Antibody-mediated (immune) transfusion-related acute lung injury

Antibody-mediated transfusion-related acute lung injury (immune TRALI) is now recognized as the most common cause of transfusion-associated major morbidity and death in the Western world. Among the implicated leucocyte antibodies, these ones directed against the human leucocyte antigens (HLA) class II, human neutrophil alloantigens (HNA)-3a and HLA-A2 antigens are frequently associated with severe (artificial ventilation required) and fatal cases. There is accumulating evidence that preventive measures such as transfusion of plasma-rich blood components from male donors or from donors tested negative for leucocyte antibodies are effective in the reduction of severe and fatal immune TRALI.     

The pathogenesis of transfusion-related acute lung injury (TRALI)

In recent years, transfusion-related acute lung injury (TRALI) has developed from an almost unknown transfusion reaction to the most common cause of transfusion-related major morbidities and fatalities. A clinical definition of TRALI was established in 2004, based on acute respiratory distress, non-cardiogenic lung oedema temporal association with transfusion and hypoxaemia. Histological findings reveal lung oedema, capillary leucostasis and neutrophil extravasation. However, the pathogenesis of TRALI remains controversial. Leucocyte antibodies, present in fresh frozen plasma and platelet concentrates from multiparous donors, and neutrophil priming agents released in stored cellular blood components have been considered to be causative. As neutrophils and endothelial cells are pivotal in the pathogenesis of TRALI, a threshold model was established to try to unify the various reported findings on pathogenesis. This model comprises the priming of neutrophils and/or endothelium by the patient's co-morbidity, neutrophil and/or endothelial cell activation by the transfused blood component, and the severity of the TRALI reaction.     

Transfusion-related acute lung injury and leucocyte-reacting antibodies

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is underdiagnosed and underreported. This is why we present cases suspected for TRALI, in which leucocyte antibodies were examined. MATERIAL AND METHODS: We analysed 44 patients with respiratory insufficiency, related to transfusion, who met criteria of acute lung injury (ALI). Lymphocyte and granulocyte antibodies were examined in donors and patients by six methods. RESULTS: Based on recent trends, we divided patients into two groups: TRALI (without risk factors for ALI) and possible TRALI (with probable risk factors). The incidence of antibodies was 68.2%, the majority were human leucocyte antigen (HLA) class I and/or II, the minority were non-specific granulocyte antibodies; half of all detected antibodies, however, reacted with granulocytes. Antibodies were found in 17 donors (more often in TRALI than in possible TRALI) and in 19 patients (in four - suspected to be of the donor origin, which would diminish the number of antibodies to 15). In seven available cases, we observed cognate antigen and/or positive cross-match. In the majority of patients, TRALI occurred after transfusion of red cells, in 56.2%- stored above 14 days; all the units were non-leucoreduced. Lookback in two donors showed that transfusions in 20 patients did not result in reported TRALI, even in the patient with cognate antigen. CONCLUSIONS: Our clinical observations suggest that to distinguish between TRALI and possible TRALI is difficult and the results are equivocal - it is worth considering whether it can be omitted. We have confirmed that antibodies are involved in TRALI, although their role is very complex. The role of stored red blood cells in the development of TRALI requires further observations in comparison with a control group of patients without TRALI.     

Implementation and outcomes of a transfusion-related acute lung injury surveillance programme and study of HLA/HNA alloimmunisation in blood donors

Background.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality. Antibodies against human leucocyte antigens (HLA) and human neutrophil antigens (HNA) are often detected in the implicated donors. We investigated the incidence and aetiology of TRALI in Lombardy. Moreover, we determined the rate of HLA and HNA alloimmunisation and the HNA genotype in a cohort of local blood donors.

Materials and methods.

During a 2-year observational study in eight blood transfusion services, suspected TRALI cases were collected and characterised by means of HLA and HNA antibody screening of implicated donors, donor/recipient cross-matching and HLA/HNA molecular typing. In addition, 406 Italian donors were evaluated for alloimmunisation and in 102 of them HNA gene frequencies were determined.

Results.

Eleven cases were referred to the central laboratory, of whom three were diagnosed as having TRALI, seven as having possible TRALI and one as having transfusion-associated circulatory overload. Seven TRALI cases were immune-mediated whereas in three we did not find either alloantibodies in implicated donors or a positive reaction in the cross-match. The most frequently implicated blood component was red blood cells (in 5 males and in 1 female), whereas four cases of TRALI were associated with transfusion of fresh-frozen plasma (in 3 females and in 1 male). The frequency of reported TRALI/possible TRALI cases was 1:82,000 for red blood cells and 1:22,500 for fresh-frozen plasma. No cases were observed for platelets. Overall, the frequency of HLA or HNA alloimmunisation in blood donors was 29% for females and 7% for males. The latter could be related, at least in part, to natural antibodies. HNA gene frequencies showed that HNA-1b is more frequent than HNA-1a in our sample of donors.

Discussion.

The recently adopted national policy to prevent TRALI, i.e. using only plasma donated by males, would have had a positive impact in our setting.     

输血相关性急性肺损伤研究进展

输血相关性急性肺损伤（transfusion-related acute lung injury,TRALI）是输血相关性疾病中最常见的类型.其发病率及病死率高,定义基于临床和影像学参数.TRALI分为免疫介导性和非免疫介导性,患者基础情况和输血因素共同决定着TRALI的发生.TRALI的预防主要包括避免使用女性供血者血浆制品及避免输注多个供血者的混合血浆.但目前所有预防措施只能减少而不是消除TRALI的发生,且对于这种危及生命的综合征尚无明确治疗方法,因此防治TRALI的工作任重而道远.本文对TRALI的定义、发病率、发病机制、临床表现、预防及治疗作一综述.     

输血相关急性肺损伤2例报告及文献复习

目的探讨输血相关急性肺损伤的临床表现、诊断和治疗。方法报告输血相关急性肺损伤2例并对相关文献进行复习。结果输血相关急性肺损伤是一种输血引起的急性呼吸窘迫综合征,报告的2例患者均发生在输血后6 h内,表现为急性呼吸窘迫、双肺水肿、低氧血症、肺部弥漫的毛玻璃样影。通常需要吸氧、机械通气等治疗。结论如果患者在输血后出现迅速进展的低氧血症,应考虑本病,早期诊断和治疗是提高生存率的关键。     

Benefit of transfusion-related acute lung injury risk-minimization measures--German haemovigilance data (2006-2010)

Objective Based on the frequency of immune‐mediated and non‐immune‐mediated transfusion‐related acute lung injury (TRALI), the effect of risk‐minimization measures was evaluated during a period of 5 years (2006–2010). Risk‐minimization measures were implemented in 2008/2009, consisting of exclusion of female donors with a history of pregnancy or exclusion of female donors with human leucocyte antigen (HLA)/human neutrophil alloantigen (HNA) antibodies. Methods TRALI was confirmed according to the criteria of the International Haemovigilance Network. Based upon the results of donor testing of white‐blood‐cell antibodies (WBC‐Ab) against HLA or HNAs, confirmed cases were classified as immune‐ or non‐immune‐mediated TRALI. Reporting rates were calculated on the basis of the annually transfused blood components, and pre‐ and post‐implementation periods were compared. Results In total, 60 immune‐mediated (75%) and 20 non‐immune‐mediated (25%) TRALI reactions were confirmed. A total of 68 (64 women and four men) donors were involved: seven red‐blood‐cell concentrates donors (13%), six platelet concentrate donors (10%), and 48 fresh frozen plasma (FFP) donors (77%). The reporting rate of immune‐mediated TRALI caused by FFP decreased continuously; from 12·71 per million units in 2006/2007 to 6·81 per million units in 2008/2009 and no case in 2010. Conclusion The comparison of the pre‐ and the post‐implementation period demonstrated a significantly reduced risk of TRALI events comparing 2006/2007 with 2010 (P‐value: < 0·01). Furthermore, no case of TRALI‐induced fatality occurred after the implementation of risk‐minimization measures.     

Antibody‐mediated transfusion‐related acute lung injury; from discovery to prevention

Transfusion‐related acute lung injury (TRALI), a syndrome of respiratory distress caused by blood transfusion, is the leading cause of transfusion‐related mortality. The majority of TRALI cases have been related to passive infusion of human leucocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies in donor blood. In vitro, ex vivo and in vivo animal models have provided insight in TRALI pathogenesis. The various classes of antibodies implicated in TRALI appear to have different pathophysiological mechanisms for the induction of TRALI involving endothelial cells, neutrophils, monocytes and, as very recently has been discovered, lymphocytes. The HLA and HNA‐antibodies are found mainly in blood from multiparous women as they have become sensitized during pregnancy. The incidence of TRALI has decreased rapidly following the introduction of a male‐only strategy for plasma donation. This review focuses on pre‐clinical and clinical studies investigating the pathophysiology of antibody‐mediated TRALI.     

Transfusion‐related acute lung injury after intravenous immunoglobulin treatment in a lung transplant recipient

Three weeks after single‐lung transplantation for pulmonary fibrosis, a patient with high serum levels of de novo donor‐specific antibodies received high‐dose intravenous immunoglobulin (IVIG) infusion (scheduled dose: 2 g/kg on 2 days) to prevent antibody‐mediated rejection. Within the first hours after completion of infusions, he experienced acute lung injury involving the transplanted lung. Given the clinical evolution and the absence of an alternative diagnosis, transfusion‐related acute lung injury (TRALI) was diagnosed. The IVIG administered on each day was from the same batch. At day 110, because of an increase in the serum titers of donor‐specific antibodies, IVIG therapy was reintroduced but from a different batch, with excellent clinical tolerance. The lung injury was explored biologically, but no mechanism was revealed. Given the increasing use of IVIG in solid‐organ recipients, clinicians should be aware of possible TRALI after IVIG infusion.     

Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion

BACKGROUND AND OBJECTIVES: Analyses of fatal transfusion reactions in the UK and USA have shown that transfusion-related acute lung injury (TRALI) is among the most common causes of fatal transfusion reactions. MATERIAL AND METHODS: Review of the literature was used to analyse TRALI. RESULTS: TRALI is characterized by acute respiratory distress and non-cardiogenic lung oedema developing during, or within 6 h of, transfusion. In atypical cases, TRALI can become symptomatic much later. TRALI must be carefully differentiated from transfusion-associated circulatory overload. In its fulminant presentation, TRALI can be clinically indistinguishable from acute respiratory distress syndrome occurring as a result of other causes. The severity of TRALI depends upon the susceptibility of the patient to develop a more clinically significant reaction as a result of an underlying disease process, and upon the nature of triggers in the transfused blood components, including granulocyte-binding alloantibodies (immune TRALI) or neutrophil-priming substances such as biologically active lipids (non-immune TRALI). Immune TRALI, which occurs mainly after the transfusion of fresh-frozen plasma and platelet concentrates, is a rare event (about one incidence per 5000 transfusions) but frequently ( approximately 70%) requires mechanical ventilation (severe TRALI) and is not uncommonly fatal (6-9% of cases). Non-immune TRALI, which occurs mainly after the transfusion of stored platelet and erythrocyte concentrates, seems to be characterized by a more benign clinical course, with oxygen support sufficient as a form of therapy in most cases, and a lower mortality than immune TRALI. CONCLUSIONS: By virtue of its morbidity and mortality, TRALI has become one of the most serious current complications of transfusion. To prevent further antibody-mediated cases, the evaluation of TRALI should include leucocyte antibody testing of implicated donors. However, further studies are necessary for the prevention of this serious transfusion complication.     

Transfusion-related acute lung injury in a neutropenic patient

Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion related morbidity and mortality. Current concepts regarding the pathogenesis of this disorder imply a "two-hit" model in which neutrophils are sequestered in the pulmonary capillary bed, and subsequently activated by substances in the transfused blood product. We report a case of TRALI in a patient with neutropenia and discuss the possible factors contributing to the respiratory symptoms in this patient. We also emphasise the importance of recognising mild cases of TRALI in order to investigate the implicated donor/s appropriately, and to minimise the risk for more severe episodes in other patients.     

Transfusion-related acute lung injury due to HLA-A2-specific antibodies in recipient and NB1-specific antibodies in donor blood

Transfusion-related acute lung injury (TRALI) is a hazardous but little-known complication of blood transfusion, characterized by non-cardiogenic lung oedema after blood transfusion. Leucoagglutinating antibodies in the donor plasma are considered to play a central role in the pathogenesis of TRALI but no recommended procedure currently exists for their detection, and most of them have not yet been well characterized. Serum samples of two patients who have developed TRALI within 30 min of blood transfusion and the sera of the involved blood donors were investigated for leucocyte antibodies by granulocyte immunofluorescence, granulocyte agglutination and lymphocytotoxicity assays using typed test cells. Suspected specificities of the detected antibodies were confirmed by a luminoimmunoblot assay and the antigen capture assay MAIGA. One case was associated with granulocyte agglutinating anti-HLA-A2 antibodies in the recipient's (i.e. patient's) own blood and the other with donor-related non-agglutinating antibodies directed against the granulocyte-specific antigen NB1. Leucocyte incompatibility between donor and recipient was shown in both cases by crossmatching and typing of the incompatible cells for the appropriate antigen. The results show that TRALI is associated not only with donor- but also with recipient-related leucocyte antibodies. In addition to leucoagglutinating antibodies, non-agglutinating granulocyte-specific antibodies can be also involved. For immunodiagnosis, sera from both must be investigated by a combination of granulocyte and lymphocyte (HLA) antibody screening tests and leucocyte incompatibility verified by crossmatching.     

Cytophilic immunoglobulin G binding on neutrophils from a child with malignant osteopetrosis who developed fatal acute respiratory distress mimicking transfusion-related acute lung injury

A 16-month-old boy, diagnosed at age 3 months with osteopetrosis, was treated since age 6 months with rhlFN-γ in combination with rhM-CSF. The child developed acute respiratory distress within 1 hr of a paternal platelet transfusion. Both the child and the father were blood group type O, and platelets were collected the previous day from the father. Chest X-ray revealed right pulmonary consolidation and a complete “whiteout” on the left. By 24 hr, the lungs had the appearance of adult respiratory distress syndrome (ARDS). Over the course of the next 11 days, the child remained intubated and hypotensive, and died of respiratory insufficiency 11 days later. ARDS was confirmed at autopsy. Pre- and posttransfusion patient's sera, as well as paternal serum, were tested by granulocyte agglutination and flow cytometry against granulocytes (PMN) from the patient, father, mother, and routine cell-panel donors and lymphocytes for the presence of neutrophil-specific and lymphocyte (HLA) antibodies, to rule out classical transfusion-related acute lung injury (TRALI). Both the patient's and the paternal sera were devoid of antibodies, but the patient's neutrophils demonstrated strong binding of cytophilic IgG accompanied by extremely low serum IgG and IgG1 levels. Since rhlFN-γ is known to upregulate Fc gamma receptor type I (FcγRI) with high affinity for IgG1, the binding of cytophilic IgG suggests that the patient's neutrophils may have been activated in vivo. The case report of another child with osteopetrosis has also been described. Although the blood specimen was not available for serological studies, this 4½-year-old child treated with rhlFN-γ and rhM-CSF also died of adult respiratory distress syndrome, with similar clinical presentations. © 1996 Wiley-Liss, Inc.     

Neutrophil elastase activity in acute lung injury and respiratory distress syndrome

Background and objective:   Neutrophil elastase (NE) may play a key role in the development of acute lung injury (ALI) or ARDS. NE activity (NEA) was measured in patients with ALI treated with a selective NE inhibitor.
Methods:   NEA and NE-α1-antitrypsin (NE-AT) complex were measured in plasma before, during and after the administration of the selective NE inhibitor, sivelestat, in 32 patients with a diagnosis of ALI or ARDS. NEA index (NEAI) was calculated as NEA/NE-AT. The sequential organ failure assessment (SOFA) score and the ratio PaO₂/fraction of inspired oxygen (FiO₂) were measured.
Results:   NEA and NE-AT was raised in all patients. Sivelestat reduced NEAI and NEA ( P  < 0.01 for both) but not NE-AT and NEA, and NEAI returned to pretreatment levels. NEA correlated closely with NE-AT before, but not after treatment. No relationship was observed between these indices and SOFA score or PaO₂/FiO₂ ratio.
Conclusions:   Sivelestat reduced NEA and NEAI in patients with ALI or ARDS suggesting NE inhibition. A larger study is needed to determine the relationship of NEA, NE-AT and NEAI with the outcome of ALI/ARDS.     

Transfusion‐related acute lung injury risk mitigation: an update

Transfusion‐related acute lung injury (TRALI) is a life‐threatening complication of transfusion. Greater understanding of the pathophysiology of this syndrome has much improved during the last two decades. Plasma‐containing components from female donors with leucocyte antibodies were responsible for the majority of TRALI fatalities before mitigation strategies were implemented. Over the past 15 years, measures to mitigate risk for TRALI have been implemented worldwide and they continued to evolve with time. The AABB requires that all plasma containing components and whole blood for transfusion must be collected from men, women who have not been pregnant, or women who have tested negative for human leucocyte antigen antibodies. Although the incidence of TRALI has decreased following the institution of TRALI mitigation strategies, TRALI is still the most common cause of transfusion‐associated death in the United States. In this review, we focus on TRALI risk mitigation strategies. We describe the measures taken by blood collection facilities to reduce the risk of TRALI in the United States, Canada and European countries. We also review the literature for the effectiveness of these measures.     

Heat shock response decreases endotoxin-induced acute lung injury in rats

OBJECTIVE: Transient whole-body hyperthermia was reported to reduce lung damage in a rat with intra-abdominal sepsis produced by caecal perforation. METHODOLOGY: In order to determine the effect of heat shock response on acute lung injury induced by endotoxin, which plays a central role in the pathogenesis of sepsis, we instilled either saline or lipopolysaccharide (LPS) intravenously with and without heat pretreatment in rats. The heated rats had their rectal temperature raised to more than 40 degrees C for 13 min 18 h before intravenous administration of saline or LPS. RESULTS: We found that the lung leak was significantly increased among the rats given LPS intravenously with (median, 0.17; range, 0.15-0.22; n = 10) and without heat pretreatment (0.23; 0.17-0.30; n = 10) compared with those of saline-treated rats (0.13; 0.10-0.14; n = 10) (P < 0.05 in each). However, rats given LPS after heat pretreatment had significantly decreased lung leak index compared with those of LPS-treated rats without heat pretreatment (P < 0.05). Rats administered LPS intravenously showed increased myeloperoxidase activity without heat pretreatment (19.01; 9.34-28.00 U/g; n = 10) compared with that of saline-treated rats (7.09; 4.49-10.56 U/g; n = 5) (P < 0.05) (Fig. 2). Myeloperoxidase activity of the rats treated with LPS with heat pretreatment (5.57; 2.87-8.96 U/g; n = 10) was significantly decreased to the level of normal control compared with that of LPS-treated rats without heat pretreatment (P < 0.05). The levels of heat shock proteins (HSP72) in lung tissue, which were examined by western blot analysis, were increased over baseline levels at 23 h after hyperthermic stress. CONCLUSIONS: These observations show that brief heat shock response is associated with the induction of HSP72 protein synthesis and attenuated neutrophil recruitment and acute lung leak is induced by endotoxin in rats.