Transfusion-Related Acute Lung Injury (TRALI)
Description and Incidence
Transfusion-Related Acute Lung Injury (TRALI) is a syndrome characterized by acute respiratory distress following transfusion. All plasma-containing blood products have been implicated including rare reports of IVIG and cryoprecipitate. It is a rare complication of allogeneic blood transfusion but the incidence has not been well established due to difficulty in defining the syndrome and to variable reporting mechanisms worldwide. Various studies have estimated the overall frequency of TRALI to be between 1/1,120 and 1/57,810 units transfused. However, there is wide discrepancy in the literature with the reported frequency is as low as 1/557,000 RBC units and as high as 1/432 platelet units.
TRALI is associated with a high morbidity with the majority of patients requiring ventilatory support. However, the lung injury is generally transient with PO2 levels returning to pretransfusion levels within 48 -96 hours and CXR returning to normal within 96 hours. TRALI is associated with a significant mortality rate, often approximated at 5 to 10%. Given the gains in safety made within the blood component production industry, particularly with respect to transmission of infectious diseases, TRALI is now among the three leading causes of transfusion related fatalities along with ABO incompatibility and bacterial contamination.
Symptoms of TRALI typically develop during, or within 6 hours of a transfusion. Patients present with the rapid onset of dyspnea and tachypnea. There may be associated fever, cyanosis, and hypotension. Clinical exam reveals respiratory distress and pulmonary crackles may be present with no signs of congestive heart failure or volume overload. CXR shows evidence of bilateral pulmonary edema unassociated with heart failure (non-cardiogenic pulmonary edema), with bilateral patchy infiltrates, which may rapidly progress to complete "white out" indistinguishable from Acute Respiratory Distress Syndrome (ARDS).
Treatment and Clinical Course
Treatment of TRALI is supportive. Mild forms of TRALI may respond to supplemental oxygen therapy. Severe forms may require mechanical ventilation and ICU support. As with ARDS there is no role for diuretics or corticosteroids. The majority of patients recover within 72 to 96 hours and subsequently recover to their baseline pulmonary function without apparent sequelae. However, some patients are slower to recover and may remain hypoxic with persistent pulmonary infiltrates up to seven days. As stated above, approximately 5 to 10% of cases are fatal in spite of aggressive supportive care.
The differential diagnosis of acute lung injury after transfusion includes transfusion-associated circulatory overload (TACO), cardiogenic edema, allergic and anaphylactic transfusion reactions, and bacteremia/sepsis due to transfusion of bacterially contaminated blood products.
TRALI may be distinguished from TACO and cardiogenic pulmonary edema by the absence of signs of circulatory overload such as a normal central venous pressure (CVP) and normal pulmonary capillary wedge pressure (PCWP). Clinical response to diuretics also suggests a diagnosis of TACO rather than TRALI. Allergic and anaphylactic transfusion reactions may be manifest as hypotension and respiratory distress but are marked by laryngeal edema or bronchospasm with wheezing and a normal CXR. Transfusion transmitted bacteremia my present with fever, hypotension, and culminate in severe sepsis with associated acute lung injury which may be difficult to distinguish from TRALI. The presence of positive blood cultures is a useful delineating finding.
The hallmark of acute lung injury (ALI) is that of increased pulmonary microvascular permeability with increased protein in the edema fluid. This is true regardless of the cause of the ALI.
It is hypothesized that TRALI may be precipitated by the infusion of donor antibodies directed against recipient leukocytes. The infusion of donor anti-HLA (human leukocyte antigens) or anti-HNA (human neutrophil antigens) antibodies is thought to directly cause complement activation, resulting in the influx of neutrophils into the lung, followed by neutrophil activation and release of cytotoxic agents, with subsequent endothelial damage and capillary leak. Donor derived antibodies to HLA class I antigens and neutrophils have been demonstrated in up to 89% of TRALI cases examined in the literature.
An alternate hypothesis argues that TRALI is the result of at least two independent clinical events: the first is related to the clinical condition of the patient (infection, cytokine administration, recent surgery, or massive transfusion) that causes activation of the pulmonary endothelium. This then leads to the sequestration of primed neutrophils to the activated pulmonary endothelium. The second event is the infusion of donor derived anti-HLA or anti-HNA antibodies directed against antigens on the neutrophil surface and/or biological response modifiers (e.g., lipids) in the stored blood component that activate these adherent, functionally hyperactive neutrophils, causing neutrophil-mediated endothelial damage and capillary leak. Many studies in the literature support this hypothesis which may explain how some TRALI reactions occur in the absence of donor HLA/HNA antibodies, or why TRALI reactions do not occur in all recipients of blood components from donors who are known to have these antibodies.
Yet a third hypothesis suggests that high levels of donor derived vascular endothelial growth factor (VEGF) or antibodies to class II HLA antigens residing on pulmonary vascular endothelium may directly cause endothelial shape change and fenestration. This theory purports to explain the syndrome in neutropenic patients.
It is imperative that medical personnel and hospitals identify suspected cases of TRALI and report them to Canadian Blood Services. The reporting of TRALI allows us to better understand the true incidence of this reaction, in addition to its clinical course and associated mortality. Further, by identifying cases of TRALI , CBS can take steps to prevent further cases of TRALI by removing companion components of units that may have caused the reaction and by investigating donors involved in these cases and deferring them from further donations if they are found to be implicated as outlined below.
Canadian Blood Services has adopted the definition put forth by the Canadian Consensus Conference Panel on TRALI as outlined below. This definition is applied consistently to all cases of TRALI reported to CBS and is used to determine whether reported cases will be investigated.
Table 1: Canadian Consensus Conference Panel TRALI definitions
|TRALI||Acute lung injury (defined below) occurring within 6 hours of completion of transfusion of blood component.
No pre-existing acute lung injury.
No other temporally associated risk factors for acute lung injury (see below).
|Possible TRALI||Acute lung injury (defined below) occurring within 6 hours of completion of transfusion of blood components. No pre-existing acute lung injury. One of more temporally associate risk factors for acute lung injury.|
Table 2: Definition of Acute Lung Injury (ALI)
|Acute Lung Injury||New onset
Hypoxemia SpO2 <90% or Pa02/Fi02 < 300 mm Hg on room air, or other clinical evidence of hypoxemia
Bilateral infiltrates on frontal chest X-ray
Table 3: Risk Factors for Acute Lung Injury
|Direct Lung Injury||Indirect Lung Injury|
Because the diagnosis of Acute Lung Injury (ALI) can be difficult, it is important for the transfusion service medical director and the patient’s physician to communicate to determine, in particular, whether a patient has evidence of volume overload. Although ALI and hydrostatic pulmonary edema may coexist, the latter is a more common complication of transfusion and must be excluded in order for a diagnosis of TRALI or possible TRALI to be made.
It is unlikely that TRALI can ever be entirely prevented, but its frequency may be reduced by the judicious use of blood components only for indications that are justified based on sound medical evidence. Hospitals should have procedures in place (e.g. blood utilization guidelines, blood conservation programs) which minimize unnecessary transfusions. In addition, hospital medical staff must continue to have a high index of suspicion in order to diagnose TRALI appropriately. All cases of TRALI or possible TRALI should be reported to Canadian Blood Services (in addition to the Provincial/Territorial Surveillance office as part of the TTISS program) who in turn is required to report all possible TRALI or possible TRALI cases to Health
Cases of suspected TRALI should be reported to CBS using standard procedure for reporting Adverse Reactions. In order to correctly and consistently diagnose TRALI, the following information must be included in the report:
- Timing of transfusion with respect to symptom onset
- Presence of other risk factors for acute lung injury (see Table 3)
- CXR findings
- Evidence of hypoxia: PaO2 or SaO2
- Clinical indicators of volume status such as clinical evaluation, response to diuretics (if given), or where available JVP, PCWP, CVP, echocardiogram report etc.
In addition to the standard procedure for reporting adverse event, and in order to fully investigate and identify TRALI cases; patient samples must be sent for further testing. Complete the TRALI Patient Data form and forward the original as instructed to the local CBS site and photocopy of the form with samples to the named testing laboratory. TRALI Patient Data Form
Recognizing that donor derived antibodies may be one of the causes of TRALI, CBS has adopted a standardized, national donor management strategy in an attempt to improve the safety of the blood supply for Canadians by reducing the risk of TRALI.
Secondary prevention refers to the management of donors whose donations have been temporally associated with a TRALI or possible TRALI reaction. In order to evaluate such donors and their continued eligibility to donate, the following definitions apply:
Table 4: Definition of Donors Temporally linked with TRALI or possible TRALI
|Implicated Donor||A donor is implicated in TRALI if they have demonstrated antibodies to an HLA Class I or II antigen or HNA; the antibody must have specificity for an antigen present on the recipient’s WBCs or there must be a positive reaction noted between donor serum and recipient WBCs, a positive crossmatch.|
|Associated Donor||A donor is associated with a TRALI reaction if a blood component was transfused during the six hours preceding the first clinical manifestation of TRALI.|
The disposition of donors associated with or implicated in a TRALI reaction is provided in the following table:
Table 5: Disposition of Donors Involved in a Reported TRALI
|Implicated donor||Positive as per definition||Defer|
|Associated donor||Negative||Washed RBC
Plasma for fractionation
|Positive for HLA antibodies but recipient crossmatch not available||Washed RBC
Plasma for fractionation
|Positive for HNA antibodies||Defer|
Note: CBS is currently implementing more sensitive testing methods which will allow donors who test negative to be redefined as not-implicated. Donors who are not implicated following a TRALI investigation will be able to continue to donate without restriction.
Primary prevention refers to measures taken to reduce TRALI that are unassociated with a particular TRALI event. In the fall of 2007, the AABB published the recommendation that “...blood collecting facilities should implement interventions to minimize the preparation of high plasma-volume components from donors known to be leukocyte-alloimmunized (i.e. donors with antibodies to leukocytes) or who are at increased risk of leukocyte alloimmunization”.
In an effort to reduce the incidence of TRALI, Canadian Blood Services has implemented several measures to institute the use of predominantly male plasma for preparation of high-volume plasma components and to reduce the use of plasma from donors at high risk for HLA immunization, particularly previously pregnant females.
TRALI reduction measures began with the use of predominantly male plasma for production of Frozen Plasma, Fresh Frozen Plasma, cryosupernatant plasma and plasma for resuspension of platelet pools in October 2007.
In March 2008 these measures were expanded to include predominately male apheresis plasma donations.
On July 20, 2009 CBS began collecting apheresis platelets from males and females without a history of pregnancy.
The majority of plasma made from female whole blood donors is sent to the fractionator to be processed into plasma protein products such as intravenous immunoglobulin (IVIG) and albumin.
CBS no longer issues plasma or platelets made from female directed donors unless there is a clear medical indication for their use and after consultation and approval of the site Medical Director. Red cells may be issued from female directed donors as well as red cells, platelets and plasma, as required, from male directed donors.
Despite the move towards predominantly male plasma for transfusion, female plasma from female donors continues to be critically important to support the blood product needs of Canadian patients and may still be issued to meet group or component specific urgent shortfalls eg, Group group AB FFP, HLA or HPA matched platelets, IgA deficient donors.
The CBS TRALI Review Group
The TRALI Medical Review Group (TMRG) was established at Canadian Blood Services in 2006 as a national resource team to assist physicians at CBS in the management of reported TRALI cases. The TMRG is available to CBS physicians to review the results of TRALI investigations, to determine donor management in cases where the results are not straightforward, to assist CBS physicians in applying the definition of TRALI consistently and investigating/managing donors when the diagnosis is not immediately apparent. In addition, the TMRG is responsible for developing national policies with respect to the investigation of TRALI within CBS, for developing educational strategies for hospitals, community physicians and other health care providers and health authorities with respect to TRALI identification and reporting.
This is a comprehensive list of pertinent TRALI related articles where the reader may find further information.
- Marik PE, Corwin, HL. Acute lung injury following blood transfusion: Expanding the definition. Crit Care Med 2008; 36 (11): 3080- 84.
- Triulzi, DJ. Transfusion Related Acute lung injury: current concepts for the clinician. Anesthesia and analgesia. 2009;108 (3): 770-76
- Chapman CE, Stainsby D, Jones H, Love E, Massey E, Win N, Navarrete C, Lucas G, Soni N, Morgan C, Choo L, Cohen H, Williamson LM. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma. Transfusion. 2008 Oct 28. [Epub ahead of print]
- Silliman CC, McLaughlin NJ.Transfusion-related acute lung injury. Blood Reviews 2006; 20(3):139-59.
- Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005; 105(6):2266-73.
- Bux J.Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sanguinis 2005; 89(1):1-10.
- Shander A, Popovsky MA. Understanding the consequences of transfusion-related acute lung injury. Chest.2005; 128(5 Suppl 2):598S-604S.
- Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Crit Care Med. 2005;33(4):721-6.
- Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S, Meade M, Morrison D, Pinsent T, Robillard P, Slinger P. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004;44(12): 1774-89.
- Skeate RC, Eastlund T. Distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload. Current Opinion in Hematology. Nov 2007; 14(6):682-687.
- Gajic O, Gropper MA, Hubmayr RD. Pulmonary edema after transfusion: How to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury. Crit Care Med. 2006;34(5) Suppl:S109-S113.
- Jacobi KE, Wanke C, Jacobi A, Weisbach V, Hemmerling TM. Determination of Eicosaniod and cytokine production in salvaged blood, stored red blood cell concentrates, and whole blood. J Clin Anesth 12: 94-99, 2000.
- Kopko PM, Paglieroni TG, Popovsky et al. TRALI: correlation of antigen-antibody and monocyte activation in donor-recipient pairs. Transfusion 2003;43:177-184.
- Densmore, TL, Goodnough, LT, Ali S, Dynis M, Chaplin H. Prevalence of HLA sensitization in female apheresis donors. Transfusion 1999; 39:103-6.
Pathophysiology of TRALI
- Silliman CC, Curtis BR, Kopko PM, et al. Donor antibodies to HNA-3a implicated in TRALI reactions prime neutrophils and cause PMN-mediated damage to human pulmonary microvascular endothelial cells in a two-event in vitro model. Blood. 2007;109(4): 1752-1755.
- Curtis BR, McFarland JG. Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies. Critical Care Medicine. 2006; 34(5 Suppl):S118-23.
- Silliman CC.The two-event model of transfusion-related acute lung injury. Critical Care Medicine. 2006; 34(5 Suppl):S124-31.
- Toy P, Hollis-Perry KM, Jun J, Nakagawa M. Recipients of blood from a donor with multiple HLA antibodies: a lookback study of transfusion-related acute lung injury. Transfusion. 2004 Dec; 44(12): 1683-8.
- Kopko PM. Leukocyte antibodies and biologically active mediators in the pathogenesis of transfusion-related acute lung injury. Curr Hematol Rep. 2004 Nov;3(6): 456-61.
- Silliman CC, Bjornsen AJ, Wyman TH, Kelher M, Allard J, Bieber S, Voelkel NF. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion. 2003 May; 43(5): 633-40.
- Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, Clarke G, Ambruso DR. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood. 2003; 101(2): 454-62
Triulzi DJ, Kleinman S, Kakaiya RM et al. The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion related acute lung injury risk reduction strategy. Transfusion 2009; 49(9):1825-35.
- Engelfriet CP, REesink HW, Wendel S et al. Measures to prevent TRALI. Vox Sang 2007; 92 (3): 258-77.
- AABB association bulletin #05-09
- AABB association bulletin #06-07
- Knippen MA. Transfusion-related acute lung injury. Am J Nursing. 2006;106(6):61-4.
- Kopko PM. Review: transfusion-related acute lung injury: pathophysiology, laboratory investigation, and donor management. Immunohematol. 2004; 20(2): 103-11.
- Looney MR, Gropper MA, Matthay M. Transfusion-related acute lung injury: a review. Chest. 2004 Jul; 126(1): 249-58.
- Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev. 2003 Oct; 17(4): 252-62.
- Toy P, Gajic O. Transfusion-related acute lung injury. Anesth Analg. 2004 Dec; 99(6): 1623-4.