Transfusion-related acute lung injury: Current understanding and preventive strategies

Transfusion-related acute lung injury (TRALI) is the most serious complication of transfusion medicine. TRALI is defined as the onset of acute hypoxia within 6 hours of a blood transfusion in the absence of hydrostatic pulmonary oedema. The past decades have resulted in a better understanding of the pathogenesis of this potentially life-threating syndrome. The present notion is that the onset of TRALI follows a threshold model in which both patient and transfusion factors are essential. The transfusion factors can be divided into immune and non-immune mediated TRALI. Immune-mediated TRALI is caused by the passive transfer of human neutrophil antibodies (HNA) or human leukocyte antibodies (HLA) present in the blood product reacting with a matching antigen in the recipient. Non-immune mediated TRALI is caused by the transfusion of stored cell-containing blood products. Although the mechanisms behind immune-mediated TRALI are reasonably well understood, this is not the case for non-immune mediated TRALI. The increased understanding of pathways involved in the onset of immune-mediated TRALI has led to the design of preventive strategies. Preventive strategies are aimed at reducing the risk to exposure of HLA and HNA to the recipient of the transfusion. These strategies include exclusion of “at risk” donors and pooling of high plasma volume products and have shown to reduce the TRALI incidence effectively. This review discusses the current understanding of TRALI and preventive strategies available.     

Recent insights into the mechanism of TRALI

This paper will summarize the experimental and clinical literature on the pathogenesis of transfusion-related acute lung injury (TRALI). Several mechanisms by which leukocyte antibodies including, HLA class I, HLA class II, and HNA-3a antibodies, induce TRALI have been unraveled, although some aspects remain a matter of debate. Significant advances have also been made in the field of recipient-related factors that contribute to the development of TRALI. In contrast, the pathomechanism behind antibody-negative TRALI (associated with the transfusion of blood components which do not contain antibodies) is less well understood, and further research is urgently required.     

Two Cases of Transfusion-related Acute Lung Injury Triggered by HLA and Anti-HLA Antibody Reaction

Transfusion-related acute lung injury (TRALI) is a serious adverse transfusion reaction that is presented as acute hypoxemia and non-cardiogenic pulmonary edema, which develops during or within 6 hr of transfusion. Major pathogenesis of TRALI is known to be related with anti-HLA class I, anti-HLA class II, or anti-HNA in donor''s plasma. However, anti-HLA or anti-HNA in recipient against transfused donor''s leukocyte antigens also cause TRALI in minor pathogenesis and which comprises about 10% of TRALI. Published reports of TRALI are relatively rare in Korea. In our cases, both patients presented with dyspnea and hypoxemia during transfusion of packed red blood cells and showed findings of bilateral pulmonary infiltrations at chest radiography. Findings of patients'' anti-HLA antibodies and recipients'' HLA concordance indicate that minor pathogenesis may be not as infrequent as we''d expected before. In addition, second case showed that anti-HLA class II antibodies could be responsible for immunopathogenic mechanisms, alone.     

Transfusion-related acute lung injury investigation insights

Background From 2005 to 2009 transfusion-related acute lung injury (TRALI) has maintained its ranking as the number one cause of transfusion-related fatalities reported to the FDA. This confirms that TRALI remains a serious and potentially fatal transfusion complication. As over 80% of TRALI events have been attributed to donor derived leucocyte antibodies the detection and management of donors with these antibodies is crucial to reducing the TRALI risk. Objective Because blood is a precious medical commodity in limited supply, it would be more effective to exclude only those donors with a risk of triggering TRALI substantiated by objective laboratory evidence (i.e. implicated). This would allow implicated donors to be confidently excluded and would allow other donors only clinically associated with TRALI to be reassessed for continuing to donate. Therefore, the design of an effective and objective TRALI laboratory investigation strategy has to be based on current knowledge of the mechanism of antibody mediated TRALI. Discussion Leucocyte antibodies in the transfused blood product are thought to activate neutrophils in the pulmonary microvasculature. The by-products of neutrophil activation (e.g. reactive oxygen species and enzymes) consequently cause injury to the pulmonary microvasculature resulting in respiratory distress. There is strong evidence for the role of neutrophil reactive antibodies to human neutrophil antigen (HNA)-3a and human leucocyte antigen (HLA)-A2 in serious TRALI events. HLA Class II antibodies have also been implicated and they are thought to activate monocytes, which subsequently activate neutrophils. Neutrophils, which express human neutrophil antigens (HNA) and HLA Class I, are thus key effector cells in TRALI injury. Because of the pivotal role of neutrophils, effective TRALI investigations must include well validated neutrophil assays such as the granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT). This article will discuss: – TRALI investigation strategy, – assays for detection of antibodies to HNA and HLA, – how to differentiate associated from implicated donors, – and provide thoughts on the remaining 20% of TRALI events (i.e. non-immune mediated).     

New insights in mechanisms of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a syndrome characterized by acute respiratory distress following the transfusion of blood components. The pathophysiological hallmark of TRALI is an increased pulmonary microvascular permeability. Several reports demonstrate that the majority of TRALI cases are precipitated by the transfusion of donor antibodies directed against HLA (human leukocyte antigens) or HNA (human neutrophil antigens) expressed on the neutrophils’ surface of the recipient. This antibody- antigen interaction is thought to directly cause neutrophil activation and release of cytotoxic agents, with subsequent endothelial damage and capillary leak. Recent observations, however, indicate that other cells may also play a significant role in TRALI. This review will introduce several possible mechanisms of TRALI including the involvement of other blood cells and of the pulmonary endothelium.     

Evidence behind the pathophysiology of TRALI

Transfusion-related acute lung injury (TRALI) is a serious transfusion complication that may lead to significant morbidity and mortality. This has driven a significant research effort focused on understanding why and how TRALI develops. The ultimate goal must be prevention or at least mitigation of the clinical consequences of TRALI. The underlying pathophysiology of TRALI is presently best described by two hypotheses which are not mutually exclusive. These are the antibody mediated TRALI mechanism and the two-event or priming TRALI mechanism. One of the key initial findings in TRALI research was the frequent presence of leucocyte antibodies in associated blood products, providing strong evidence for an antibody driven pathogenesis. In contrast, the two-event mechanism proposed that these transfused antibodies activated neutrophils that had first been primed by the patient’s clinical condition. Together, data from haemovigilance programs, clinical reports and experimental findings have led several countries to introduce TRALI risk-reduction strategies. These include either limiting the transfusion of plasma from female donors or, screening female donors for the presence of leucocyte antibodies. Both approaches are justified by adoption of the immune mechanism as the prime driver of the pathogenesis of TRALI. TRALI incidence has gratifyingly been reduced by these measures. Nevertheless, TRALI cases persist and they remain a major concern because of continuing significant morbidity and mortality. While the majority of earlier TRALI research has focused on the role of antibodies in TRALI, evidence for the role of non-antibody factors in TRALI is now growing, based on an increasing number of in vitro, ex vivo and in vivo models. This review aims to present data from such models, which are the foundation for our current understanding of the pathophysiology behind antibody mediated and non-antibody mediated TRALI.     

The recipient side of TRALI – the role of patient neutrophils

Transfusion‐related acute lung injury (TRALI) is a serious and potentially fatal complication of blood transfusions. The fact that TRALI has been the top cause of transfusion‐related mortalities in the USA over the last 3 years (2004–06) [ 1 ] provides irrefutable evidence of the clinical significance of this syndrome. From this perspective, its importance in transfusion complications surpasses that of blood‐borne viruses and bacterial infections. Despite this, we still do not clearly understand the pathophysiology and pathogenesis of TRALI. This paper presents a TRALI patient or recipient perspective by discussing how thorough serological investigations can be utilized to provide evidence that patient neutrophils are the target cell and to identify the implicated donation/s when there are multiple associated donations.     

TRALI-new challenges for histocompatibility and immunogenetics in transfusion medicine

Antibodies against human leukocyte antigens (HLAs) have long been associated with transfusion-related acute lung injury (TRALI). In contrast to febrile transfusion reactions and refractoriness to platelet transfusions in immunized patients, the causative antibodies in TRALI are present in the transfused blood component, i.e. they are formed by the blood donor and not by the recipient. Consequently, blood components with high plasma volume are particularly associated with TRALI. In addition to antibodies against HLAs, antibodies directed against human neutrophil antigens (HNAs) present in the plasma of predominantly multiparous female blood donors can induce severe TRALI reactions. Especially, antibodies to HLA class II and HNA-3a antigens can induce severe or even fatal ALI in critically ill patients. Over the last decade, the clinical importance of TRALI as major cause for severe transfusion-related morbidities has led to the establishment of new guidelines aimed at preventing this condition, including routine testing for HLA and -HNA antibodies for plasma donors with a history of allogeneic sensitization. This, in turn, poses new challenges for close collaboration between blood transfusion centers and histocompatibility and immunogenetics laboratories, for sensitive and specific detection of the relevant antibodies.     

Transfusion related acute lung injury (TRALI): an unrecognised pathology

Transfusion related acute lung injury (TRALI) is a rare but potentially severe complication of blood transfusion, manifested by pulmonary oedema, fever and hypotension. The signs and symptoms are often attributed to other clinical aspects of a patient's condition, and therefore, TRALI may go unrecognised. It has been estimated to be the third cause of transfusion related mortality, so it should be better diagnosed. Cases are related to multiple blood units, such as white blood cells, red blood cells, fresh frozen plasma, platelets or intravenous immunoglobulins. Physiopathology of TRALI is poorly understood, and still controversial. It is often due to an immunological conflict between transfused plasma antibodies and recipients' blood cells. These antibodies are either HLA (class I or II) or granulocyte-specific. They appear to act as mediators, which result in granulocytes aggregation, activation and micro vascular pulmonary injury. Lipids or cytokines in blood units are also involved as TRALI priming agents. Diagnosis is based on antibody screening in blood components and on specific-antigen detection in the recipient. The screening of anti-HLA or anti-granulocytes is recommended as part of prevention for female donors who had been pregnant. Preventative measures should also include leucoreduction and measures to decrease the amount of priming agents in blood components. In this article, we summarise what is known about TRALI, and we focus attention on unanswered questions and controversial issues related to TRALI.     

Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity

According to Food and Drug Administration data, transfusion-related acute lung injury (TRALI) is the third most frequent cause of transfusion-associated death in the United States and is characterized by an acute respiratory distress syndrome-like clinical picture following transfusion of plasma-containing blood components. It may be underdiagnosed due to unfamiliarity of clinicians with the syndrome. This report describes the largest series to date, 46 cases, occurring between 1992 and 1998. The male-to-female ratio was approximately 1:1. The mean age at diagnosis was 54 years. The most frequent presenting symptom or signs were acute respiratory distress, hypotension, and hypertension. Antibodies to human leukocyte antigens or granulocytes were identified in 61 percent of cases, with 50 percent associated with antibodies in a donor whose blood had been transfused to a patient developing TRALI. Clinical recovery occurred in 87 percent of patients, but TRALI contributed to deaths in 13 percent. Clinicians need to recognize and diagnose this syndrome in order to respond with appropriate interventions.     

Review: transfusion-related acute lung injury: pathophysiology, laboratory investigation, and donor management

Transfusion-related acute lung injury (TRALI) is a serious clinical syndrome that is temporally associated with the transfusion of plasma-containing blood components. The syndrome typically occurs within 6 hours of transfusion. Approximately 80 percent of cases will resolve within 96 hours with supportive care. The syndrome has been associated with antibodies to WBC antigens and generation of biologically active mediators in stored cellular blood components. Appropriate laboratory investigation of TRALI can be crucial in confirmation of the clinical diagnosis, as well as in decisions regarding donor management.     

Réalité et importance du paludisme transfusionnel dans un contexte d’endémie stable : cas de Cotonou (Bénin)

Malaria endemic status of our countries supports avoiding malaria screening for the blood qualification. But this attitude makes young children, pregnant women and people without semi-immunity incur a high risk of malaria. The goal of the survey was to value the reality and the importance of transfusion-transmitted malaria and to assess its determining factors. The study included 141 packed-red-cells units transfused to 77 hospitalized recipients, not suffering from malaria and not having been transfused the last two weeks. Every packed-red-cells assigned to a patient was tested for malaria before use. Thick and thin blood film were performed 96 hours after transfusion. A clinical follow-up was undertaken as well as in the hospital and at home after release. In all, 13.47% of the transfused packed-red-cells were positive for the thick blood film. Plasmodium research in patients was negative 96 hours after transfusion, even in the 19 patients who had received parasitized blood units! The home follow-up had permitted to note that 15.78% of blood recipients had developed clinical malaria. Parasitic density ≥ 240 parasites/mm³ seems to be a determining factor. Transfusion-transmitted malaria is a reality we ought to consider. Introduction of malaria screening in donated blood qualification testings simultaneously with a framing of the blood donors appear the lasting solution to hope in the future to limit the waited excessive blood evictions.     

Donor characteristics do not influence transfusion-related acute lung injury incidence in a secondary analysis of two case-control studies

Objective

To investigate the relation between donor characteristics and TRALI incidence.

Platelet and TRALI: From blood component to organism

Even though used systematically with leukocyte reduction, platelet transfusions still cause adverse reactions in recipients. They include Transfusion-Related Acute Lung Injury (TRALI), respiratory distress that occurs within six hours of the transfusion. The pathophysiology of this transfusion complication brings complex cellular communication into play. The role, particularly inflammatory, played by blood platelets in TRALI pathophysiology has been demonstrated, but is still under debate. Blood platelets play a role in inflammation, particularly via the CD40/CD40L (sCD40L) immunomodulator complex. In this study, we examine in particular the specific involvement of the CD40/CD40L (sCD40L) complex in the inflammatory pathogenesis of TRALI. This molecular complex could be a major target in a TRALI prevention strategy. Improving the conditions in which the platelet concentrates (PC) are prepared and stored would contribute to controlling partly the risks of non-immune TRALI.     

Transfusion and lung injury.

The respiratory tree has been viewed as an infrequent site of injury arising as a complication of transfusion. In recent years, this view has changed as investigators have shown that two complications--circulatory overload and transfusion-related acute lung injury--are relatively frequent events. Circulatory overload is a result of hypertransfusion to individuals at risk, the very young or old recipient. The reaction is due to fluid infusion which overwhelms the capacity of the left ventricle, resulting in pulmonary edema. While rarely fatal, studies have shown that such incidents result in intensive care and extended hospitalization. In the setting of orthopedic surgery, 1% of elderly patients undergoing hip or knee surgery experience circulatory overload. These events are associated with autologous, as well as allogeneic red blood cells (RBC) and fresh frozen plasma. Transfusionists need to be vigilant with transfusion therapy in this population. Phlebotomy and supplemental oxygen are the key therapies. Transfusion-related acute lung injury (TRALI) is the adult respiratory distress syndrome due to transfusion. It is associated with a significant morbidity and mortality of 5-14%, making it the third most common cause of death from transfusion in developed countries. It is characterized by the onset of acute respiratory distress, bilateral pulmonary edema and hypoxemia. It occurs within 1-2 hours of transfusion of a plasma-containing blood product. All blood components have been associated with the reaction, and rarely, intravenous immune globulin. There is no recognized profile of individuals at increased risk for TRALI. There are two purported mechanisms of injury; the vast majority of cases are associated with passively transfused complement-activating antibodies. These antibodies are either HLA (Class I or II) or granulocyte-specific. These antibodies appear to act as mediators, which result in granulocyte aggregation, activation, and microvascular pulmonary injury. With appropriate respiratory intervention, 80% of patients recover within 96 hours of the original insult. There are no permanent pulmonary sequelae.     

Transfusion‐related acute lung injury and transfusion‐associated circulatory overload

Pulmonary complications of transfusion were once believed to be infrequent and relatively unimportant in terms of morbidity. Transfusion‐related acute lung injury (TRALI) and transfusion‐associated circulatory overload (TACO) are now appreciated as being relatively common and clinically important. TRALI is one of the two most frequent causes of transfusion‐associated death and patients with TACO have longer hospitalizations and increased morbidity. Both entities are diagnosed primarily on clinical grounds but laboratory tests are available which can confirm or supplement the clinical impression. The high‐risk patient for TRALI has not been identified but in TACO, very young or older patients who are transfused too rapidly or with too much volume are the most vulnerable. The mechanism of TRALI is incompletely understood but antibodies in stored blood components certainly play an important role. In TACO, the problem is primarily a mechanical issue. Prompt recognition is the key to successful treatment for both entities.     

Transfusion-related respiratory complications in intensive care: A diagnosis challenge

Transfusion-related respiratory complications can be challenging to diagnose especially in mechanically-ventilated patients in the intensive care unit (ICU) due to the concurrent respiratory symptoms associated with the patients’ primary diagnoses. In this narrative review, transfusion-related respiratory complications, including transfusion-associated dyspnea (TAD), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and transfusion-related allergic reaction (TRAR), are briefly presented in light of the recent consensus or experts’ definitions; and the diagnosis issues for ICU patients are discussed. Acute respiratory failure occurring during, or within 6 to 24 hours, of transfusion might be a transfusion-related respiratory complication. The recent updated definitions for TRALI and TACO should assist clinicians to differentiate between possible diagnoses. The issues for ICU clinicians are first to recognize the acute respiratory deterioration and the possible causality between the deterioration and blood transfusion and secondly to make the proper diagnosis. This remains challenging for mechanically-ventilated patients. Clinical assessment to identify ICU patients at particular risk of transfusion-related respiratory complications and non-invasive investigation tools could be beneficial and may help to remind clinicians to be alert to the link between transfusion and worsening of respiratory symptoms in these vulnerable critically ill patients.     

Transfusion-related acute lung injury resulting from designated blood transfusion between mother and child: a report of two cases

Transfusion-related acute lung injury (TRALI) is an underdiagnosed serious complication of blood transfusion characterized by the rapid onset of respiratory distress, hypoxia, and noncardiogenic pulmonary edema during or soon after blood transfusion. The presence of anti-HLA and/or antigranulocyte antibodies in the plasma of donors is implicated in the pathogenesis of TRALI. We report 2 cases of TRALI that were caused by designated blood transfusion between mothers and their daughters; one in a 4-month-old girl who received designated packed RBCs donated by her mother and the second in a 78-year-old mother who received blood from her daughter. In both cases, examination of mother's serum revealed panel-reactive cytotoxic HLA antibodies. It is most likely that the mothers were sensitized from earlier pregnancy and produced HLA antibodies against the daughters' paternally derived HLA antigens. Designated blood transfusion between multiparous mothers and children might add an additional transfusion-related risk owing to the higher likelihood of the HLA antibody-antigen specificity between mother and child.