Transfusion-related Acute Lung Injury Patients Research Articles

Pathogenetic analysis of transfusion-related acute lung injury caused by human leukocytes antigen antibody against human leukocyte antigen

From September 2019 to October 2020, pathogenetic analysis of three patients clinically diagnosed as transfusion-related acute lung injury (TRALI) caused by human leukocyte antibodies was conducted by Guangzhou Blood Centre, including 2 males and 1 female, aged 56, 50 and 20 years old, respectively. Solid phase agglutination, anti-human globulin test and flow cytometry method were used to detect the presence of antibodies against patients. Sequencing-based human leukocyte antigen (HLA-SBT) typing technique was used to detect the human leukocyte antigen (HLA) genotypes of patients. Lifecodes single antigen class Ⅰ/Ⅱ kit (LSA-Ⅰ/Ⅱ) were used to detect the specificity of HLA-class Ⅰ and class Ⅱ antibodies in donor blood by Luminex 200 liquid suspension chip system. The HLA specific antibodies and corresponding epitopes in donors were also analyzed. The results showed that HLA class Ⅰ or class Ⅱ specific antibodies against TRALI patients were detected in the blood donors. The plasma of donor 3 received by patient 1 contained antibodies against the patient's HLA-DRB1*09∶01 antigen, and the epitopes mediating the antibody reaction of the donor and recipient were 70R, 31I, 70QA. There were antibodies against the HLA-A*11∶02, HLA-A*11∶01, DRB1*12∶02, and DRB1*09∶01 antigens of patient 2 in the plasma of donor 4, and the associated antigenic epitopes were 151AHA, 57V, and 16Y. Antibodies against the HLA-DRB1*14∶04, DRB1*11∶01, and DPB1*05∶01 antigens of patient 3 were present in the plasma of donor 6 and donor 7, and the associated epitopes were 96HK, 140TV, 13SE, and 111K. Three cases of TRALI were confirmed to be caused by HLA antibodies through laboratory analysis, and human leukocyte antibody detection should be paid attention in clinically suspected cases of TRALI, and targeted diagnosis and treatment should be given.

Fc-Mediated Complement Activation Is Associated with Macrophage Trafficking and Induction of Neutrophil Extracellular Traps in Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is a leading cause of blood transfusion-related fatalities without available therapies. The pulmonary endothelium is damaged in TRALI, through incompletely understood pathogenic mechanisms, resulting in pulmonary edema. Generally, anti-leukocyte antibodies or biological response modifiers in the transfusion product, in combination with predisposing risk factors in the transfused recipient (e.g. inflammation), are responsible for initiation of TRALI. Remarkably, not all anti-leukocyte antibodies cause TRALI. In a previous in vitro study, we identified increased Fc-mediated complement activation to be a key feature of murine TRALI-inducing antibody 34-1-2S (anti-H-2K d) compared to TRALI-resistant antibody SF1.1.10 (anti-H-2K d) (Zeeuw van der Laan et al, Blood Adv 2020).In the current study, we further explored antibody-mediated TRALI mechanisms in vivo using our previously established TRALI mouse model in which mice are pre-depleted of protective CD4+ T cells and primed with LPS, followed by infusion of antibody 34-1-2S (Kapur et al, Blood 2017, Blood Adv 2018, Blood 2019). A key read-out for TRALI was the lung wet/dry weight ratio (Lung W/D, measure for pulmonary edema). We found that in vitro antibody-mediated complement activation was associated with in vivo antibody-mediated TRALI. 34-1-2S caused severe TRALI (complement activation: +++, Lung W/D: 7.4 ± 0.21), while SF1.1.10 did not cause TRALI (complement activation: +, Lung W/D: 4.68 ± 0.16). Furthermore, Fc-deglycosylated 34-1-2S still caused significant TRALI (complement activation: ++, in vivo Lung W/D: 5.16 ± 0.52). TRALI development was fully Fc-dependent as 34-1-2S-Fab did not cause any TRALI (no complement activation, Lung W/D: 4.35 ± 0.18). Importantly, we found significantly increased levels of complement C1q-C4 complexes in plasma samples of TRALI patients (n=46) compared to healthy controls (n=25): 6.49 ± 5.27 vs 3.84 ± 2.27 AU/ml, respectively, P: 0.0005,***. Similarly, C5a levels were significantly elevated in plasma samples of TRALI patients (n=53) compared to healthy controls (n=30): 2.52 ± 2.17 vs 1.37 ± 1.08 ng/ml, respectively, P: 0.0006,***. To further dissect the effect of the Fc-part of 34-1-2S in TRALI-induction, we aim to investigate the contribution of Fc-mediated complement activation vs Fc-receptor interaction. We therefore successfully generated chimeric variants of 34-1-2S with a humanized IgG1 Fc-domain containing mutations making them functionally complement dead (K322A), Fc-receptor dead (dG236) or both complement and Fc-receptor dead (PG LALA). We are currently investigating the effects of these variants on in vivo TRALI induction.We next investigated how the in vivo murine TRALI reaction was related to numbers of macrophages, monocytes and neutrophils in blood and lungs. We found that 34-1-2S-TRALI was associated with significantly decreased levels of macrophages in the lungs and increased levels in blood, compared to mice infused with PBS, SF1.1.10 or 34-1-2S-Fab, suggesting that Fc-mediated complement activation and TRALI induction is related to macrophage trafficking from lungs to blood.We did not observe any significant differences between blood and lung neutrophil levels of 34-1-2S-TRALI mice compared to SF1.1.10 TRALI-resistant mice. We hypothesized that in TRALI neutrophils undergo formation of neutrophil extracellular traps (NETs) induced by complement. We observed that C5a enabled potent neutrophil-chemotaxis in vitro (P: 0.0048,**). In addition, using direct immunofluorescence staining of extracellular DNA and Citrullinated histone H3, we observed that both LPS and C5a on their own could induce NET formation in vitro, which was synergistically increased with a combination of both LPS and C5a (P: 0.0417,*), as occurring during TRALI. Furthermore, we found increased levels of NETs to be present in plasma samples of TRALI patients (n=53) compared to healthy controls (n=30): 1.64 ± 0.97 vs 0.80 ± 0.34 MPO-DNA OD, respectively, P: 0.0002,***.Finally, we targeted the C5a-receptor (C5aR) using a C5aR-antagonist in our TRALI mouse model. Surprisingly, this did not prevent but even worsened TRALI (P: 0.0398,*), with elevated levels of blood monocytes and macrophages. This suggests that an approach directly targeting complement components may be a more promising therapeutic strategy to explore in combatting TRALI. DisclosuresNo relevant conflicts of interest to declare.

TRANSFUSION-RELATED ACUTE LUNG INJURY ASSOCIATED WITH BANLAMIVIMAB INFUSION

TOPIC: Lung Pathology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Transfusion-related acute lung injury (TRALI) is a well-known risk of intravenous infusions, but the true incidence is poorly defined. With the arrival of COVID-19, a new intravenous medication, Banlamivimab, may be associated with TRALI. We present a unique case of Banlamivimab TRALI from COVID-19 treatment. CASE PRESENTATION: A 69-year-old female presented to the Emergency Department with complaints of fevers, generalized weakness, nausea, vomiting, and dyspnea on exertion. She was febrile to 101.2 Fahrenheit and maintaining a normal oxygen saturation level on ambient air. Laboratory tests were positive for SARS-COV-2, elevated CRP, and troponin up to 1.37 ng/mL. Complete blood count and chemistry were both normal. Chest x-ray was unremarkable. Initially, she was set to be discharged home. Infectious Disease was consulted regarding her COVID infection and recommended Banlamivimab infusion prior to discharge. Approximately 45 minutes after starting the infusion, the patient experienced sudden onset shortness of breath and rigors. She was hypoxic to 85% on ambient air, tachypneic, febrile to 102.9 Fahrenheit, hypertensive and in acute respiratory distress. She had no evidence of an allergic reaction nor anaphylaxis. The infusion was stopped immediately and she was given Solumedrol and Benadryl. Her troponin increased to 3.23 ng/mL, white blood cell count rose to 19,300/mL and her lactic acid was 6.8. Chest x-ray showed new pulmonary edema. Echocardiogram showed normal systolic and diastolic function. She was diagnosed with transfusion related lung injury and fully recovered with supportive treatment. DISCUSSION: Banlamivimab is an investigational medicine used in patients who are considered high risk for being hospitalized or progressing to severe COVID-19 infection. Although TRALI is a well-defined risk factor of blood transfusions, there is insufficient data related to transfusion related lung injuries caused by Banlamivimab infusion or other human monoclonal antibodies. When treating COVID-19 patients with Banlamivimab, TRALI must be a side effect taken into consideration due to the possibility of causing a second hit to COVID-19 damaged lungs. As highlighted by the acuity of our patient's illness, it is feasible that such an event could increase patient mortality. CONCLUSIONS: This case uniquely demonstrates the possibility of TRALI with Banlamivimab infusions and highlights the importance of early recognition and management. Furthermore, clinicians should maintain a high index of suspicion for TRALI in patients receiving not only blood transfusions, but also any human monoclonal antibody infusions. REFERENCE #1: (2021, March 18). FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB AND ETESEVIMAB. Eli Lilly and Company. Retrieved April 30, 2021, from https://www.covid19.lilly.com/bam-ete/getting-started REFERENCE #2: Petraszko, T. (2019, February 26). Transfusion-related acute lung Injury (trali). Retrieved April 30, 2021, from https://professionaleducation.blood.ca/en/transfusion/publications/transfusion-related-acute-lung-injury-trali REFERENCE #3: Kleinman, S., MD. (n.d.). Transfusion-related acute lung injury (TRALI). Retrieved April 30, 2021, from https://www.uptodate.com/contents/transfusion-related-acute-lung-injury-trali#H1588910 DISCLOSURES: No relevant relationships by Pankaj Aggarwal, source=Web Response No relevant relationships by Jenna Dumovich, source=Web Response No relevant relationships by Justin Haloot, source=Web Response No relevant relationships by Jane O'Rorke, source=Web Response

Pulmonary disease as a risk factor for transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a severe condition characterised by noncardiogenic pulmonary oedema that develops within 6 h of blood transfusion. Patient factors and blood products have both been implicated in the development of TRALI; however, the role of pulmonary disease has not been investigated. We aimed to determine whether pulmonary disease is a risk factor for TRALI.We conducted a nested case-control study using data from the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan, between July 2010 and March 2015. Case patients who developed TRALI were 1:4-matched with control patients for sex, age and same hospital for receipt of blood transfusion. We conducted a multivariable conditional logistic regression analysis to evaluate the associations of TRALI with various factors including comorbidities, body mass index (BMI) and plasma-containing blood products.We identified 2 019 501 hospitalised patients who received a blood transfusion. Among these patients, 72 developed TRALI. The 72 case patients had higher proportions of haematological malignancy, trauma and interstitial lung disease (ILD) than the 288 matched control patients. The multivariable conditional logistic regression analysis showed that occurrence of TRALI was associated with ILD (odds ratio, 3.88; 95% confidence interval, 1.11–13.6), BMI ≥25.0 kg·m−2 (2.10; 1.05–4.24) and plasma-containing blood products (1.94; 1.10–3.42), but not with infectious lung disease or obstructive airway disease.In conclusion, ILD was an independent risk factor for the development of TRALI. Physicians should be aware of the increased risk of TRALI in patients with ILD.

Low levels of interleukin-10 in patients with transfusion-related acute lung injury.

Transfusion related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities (FDA Report 2016) (1) and is characterized by the acute onset of respiratory distress within 6 hours following blood transfusion (2,3). The clinical diagnosis is confirmed in case of newly developing acute respiratory distress: PaO 2 /FiO 2 ratio (ratio of arterial oxygen partial pressure to fractional inspired oxygen) <300 mmHg or arterial oxygen saturation <90% at room air; newly developed or worsened bilateral pulmonary infiltrates indicative of pulmonary edema on chest X-ray; emergence of all symptoms within 6 hours upon blood transfusion and exclusion of cardiac ischemia and transfusion associated circulatory overload (TACO). Apart from supportive measures, such as oxygen or ventilation, no specific therapies are available. The pathogenesis is incompletely understood, however, a two-hit model is usually assumed to underlie the disease pathology. The first hit consists of a pre-disposing factor present in the recipient such as inflammation while the second hit is conveyed by factors present in the transfused blood product such as anti-leukocyte antibodies (3). For example, the acute phase protein C-reactive protein (CRP) which rapidly increases during infection and inflammation was shown to enhance antibody-mediated TRALI in mice (4) and in line with that data, CRP was found to be elevated in human TRALI patients (5) confirming its role as a first hit risk factor in human TRALI.

Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion-Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013.

Using the French Hemovigilance Network database from 2007 to 2013, we provide information on demographics, incidence, and risk factors of reported transfusion-related acute lung injury (TRALI) and possible TRALI, analyze TRALI mitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impact of platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions for TRALI and possible TRALI. Two TRALI subgroups were considered: "antibody positive" when a donor has human leukocyte antigen (class I or II) and/or human neutrophil antigen antibodies and the recipient has cognate antigen, and "antibody negative" when immunological investigation is negative or not done. The analysis targeted 378 cases, divided into antibody-positive TRALI (n=75), antibody-negative TRALI (n=100), and possible TRALI (n=203). TRALI patients were younger and received more blood components than the general population of transfused patients. Moreover, we identified the following clinical conditions where patients seemed to be at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allogeneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy. Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concentrates and fresh frozen plasma but not for whole blood-derived platelet concentrates. The use of platelet additive solutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffy coat-derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce the concept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many characteristics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact on transfusion safety. Despite TRALI mitigation measures, the overall incidence of TRALI cases reported to the French Hemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if not eradicate, all TRALI categories.

Elevation of C-reactive protein levels in patients with transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within six hours following blood transfusion. In most cases, donor antibodies are suggested to be involved, however, the pathogenesis is poorly understood. A two-hit model is generally assumed to underlie TRALI pathogenesis where the first hit consists of a patient predisposing factor such as inflammation and the second hit is due to donor antibodies present in the transfused blood. We recently demonstrated that the acute phase protein C-reactive protein (CRP) could enhance murine anti-major histocompatibility complex (MHC) class I-mediated TRALI. Whether CRP is increased in human TRALI patients which would support its role as a risk factor for human TRALI, is currently unknown. For that purpose, we measured CRP levels in the plasma of human TRALI patients and found CRP levels to be significantly elevated compared to transfused control patients. These data support the notion that CRP may be a novel first hit risk factor in human TRALI and that modulation of CRP levels could be an effective therapeutic strategy for this serious adverse event of transfusion.

Transfusion Related Acute Lung Injury (TRALI): A Single Institution Experience of 15Years.

Transfusion related acute Lung injury (TRALI) though a serious blood transfusion reaction with a fatality rate of 5-25% presents with acute respiratory distress with hypoxaemia and noncardiac pulmonary oedema within 6h of transfusion. In non fatal cases, it may resolve within 72h or earlier. Although reported with an incidence of 1:5000, its true occurrence is rather unknown. Pathogenesis is believed to be related to sequestration and adhesion of neutrophils to the pulmonary capillary endothelium and its activation leading to its destruction and leaks. The patient's underlying condition, anti-neutrophil antibody in the transfused donor plasma and certain lipids that accumulate in routinely stores blood and components are important in its aetiopathogenesis. Patient's predisposing conditions include haematological malignancy, major surgery (especially cardiac), trauma and infections. The more commonly incriminated products include fresh frozen plasma (FFP), platelets (whole blood derived and apheresis), whole blood and Packed RBC. Occasional cases involving cryoprecipitate and Intravenous immunoglobulin (IVig) have also been reported. We present a 15year single institution experience of TRALI, during which we observed 9 cases among 170,871 transfusions, giving an incidence of 1:19,000. We did not encounter cases of haematological malignancy or cardiac surgery in our TRALI patients. Among the blood products, that could be related to TRALI in our patients included solitary cases receiving cryoprecipitate, IVIg, and recombinant Factor VII apart from platelets and FFP. All patients were treated with oxygen support. Six patients required mechanical ventilation. Off label hydrocortisone was given to all patients. There were no cases of fatality among our patients.

Perioperative transfusion-related acute lung injury: the Canadian Blood Services experience.

Transfusion-related acute lung injury (TRALI) is a devastating transfusion-associated adverse event. There is a paucity of data on the incidence and characteristics of TRALI cases that occur perioperatively. We classified suspected perioperative TRALI cases reported to Canadian Blood Services between 2001 and 2012, and compared them to non-perioperative cases to elucidate factors that may be associated with an increased risk of developing TRALI in the perioperative setting. All suspected TRALI cases reported to Canadian Blood Services (CBS) since 2001 were reviewed by two experts or, from 2006 to 2012, the CBS TRALI Medical Review Group (TMRG). These cases were classified based on the Canadian Consensus Conference (CCC) definitions and detailed in a database. Two additional reviewers further categorized them as occurring within 72 h from the onset of surgery (perioperative) or not in that period (non-perioperative). Various demographic and characteristic variables of each case were collected and compared between groups. Between 2001 and 2012, a total of 469 suspected TRALI cases were reported to Canadian Blood Services; 303 were determined to be within the TRALI diagnosis spectrum. Of those, 112 (38%) were identified as occurring during the perioperative period. Patients who underwent cardiac surgery requiring cardiopulmonary bypass (25.0%), general surgery (18.0%) and orthopedics patients (12.5%) represented the three largest surgical groups. Perioperative TRALI cases comprised more men (53.6% vs. 41.4%, p=0.04) than non-perioperative patients. Perioperative TRALI patients more often required supplemental O2 (14.3% vs. 3.1%, p=0.0003), mechanical ventilation (18.8% vs. 3.1%), or were in the ICU (14.3% vs. 3.7%, p=0.0043) prior to the onset of TRALI compared to non-perioperative TRALI patients. The surgical patients were transfused on average more components than non-perioperative patients (6.0 [SD=8.3] vs. 3.6 [5.2] products per patient, p=0.0002). Perioperative TRALI patients were transfused more plasma (152 vs. 105, p=0.013) and cryoprecipitate (51 vs. 23, p<0.01) than non-perioperative TRALI patients. There was no difference between donor antibody test results between the groups. CBS data has provided insight into the nature of TRALI cases that occur perioperatively; this group represents a large proportion of TRALI cases.

Possible transfusion-related acute lung injury (TRALI) in cardiac surgery patients

AimTo determine the incidence of possible transfusion-related acute lung injury (TRALI) and related risk factors in cardiac surgery patients.MethodsA single-center prospective cohort study was conducted from January 2009 to March 2010 at the Zagreb University Hospital Center, Croatia. Patient-, transfusion-, and surgery-related data were collected. The study included 262 patients who were observed for respiratory worsening including measurements of arterial oxygen saturation (SaO2), fraction of inspired oxygen (FiO2), and partial pressure of arterial oxygen (PaO2). Possible TRALI was defined according to the Toronto Consensus Conference definition broadened for 24-hour post-transfusion. This cohort was divided in two groups. TRALI group included 32 participants with diagnosis of TRALI and the control group included 220 patients with or without respiratory worsening, but with no signs of ALI.ResultsPossible TRALI was observed in 32 (12.2%) patients. Compared with the control group, possible TRALI patients had higher American Association of Anesthesiology scores, higher rate of respiratory comorbidity (43.8% vs 15.5%), and required more red blood cells (median 4, range [2.5-6] vs 2 [1-3]), plasma (5 [0-6] vs 0 [0-2]), and platelet units (0 [0-8] vs 0 [0-0]) (P < 0.001 all). Risk factors for possible TRALI were total number of transfused blood units (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.10-1.37) and duration of cardiopulmonary bypass (OR 1.08; 95% CI 1.05-1.11). Post-transfusion PaO2/FiO2 ratio was significantly decreased in possible TRALI patients and significantly increased in transfused controls without acute lung injury.ConclusionWe observed a higher rate of possible TRALI cases than in other studies on cardiac surgery patients. Serial monitoring of PaO2/FiO2 ratio and detection of its post-transfusion worsening aids in identification of possible TRALI cases.

Pregnancy-Related Hypertensive Disorders Are The Major Risk Factor For TRALI In Patients With Severe Post-Partum Hemorrhage

Hemovigilance studies report that from 6.7% to 15% of overall transfusion-related acute lung injury (TRALI) events occur among obstetrics-gynecological patients (Chapman et al, 2009, Transfusion, 49:440; Ozier et al, 2011, Transfusion, 51: 2102). Severe postpartum hemorrhage (sPPH, i.e. the blood loss in excess of 1000 ml), complicates from 1 to 5% of all deliveries and requires massive transfusion, which is a well acknowledged TRALI risk factor. In this retrospective study we evaluate the incidence and risk factors for TRALI among patients with sPPH. We identified in the blood bank database EmoNet those patients admitted to the delivery room of our hospital from January 2005 to December 2011, necessitating the urgent transfusion of a minimum of 3 red blood cell (RBC) units, with or without fresh frozen plasma (FFP) and platelet (PLT) concentrates. Clinical records of identified patients were then retrieved and demographics, clinical and obstetric data and laboratory and radiological findings were collected. Two anesthesiologists blinded to all information of transfused units independently examined clinical records. Suspected or possible TRALI were diagnosed according to the 2004 consensus criteria; (Kleinman et al. 2004; Transfusion 44: 1774; Toy et al. 2005; Crit Care Med 33:721). In total 71 patients received at least 3 RBC units for sPPH; suspected or possible TRALI was identified in 14 cases (overall incidence 21,6%). The 2 patients with possible TRALI had pneumonia and pulmonary embolism, respectively. On the whole, patients with TRALI were more frequently admitted to the intensive care unit and had a longer hospitalization (p=0.021 and p=0.001, respectively). At univariate analysis, patients with TRALI received a higher number of RBC (p=0,008), PLT (p =0,008,) and FFP units (p =0,034). No difference were found between TRALI and no TRALI groups according to the number of PLT and FFP units from female donors, the storage time of RBC and PLT units or the number of transfused RBC units with a storage time longer than 14 days. Relatively to patient-related factors, TRALI was not associated with age or smoke habit, or with the presence of co-morbidities pre-existing to pregnancy. In contrast, the presence of pregnancy-related hypertensive disorders (PR-HD, including gestational hypertension and preeclampsia /eclampsia) (8 patients, p=0.006) was an important risk factor for TRALI. The poor adverse role was confirmed also in gestational hypertension (6 patients, p=0.012 ) or preeclampsia/eclampsia (4 patients, p=0.022) separately evaluated. In a multivariate model combining both transfusion- and patient-related factors with significance level equal or inferior to 10% at univariate analysis, only PR-HD, gestational hypertension and preeclampsia/eclampsia maintained their significance. In particular, we found that the odds ratio for TRALI was 15.98 (95% IC 2.5-103.5, p=0.004) in PR-HD in total, 24.8 (95% IC 2.5 - 248.4, p=0.006) in gestational hypertension and 33.8 (95% IC 2.2-484.1, p=0.011) in preeclampsia/eclampsia. The strong association between PR-HD and TRALI has never been reported before and it is probably due to the widespread endothelial cell activation occurring in PR-HD. These results impose a careful observation when PR-HD patients receive transfusions.The study was supported by the “Gruppo Donatori Sangue, Francesco Olgiati” Disclosures:No relevant conflicts of interest to declare.

Methylprednisolone fails to attenuate lung injury in a mouse model of transfusion related acute lung injury

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Anecdotally, TRALI patients have been treated with corticosteroids. However, evidence for its therapeutic rationale in TRALI is lacking. We determined the effects of corticosteroids on lung injury in a "two-hit" mouse model of antibody-mediated TRALI. BALB/c mice were primed with lipopolysaccharide, after which TRALI was induced by injecting major histocompatibility complex (MHC)-I antibody against H2K(d) . Mice infused with phosphate-buffered saline served as controls. Simultaneously, one group of TRALI mice was infused with methylprednisolone (MPS; 2 mg/kg). Mice were supported by mechanical ventilation for 2 hours, after which bronchoalveolar lavage fluid (BALF) and lung homogenate were obtained. Statistics were obtained by one-way analysis of variance or Kruskal-Wallis. Injection of MHC-I antibodies resulted in TRALI, indicated by pulmonary edema and increased BALF levels of protein and the proinflammatory mediators macrophage inflammatory protein-2, keratinocyte-derived chemokine, and interleukin (IL)-6. Administration of MPS did not affect the amount of edema nor pulmonary protein and chemokine levels. MPS reduced systemic inflammatory reaction as well as IL-6 levels in the BALF. In a two-hit model of antibody-mediated TRALI, MPS attenuated the IL-6 host response, but failed to prevent the development of lung injury.

Transfusion‐related lung injury in children: a case series and review of the literature

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. The majority of the literature involves adult patients. The main objective of this study was to characterize the demographic features, clinical presentation, patient outcomes, and antibody profiles of TRALI patients reported to the Canadian Blood Service (CBS) and to assess similarities and differences between adult and pediatric TRALI cases. A retrospective review of cases of TRALI submitted to the CBS from 2001 to 2011 was performed. Information collected included recipient demographics, event details, blood component transfused, morbidity and mortality data, and donor antibody results. A total of 284 cases of definite, possible, or probable TRALI were reported. Six percent (n = 17) occurred in children. There were no significant differences between pediatric or adult patients with TRALI. Most of the children who presented with TRALI were either teenagers or less than 1 year of age. The incident rate of reported TRALI cases in Canada per 100,000 red blood cell transfusions was estimated at 5.58 for children and 3.75 for adults. This study is the largest case series of reported TRALI cases in children. Crude modeling suggests that the incidence of TRALI in children is similar to that of adults. Although the numbers are small, there do not appear to be differences in presentation or outcome between adults and children with TRALI. TRALI is associated with significant morbidity and mortality and pediatricians need to consider this diagnosis in children who experience respiratory distress after transfusions.

Allo‐exposure status and leucocyte antibody positivity of blood donors show a similar relation with TRALI

The fraction of transfusion-related acute lung injury (TRALI) cases preventable by deferral of allo-exposed donors has previously been estimated, under the assumption this indirectly estimated the contribution of leucocyte antibodies to the occurrence of TRALI. Our aim was to estimate the fraction preventable by deferral of leucocyte antibody positive donors and to investigate the validity of allo-exposure as a marker for leucocyte antibodies. All donors involved in a series of previously published TRALI patients were tested for leucocyte antibodies. The observed number of antibody positive donors was compared to the expected number. From this comparison we estimated the contribution of leucocyte antibodies to the occurrence of TRALI and compared this to the previously reported estimate for allo-exposed donors. Sixty-one TRALI patients were included. Of 288 involved donors 43 were expected and 67 were observed to be leucocyte antibody positive. The observed percentage of positive donors was 8.3% (95% confidence interval (CI): 5.1-11.5%) in excess of the expected. Overall 59% (95% CI: 34-85%) of TRALI cases was estimated to be preventable by the exclusion of all leucocyte antibody positive donors. For plasma-poor products this was 16% (95% CI: -5.0 to 36%). These estimates were similar to those previously published for allo-exposed donors. This suggests allo-exposure status can effectively be used in donor deferral strategies.

Storage time of blood products and transfusion‐related acute lung injury

Besides white blood cell antibodies in plasma-rich products, another cause of transfusion-related acute lung injury (TRALI) could be release of biologically active substances during storage of cellular blood products. We aimed to investigate the association of storage time and risk of TRALI for different product types. We compared storage time of blood products transfused within 6 hours before the onset of TRALI to storage time of a representative sample of all blood products transfused in the Netherlands. Generalized linear models were used to correct for confounding variables. Platelets (PLTs) in plasma transfused to TRALI patients were stored for 0.7 (95% confidence interval [CI], 0.073 to 1.3) days longer than those transfused to controls. The relative risk of TRALI, after receiving PLTs stored for 4 or 5 days, compared to 3 days or less, was 5.8 (95% CI, 0.99 to 110) and increased to 6.3 (95% CI, 1.1 to 118) after more than 5 days (i.e., 6 or 7 days). While longer storage of buffy coat-derived PLTs was associated with an increased risk of TRALI, storage of plasma for up to 2 years and red blood cells for up to 35 days was not associated with the risk of 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.

Alloexposed blood donors and transfusion‐related acute lung injury: a case‐referent study

Donor white blood cell (WBC) antibodies are thought to increase the risk of transfusion-related acute lung injury (TRALI). WBC antibodies can be present in blood products from donors who have been alloexposed. Alloexposed donors are increasingly excluded from donating plasma, but can still donate plasma-poor products. We aimed to quantify the contribution of alloexposed donors to the occurrence of TRALI for different blood product types. We performed a case-referent study including all reported TRALI patients and all Dutch blood donors. Data on alloexposure status of donors of all TRALI cases reported between January 2004 and October 2008, in the Netherlands, were compared to information on the total donor population. Alloexposure status of all 223 involved donors was compared to the expected status. The overall percentage of TRALI cases that could have been prevented by the deferral of all alloexposed donors (i.e., population-attributable risk [PAR]) was 51% (95% confidence interval [CI], 14%-88%). In 19 recipients of exclusively plasma-poor products (mostly red blood cells [RBCs]), alloexposure of the donors was not associated with TRALI, while in 28 recipients of both plasma-poor and plasma-rich products (>200 mL plasma), the PAR was 94% (95% CI, 34%-100%). Alloexposed donors conferred an increased risk of TRALI in recipients of plasma-rich products, but not in recipients of plasma-poor products. Although WBC antibodies are an important risk factor for TRALI, among RBC recipients another risk factor must be more important.

Transfusion‐related acute lung injury: reports to the French Hemovigilance Network 2007 through 2008

Transfusion-related acute lung injury (TRALI) is a major cause of transfusion-related mortality and morbidity. Epidemiologic studies using data from national transfusion schemes can help achieve a better understanding of TRALI incidence. A multidisciplinary working group analyzed TRALI cases extracted from the French Hemovigilance Network Database (2007-2008). All notified cases were reviewed for diagnosis. Those meeting the Canadian Consensus Conference criteria for TRALI were classified according to imputability to transfusion and clinical severity. Patient data (clinical characteristics, number and types of products transfused, and serology results) were obtained. There were 62 TRALI cases and 23 possible TRALI cases during the 2-year period. An immune-mediated mechanism was identified in 30 of 50 TRALI cases with complete serology. TRALI was considered to be the cause of death in 7.1% of patients and might have contributed to death in an additional 9.4% of TRALI or possible TRALI patients. Occurrence ranked high in obstetrics (15%), after surgery (34%), and in hematologic malignancies (21%). Single-donor high-plasma-volume components were involved in half of the cases where the implicated blood product could be determined and carried the highest risk per component (1:31,000 for single-donor fresh-frozen plasma units and apheresis platelet [PLT] concentrates, and 1:173,000 for red blood cells). No incident could be definitively related to the transfusion of solvent/detergent-treated pooled plasma (>200,000 units transfused), nor to pooled PLT concentrates. The proportion of TRALI cases related to plasma-rich components was lower than previously described.

Role of CD40 ligand in transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is an important problem in the critically ill. CD40L has been implicated as a cofactor or even the cause of TRALI [1]. (1) We hypothesized that blocking of the CD40-CD40L interaction protects against lung injury in a murine model of TRALI. (2) Furthermore, we hypothesized that plasma sCD40 levels are elevated in TRALI patients compared with controls.

Female donors and transfusion‐related acute lung injury

Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion-related acute lung injury (TRALI) are caused by female blood donors. We aimed to examine the relation between female donors and the occurrence of TRALI. We performed an international, multicenter case-referent study. TRALI patients who were diagnosed clinically, independent of serology or donor sex, and had received transfusions either only from male donors or only from female donors (unisex cases) were selected. The observed sex distribution among the donors of these TRALI patients was compared to the expected sex distribution, based on the relevant donor populations. Eighty-three clinical TRALI cases were included; 67 cases received only red blood cells (RBCs), 13 only plasma-rich products, and three both. Among RBC recipients the relative risk (RR) of TRALI after a transfusion from a female donor was 1.2 (95% confidence interval [CI], 0.69-2.1) and among plasma-rich product recipients the RR was 19 (95% CI, 1.9-191). The p value for the difference between RBCs and plasma was 0.023. Our data support the notion that plasma from female donors is associated with an increased risk of TRALI, while RBCs from female donors are not.