Prevention Of Transfusion-related Acute Lung Injury Research Articles

The Immune System in Transfusion-Related Acute Lung Injury Prevention and Therapy: Update and Perspective.

As an initiator of respiratory distress, transfusion-related acute lung injury (TRALI) is regarded as one of the rare complications associated with transfusion medicine. However, to date, the pathogenesis of TRALI is still unclear, and specific therapies are unavailable. Understanding the mechanisms of TRALI may promote the design of preventive and therapeutic strategies. The immune system plays vital roles in reproduction, development and homeostasis. Sterile tissue damage, such as physical trauma, ischemia, or reperfusion injury, induces an inflammatory reaction that results in wound healing and regenerative mechanisms. In other words, in addition to protecting against pathogens, the immune response may be strongly associated with TRALI prevention and treatment through a variety of immunomodulatory strategies to inhibit excessive immune system activation. Immunotherapy based on immune cells or immunological targets may eradicate complications. For example, IL-10 therapy is a promising therapeutic strategy to explore further. This review will focus on ultramodern advances in our understanding of the potential role of the immune system in TRALI prevention and treatment.

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.

Gastrointestinal Flora Dictates the Biological Response in Murine Transfusion Related Acute Lung Injury (TRALI)

Transfusion related acute lung injury (TRALI) is a syndrome of respiratory distress which occurs within 6 hours of blood transfusion. It is the leading cause of transfusion-related fatalities and the pathogenesis is incompletely understood. In the majority of the cases, anti-leukocyte antibodies present in the transfused blood product, in combination with recipient predisposing risk-factors such as inflammation, are implicated to be responsible for the onset of TRALI. Unfortunately, no therapies are available for TRALI. Recently, using novel murine models of TRALI, CD4+T cells were found to be important protector cells against antibody-mediated TRALI and administration of interleukin (IL)-10 was demonstrated to be a successful treatment strategy for TRALI, rescuing mice therapeutically from pulmonary edema, the hallmark of acute lung injury (Kapur et al, Blood 2017, 129(18):2557-2569). Whether the gut microbiome plays any role in the development of TRALI is currently unknown. For that purpose, we compared the biological TRALI response in mice housed in a barrier-free (BF) setting versus mice housed in a specific pathogen-free (SPF) environment. We utilized our TRALI model in which C57BL/6 mice were first depleted of CD4+ T cells in vivo followed by injection of anti-major histocompatibility complex class I antibodies (clones 34-1-2s and AF6-88.5.5.3). The TRALI response was analyzed after 90 minutes for several parameters including pulmonary edema (lung wet-to-dry weight ratios, W/Ds), rectal temperatures (indicative of systemic shock), plasma levels of macrophage inflammatory protein (MIP)-2 (murine homologue of IL-8, a neutrophil chemoattractant), levels of pulmonary neutrophils (major effector cells in TRALI) and lung histology. We observed that after one week of housing, baseline rectal temperatures of BF mice significantly increased from 38.7o C to 39.5° C (p<0.001) while SPF mice remained stable around 38.3 °C. When comparing BF versus SPF mice, the baseline temperature of BF mice was significantly higher than SPF mice after one week of housing (P<0.0001). The gut flora was subsequently depleted in BF mice via administration of broad-spectrum antibiotics through the drinking water. When both aerobic and anaerobic gut microbes were efficiently depleted after a week of antibiotic treatment, rectal temperatures of the treated BF mice significantly dropped again to 38.7 °C (P<0.05). When inducing TRALI by depleting CD4+ T cells and injecting TRALI-antibodies, the rectal temperatures of the untreated BF mice remained low while the rectal temperatures of SPF mice and gut flora depleted-BF mice normalized again from 60 minutes onwards (34.9 versus 36.8 versus 37.8 °C, respectively). Moreover, the untreated BF mice suffered from TRALI while the SPF mice and the gut flora depleted-BF mice were protected from TRALI development (lung W/Ds 5.77 versus 4.63 versus 4.49, respectively) which was also evident from lung histology-analyses. The prevention of TRALI in SPF mice and gut flora depleted BF mice was paralleled by decreased plasma MIP-2 levels compared to the untreated BF mice which suffered from TRALI (MIP-2: 0.09 versus 0.08 versus 82.94 pg/ml, respectively) which also corresponded to pulmonary neutrophil numbers. As previously shown, low IL-10 levels were associated with TRALI development and IL-10 KO mice were found to be susceptible to antibody-mediated murine TRALI (without prior in vivo cell-depletion). However, when IL-10 KO mice were housed under SPF conditions and injected with TRALI-inducing antibodies, they did not display increased lung W/Ds levels compared to naïve SPF mice indicating that the gut flora precedes and dictates the biological TRALI response. These data collectively link the gut flora to the development of antibody-mediated TRALI in mice and antibiotic treatment prevents TRALI and may perhaps prevent the onset of human TRALI which may help in TRALI risk-assessment prior to transfusion. DisclosuresSemple:Rigel: Consultancy; Novartis: Consultancy; Amgen: Consultancy; UCB: Consultancy.

Redefining transfusion-related acute lung injury: don't throw the baby out with the bathwater.

Recently two articles have been published in TRANSFUSION in which the authors propose to change the current definition on transfusion-related acute lung injury (TRALI). It was proposed to view TRALI from the perspective of detectability versus nondetectability of leukoreactive alloantibodies (Transfusion 2015;55:1128-34). The authors argue that only cases in which leukoreactive alloantibodies can be detected should be defined as "true" TRALI in analogy with the understanding of the pathophysiology of heparin-induced thrombocytopenia. In the other article (Transfusion 2015;55:947-52), the authors propose to redefine possible TRALI to transfused acute respiratory distress syndrome (ARDS) as their study in intensive care unit patients did not show a relation between the number of transfusions and possible TRALI.We discuss these two propositions in light of the current evidence on pathophysiology of TRALI and possible TRALI. We argue that it is too early to redefine TRALI, as 1) factors, such as storage time of platelets, which induce TRALI in preclinical studies, have not yet been properly investigated in humans. Further research is needed on these agents before it is concluded that antibody-mediated TRALI is the only "true" TRALI. 2) In light of the current knowledge, it makes perfect sense that multiple transfusion is not related to possible TRALI: ARDS risk factors in these patients result in a very sensitive equilibrium in which even only one transfusion induces TRALI. Excluding possible TRALI from the TRALI definition would result in further underrecognition of TRALI induced by alloantibodies and interferes with exclusion of donors related to TRALI cases and thus TRALI prevention.

Transfusion-related acute lung injury; clinical perspectives.

Transfusion-related acute lung injury (TRALI) was introduced in 1983 to describe a clinical syndrome seen within 6 h of a plasma-containing blood products transfusion. TRALI is a rare transfusion complication; however, the FDA has suggested that TRALI is the leading cause of transfusion-related mortality. Understanding the pathogenesis of TRALI will facilitate adopting preventive strategies, such as deferring high plasma volume female product donors. This review outlines the clinical features, pathogenesis, treatment, and prevention of TRALI.

Role of Riboflavin- and UV Light-Treated Plasma in Prevention of Transfusion-Related Acute Lung Injury

Introduction: Risk reduction strategies for transfusion-related acute lung injury (TRALI) include the preferential use of male donors to provide fresh frozen plasma (FFP). Implementing this measure based on FFP quarantine program is a very complex process. To improve FFP inventory management and the availability of FFP from male donors, the Mirasol Pathogen Reduction Technology® (PRT) system for FFP using riboflavin and UV light was adopted in our region in 2012. Methods: The percentage of male/female FFP units issued and TRALI cases in patients receiving FFP in the period before implementing riboflavin and UV light (2010-2011) was compared with the period post implementation of riboflavin and UV light (2012-2013). Results: In 2010 and 2011, there was one FFP transfusion-related TRALI case reported per year, when the proportion of male/female FFP distributed to the hospitals was 60/40. During 2012 and 2013, there have been no FFP transfusion-related TRALI cases, when the proportion of male/female FFP distributed to the hospitals was around 97/3. Mirasol PRT allows quick availability (24 h from collection) compared to quarantined FFP (≥3 months from collection). Conclusion: Thanks to its readiness, simplicity and feasibility, riboflavin- and UV light-treated FFP implementation can facilitate the preferential use of FFP from male donors as a TRALI prevention strategy.

Anti-leucocyte antibodies in platelet apheresis donors with and without prior immunizing events: implications for TRALI prevention

Transfusion-related acute lung injury (TRALI) prevention strategies in platelet (PLT) apheresis donors focus on identifying antileucocyte antibody-positive donors. The use of microbead based assays for screening purposes is hampered by the lack of a consensus cut-off for TRALI prevention and the undefined role of anti-leucocyte antibodies in never-alloexposed donors. This study evaluated anti-leucocyte antibody assays in PLT apheresis donors with and without prior immunizing events with special focus on microbead assay cut-offs, antibody specificities and their potential significance in never-alloexposed donors. Blood samples of male and female PLT apheresis donors with and without history of prior immunization were tested for anti-leucocyte antibodies. Of 262 female and 118 male PLT apheresis donors, 37·4% had prior immunizing events. Fifty-eight of 238 (24·4%) donors without prior immunizing event had anti-HLA antibodies confirmed in microbead single antigen assay (mean fluorescence intensity (MFI) >500). Even with a cut-off MFI >3000, anti-HLA antibodies were detected in 10·6% of female and 4·3% of male donors without history of immunization. Of the antibody specificities found, 6 of 17 (35·3%) anti-HLA-A, 4 of 8 (50·0%) anti-HLA-B and 4 of 6 (66·6%) anti-HLA class II antibodies have been detected in donors associated with TRALI cases in the literature. Platelet apheresis donors without history of immunization have anti-leucocyte antibodies that potentially can cause TRALI. In our opinion, this cohort should be included in screening strategies for TRALI prevention. As references and consensus cut-offs have not yet been established, it is premature to use microbead assays as standard for donor screening.

State of the Art Management of Transfusion-Related Acute Lung Injury (TRALI)

Transfusion-Related Acute Lung Injury (TRALI) is the leading cause of transfusion-related mortality in most developed countries. Despite this fact, well-designed investigations on specific management strategies for TRALI are lacking. Indeed, current recommendations are primarily based on data extrapolated from trials of the histo-pathologically similar Acute Lung Injury and Acute Respiratory Distress Syndromes. The cornerstone of TRALI management is supportive care with oxygen supplementation and ventilatory assistance when needed. When mechanical ventilation is required, attenuating additional ventilator-induced lung injury through the avoidance of high tidal volumes and elevated airway pressures, with additional measures such as positive end-expiratory pressure to prevent low-volume shear stress injury, are recommended. The literature is not currently sufficient to support either corticosteroids or statins as effective therapies in TRALI. Conservative fluid practices are desirable, provided care is taken to avoid hypotension. Preventative strategies have shown the most promise in mitigating this transfusion-related pulmonary complication. Specifically, conservative transfusion practices and deferral of high-plasma component donors who have, or at high risk of having, anti-human leukocyte antigen and/or anti-human neutrophil antigen antibodies have meaningfully impacted the incidence of TRALI. Future considerations for patients who are at increased risk for developing TRALI may include therapies such as anti-platelet agents and alternatives to traditional blood components such as prothrombin complex concentrates (PCC). However, these potential TRALI prevention strategies are insufficiently studied, have unclear risk/benefit profiles and cannot be currently recommended.

Relationship of donor HLA antibody strength to the development of transfusion‐related acute lung injury

Antibodies against the human leukocyte antigen (HLA) in donors' blood are implicated in the development of transfusion-related acute lung injury (TRALI). Screening of female donors for HLA antibodies has been introduced to prevent TRALI; however, the relationship of HLA antibody strength in the transfused components to the development of TRALI has not been evaluated in detail. Donors involved in 1038 cases of nonhemolytic transfusion reactions (NHTRs) including 283 cases of TRALI were screened for HLA antibodies by the fluorescence beads method. HLA antibody specificity and strength were analyzed in detail. The usefulness of enzyme-linked immunosorbent assay (ELISA) for screening HLA antibodies was also evaluated. Among 21 cases of TRALI, four cases of possible TRALI, and five cases of other NHTRs, the sum of mean fluorescence intensity (MFI) of donors' HLA antibodies to patients' cognate antigen(s) was determined in 18, four, and three cases, respectively. The sum of MFI in TRALI cases was significantly higher than that in other NHTR cases (p<0.05). When HLA antibody-positive samples were reevaluated by ELISA, the ELISA optical density ratio was significantly higher in donors' samples associated with TRALI than in those associated with other NHTRs (p<0.01) A correlation between the HLA antibody strength and development of TRALI was indicated. The antibody strength measured by ELISA could be used as the basis for the screening of HLA antibodies in place of the fluorescence beads method. This study provided clues to the establishment of a cutoff value for HLA antibody screening in an evidence-based manner for the prevention of TRALI.

Fight against TRALI

Transfusion‐related acute lung injury (TRALI) is a life‐threatening adverse reaction to transfusion. It is characterized by non‐cardiogenic pulmonary edema that develops during or within 6 h after transfusion. Transfusion of blood products or massive transfusion has long been known as a rare cause of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Because the main causes of ALI/ARDS are sepsis and/or pneumonia, little attention has been paid to transfusion as a cause of lung injury. Owing to indifference to and underrecognition of this complication, ALI after transfusion may be attributed to other causes. Moreover, physicians tend to attribute the cause of respiratory failure to more common complications of transfusion such as allergic reaction and circulatory overload. Even if an appropriate diagnosis of non‐cardiogenic pulmonary edema is made, transfusion may not be identified as its cause. Although anti‐leukocyte antibodies have been proved to be one of the main causes of TRALI, the precise mechanism of this syndrome is poorly understood. Anti‐HLA and ‐HNA antibodies in labile blood products are reported to cause TRALI, and animal models of TRALI show that these antibodies induce lung injury under certain experimental conditions. We have recently showed that anti‐CD36 antibody caused TRALI in two patients. This finding suggests that as‐yet‐unknown antibodies other than anti‐HLA or ‐HNA antibodies might cause TRALI. According to current haemovigilance reports and previous look‐back studies, the incidence of TRALI is not very high. This finding supports the concept of the two‐hit theory of ALI, where certain patients’ clinical conditions are prerequisite in addition to transfusion for developing TRALI. A recent study in the ICU of a tertiary care medical centre has revealed a high incidence of suspected TRALI cases. This study revealed that female plasma, number of pregnancies in donors, number of donor units positive for anti‐granulocyte antibodies and anti‐HLA class II antibodies and concentration of lysophophatidylcholine in donor products are associated with developing TRALI. Our recent prospective study has revealed the predominance of male Fresh frozen plasma (FFP) FFP in post‐transfusion respiratory function when comparing male only FFP and mixed FFP in surgical patients. The incidence of TRALI in the UK was successfully reduced by using preferentially male plasma. Although TRALI has a relatively better prognosis than ALI with other causes, TRALI has still been the leading cause of transfusion‐related death in the United States in recent years. The prevention of TRALI caused by plasma products has been successful, but TRALI caused by apheresis platelets is still problematic. A recent study has suggested that the prevalence of anti‐HLA antibodies in female donors increases with the number of pregnancies. Thus, screening for anti‐HLA antibodies has emerged as an effective measure to prevent TRALI caused by apheresis platelets. At present, no single measure can thoroughly eliminate TRALI; however, early diagnosis and intervention may improve the outcome for patients with TRALI. Further study is required to elucidate the mechanisms of TRALI, which may lead to the development of preventive measures and treatment.

Testing only donors with a prior history of pregnancy or transfusion is a logical and cost‐effective transfusion‐related acute lung injury prevention strategy

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatality reported to the Food and Drug Administration. Donor screening may reduce TRALI risk. This study sought to compare the efficacy and safety of different TRALI risk-reduction strategies at a hospital-based donor center. Samples from 1053 donors who answered questions regarding pregnancy and transfusion history were tested for HLA Class I and II antibodies using a flow cytometry-based screening assay. Donor history was compared with the presence of HLA alloantibodies. These data were used to model several TRALI risk-reduction strategies. The medical records of patients transfused fresh-frozen plasma (FFP) from highly alloimmunized donors were retrospectively reviewed for TRALI. HLA alloimmunization was observed among 25.4 percent (256/1009) of all female donors and among 12.0 percent (3/25) of those male donors who gave a history of prior transfusion. Prior pregnancy, reported by 52.6 percent (531/1009) of females, correlated significantly with HLA alloimmunization (p < 0.0001). The rate of HLA alloimmunization increased with parity. A positive pregnancy history was a sensitive (87.9%) screen for HLA alloimmunization with a negative predictive value of 93.5 percent (95% confidence interval, 91.3%-95.7%). Although 5.9 percent (27/459) of nulliparous, untransfused females demonstrated a positive screening test, only 1 percent (7/459) had a confirmed HLA alloantibody. Transfusion of FFP from donors found retrospectively to be highly alloimmunized led to reactions suggestive of TRALI in 2 of 26 recipients. Donor history is a reliable predictor of HLA alloimmunization. Testing only donors with a prior history of pregnancy or transfusion is a logical and cost-effective TRALI prevention strategy.

Promoting Recognition and Prevention of Transfusion-Related Acute Lung Injury

CRITICALCARENURSE Vol 27, No. 4, AUGUST 2007 49 transfusion-related death in the United States, surpassing deaths caused by ABO incompatibility and bacterial contamination. The actual incidence of TRALI remains unknown in the United States; however, with improved recognition, the number of cases of TRALI reported in the literature has increased significantly since the initial case series was reported in 1985. Nevertheless, much about this clinical syndrome that may complicate blood transfusions remains poorly understood, and TRALI remains an important topic of research in transfusion medicine. In 2006, the AABB (formerly the American Association of Blood Banks) assembled a TRALI task force to develop recommendations for the prevention of TRALI. This article is a summary of AABB actions on TRALI and includes a summary of the recommendations made by the AABB task force.

Blood donor and component management strategies to prevent transfusion-related acute lung injury (TRALI)

Discuss the pros and cons of using donor and blood product-management strategies to prevent transfusion-related acute lung injury (TRALI). A review of the literature was performed. Despite therapeutic advances in pulmonary and critical care medicine, TRALI is now considered to be one of the leading causes of transfusion-associated mortality, and thus determining how to prevent TRALI is extremely important. Donor and product-management strategies to prevent this life-threatening condition have been suggested, but because of gaps in our understanding of TRALI, blood-bankers do not know how beneficial these interventions will be, nor the amount of potential harm-such as decreasing the availability of blood-that could arise if they were implemented. This article discusses the advantages and disadvantages of the various preventive measures that have been described in the literature. Preventing TRALI poses a difficult challenge for blood-banking experts, because it is unknown which measures will be effective in decreasing the incidence of TRALI and which could have significant drawbacks. Only additional research into TRALI prevention will provide the answers on how to best protect patients from this potentially fatal reaction.

Understanding the Consequences of Transfusion-Related Acute Lung Injury

Although the blood supply has become safer with regard to transmission of infectious agents, attention should continue to focus on understanding and eliminating the other serious risks associated with transfusion. Transfusion-related acute lung injury (TRALI) is one such risk, only recently becoming recognized as an important and potentially preventable clinical syndrome. Strategies for prevention of TRALI, however, must rely on knowledge regarding its etiology and diagnosis, and significant gaps in our understanding of the syndrome currently exist. This review summarizes what is known and unknown about the incidence, severity, etiology, diagnosis, and prevention of TRALI and the potential consequences of these knowledge gaps.

Transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is an uncommon complication of allogeneic blood transfusion manifested typically by shortness of breath, fever, and hypotension. It has been estimated to occur in 0.04% to 0.16% per patient transfused. TRALI has been identified as an important cause of transfusion-related morbidity and mortality. Despite the increasing recognition that TRALI represents an important clinical syndrome, much about the pathogenesis, treatment, and prevention of TRALI is poorly understood or is controversial. In this report, what is known about TRALI is summarized and some of the areas in which knowledge and/or consensus are currently lacking are identified.