The influence of donor antibody strength and recipient antigens on transfusion‐related acute lung injury development

Clinical observations and animal models support the association of donor white blood cell (WBC) antibodies in transfusion-related acute lung injury (TRALI). In approximately 80% of TRALI cases it is believed that passive transfer of donor WBC antibodies to the recipient results in acute lung injury within 6 hours of transfusion. The injury consists of noncardiogenic pulmonary edema, which is often quite severe. In the remaining 20%, the recipient's antibodies that are directed toward donor WBCs are responsible. Many in the field believe that the frequency and the severity of TRALI most likely relate to the properties of donor antibodies and the recipient's antigenic make-up. Even then, we still have incomplete information about several aspects of antibody properties and the recipient's antigens. A number of case reports and case series of TRALI provide considerable information about donor antibodies, briefly summarized as follows: 1) they are directed toward WBCs (lymphocytes, monocytes, neutrophils); 2) their antigen specificity can include HLA, neutrophil, and monocyte antigens; 3) HLA antibodies can be directed to antigens of Class I (A, B, and C loci) and Class II (DR and DQ loci); 4) HLA antibodies can be monospecific, duospecific, multispecific, or nonspecific; 5) antibodies are of the IgG class of immunoglobulins that could be the complement-fixing variety; and 6) there is correspondence between the antibody specificity and the presence of matching antigen(s) in the recipient. Therefore, although we have considerable knowledge about donor antibodies, many questions remain to be addressed fully, including: Why does TRALI not manifest itself after passive transfusion of donor antibodies, even when antibody specificity matches with the recipient's antigens?1 Why does TRALI occur at a much lower rate than expected even though the donor antibodies can be found in approximately 10% of the transfused blood components? Does a combination of antibodies of different HLA classes have an additive and/or synergistic effect? What is the importance of epitope specificities of the antibodies? Can HLA antibodies that have specificity toward cross-reactive antigens of the recipients induce TRALI? Are antibodies of the IgA or IgM class of immunoglobulins important? Could naturally occurring HLA antibodies cause TRALI? Could other yet unexplored antibodies—such as those directed towards HLA DP, MHC Class I–related chain A (MICA), and endothelial cells—cause TRALI? Why are antibodies against human neutrophil antigen 3a (HNA-3a) more likely to cause fatal TRALI than other HNA antibodies?2 This extensive list of questions is by no means exhaustive and other experts would most likely identify other grounds for future research. We also have limited information about the significance of the amount, strength, and titer of antibodies. The amount of antibody infused seems to be important because there is known to be a higher risk with transfusion of plasma-rich components compared to non–plasma-rich components. The lack of TRALI from transfusion of solvent/detergent (S/D)-treated plasma prepared from a pool of a large number of plasma units also implies that the dilution does not permit infusion of a threshold dose of antibodies that can induce TRALI.3 Since as little as 10 to 20 mL of plasma is sufficient to cause TRALI when multiple antibodies of sufficient strength are transfused, the strength of the antibody is clearly important.4 It is possible that milder forms of TRALI may be caused by low-strength antibodies. The antibody properties described above cannot be viewed in isolation and should be considered in conjunction with the antigenic make-up of the recipient of such antibodies (i.e., the “seed and soil” theory). In fact, consideration of the recipient's antigenic make-up is a requirement for serologic confirmation of a TRALI diagnosis, since there must be a positive crossmatch between the donor antibodies and the recipient's cells or the recipient must possess antigens that match the specificities of the donor antibodies. One explanation for why the injury is confined to the lungs may be that all of the infused antibodies are trapped in the lungs during the first pass.5 Other tissues and organs are spared from the damage because the antibodies never reach them. Alternatively, some antibodies do escape the lungs but are neutralized by circulating soluble antigens before they reach other tissues and organs. Heterogeneous antigen expression among different tissues and organs might also account for why the injury seems to be localized to the lungs.6 There is also uncertainty about how well the cognate antigens are expressed on target cells. In TRALI, a transient decrease in the total circulating WBC count is seen in some patients and not others7 and this difference may be due to the variable expression of the antigens on circulating WBCs. Up or down regulation of the antigens resulting from comorbid factors—referred to as “first hit”—also supports variable expression of antigens. The role of soluble antigens in plasma has not been explored in TRALI development. It is possible that soluble antigens in plasma can neutralize passively administered antibodies, thus mitigating injury to the lungs. Supporting this argument is the observation that there are no reports of TRALI from S/D plasma, in which HLA antibodies are diluted and possibly neutralized by the soluble HLA antigens.3 In contrast to this sparing effect of the soluble antigens, they might be harmful if they first form circulating immune complexes with their corresponding antibodies. These immune complexes may bind to the Fcγ receptors of target cells, which can cause lung injury.8 Thus, several aspects of the recipient's antigenic make-up require further research. According to the threshold model of TRALI, the occurrence and severity of TRALI is dependent on the degree of neutrophil activation by the transfused mediators and the individual patient's susceptibility.9 In this regard, the strength of the transfused mediators (antibodies, lipids, etc.) is an important determinant for the occurrence and severity of TRALI.9 The Canadian Consensus Conference did recognize the possibility of mild to moderate forms of TRALI, but the conference elected to include only the more severe forms in its diagnostic definition of TRALI.10 Mild forms of TRALI have been recognized as “touch of TRALI,” in which the implicated donors had low-titer HLA antibodies (2-8).11 Milder forms have also been noted on lookback studies of previously donated blood components from an implicated donor with neutrophil antibody.12 Aside from these milder forms of TRALI, other cases of respiratory symptoms after transfusion that do not fit into these categories have been described. The biovigilance component of the Health Care Safety Manual of the Centers for Disease Control includes transfusion-associated dyspnea (TAD), defined as respiratory distress within 24 hours of transfusion that does not meet the criteria of TRALI, transfusion-associated cardiac overload (TACO), and allergic reaction.13 Whether these protean manifestations after transfusion are milder forms of acute lung injury or not remains a question. In this issue of the journal, Hashimoto and colleagues14 conducted a study to determine whether patients with TRALI received donor units with a higher cognate HLA Class I and II antibody signal than the units received by patients who had possible TRALI or febrile nonhemolytic transfusion reaction (FNHTR). They present data on 21 cases of TRALI, four cases of possible TRALI, and five cases of FNHTR. They found that in the majority of TRALI cases, there was more than one donor HLA antibody that was matched with the recipient antigens, which suggests synergism among different cognate antibodies in TRALI development. These investigators measured the strength of donor antibodies as mean fluorescence intensity (MFI) with the single-antigen bead assay and found that the sum of the MFI of antibodies in TRALI cases was significantly higher than the sum of the MFI observed in FNHTR. The antibody strength in possible TRALI was midway between that seen in TRALI and FNHTR. MFI was used as a surrogate for antibody strength because it has been correlated previously with molecules of equivalent soluble fluorochrome and antibody titer. Some samples were tested by enzyme immunoassay and higher optical density values were seen with cognate antibodies in TRALI cases when compared to the values in FNHTR cases. They concluded that the HLA antibody strength correlates with TRALI development. According to these observations, lower-strength antibody can produce possible TRALI (i.e., TRALI with risk factors for acute lung injury) because of the possibility that the antigen expression may have been up regulated or the target cells may have been primed by the coexisting clinical conditions. One limitation of data of Hashimoto and colleagues is that they were unable to test a significant number of the involved donors and patients referred to their laboratory for evaluation due to a lack of adequate sample available for testing. Also, their data cannot be applied to neutrophil antibody–mediated TRALI because they did not test donors for neutrophil antibodies. The data of Hashimoto and colleagues may be relevant for understanding the etiology of unclassified TAD. It is possible that such cases are the result of minor forms of acute lung injury caused by low-strength donor antibodies. However, we should be cautious in arriving at such a conclusion because of the lack of supporting clinical or laboratory data for TAD. Nonetheless, measurement of antibody strength in such cases may provide some insight to this entity. The data of Hashimoto and colleagues should serve as an impetus to undertake further research to advance our understanding of the grades of acute lung injuries that result from a combination of low-strength donor antibodies and specific characteristics of the recipient's antigen make-up. None.

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