Transfusion-related acute lung injury (TRALI)
Author: Tanya Petraszko, MD, FRCPC
Online publication date: February 2019
Transfusion-related acute lung injury (TRALI) is a rare but serious syndrome characterized by sudden acute respiratory distress following transfusion. It is defined as new, acute lung injury (ALI) during or within six hours after blood product administration in the absence of temporally-associated risk factors for ALI. All plasma-containing blood products have been implicated in TRALI, including rare reports with IVIg and cryoprecipitate. Despite the very small amount of plasma contained in red blood cells, this product is associated with the largest number of reported cases of TRALI. TRALI is thought to be caused by activation of recipient neutrophils by donor-derived antibodies targeting human leukocyte antigen (HLA) or human neutrophil antigen (HNA), in most cases. Non-antibody-mediated cases occur and may be mediated by biologic response modifiers present in the transfused blood product, along with recipient factors.
TRALI is rare and its incidence has not been well-established due to difficulty in recognizing the syndrome, inconsistent application of standard definitions, and variability in worldwide reporting mechanisms. Historically, the frequency of TRALI was estimated at approximately 1 in 5,000 blood products. More recently, prospective identification of cases in an American study placed the risk at just under 1 in 12,000 transfused units.
Although the rate of reported TRALI has been declining since 2007, it remains the leading cause of transfusion related mortality in the United States (based on 2015 data) and second behind transfusion-associated circulatory overload (TACO) in the International Haemovigilance Network Database reports. TRALI is responsible for 34% of transfusion-related mortalities reported to the US FDA 2012-2016 although the reports have decreased to only 19% for the fiscal year 2016. In Canada, it remains the highest cause of transfusion-related morbidity as per the Transfusion Transmitted Injuries Surveillance System (TTISS) report which has not been updated since 2012.
Symptoms of TRALI typically develop during or within six hours of a transfusion. Patients present with the rapid onset of dyspnea and tachypnea. There may be associated fever, cyanosis and hypotension. Clinical examination reveals hypoxic respiratory distress, and pulmonary crackles may be present without signs of congestive heart failure or volume overload. In general, however, chest findings on auscultation tend to be minimal. Chest x-ray (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). Physiologic findings include acute hypoxemia with normal cardiac function on echocardiogram. Up to a third of patients exhibit transient leukopenia and patients may have a low level of brain natriuretic peptide (BNP).
Treatment and clinical course
TRALI is associated with a high morbidity and the majority of patients require ventilatory support. However, with supportive care, the lung injury is generally transient, with oxygen levels returning to pre-transfusion levels within 48 to 96 hours and CXR returning to normal within 96 hours. However, some patients are slower to recover and may remain hypoxic with persistent pulmonary infiltrates for several days although pulmonary function eventually returns to baseline without apparent sequelae. As with ARDS, there is no role for diuretics or corticosteroids.
The mortality rate of TRALI is reported as high as 20% in general populations and up to 58% in critically ill patient populations.
The differential diagnosis of hypoxia after transfusion includes TACO, cardiogenic pulmonary edema, allergic and anaphylactic transfusion reactions, transfusion-associated dyspnea (TAD), 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 manifest as hypotension and respiratory distress but are marked by laryngeal edema or bronchospasm with wheezing and a normal CXR. An urticarial rash may be present.
TAD is acute respiratory distress occurring within 24 hours of transfusion which fails to meet criteria for TRALI, TACO or anaphylactic transfusion reaction.
Transfusion-transmitted bacteremia may present with fever and rigors with or without hypotension and culminate in severe sepsis with associated ALI which may be difficult to distinguish from TRALI. The presence of positive blood cultures with the same organism cultured from the implicated blood product is a useful delineating finding.
The most widely accepted hypothesis suggests 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, burns) that causes activation of the pulmonary endothelium. This leads to the sequestration of primed neutrophils to the activated pulmonary endothelium. The second event is the infusion of either donor-derived anti-HLA or anti-HNA antibodies directed against antigens on the neutrophil surface and/or biological response modifiers that activate these adherent and functionally hyperactive neutrophils.
Whether activated by antibodies or by some other modifier, this activation causes 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-derived anti-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. That is, in the absence of neutrophil priming by recipient factors TRALI will not occur despite the transfusion of antibodies or biologic response modifiers.
More recently, a threshold hypothesis has been postulated. In cases where the second event is sufficiently strong, TRALI may occur in the absence of the first clinical event. This threshold model could explain why TRALI may be observed in some transfusion recipients who are quite well prior to transfusion without predisposing risk factors.
The activation of recipient neutrophils through donor-derived anti-HLA/HNA antibodies is often referred to as immune TRALI. The term non-immune TRALI is used to describe cases where soluble biological response modifiers in the transfused components are felt to be the causative agent in the absence of donor-derived antibodies. It is unknown what proportion of TRALI is mediated through immune or non-immune mechanisms, although published literature suggests that 80–85% of TRALI cases are immune TRALI.
Reporting TRALI events
Health Canada mandates that hospitals identify and report adverse transfusion reactions, including those suspected to be TRALI related. This reporting must be completed using the standard procedure for reporting adverse reactions. A guide on how to report adverse reactions and data on events reported to Canadian Blood Services are available on this page of the website.
In order to correctly and consistently diagnose TRALI, the following information must be included in the adverse reaction report:
- Timing of transfusion with respect to symptom onset
- Presence of other risk factors for acute lung injury (Table 1)
- 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.
Table 1: Risk factors for acute lung injury
|Direct Lung Injury||Indirect Lung Injury|
Canadian Blood Services defines TRALI using the Canadian Consensus Conference Panel definition (Table 2). Using this definition, Canadian Blood Services reports all reported cases of TRALI or possible TRALI to Health Canada, including cases which fail to meet the definition but where TRALI cannot be excluded. New definitions for TRALI and possible TRALI have been proposed as have new definitions of ALI, however, at this time Canadian Blood Services continues to use the Canadian Consensus Conference Panel definition.
Table 2: Canadian Consensus Conference Panel TRALI and ALI definitions
|TRALI||Acute lung injury (defined below) occurring within six hours of completion of transfusion of blood product.
No pre-existing acute lung injury.
No other temporally-associated risk factors for acute lung injury (Table 1).
Acute lung injury (defined below) occurring within six hours of completion of transfusion of blood product.
No pre-existing acute lung injury.
One or more temporally-associated risk factors for acute lung injury.
|Acute lung injury (ALI)||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.
Because the diagnosis of 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.
The role of health-care professionals
It is unlikely that TRALI can ever be entirely prevented, but its frequency may be reduced by the judicious use of blood products only for appropriate indications. 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 suspected 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 Canada.
The role of Canadian Blood Services
Primary prevention refers to measures taken to reduce TRALI that are not associated with a particular TRALI event. In accordance with AABB recommendations, between 2007 and 2009, Canadian Blood Services implemented several measures to reduce the levels of donor-derived antibodies in blood products containing high volumes of plasma. Those measures are primarily based on the observation that females with a history of pregnancy have a higher risk of anti-HLA antibodies than males or females who have never been pregnant.
1. In October 2007, Canadian Blood Services switched to using plasma from predominantly male donors for production of plasma for transfusion (frozen plasma and fresh frozen plasma), and for production of cryosupernatant plasma.
2. In March 2008, these measures were expanded to include predominantly male apheresis plasma donations for fresh frozen plasma.
3. In November 2008, Canadian Blood Services implemented the buffy coat method for pooled platelets production. This method allows resuspension of platelet pools in plasma from male donors exclusively.
4. In July 2009, Canadian Blood Services began collecting apheresis platelets exclusively from males and females without a history of pregnancy.
Recognizing that donor-derived antibodies may be one of the causes of TRALI, Canadian Blood Services has adopted a standardized, national donor management strategy as part of a secondary prevention measure. Any blood donors involved in cases defined as TRALI or suspected TRALI are deferred from further whole blood or apheresis platelet donation. These donors are tested for anti-HLA antibodies and at this time donors may be acceptable for source plasma for fractionation, or donation of frozen or washed red blood cells if they have a rare red blood cell phenotype if their antibody test results are negative. All involved donors who have demonstrable anti-HLA antibody (regardless of cognate antigen match) are deferred from all types of blood donation. In cases where TRALI definitions cannot be applied, donors are neither tested nor deferred, but are flagged with a special code so that they can be identified and subsequently investigated in the event that they are later associated with another TRALI suspected reaction.
The Canadian Blood Services TRALI Medical Review Group
The TRALI Medical Review Group (TMRG) was established at Canadian Blood Services in 2006 as a national resource team to assist Canadian Blood Services’ physicians in the management of donors associated with reported TRALI cases. TMRG members independently review all cases of suspected TRALI reported to Canadian Blood Services and meet monthly to attain consensus on whether the case meets the definition for TRALI or possible TRALI. The role of the TMRG is to determine donor management in order to ensure that donors who may represent a risk for a future TRALI reaction are removed from the donor pool. The consensus of the TMRG is communicated to the Canadian Blood Services physicians and may be included in the final report to the hospital.
TRALI remains a clinical diagnosis and as such the TMRG classification may not align with that of the reporting physician. Classification by TMRG should not be used to guide clinical assessment nor management of patients suffering transfusion reactions.
Current members (January 2019) of the TMRG are Ms. L. Beaudin (Winnipeg), Dr. G. Clarke (Edmonton), Dr. J. Hannon (Edmonton), Ms. M. Huang (Toronto), Dr. D. Lane (Winnipeg), Dr. T. Petraszko (Vancouver), Dr. K. Webert (Hamilton), Dr M. Yan (Vancouver), Dr. D. Young (Calgary), and Dr. M. Zeller (Hamilton).
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