Transfusion-related acute lung injury (TRALI)
Previously known as transfusion-induced non-cardiogenic lung oedema, TRALI was first described in 1951 (2). In 1983, this pulmonary transfusion reaction was recognized as a distinct clinical entity and the term transfusion-related acute lung injury (TRALI) was coined (3). In 2004, a clinical definition of TRALI (4) has been established based on
- acute respiratory distress in temporal association (within 6 h) with transfusion,
- thorough exclusion of cardiogenic lung oedema and
- signs of hypoxaemia.
Pathogenesis (6): The specific architecture of the lung leads to unique properties of the pulmonary microcirculation. Since the diameters of 50% of the pulmonary capillaries are smaller than the average neutrophil size, even under physiologic conditions, neutrophils must stop several times and change their shape to squeeze through the narrow pulmonary capillaries resulting in a physiologic accumulation of neutrophils in the pulmonary microvasculature. In lung sections from TRALI patients, the number of neutrophils was further increased and the histological findings were consistent with early acute respiratory distress syndrome showing interstitial and intra-alveolar protein-rich oedema and extravasation of neutrophils. According to the nature of the neutrophil priming/activating factors (= TRALI triggers) antibody-mediated (immune) TRALI is distinguished from non-immune TRALI.
Antibody-mediated (immune) TRALI: In 1985, Popovsky and Moore (7) analysed a series of 36 patients with TRALI and reported a ventilation rate of 70%, a fatality rate of 6% and the presence of leukocyte antibodies in the blood of 89% of implicated donors. The leukocyte antibodies implicated in TRALI reactions are directed against human neutrophil alloantigens (HNA) and human leukocyte antigens (HLA). Among them antibodies to HNA-3a, the former 5b, HLA-A2 and to HLA class II antigens were very often implicated in severe and fatal cases (8). With the exception of HLA class II antibodies, these antibodies bind to recipient's neutrophils causing the cells to lose their ability to deform and to become primed or even activated. Sufficiently stimulated neutrophils release their microbicidal arsenal including lytic enzymes and reactive oxygen species (ROS) which damage the pulmonary endothelium resulting in increased plasma permeability for plasma and, especially in severe cases, in transendothelial migration of the neutrophils. The result is a protein-rich non-cardiogenic lung oedema. Since HLA class II antigens are not expressed on resting neutrophils, binding of HLA class II antibodies to monocytes with subsequent release of cytokines activating endothelial cells and neutrophils has been shown to be a likely mechanism (9).
Non-immune TRALI): The working group of Silliman, Boshkov and Ambruso has published a number of studies indicating that, in patients with a predisposing underlying disease, TRALI might be triggered by substances formed in platelets and red cells during storage. These substances include neutrophil-priming lipids such as platelet-activating factor (PAF) and CD40 ligand which prime neutrophils or which can enhance production of reactive oxygen species by primed neutrophils. In a large study of 90 non-immune TRALI reactions in 81 patients, those with haematological malignancies and cardiac diseases were identified as patients at risk for non-immune TRALI (10). In this study, non-cardiogenic lung oedema was not documented in all cases by chest radiography. With only one exception, all TRALI reactions were secondary to transfusion of platelets and red cells. Mechanical ventilation was required in 3% of the cases and, in a single patient, TRALI precipitated his death. It appears that a mild reaction is characteristic of non-immune TRALI, whereas leukocyte antibodies cause more severe TRALI reactions.
Differential diagnosis: It is important to exclude pulmonary oedema is due to cardiac disease, or due to volume overload, i.e. TACO. In contrast to TRALI, TACO is not accompanied by fever and hypertension is typical. Cardiogenic lung oedema shows also characteristic findings in the chest X-ray (enlarged cardiac silhouette, central infiltrates, enlargement of peribronchovascular spaces and presence of Kerley`s B lines), and in echocardiography (reduced myocardial function, valvular function); the pulmonary artery occlusion pressure is above 18 mm Hg and the plasma concentration of the brain natriuretic peptide (BNP) level is increased.
Leukocyte antibody detection (11) enables diagnosis of immune TRALI and prevention of further TRALI reactions by identification of the implicated donor and exclusion of their donated high plasma blood components. For standard leukocyte antibody detection, the recipient and the female parous donors of all blood components transfused within 6 hours prior to the reaction should be tested. In the case of inconspicuous findings and life-threatening or fatal TRALI, all donors of blood components transfused 6 hours prior to the reaction should be tested for the presence of leukocyte antibodies. Leukocyte antibody detection should be performed by experienced reference laboratories that participate regularly and successfully in national and international proficiency testing programs. Leukocyte antibody screening of blood donors includes detection of HLA class I and II as well as HNA antibodies. HNA antibodies are usually detected by immunofluorescence. However, HNA-3a antibodies which are known to cause severe TRALI reactions are often better detected by agglutination. For HLA antibody screening, antibody binding tests (EIA, immunofluorescence) are preferred, as they allow the detection of non-cytotoxic HLA antibodies which would be missed by lymphocytotoxicity assays. The number of panel cells used for antibody screening can probably be kept small: On the one hand, it is extremely unlikely that a leukocyte antibody recognizing a low frequency antigen will be transfused into a cognate antigen-bearing patient susceptible to TRALI; on the other hand, HLA antibodies are usually broadly reactive by recognizing public and private epitopes on the HLA molecules. However, due to their frequent involvement in severe TRALI cases, the panel cells should cover the HNA-3a and HLA-A2 antigens. Patient relevance should be made likely by pheno- or genotyping of the blood recipient for the cognate antigen or by a granulocyte crossmatch between donor serum and recipient neutrophils, whenever possible.
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11.Recommendations of the ISBT Working Party on Granulocyte Immunobiology for leukocyte antibody screening in the investigation and prevention of antibody-mediated TRALI. Vox Sang 2009;96:266-269