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.     

Transfusion-related acute lung injury: past, present, and future

Noncardiogenic pulmonary edema caused by transfusion has been observed for almost 60 years. Today, we know this entity as transfusion-related acute lung injury (TRALI). TRALI is an uncommon but potentially fatal adverse reaction to transfusion of plasma-containing blood components. It is typified by dyspnea, cough, hypoxemia, and pulmonary edema within 6 hours of transfusion. Most commonly, it is caused by donor HLA antibodies that react with recipient antigens. It may also be caused by biologically active compounds accumulated during storage of blood products, which are capable of priming neutrophils. Without a "gold standard," the diagnosis of TRALI relies on a high index of suspicion and on excluding other types of transfusion reactions. Although current definitions of TRALI depend on symptoms, laboratory parameters can aid in the diagnosis and frequently identify the causative donor unit. As our understanding of TRALI deepens, risk reduction or prevention may become possible.     

Remote ischemic preconditioning as prevention of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. It may occur in up to 1 in 5000 transfusions and carries an elevated morbidity and mortality. Clinically it presents as hypoxia and non-cardiogenic pulmonary edema, usually within 6 h of transfusion. It consists of an immunological phenomenon involving the activation of neutrophils and endothelial injury, leading to capillary leak and pulmonary edema, mechanisms shared with lung ischemia–reperfusion (IR) injury. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIPC). Limb RIP has been shown to protect the lung against IR injury trough modulation of endothelial function as well as neutrophil activation and infiltration. The protective effects of RIPC on the lung have been confirmed in clinical trials of orthopedic and cardiothoracic surgery. RIPC is a safe, tolerable and cheap procedure. I propose that limb RIPC could be used as a preventive strategy against the development of TRALI.     

Complications pulmonaires de la transfusion (TACO–TRALI)

Pulmonary oedemas occurring during or after a blood transfusion appear as the most frequent serious immediate incidents in the French hemovigilance database. They include transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI). TACO are a major cause of transfusion-related death in France. TRALI are more and more recognized and notified. In no case, pooled fresh frozen plasma (100 donations) treated with solvent–detergent were involved in French TRALI cases. A logigrame will allow hemovigilance officers to better classify pulmonary oedemas in e-fit, the French hemovigilance database.     

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.     

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.     

Lack of evidence of CD40 ligand involvement in transfusion-related acute lung injury

Activated platelets have been implicated in playing a major role in transfusion-related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI. Mice were challenged with monoclonal major histocompatibility complex (MHC)-1 antibody which induced TRALI, evidenced by pulmonary oedema, accompanied by significantly elevated bronchoalveolar fluid (BALF) levels of total protein and elevated plasma levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) compared to infusion of isotype antibody (all Ps < 0·05). Treatment with ciglitazone, which inhibits platelet CD40L expression, had no effect on pulmonary and systemic inflammation compared to controls. In addition, treatment with anti-CD40L antibody, which antagonizes all CD40-CD40L interactions, also did not abrogate the TRALI reaction. Furthermore, levels of soluble CD40L were measured in a cohort of cardiac surgery patients, who were followed prospectively for the onset of TRALI after transfusion. Plasma levels of sCD40L at baseline and at time of developing TRALI did not differ between TRALI patients and controls (transfused cardiac surgery patients not developing acute lung injury) (275 ± 192 versus 258 ± 346 and 93 ± 82 versus 93 ± 123 pg/ml, respectively, not significant). In conclusion, these results do not support the idea that the CD40-CD40L interaction is involved in mediating TRALI.     

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.     

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.     

Aktualny stan wiedzy na temat patofizjologii,diagnostyki i zapobiegania TRALI

Transfusion-related acute lung injury (TRALI) is the leading cause of mortality following transfusion of blood components. Characteristic for TRALI is acute hypoxemia during or up to 6 h after transfusion provided that cardiogenic respiratory failure and transfusion-associated circulatory overload (TACO) are excluded.In this article we present: 1) Etiology and pathomechanism of TRALI syndrome including the numerous issues that are still unresolved. Currently accepted is the multiple-event model which involves both the patient and the transfused blood components. The TRALI syndrome may be either immunological or nonimmunological dependant on the various factors that activate neutrophils – the main cells in TRALI pathogenesis. 2) TRALI diagnosis should be based mainly on the clinical presentation due to the variety of pathomechanism of the syndrome; however testing of anti-leukocyte antibodies in transfused blood components, according to ISBT guidelines, is recommended in order to prevent TRALI incidence. 3) Different strategies of TRALI prevention, although up to date no ultimate provisions have been accepted. Transfusion of plasma collected only from men seems to be a promising solution as in many countries that adapted this preventive measure the number of TRALI cases has substantially decreased. 4) Different methods of proceeding with donors who donated blood components that were the cause of TRALI in transfused patients. It still remains an open question whether to defer donors with anti-leukocyte antibodies or multi pregnant women.     

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 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.     

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.     

Role of CD7 expressed in lung microvascular endothelial cells as Fc receptor for immunoglobulin M.

Immunoglobulins (Igs) against anti-human white blood cells are putative contributors to the development of transfusion-related adverse effects, particularly transfusion-related acute lung injury (TRALI). Studies of Igs that are considered to be implicated in transfusion-related adverse effects have mainly focused on immunoglobulin G (IgG) class antibodies (Abs). In the authors' previous in vitro study, the association of polymorphonuclear neutrophils (PMNs) and lung microvascular endothelial (LME) cells was up-regulated in the presence of normal human serum-derived IgMs, when F(ab')2 fragments of IgMs were specific to low-affinity Fc receptors (FcR) for IgG, namely, Fcgamma R III (CD16) and Fcgamma RII (CD32). In this study, the authors found that CD7 antigen notably expresses in LME cells and that it acts as an Fc receptor for IgM in LME cells.     

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.     

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.     

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.     

Designing and testing a computer-based screening system for transfusion-related acute lung injury

Computer-based systems can detect underreported adverse events. We hypothesized that a system could be designed to detect potential or unreported cases of transfusion-related acute lung injury (TRALI). We developed and tested a computer screening system using retrospective computer blood gas data after transfusions during a 45-day period at a tertiary care academic hospital. The program identified cases of posttransfusion hypoxemia. Medical records of identified cases were reviewed to diagnose TRALI. During the 45-day period, 820 patients received 6,888 blood products. Seven cases of TRALI were diagnosed, whereas only 2 had been reported. The system had 99% accuracy and 26% positive predictive value for detecting potential TRALI. Computer screening finds more cases of TRALI than are reported voluntarily, and a prospective study using this system is feasible and needed to validate this method of detecting this important adverse transfusion reaction.     

How clinicians can minimize transfusion-related adverse events?

Objectives

Transfusion-related adverse events (TRAE) can contribute to patient morbidity and mortality. In this brief narrative review, the strategies that clinicians can apply at the bedside to avoid TRAE are discussed.