Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorphonuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40Lwere measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 g/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients. IntroductionCD40 is a 48-kDa transmembrane glycoprotein and a member of the tumor necrosis factor (TNF) receptor family expressed on endothelial and epithelial cells, monocytes, and macrophages. 1 CD40 ligand (CD40L [CD154]) is a primarily platelet-derived pro-inflammatory mediator found in soluble (sCD40L) and cellassociated forms in transfused blood. 2,3 Soluble CD40L activates macrophages and elicits the production and release of multiple proinflammatory cytokines. 4 Furthermore, inhibition of the CD40-CD40L system in animal models reduces acute lung injury (ALI) caused by endotoxin (lipopolysaccharide [LPS]) or oxygen toxicity. [5][6][7] In addition, sCD40L is present in platelet concentrates and accumulates over routine 3-to 5-day storage times. 3 Polymorphonuclear leukocytes (PMNs) are critical in host defense against pathogens and exert their major microbicidal function in the tissues. 8,9 PMN priming is initiated by the attraction and adhesion of PMNs to activated vascular endothelium and continues until the pathogens are phagocytosed and destroyed. 6,[10][11][12] PMN-mediated acute lung injury (ALI) requires at least 2 separate events: endothelial activation, which includes the synthesis and release of chemokines and the increased surface expression of adhesion molecules that elicit PMN adhesion, and activation of adherent PMNs, which causes the release of their microbicidal arsenal and results in endothelial damage, capillary leak, and ALI. 10,11,[13][14][15][16] Such a 2-event model has been proposed for ALI, especially for transfusion...

When data restricted to patients receiving transfusions are analyzed, and no data absent from the actual investigations are introduced, leukoreduced transfusions substantially and significantly reduce the odds of postoperative infection by approximately 50 percent. These results demonstrate the importance of including only scientifically valid data in clinical trials and meta-analyses. The intention-to-treat principle should never lead to inclusion of data not actually derived from experimental results.

These are the first data demonstrating that a PLT-derived mediator, sCD40L, is associated with adverse transfusion events. Existing clinical factors, for example, inflammation or leukopenia, may influence whether infused mediators cause reactions.