In 2004, the National Heart, Lung, and Blood Institute convened a working group to identify a common clinical definition to promote research in TRALI. The diagnosis must satisfy the criteria for acute lung injury (ALI), including (1) acute onset, (2) hypoxemic lung disease with (3) bilateral infiltrates on frontal chest radiograph, and (4) no evidence of left atrial hypertension (Table 1).⁹ If an arterial blood gas is not available, an oxygen saturation (SPo₂) of 90% or less meets the acute hypoxemia criterion when a patient is breathing room air at sea level.²

Table 1 Diagnostic criteria for transfusion-related acute lung injury (TRALI)

In addition to meeting the standard criteria for ALI, TRALI requires further criteria (see Table 1). A patient must develop ALI during or within 6 hours of transfusion and no ALI may be present before transfusion. If alternative ALI risk factors exist (ie, sepsis, trauma, aspiration), TRALI can still be diagnosed if the clinical course of the patient suggests that ALI resulted mechanistically from the transfusion alone or a synergistic relationship between the transfusion and the underlying risk factor. If the temporal relationship between the transfusion and ALI (within 6 hours) is considered coincidental to the development of ALI from an alternate risk factor, a diagnosis of TRALI should not be used.² Laboratory findings are not included as diagnostic criteria for TRALI; however, transient acute leukopenia, leukocyte antigen–antibody match between donor and recipient (HLA class I or II, anti-granulocyte or anti-monocyte), or increased neutrophil priming activity in the plasma of blood products have been described and support the diagnosis of TRALI.²

The differential diagnosis for patients who develop respiratory distress during or within a few hours after transfusion include TRALI, TACO, an anaphylactic transfusion reaction, and transfusion of contaminated (bacteria) blood products. Differentiating these four syndromes is difficult due to similarities in their clinical presentation. Pulmonary complications of TRIM are delayed, so this transfusion complication is not considered in the context of an acute onset.

Differentiating TRALI (permeability pulmonary edema) from TACO (hydrostatic pulmonary edema) is difficult in the setting of underlying heart failure, renal failure, massive transfusion, or resuscitation.¹⁰ In both syndromes the acute onset of pulmonary edema results in severe dyspnea, tachypnea, and worsening or new hypoxemia. Transient neutropenia may support the diagnosis of TRALI due to neutrophil sequestration in the lung, but if not present it does not rule out TRALI.¹¹ TRALI is more commonly associated with relative hypotension while TACO results in relative hypertension from pre-transfusion to post-transfusion. Clinical factors differentiating TACO from TRALI include distended neck veins, S3 on cardiac examination, and peripheral edema consistent with volume overload. A chest radiograph with septal lines, cephalisation, and an enlarged vascular pedicle (>65 mm) is more consistent with TACO. The most important clinical determinant of TACO is the rapid resolution time of the patient’s pulmonary edema after successfully reducing pulmonary capillary pressures through diuresis. Antibody testing of the implicated blood components lacks sensitivity for TRALI because non-antibody–mediated mechanisms are common. However, testing is still recommended and may be helpful if antibody levels are detected.

Unlike TRALI and TACO, anaphylactic transfusion reactions usually present with bronchospasm rather than pulmonary edema. As a result, wheezing rather than crackles are heard during pulmonary auscultation and a clear chest radiograph rather than new infiltrates will accompany the respiratory distress. Similar to TRALI, fever and vasodilatory shock is common with anaphylaxis, but erythema and edema with associated urticaria over the head, neck, and trunk is more consistent with anaphylaxis.¹² Lastly, the transfusion of contaminated PRBCs or platelet concentrates may result in transfusion-related bacterial sepsis that manifests as septic shock and acute lung injury. Transfusion-related bacterial sepsis must be considered if septic shock is the overriding clinical presentation, and culturing the component bags is essential for diagnosis.¹²

Multiple animal studies as well as epidemiologic and translational observations in humans with TRALI support a two-event mechanism. First, the pulmonary vascular endothelium is activated resulting in neutrophil “priming” and adhesion within the pulmonary microvasculature. Many different clinical states can trigger this “first event” (ie, sepsis, surgery, trauma, systemic inflammatory state). These primed, sequestered neutrophils are hyperactive and easily activated by a “second event.” Identified triggers in blood components known to induce a “second event” and subsequent TRALI in humans and animals include donor antibodies to recipient leukocyte antigens, bioactive lipids, soluble CD40-ligand, microparticles, and others.^13,14 Animals develop TRALI after transfusion of blood components with high concentrations of known TRALI mediators (second event) only when administered lipopolysaccharide (first event) before transfusion.^15,16 In rare situations, a “first event” is not required because certain antibody–antigen interactions (most commonly HNA-3a, an anti-neutrophil antibody) from blood components alone have enough activation energy to trigger the whole chain of events.¹⁷

Multiple disease processes are capable of activating the pulmonary vascular endothelium and inducing adherence of neutrophils.¹⁷ The higher incidence of TRALI in ICU patients (8%), as compared to a mixed population of hospitalized patients (0.16%) at the same institution, is likely a result of the “primed” state induced by critical illness.^18,19

The reported incidence of TRALI is extremely variable and highly dependent on the inflammatory state and characteristics of the patient population studied.^20,21 Retrospective “look-back” studies suggest that TRALI is grossly under-recognized, so the incidence reported in studies utilizing passive surveillance underestimates the true incidence.^22,23 Only recently have prospective surveillance studies of transfused critically ill and operative patients recognized the alarming incidence of TRALI in the critically ill.^18,24–27 In the ICU, 37% to 44% of patients receive blood products, with the incidence rising to 85% in patients in the ICU for 7 days or longer.^1,28 Recent prospective observational trials demonstrate that 5% to 8% of all transfused patient admitted to a medical and surgical ICU develop TRALI. The incidence of TRALI is 2.4% in cardiac surgery and 1.3% in patient undergoing liver transplantation, but rises to 29% intransfused patients with chronic liver disease who are actively bleeding from varices.^24,27,29

When evaluating TRALI risk, two questions should be asked: what is the inflammatory state of the patient and what type and volume of planned blood component exposure is planned?

TRALI risk is highly dependent on the pretransfusion clinical state of the patient and the amount of exposure to blood components. In addition, different types of blood components carry different risks that are independent of the patient’s clinical state. Therefore, both patient-specific and transfusion-specific factors need to be considered when determining the patient-specific risk versus benefit for each planned unit of transfused blood component.

TRALI is common in critically ill patients

The presence of multiple clinical risk factors for acute lung injury (ALI) increase the susceptibility to the subsequent development of TRALI.^30–32 Common risk factors for ALI include sepsis, trauma, aspiration, heavy alcohol use, mechanical ventilation, massive transfusion, and pneumonia.^14,24 More specifically, transfusion is an independent risk factor, in a dose-dependent manner, for the subsequent development of TRALI in patients with these preexisting ALI risk factors.^30,33–37 Consistent with the “two-event” mechanism, transfusion appears to act synergistically with other diagnoses that predispose patients to ALI. Two large prospective trials performed in the Unites States (n = 901) and Europe (n = 2024) demonstrate a TRALI incidence of 8% and 5% respectively. In these studies, sepsis and emergent surgery were strong independent risk factors for the development of TRALI. In addition, a cohort study of 225 patients admitted to an ICU due to gastrointestinal bleeding revealed a TRALI incidence of 29% in bleeding patients with chronic liver disease. In critically ill patients receiving massive transfusion the incidence of ALI is 21% to 45%, though these studies do not report the number of cases that were temporally related to transfusion (within 6 hours).^30,32,35 Collectively, these studies confirm the extraordinary high and variable incidence of TRALI in critically ill patients (Fig. 1).

Fig. 1 Definition and risk factors for TRALI. TRALI is defined as ALI that develops within 6 hours of a transfused blood component and has a high mortality in ICU patients. TRALI is commonly due to plasma-containing blood components and is prevalent in ICU patients due to both antibody-mediated and non-antibody–mediated mechanisms.

When TRALI is diagnosed, the management is similar to the management of ALI from other causes. This includes supportive care that entails optimization of mechanical ventilator parameters (low tidal volume) to avoid further injury to the lung while reducing pulmonary venous pressures with diuretics in patients without shock.^25,48 A restrictive transfusion strategy should be employed because transfusions in patients with existing ALI worsen outcomes.³⁵