Transfusion-related Acute Lung Injury

Vol. 15 •Issue 9 • Page 22
Transfusion-related Acute Lung Injury

Many times TRALI is under-recognized and under-reported.

Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related death in North America with an increasing incidence; however, research in this area has been plagued by the use of different definitions dependent upon the locale where TRALI occurred.1

Universally, TRALI is under-recognized and under-reported due to many factors. It’s imperative for pulmonologists, intensivists, surgeons, and other specialists to understand transfusions play a role in the genesis and propagation of acute lung injury (ALI). They should consider the diagnosis of TRALI in all cases of respiratory distress with significant hypoxemia temporally related to a transfusion.

Although first reported in the 1950s, TRALI wasn’t recognized as a distinct clinical entity until 1985.2 TRALI isn’t physiologically different from other forms of ALI, including acute respiratory distress syndrome (ARDS).3

Because the incidence of TRALI is increasing in the U.S., the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health crafted a consensus definition.4 A number of other countries have followed suit, but the definition still varies.

In North America, the reported incidence of TRALI ranges from one in 100,000 to one in 1,323 (depending upon the transfused product), with an increased number of cases annually.5-7 All blood components have been implicated in TRALI reactions.6-8

Clinical presentation and treatment

TRALI occurs within six hours of transfusion with the majority of cases presenting either during or within the first two hours. The clinical findings are those of respiratory distress with the rapid onset of tachypnea, cyanosis, dyspnea, and fever.2,9

The physiologic findings include acute hypoxemia and decreased pulmonary compliance despite normal cardiac function. The NHLBI panel suggests pulse oximetry, in addition to the usual vital signs monitoring, may be reasonable in all transfused patients.4 Radiographic examination reveals diffuse, bilateral, fluffy infiltrates consistent with pulmonary edema.

Treatment consists of aggressive respiratory support, including supplemental oxygen and mechanical ventilation. Milder forms of TRALI have been described that may require prompt delivery of oxygen alone, and there’s no role for treatment with corticosteroids or diuretics.2,9 The mortality from TRALI is 5 percent to 25 percent, with lower mortality rates being more common, and most patients recover within 72 hours.2,6,9

The differential diagnosis of patients who have the sudden onset of respiratory distress during or following transfusion must include circulatory overload, allergic transfusion reactions, and transfusion of blood products contaminated with bacteria.7

Patient predisposition

Researchers postulate TRALI is the result of two distinct clinical events: the first linked to the patient’s clinical condition and the second to the transfusion itself.5,6

A number of patient groups appear to be predisposed to TRALI as compared to control groups of transfused patients. Pediatric patients have the same risk factors as adults; however, as with any form of ALI, TRALI is less frequent in the young.

Active infection is the most common predisposing clinical condition for the development of ALI.3,7,9 In addition, patients receiving fresh, frozen plasma for coumadin reversal and patients with thrombotic thrombocytopenic purpura who have widespread endothelial activation also appear to be predisposed to TRALI.7,9 Lastly, in the largest epidemiological study of ARDS, blood transfusion was implicated as the most common risk factor for its genesis; however, TRALI was never considered.10

Pathogenesis: vascular endothelium

The pulmonary vascular endothelium is an important part of the innate immune system, and its interaction with polymorphonuclear cells (PMNs) is crucial for eradicating inhaled pathogens.7,11 In response to infection, neutrophils accumulate (sequester) in the capillary beds prior to emigration into the lung proper. PMN emigration is directed by the endothelial cells and is comprised of adhesive events and squeezing of the PMNs between endothelial cells (diapedesis) to enter the lung.7,11

If this orderly process is out of sequence — for instance, if the endothelium is activated by intravascular stimuli — it may result in sequestration of PMNs in the capillaries that are unable to traverse the lung. Such sequestration could result in ALI if a second event activates these adherent granulocytes and causes a focused release of the neutrophil microbicidal arsenal (defense against bacteria) into the pulmonary endothelial cells to which they adhere, resulting in endothelial damage and capillary leak of blood and plasma into the lung.7,11

Antibody-mediated TRALI

The pathogenesis initially was thought to be due to the infusion of donor antibodies directed against discrete antigens (HLA class I, class II, or granulocyte-specific antigens) on the surface of the recipient’s leukocytes.2,12

This antigen-antibody reaction then caused activation of the complement cascade, sequestration of neutrophils into the patient’s lungs, and activation of these PMNs, resulting in capillary leak, pulmonary edema, and ALI (or in the case of class II antibodies, activation of circulating monocytes, and the release of cytokines that also cause identical PMN sequestration and ALI).2,12

This antibody-mediated pathogenesis has been reinforced by the publication of animal models employing anti-granulocyte antibodies; however, some problems exist with this antibody-induced hypothesis:

  • Only 50 percent of donor anti-leukocyte antibodies implicated in TRALI display specific reactivity to recipient antigens.13
  • The ability of these antibodies to fix complement has been questioned, and a recent report has demonstrated that complement activation isn’t required.14
  • Numerous cases of antibody negative TRALI have been reported or simply diagnosed as ALI because of the lack of specific immunoglobulins.
  • The animal models employed isolated, perfused rodent lungs with human antibodies and human granulocytes in the perfusate, procedures that normally make the granulocytes “stiff” and unable to traverse the pulmonary circulation, resulting in artifactual pulmonary sequestration such that these PMNs may then be activated by a discrete antibody.
  • Neutrophils don’t express HLA class II antigens. Although antibodies directed against monocytes may cause the synthesis of pro-inflammatory cytokines, these agents require synthesis and release, which hasn’t been demonstrated in TRALI or models of TRALI.7,9
  • TRALI can be caused by the binding of recipient antibodies to discrete antigens on transfused, donor granulocytes; however, the number of viable PMNs is an issue because they’re only viable for 24 to 72 hours. This mechanism has particular importance with the resurgence of granulocyte transfusion for immunocompromised hosts.15

    The two-event model of TRALI

    All proposed models of TRALI in immunocompetent patients implicate the PMN as the effector cell.2,5,6,12,16 Moreover, the underlying clinical condition of the patient is important as demonstrated in four “look back” studies of donors with known high titer antibodies implicated in TRALI reactions.

    If the antibodies alone cause TRALI, then patients who received transfusions with these antibodies would develop TRALI; however, only a few patients did.17-19

    The two-event model postulates TRALI is caused by at least two independent events. The first event relates to the underlying clinical condition of the patient such that this individual has pulmonary endothelial activation resulting in pulmonary sequestration of neutrophils.

    The second is the passive infusion of specific antibodies directed against the adherent PMNs in the lung or other biologic response modifiers (BRMs), including lipophilic compounds (signaling fat), pieces of platelet membranes (soluble CD40 ligand), or even complement that cause activation of the microbicidal arsenal of these adherent, sequestered PMNs, resulting in endothelial damage, capillary leak, and TRALI.5,6,8,16

    Many of these BRMs accumulate during routine storage of cellular blood components, especially lipids or complement; a normal component of human plasma may be activated as the result of the clinical condition of the donor and separation of the plasma.7 These BRMs may activate the adherent sequestered (known as “primed”) PMNs in the pulmonary vasculature but have no effect on quiescent neutrophils in the circulation.

    This two-event model of TRALI has been verified in an animal model in which stored, but not fresh plasma from cellular components, caused TRALI.16 Because this model requires that PMNs are sequestered in the pulmonary vasculature, healthy patients who experience TRALI seem to be obviated from this pathogenesis.

    However, one must remember patients who require transfusion aren’t healthy by definition. In this light, a study of the PMNs from five “healthy” donors, by history, demonstrated their PMNs were grossly primed, as determined by the appearance and activity of these PMNs. In fact, all of these donors developed infections, either viral or bacterial, over the next 24 hours, demonstrating it may be difficult to determine if patients are indeed healthy.20

    Lastly, albeit rarely, TRALI has been reported in neutropenic patients.7 In these cases, TRALI was postulated to be caused by the infusion of vascular endothelial growth factor, an effective permeability factor, or by the infusion of antibodies against HLA antigens that reside on pulmonary vascular endothelium that cause endothelial shape change, fenestration of the endothelial layer with mild capillary leak, and TRALI.


    Decreasing blood usage will likely diminish TRALI through the use of restrictive transfusion protocols. Secondly, all donors implicated in TRALI reactions should be temporarily disqualified until leukocyte antibody testing can be completed. If positive, these donors should be disqualified from blood donation; if negative, they should be returned to the donor pool.

    In an effort to make the blood supply safer, the United Kingdom has disqualified all women who have had multiple pregnancies from plasma donation because of the possibility that multiparous female plasma may be the major factor in TRALI.

    The safety of this “female” plasma is controversial, and until there’s convincing data to support disqualification of multiparous females, disqualification of such donors seems unwarranted. Such a move could be disastrous to blood centers in which these multiparous females comprise 20 percent to 30 percent of the donor pool.

    For scheduled surgical procedures requiring transfusions, washing of cellular components removes all BRMs from the blood and is a reasonable method to obviate the effects of these agents in patients at high risk for lung injury.

    In addition, fresher products also may be used to obviate the effects of BRMs in high-risk patients who aren’t neutropenic. The use of packed red blood cells within 14 days and platelet concentrates within two days may avoid much of the effects of these agents that accumulate during storage; these storage times aren’t associated with significant accumulation of non-antibody BRMs.9

    TRALI is a multi-factorial syndrome brought on by at least two distinct clinical events: the first related to the clinical condition of the patient, and the second is the infusion of BRMs (including antibodies) with the transfusion.

    Further work is required to describe the effects of this life-threatening syndrome, identify the patients who are at particular risk, and craft a consensus international definition so clinicians and nursing staff may properly diagnose TRALI.

    For a list of references, look under the “From Print” toolbar on the left side of our home page at

    Christopher C. Silliman, MD, PhD, is associate medical director of the Bonfils Blood Center and professor at the University of Colorado School of Medicine, Denver.

    This work was supported in part by Bonfils Blood Center, grant #HL59355 from the National Heart, Lung, and Blood Institute, and grant #P50 GM49222 from the National Institute of General Medical Sciences, National Institutes of Health, and the departments of pediatrics and surgery, University of Colorado School of Medicine.