Transfusion-related acute lung injury (TRALI)

Author: Akash Gupta, MD, FRCPC; Matthew Yan, MD, FRCPC
 

Introduction

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 respiratory distress during or within six hours of blood component (i.e., red blood cells, plasma, platelets) or blood product (i.e., plasma protein product) administration in the absence of temporally-associated risk factors for acute respiratory distress syndrome (ARDS). All plasma-containing blood components and plasma protein products have been implicated in TRALI, including rare reports with intravenous immunoglobulin (IVIg) and cryoprecipitate. Despite the very small amount of plasma contained in red blood cells, this component 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 antigens (HLA) or human neutrophil antigens (HNA). Non-antibody-mediated cases also occur and may be mediated by biologic response modifiers present in the transfused blood component or plasma protein product, along with recipient factors.

Epidemiology

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 to occur at approximately 1 in 5,000 transfused blood components. Prospective identification of cases in an American study placed the risk at just under 1 in 12,000 transfused units.¹

In Canada, as per the Transfusion Transmitted Injuries Surveillance System (TTISS) 2011-2015 report, TRALI and possible TRALI, when considered in combination, are the second leading cause of transfusion-related morbidity (22.0%), after transfusion-associated cardiac overload (TACO, 42.6%).

Similarly, in the United States, reactions reported as TRALI and possible TRALI are the second leading cause of transfusion-related mortality at 24%, second behind TACO at 34%.²

Clinical presentation

Symptoms of TRALI typically develop during or within 6 hours of a transfusion. Patients present with rapid onset of dyspnea and tachypnea, with an SpO₂ < 90% on room air. There may be associated fever, cyanosis and hypotension. Clinical examination may reveal 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 imaging should show clear 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). There should be no evidence of left atrial hypertension (LAH); however, if LAH is present, it should not be the main contributor to the hypoxemia. 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 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 chest X-ray 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.

Differential diagnosis

The differential diagnosis for hypoxia after transfusion includes TRALI, TACO, cardiogenic pulmonary edema, allergic and anaphylactic transfusion reactions, transfusion-associated dyspnea (TAD), and bacteremia/sepsis due to bacterial contamination of transfused blood components.

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. Patients with TACO will also demonstrate biochemical evidence of cardiac overload, such as an elevated BNP or NT-proBNP level or a pre-/post-transfusion NT-proBNP ratio greater than 1.5.³

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 chest X-ray. An urticarial rash may also be present. These reactions will respond quickly to treatment with corticosteroids, antihistamines, and/or may require vasopressors and other supportive care.

TAD is an 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 ARDS, 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.

Pathophysiology

The most widely accepted hypothesis suggests that TRALI is the result of at least two independent clinical events. The first relates to the clinical condition of the patient (e.g., active infection, history of cytokine administration, surgery, severe burn injury) 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,^4-7 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 suspected to be TRALI related. This reporting must be completed using a 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 in A Guide to Reporting Adverse Transfusion Reactions.

In order to correctly and consistently diagnose TRALI, the completion and submission of Canadian Blood Services’ TRALI Patient Data Form, is mandatory. For further details on submitting the TRALI Patient Data Form and possible patient samples for TRALI investigation, please refer to Canadian Blood Services customer letter CL 2021-01. In general, the following clinical information is requested by Canadian Blood Services:

• Timing of transfusion with respect to symptom onset
• Presence of other risk factors for acute respiratory distress syndrome (see Table 1)
• Chest imaging 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, BNP, etc.

Table 1: Updated Risk Factors for Acute Respiratory Distress Syndrome (Vlaar et al. 2019)⁸

Historically, Canadian Blood Services defined TRALI using the 2004 Canadian Consensus Conference Panel definition (Table 2). In 2012, the definition of ARDS (known as the Berlin definition) was revised resulting in removal of the term acute lung injury (ALI) among the critical care community internationally. To align with this change in terminology, Vlaar et al. revised the definitions of TRALI and possible TRALI, including a new naming convention of TRALI type 1 and TRALI type 2 (Table 3)⁸ 

Canadian Blood Services reports all reported cases of TRALI or possible TRALI (or cases redefined as TRALI type 1 or type 2) to Health Canada, including cases which fail to meet the definition but where TRALI cannot be excluded due to incomplete clinical information.

Because the diagnosis of ARDS can be difficult, communication between the transfusion service medical director and the patient’s physician is critical to determine, in particular, whether a patient has evidence of volume overload. Although ARDS 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 to be made.

Table 2: 2004 Canadian Consensus Conference Panel TRALI and Acute Lung Injury (ALI) definitions⁹

Table 3:  2019 Updated Consensus Redefinition of TRALI (Vlaar et al. 2019)⁸

Prevention

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 components and plasma protein products only for appropriate indications. Hospitals should have procedures in place (e.g., blood utilization guidelines, blood conservation programs) that minimize unnecessary transfusions. In addition, hospital medical staff must continue to have a high index of suspicion in order to diagnose TRALI appropriately. As noted above, all cases of suspected TRALI must be reported to Canadian Blood Services (in addition to the Provincial/Territorial Surveillance office as part of the TTISS program).

The role of Canadian Blood Services

Primary prevention

Primary prevention refers to measures for reducing incidence of TRALI that are not associated with a particular TRALI event. In accordance with AABB recommendations,^10-14 Canadian Blood Services implemented several measures between 2007 and 2009 to reduce the levels of donor-derived antibodies in blood components and plasma protein products containing high volumes of plasma. These measures are primarily based on the observation that females with a history of pregnancy have a higher risk of anti-HLA antibodies than females who have never been pregnant or males:

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 females without a history of pregnancy and from males.

Secondary prevention

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 (including possible TRALI or TRALI type 2, or cases where TRALI cannot be excluded) are deferred from further whole blood or apheresis donation. These donors are tested for anti-HLA antibodies and at this time may be acceptable to donate source plasma for fractionation if their HLA antibody results are negative. Donors with rare red blood cell phenotypes are an exception to the deferral policy: if they are involved in cases defined as TRALI and have positive HLA antibody results they may still be able to donate frozen or washed red blood cells. All other involved donors not mentioned above who have demonstrable anti-HLA antibody (regardless of cognate antigen match) are deferred from all types of blood donation. In cases where the criteria for TRALI are not met, 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 these cases meet the definition for TRALI or possible TRALI (or redefined as TRALI type 1 or TRALI type 2). 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 recommendation of TMRG regarding donor management for specific cases is communicated to the hospital via a summary report.

TRALI remains a clinical diagnosis and as such the TMRG classification may not align with that of the reporting physician. Classification by the TMRG should not be used to guide clinical assessment nor management of patients suffering transfusion reactions. The role of TMRG is primarily to determine donor—not patient—management.

Current (June 2021) members of the TMRG include, Dr. G. Clarke (Edmonton), Dr. J. Hannon (Edmonton), Ms. M. Huang (Toronto), Dr. A. Khandelwal (Toronto), Dr. D. Lane (Winnipeg), Ms. J Wong (Winnipeg), Dr. M. Yan (Vancouver) and Dr. M. Zeller (Hamilton).

Further reading

Recent articles and reviews

1. Politis C, Wiersum JC, Richardson C, Robillard P, Jorgensen J, Renaudier P, Faber JC, Wood EM. The International Haemovigilance Network Database for the Surveillance of Adverse Reactions and Events in Donors and Recipients of Blood Components: technical issues and results. Vox Sang 2016; 111: 409-17.
2. Lieberman L, Petraszko T, Yi QL, Hannach B, Skeate R. Transfusion-related lung injury in children: a case series and review of the literature. Transfusion 2014; 54: 57-64.
3. Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R, Matthay MA, Group TS. Transfusion-related acute lung injury: incidence and risk factors. Blood 2012; 119: 1757-67.
4. Transfusion Transmitted Injuries Surveillance System (TTISS). Summary Results for 2006-2012.
5. 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, Serious Hazards of Transfusion Steering G. 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 2009; 49: 440-52.
6. Silliman CC, McLaughlin NJ. Transfusion-related acute lung injury. Blood Rev. 2006; 20: 139-59.  
7. Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang 2005; 89: 1-10.
8. Looney MR, Gropper MA, Matthay M. Transfusion-related acute lung injury: a review. Chest 2004 Jul; 126(1): 249-58.
9. Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev. 2003 Oct; 17(4): 252-62.

Definition/consensus articles

1. 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: 1774-89.
2. Vlaar APJ, Toy P, Fung M, Looney MR, Juffermans NP, Bux J, Bolton-Maggs P, Peters AL, Silliman CC, Kor DJ, Kleinman S. A Consensus Redefinition of Transfusion-Related Acute Lung Injury. Transfusion 2019; 59: 2465-76.
3. Bux J, Sachs UJ. Pulmonary transfusion reactions. Transfus Med Hemother. 2008;35(5):337-345. doi:10.1159/000151349

For Nurses

1.    Knippen MA. Transfusion-related acute lung injury. Am J Nursing. 2006;106(6):61-4.