND METHODS: Donors involved in 1038 cases of nonhemolytic transfusion reactions (NHTRs) including 283 cases of TRALI were screened for HLA antibodies by the fluorescence beads method. HLA antibody specificity and strength were analyzed in detail. The usefulness of enzyme‐linked immunosorbent assay (ELISA) for screening HLA antibodies was also evaluated. RESULT: Among 21 cases of TRALI, four cases of possible TRALI, and five cases of other NHTRs, the sum of mean fluorescence intensity (MFI) of donors' HLA antibodies to patients' cognate antigen(s) was determined in 18, four, and three cases, respectively. The sum of MFI in TRALI cases was significantly higher than that in other NHTR cases (p < 0.05). When HLA antibody–positive samples were reevaluated by ELISA, the ELISA optical density ratio was significantly higher in donors' samples associated with TRALI than in those associated with other NHTRs (p < 0.01) CONCLUSIONS: A correlation between the HLA antibody strength and development of TRALI was indicated. The antibody strength measured by ELISA could be used as the basis for the screening of HLA antibodies in place of the fluorescence beads method. This study provided clues to the establishment of a cutoff value for HLA antibody screening in an evidence‐based manner for the prevention of TRALI.     

Redefining transfusion‐related acute lung injury: don't throw the baby out with the bathwater

Recently two articles have been published in TRANSFUSION in which the authors propose to change the current definition on transfusion‐related acute lung injury (TRALI). It was proposed to view TRALI from the perspective of detectability versus nondetectability of leukoreactive alloantibodies (Transfusion 2015;55:1128‐34). The authors argue that only cases in which leukoreactive alloantibodies can be detected should be defined as “true” TRALI in analogy with the understanding of the pathophysiology of heparin‐induced thrombocytopenia. In the other article (Transfusion 2015;55:947‐52), the authors propose to redefine possible TRALI to transfused acute respiratory distress syndrome (ARDS) as their study in intensive care unit patients did not show a relation between the number of transfusions and possible TRALI.We discuss these two propositions in light of the current evidence on pathophysiology of TRALI and possible TRALI. We argue that it is too early to redefine TRALI, as 1) factors, such as storage time of platelets, which induce TRALI in preclinical studies, have not yet been properly investigated in humans. Further research is needed on these agents before it is concluded that antibody‐mediated TRALI is the only “true” TRALI. 2) In light of the current knowledge, it makes perfect sense that multiple transfusion is not related to possible TRALI: ARDS risk factors in these patients result in a very sensitive equilibrium in which even only one transfusion induces TRALI. Excluding possible TRALI from the TRALI definition would result in further underrecognition of TRALI induced by alloantibodies and interferes with exclusion of donors related to TRALI cases and thus TRALI prevention.     

Screening of multiparous women to avoid transfusion‐related acute lung injury: a single centre experience

summary The aim of this study was to investigate which approach for serological testing of multiparous donors might be feasible and effective to reduce the risk of transfusion‐related acute lung injury (TRALI). TRALI is a serious adverse event of blood transfusion. Antibodies to granulocytes and human leucocyte antigens (HLAs) are frequently detected in sera of implicated donors. These donors are often multiparous women. A general deferral of female plasma or screening strategies for leucocyte antibodies has been proposed to increase blood safety. A prospective study was initiated in 2003. Until 2006, serum samples from all female donors reporting three or more pregnancies (n = 229) were screened for the presence of antibodies against granulocytes and HLAs by immunofluorescence and agglutination tests as well as by a commercial HLA enzyme immunoassay. In total, 40% of all multiparous women were reactive in one of the assays. Twenty‐nine percent of the reactive sera contained antibodies to granulocytes but not to HLAs. During the observation period, three TRALI reactions occurred in our hospital, two of which would have been prevented if the screening program had been extended to all previously pregnant donors. We conclude from these data that, not unexpectedly, the number of previous pregnancies is not a reliable indicator for the likelihood of inducing TRALI. More importantly, screening strategies for antibodies that might induce TRALI should probably not be reduced to HLA antibody screening. This finding awaits further research.     

A comparison of two robotic platforms to screen plateletpheresis donors for HLA antibodies as part of a transfusion‐related acute lung injury mitigation strategy

BACKGROUND: Efforts to minimize white blood cell alloantibodies, responsible for transfusion‐related acute lung injury (TRALI) in components with high‐volume single‐donor plasma include consideration of plateletpheresis donor screening for human leukocyte antigen (HLA) antibodies. High‐throughput screening platforms make this feasible for large blood centers. Which platform to use, donor subgroups to screen, characteristics of detected antibodies, and operational impact of deferring reactive donors are important questions. STUDY DESIGN AND METHODS: We screened 2462 plateletpheresis donor sera for HLA antibodies on automated instruments using HLA Class I and II enzyme‐linked immunosorbent assays (ELISA) or a mixed Class I/II Luminex flow analyzer. Screen‐reactive samples were further tested by manual Luminex single‐antigen assay to determine antibody specificity, estimated corresponding antigen frequency, and signal strength. RESULTS: Alloexposed females had the highest reactivity rate on both platforms (21.0%), with much lower rates for nonexposed individuals or transfused males (1.4%‐5.4%). Increasing parity and more recent pregnancy increased their likelihood of screen reactivity. Deferring screen‐reactive parous females would result in at least a 4.8% plateletpheresis donor base decrement. Supplemental testing showed higher rates of nonspecific or natural antibodies in ELISA screen‐reactive alloexposed females (2.5%) than Luminex (0%). Both assays were more likely to identify antibodies directed against a larger number of HLA antigens and/or of presumed higher titer in alloexposed donors. CONCLUSION: A strategy screening only parous female donors is reasonable. Both automated HLA antibody detection platforms are easy to use and preferentially identify alloexposed individuals with antibodies of presumed higher titer directed against more recipient HLA antigens.     

An association between decreased cardiopulmonary complications (transfusion‐related acute lung injury and transfusion‐associated circulatory overload) and implementation of universal leukoreduction of blood transfusions

BACKGROUND: Cardiopulmonary adverse events after transfusion include transfusion‐related acute lung injury (TRALI) and transfusion‐associated circulatory overload (TACO), which are potentially lethal and incompletely understood. STUDY DESIGN AND METHODS: To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective, before‐and‐after study of acute transfusion reactions for the 7 years before and after introduction of universal leukoreduction in 2000, involving 778,559 blood components. RESULTS: Substantial decreases occurred in the rates of TRALI (?83%; from 2.8 cases per 100,000 components before to 0.48 after universal leukoreduction; p = 0.01), TACO (?49%; 7.4 to 3.8 cases per 100,000; p = 0.03), and febrile reactions (?35%; 11.4 to 7.4 cases per 10,000; p < 0.0001). The incidence of allergic reactions remained unchanged (7.0 per 100,000 before and after universal leukoreduction). These outcomes were primarily attributable to decreased TRALI and/or TACO associated with red blood cell (RBC) and platelet (PLT) transfusions (?64%) with notably smaller decreases associated with fresh‐frozen plasma or cryoprecipitate transfusions (?29%). The incidence of TRALI and/or TACO after 28,120 washed RBC and 69,325 washed transfusions was zero. CONCLUSION: These data suggest novel hypotheses for further testing in animal models, in prospective clinical trials, and via the new US hemovigilance system: 1) Is TACO or TRALI mitigated by leukoreduction? 2) Is the mechanism of TACO more complex than excessive blood volume? and 3) Does washing mitigate TRALI and TACO due to PLT and RBC transfusions?     

The practice of reporting transfusion‐related acute lung injury: a national survey among clinical and preclinical disciplines

BACKGROUND: Transfusion‐related acute lung injury (TRALI) is hypothesized to be a “two‐hit” entity, in which an inflammatory condition (e.g., sepsis) predisposes to TRALI. TRALI is a clinical diagnosis. Disciplines involved in managing TRALI may differ in decision‐making on the reporting of TRALI. STUDY DESIGN AND METHODS: A survey was conducted among critical care physicians, hematologists, hemovigilance workers, and transfusion medicine physicians, using case vignettes and a questionnaire. The vignettes varied in patient‐ and blood product–related factors that may influence the decision to report a TRALI case. Multiple linear regression analysis was performed. A positive β‐coefficient is in favor of reporting. RESULTS: Ninety‐two questionnaires were returned (response rate, 68%). For all disciplines, preferences in favor of reporting TRALI were onset of symptoms within 1 hour (β = 0.4), after transfusion of a single unit of FFP (β = 0.5), and in the absence of acute lung injury before transfusion (β = 1.3). An admission diagnosis of sepsis was a negative preference (β = ?0.3). Massive transfusion (6 RBC plus 4 FFP units) was a negative preference for transfusion medicine physicians (β = ?0.3), but a positive preference for the other disciplines. The questionnaire revealed that massive transfusion and the age of blood products were considered relatively more important reasons to report TRALI by critical care physicians compared to the other disciplines (p < 0.05). CONCLUSION: A pretransfusion inflammatory condition is a reason to withhold from reporting of a suspected TRALI case. Disciplines involved in managing TRALI differ in decision‐making of reporting TRALI, which may contribute to variance in incidence.     

A national survey of transfusion‐related acute lung injury risk reduction policies for platelets and plasma in the United States

BACKGROUND: Little information exists on the specific transfusion‐related acute lung injury (TRALI) risk reduction practices used by multiple blood collecting institutions in the United States. STUDY DESIGN AND METHODS: An AABB‐appointed TRALI working group designed a set of questions about TRALI risk reduction for platelets (PLTs) and plasma. AABB member institutions were asked to respond via an Internet‐based survey during a 3‐week period in August through September 2009. RESULTS: Valid responses were received from 47 US blood centers (accounting for 1.57 million apheresis PLT units and 3.15 million whole blood–derived transfusable plasma units) and 56 hospital blood collectors. Among the blood centers, 87 and 98% had initiated some PLT and plasma risk reduction, respectively. HLA antibody testing of plateletpheresis donors was performed by 20 (43%) blood centers. There was substantial variation in the number of pregnancies (from one to more than four) that triggered testing and most centers did not screen based on a transfusion history. Almost all centers had policies to redirect HLA antibody–positive donors to whole blood donation and to potentially retest HLA antibody–negative donors. There were no blood centers performing HNA antibody testing. Sex‐based risk reduction policies for plasma included all male, or predominantly male, and never‐pregnant females; these varied by blood center, blood group, and method of plasma collection. A majority of centers indicated increased production of plasma frozen within 24 hours after phlebotomy. CONCLUSIONS: Almost 3 years after the publication of the initial AABB bulletin on this issue, TRALI risk reduction strategies are commonly employed at most US blood centers. However, procedures are not uniform.     

Effective reduction of transfusion‐related acute lung injury risk with male‐predominant plasma strategy in the American Red Cross (2006‐2008)

BACKGROUND: Plasma components from female donors were responsible for most cases of transfusion‐related acute lung injury (TRALI) reported to the American Red Cross (ARC) between 2003 and 2005. Consequently, we began preferentially distributing plasma from male donors for transfusion in 2006 and evaluated the effect on reported TRALI cases in the ensuing 2 years. STUDY DESIGN AND METHODS: Suspected TRALI cases reported to the ARC Hemovigilance Program in calendar years (CY) 2006, 2007, and 2008 are described. Any case involving a fatality was also independently reviewed by three ARC physicians and classified as probable TRALI or not TRALI. RESULTS: The percentage of plasma collected from male donors and distributed for transfusion increased each year from 55% in CY2006 to 79% in CY2007 and 95% in CY2008. Independent medical review of the 77 reported TRALI cases involving a fatality identified 38 cases as probable TRALI. Plasma was the only component transfused in six of these cases in 2006, five in 2007, and zero in 2008. Overall, the analysis of reported fatalities and nonfatal cases demonstrates that TRALI involving only plasma transfusion was significantly reduced in 2008 compared to 2006 (32 vs. 7 cases; odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08‐0.45), to a level that was no longer different from the rate of TRALI observed for RBC transfusion (4.0 vs. 2.3 per 10⁶ distributed components; OR = 1.78; 95% CI = 0.67‐4.36). CONCLUSIONS: Reported TRALI cases from plasma transfusion decreased in 2008 compared to the prior 2 years simultaneously with the conversion to male‐predominant plasma for transfusion.