Transfusion-related acute lung injury

Did You Know?

• The mainstay of therapy in TRALI is supportive care; 72% of patients require aggressive respiratory support.
• Diuretics are to be avoided in treating TRALI, although they are indicated for transfusion-associated circulatory overload.
• Corticosteroids can be beneficial in TRALI treatment.

Signs and symptoms

TRALI often cannot be distinguished from acute respiratory distress syndrome (ARDS). Typical presentation includes sudden shortness of breath, severe hypoxemia (oxygen saturation below 90% on room air), low blood pressure, and fever developing within 6 hours of transfusion, usually resolving with supportive care in 48 to 96 hours. Although low blood pressure is a key diagnostic sign, high blood pressure may occur in some cases. Delayed TRALI, occurring 6 to 72 hours after transfusion, carries a higher mortality rate.

Cause

The cause of TRALI is not fully understood. About 80–85% of cases are thought to be immune mediated, involving antibodies against human leukocyte antigens (HLA) or human neutrophil antigens (HNA). These transfused antibodies bind to antigens on pulmonary endothelial cells, triggering acute lung inflammation. Multiparous women often develop such antibodies through fetal blood exposure, and transfusion of their plasma-rich components carries higher risk. A two-hit hypothesis is proposed: pre-existing pulmonary pathology (first hit) localizes neutrophils to lung microvasculature; the second hit occurs when transfused antibodies activate those neutrophils, releasing cytokines and vasoactive substances that cause non-cardiac pulmonary edema. Non-antibody-mediated TRALI may involve bioactive lipids in stored blood components that prime neutrophils. TRALI is typically linked to plasma products like fresh frozen plasma but can also occur with packed red blood cells. To reduce risk, the AABB recommends avoiding transfusion of high-plasma-volume components from female donors; Germany since 2009 excludes female donors with a pregnancy history unless HLA/HNA screening results are available, leading to fewer TRALI reports.

Pathophysiology

First-hit risk factors for TRALI include long-term excessive alcohol use, shock, liver surgery, current smoking, high peak airway pressure during mechanical ventilation, positive fluid balance, low interleukin-10 levels, and systemic inflammation. Elevated C-reactive protein (CRP), an acute-phase biomarker, has been observed in TRALI patients and, in a mouse model, enables the first hit by increasing lung accumulation of a neutrophil homolog of interleukin-8. Pre-existing lung injury also predisposes patients by localizing white blood cells in pulmonary vessels. The second hit is conveyed by anti-leukocyte antibodies in about 80% of cases (anti-HLA class I or II or anti-HNA antibodies), with non-antibody factors such as lipid mediators, extracellular vesicles, and aged blood cells implicated in the remaining 20%.

Diagnosis

TRALI is defined as acute lung injury temporally related to blood transfusion, occurring within the first six hours after transfusion. It is typically associated with plasma components like platelets and fresh frozen plasma, though cases occur with packed red blood cells due to residual plasma, and with other products such as cryoprecipitate, granulocytes, intravenous immune globulin, and stem cells. Diagnosis is based on clinical manifestations within 6 hours of transfusion: acute respiratory distress, tachypnea, hypotension, cyanosis, and dyspnea. It is an uncommon syndrome, believed to occur in about one per 5000 transfusions, due to leukocyte antibodies in transfused plasma. Leukoagglutination and pooling of granulocytes in the lungs may occur, releasing granule contents that injure cellular membranes and lung parenchyma. Most cases result in mild dyspnea and pulmonary infiltrates that resolve spontaneously; occasionally severe lung injury leads to ARDS. Leukocyte filters do not prevent TRALI because most cases involve donor antibodies to leukocytes. Transfused plasma may also contain antibodies cross-reacting with recipient platelets, causing mild posttransfusion purpura.