Specific risk factors for TRALI can be divided conceptually into recipient-related risk factors and transfusion-related risk factors [14].

Many comorbidities have been suggested as TRALI risk factors, including end-stage liver disease, coronary artery bypass graft, hematological malignancies, massive transfusion, mechanical ventilation, sepsis, and heavy alcohol consumption [14]. Critical illness is one of the highest risks for TRALI [11,13]. A large database review of 11 million elderly patients in the United States revealed that TRALI rates are higher in patients receiving a transfusion, including platelets or plasma [15]. TRALI incidence increase as the number of units transfused increases. A review also identified that elderly female Caucasians 65-79-years-old with a 6-month history of post-inflammatory pulmonary fibrosis and tobacco use have a greater chance of developing TRALI [15].

Immunoglobulin [16] and stem cell preparations [17] are also associated with TRALI. A case-control study enrolled 89 patients with TRALI and 164 controls. The study revealed that a higher TRALI odds ratio (OR) is associated with plasma from female donors (OR, 4.5; 95% confidence interval [CI], 1.85-11.2) and a greater number of transfusions (OR, 4.5; 95% CI, 2.4-8.4). [18] Blood products including high-plasma-volume (platelet concentrates, whole blood, and FFP) have been associated with a higher incidence of TRALI [13]. High loading of anti-human neutrophil antigen antibody has also been associated with TRALI [18]. In contrast, the presence of anti-human leukocyte antigen (HLA) class II or anti-HLA class I antibodies is not associated with TRALI.

The age of a blood product has been suggested to increase the risk for TRALI [19]. Storing red blood cells (RBCs) results in a number of morphological and biochemical alterations known as RBC storage lesions. However, two studies failed to reveal blood age as a risk factor for TRALI [13,18].

A two-hit hypothesis has been suggested for developing TRALI [20]. The first hit involves neutrophil sequestration and priming in the pulmonary endothelium, which precedes transfusion. Endothelial cells are thought to be responsible for both neutrophil sequestration and priming. The second hit is caused by activation of the endothelium and neutrophils by mediators in the transfused blood, resulting in capillary leakage and pulmonary edema. The second hit differs in antibody-mediated TRALI and non-antibody-mediated TRALI. Non-antibody-mediated TRALI is caused by the accumulation of proinflammatory mediators during storage of blood products and possibly by ageing of RBCs and platelets [21], whereas antibody-mediated TRALI or immune TRALI is caused by passive transfusion of HLA or human neutrophil antigen (HNA) and corresponding antibodies from the donor directed against recipient antigens [22]. Donor anti-leukocyte antibodies interact with recipient neutrophils, monocytes, and/or the pulmonary endothelium [14]. Bioactive lipids and other factors in transfused blood act as biological response modifiers in patients with non-antibodymediated TRALI. The proportions of antibody-mediated vs. non-antibody-mediated TRALI cases remain unclear. A systemic review showed that 86% of TRALI cases are associated with leukocyte antibodies [23].

The two-hit hypothesis explains the occurrence of TRALI in high-risk patients. However, this hypothesis does not fit TRALI that develops in healthy recipients; the threshold model has been proposed to explain these cases [24]. This model generally agrees that two hits are needed to develop TRALI. However, the threshold model assumes that TRALI can occur when the second hit is so strong that an initial priming event is not needed. In other words, a large quantity of antibody (second hit) can cause TRALI in a recipient with no previous predisposition, such as in healthy individuals.

TRALI presents as sudden onset of respiratory difficulties during or shortly after transfusion. Hypoxemia and lung infiltrates are detected on chest X-rays in almost all patients with TRALI, and half of patients show a pinkish, frothy sputum [25]. Tachypnea, tachycardia, and elevated airway pressure are frequently observed. Fever, hypotension, and cyanosis occur in less than one-third of patients with TRALI.

Confirming hypoxemia, obtaining a chest X-ray, and evaluating vital signs are required to diagnose TRALI.

No laboratory test is specific for diagnosing TRALI. The greatest change is a transient drop in peripheral neutrophil count (possibly due to neutrophil sequestration in the pulmonary vasculature). Leucopenia occurs in 35% of patients after transfusion with an antibody-containing blood product [26].

TRALI should be distinguished from pulmonary edema due to other causes. Hemolytic and septic transfusion reactions present similarly to TRALI. Anaphylaxis can cause respiratory insufficiency similar to that of TRALI, but airway signs and symptoms are more common in patients with anaphylaxis. ALI/ARDS should be distinguished from TRALI in patients with risk factors for ALI/ARDS prior to a transfusion.

Transfusion-associated circulatory overload (TACO) is another cause of transfusion-related respiratory insufficiency (Table 2) [27]. Impaired myocardial function and rapid and aggressive fluid therapy are suggested risk factors for TACO. TRALI is more likely to be associated with signs and symptoms of inflammation, including fever, hypotension, and an exudative pulmonary infiltrate. In contrast, TACO is more likely to be associated with findings suggestive of cardiac dysfunction and/or volume overload.

Mortality due to TRALI is 5-10%, in contrast to ARDS [31]. However, 90-day mortality associated with TRALI can reach 47% in critically ill populations [13]. Long-term pulmonary function in TRALI survivors seems to be similar to that of patients who have never experienced TRALI, and no apparent late complications, such as fibrosis or other structural damage to the lung parenchyma occur as a result of TRALI [13]. The clinical course of patients with TRALI is suggested by quick resolution (~2 days) of hypoxemia.

Cases suspected of TRALI should be promptly reported to the blood bank. The blood bank should investigate all associated donors for the presence of anti-HLA and anti-HNA antibodies to identify donors with these antibodies and prevent them from future donation. This is particularly true if the donor has anti-HNA 3a [32].

In addition, several general blood donor management strategies are in use to reduce the incidence of TRALI [32,33,34,35,36,37,38]. First, adherence to current guidelines for utilizing blood components, particularly those for plasma, is mandatory to decrease exposure risk for patients. A restrictive transfusion strategy has been associated with a lower incidence of TRALI compared with that of a liberal transfusion strategy [39]. Clifford et al. [40] reported that patients transfused with greater volumes of blood components develop perioperative TRALI/possible TRALI more frequently than that reported previously. He reported that the overall incidence of TRALI was 22.46 per 100,000 stays. Optimal transfusion guidelines should provide sufficient blood products to maximize clinical outcomes while avoiding adverse events, such as TRALI. However, no golden transfusion guidelines exist for all patients. Clinicians should consider many factors when deciding to transfuse anemic patients, rather than basing the decision solely on a specified laboratory level. In this respect, Carson et al. [41] demonstrated that liberal blood transfusion approach with a hemoglobin concentration threshold of 90-100 g/L does not affect mortality in a high-risk group of elderly patients with underlying cardiovascular disease or risk factors, compared with that of a restrictive transfusion strategy with a hemoglobin concentration threshold of 70-80 g/L. Therefore, the final decision to transfuse should incorporate the patient's clinical condition, co-morbidities, and the individual wishes of the patient. Second, donors with little chance to be alloimmunized to leukocytes should receive high plasma volume components (e.g., FFP, plasma frozen within 24 h of phlebotomy [FP-24], plasma, cryo-reduced plasma, apheresis platelets, or whole blood). Third, use pooled solvent detergent-treated plasma as an alternative to FFP. Fourth, test for anti-HLA antibodies in pregnant donors before apheresis of platelets or plasma. In particular, several management strategies including deferral of multiparous female donors are in use to reduce the incidence of TRALI [42].