SummaryIn recent years, transfusion-related acute lung injury (TRALI) has developed from an almost unknown transfusion reaction to the most common cause of transfusion-related major morbidities and fatalities. A clinical definition of TRALI was established in 2004, based on acute respiratory distress, noncardiogenic lung oedema temporal association with transfusion and hypoxaemia. Histological findings reveal lung oedema, capillary leucostasis and neutrophil extravasation. However, the pathogenesis of TRALI remains controversial. Leucocyte antibodies, present in fresh frozen plasma and platelet concentrates from multiparous donors, and neutrophil priming agents released in stored cellular blood components have been considered to be causative. As neutrophils and endothelial cells are pivotal in the pathogenesis of TRALI, a threshold model was established to try to unify the various reported findings on pathogenesis. This model comprises the priming of neutrophils and/or endothelium by the patient's co-morbidity, neutrophil and/or endothelial cell activation by the transfused blood component, and the severity of the TRALI reaction.

Background Antibody-mediated transfusion-related acute lung injury (TRALI) is an important cause of transfusion-associated morbidity and death. Preventive strategies are currently a matter of debate.Methods Specificities of leucocyte antibodies implicated in previous severe TRALI reactions were determined using standard techniques. Based on these results, a leucocyte antibody screening strategy for the testing of parous female donors was introduced. ResultsOf 36 TRALI cases, 17, 12, four and three were due to human leucocyte antigen (HLA) class II, human neutrophil alloantigen (HNA), HLA class I, and mixtures of HLA class I and II antibodies, respectively. HNA-3a antibodies accounted for 10 of 12 HNA antibody-mediated reactions and 6 of 10 fatalities including one after transfusion of red blood cells. Investigation 5332 parous female donors showed leucocyte antibodies in 473 samples, resulting in an alloimmunization rate of 8·9%. Sixty-one per cent of these donors presented HLA class I, 19% class II, 12% HLA class I and II antibodies and 5% HNA antibodies. Additional HLA class I antibodies were found in 39% of HLA class II and in 17% of HNA antibodies containing sera. Our restrictive plasma strategy did not result in a shortage of plasma or platelets. No antibodymediated TRALI case was observed since introduction of the policy of plasma from male, nulliparous or tested multiparous donors. ConclusionCompared to HLA class I antibodies, those directed against HLA class II and HNA-3a were of greater clinical relevance. Isolated HLA class I antibody screening was found to be insufficient for leucocyte antibody screening.

Most of the HNA antigens have been well-characterized so that HNA typing as well as the detection of the corresponding antibodies are now reliably possible. This will improve diagnostics of neutrophil antibody-mediated clinical conditions as well as the prevention of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a frequent cause of transfusion-associated morbidity and mortality. Severe TRALI is often due to antibodies in blood components directed against the human neutrophil alloantigen-3a (HNA-3a). We show here that the HNA-3a antigen arises from a nucleotide polymorphism in the choline transporter-like protein-2 gene (SLC44A2), with the resulting variation at amino acid position 154 determining the reactivity of the protein with HNA-3a-specific antibodies; the variant with an arginine at this position, rather than a glutamine, constitutes the HNA-3a antigen. The molecular identification of this antigen should facilitate the development of assays for blood donor screening to lower the risk of TRALI.