Potential Pathomechanisms of Reverse Transfusion-Related Acute Lung Injury (TRALI): an Underrecognized Transfusion Complication

Transfusion-related acute lung injury (TRALI) is a potentially fatal blood transfusion complication that is characterized by noncardiogenic pulmonary edema within 6 hours post-transfusion. Specific therapies are not available, thus understanding the pathophysiological mechanisms is essential. Currently, our understanding of the TRALI pathophysiology is based on a 2-hit requirement. The first hit constitutes a priming of the immune system associated with systemic inflammation. The second hit comes through transfused antibodies reactive against recipient leukocytes and/or endothelium, or biological response modifiers. Interestingly, recent case reports suggest a so far underrecognized occurrence of TRALI by a reverse mechanism in the presence of leukoreduced products. In this so called "reverse TRALI," preexisting recipient antibodies react with transfused components such as cells or soluble antigens, triggering pulmonary endothelial cell damage culminating in pulmonary edema through predominantly unknown and unexplored mechanisms. In this review, we have summarized the published literature with suspected reverse TRALI cases, consisting of 11 clinical reports of 25 patients in total (1976-2022). Remarkably, we observed a trend in reverse TRALI cases attributed to granulocyte transfusions in 13 out of 25 cases (52%). The pathomechanisms of reverse TRALI are largely uninvestigated. To start shedding light on this, we furthermore propose several potential mechanisms for reverse TRALI based on literature. We have stratified on transfused soluble antigens, in relation to recipient cells such as polymorphonuclear leucocytes, macrophages/monocytes, and to pathogenic processes including antibody-Fc mediated complement activation, production of reactive oxygen species (ROS), formation of neutrophil extracellular traps (NETs) and secretion of pro-inflammatory cytokines. Our hypothesized pathomechanisms of reverse TRALI are a starting point to investigate this transfusion complication, with potential diagnostic, preventive and therapeutic implications.