Transfusion-related acute lung injury (TRALI)

ABSTRACT

Transfusion-related acute lung injury (TRALI) remains one of the most serious yet often overlooked complications of blood transfusion, contributing to significant morbidity and mortality worldwide. It manifests as acute respiratory distress and non-cardiogenic pulmonary edema within 6 hours of transfusion, requiring immediate recognition and intervention. However, diagnosing TRALI is complex, as its clinical presentation overlaps with other causes of acute lung injury, and its underlying mechanisms remain incompletely understood. This review examines the global burden of TRALI, shedding light on underreporting issues, particularly in resource-limited settings where surveillance systems are inadequate. It explores both antibody-dependent and antibody-independent pathways, focusing on neutrophil activation, inflammatory mediators, and donor-specific factors that drive TRALI pathogenesis. While leukoreduction and improved donor selection have contributed to risk reduction, challenges persist, including the absence of standardized diagnostic criteria, gaps in data from low-income regions, and a lack of reliable biomarkers for early detection. Despite advances in understanding TRALI, more research is needed to refine diagnostic tools, enhance blood product safety, and develop targeted preventive strategies. By addressing these gaps, we can improve transfusion safety and patient outcomes on a global scale, ensuring that life-saving transfusions do not come with life-threatening risks.

Introduction

Transfusion-related acute lung injury (TRALI) is a serious side effect of blood transfusion that often leads to death and is one of the most common causes of mortality from transfusion worldwide.^1,2 It was first described in 1951 by Barnard, who noted cases of acute lung injury associated with transfusion.³ TRALI is characterized by sudden non-cardiogenic pulmonary edema occurring within 6 hours of transfusion. Despite the progress made in transfusion medicine, TRALI remains a multifaceted clinical entity that frequently goes undiagnosed or underreported.²

To prepare this review, a comprehensive search of PubMed, Scopus, and Google Scholar databases was conducted, focusing on articles published between 2000 and 2024, using keywords such as “TRALI,” “transfusion lung injury,” “blood transfusion complications,” and “neutrophil-mediated injury.”

Blood transfusions are regarded as one of the standard therapies for various conditions ranging from acute injuries to hematologic disorders. However, this procedure also has its own risks, including severe and fatal complications like TRALI.^4,5 Clinically, it presents as rapid-onset hypoxemia and non-cardiogenic pulmonary edema that may present on chest x-rays as bilateral infiltrates.⁶ In addition to traditional radiography, computed tomography (CT) scans can provide detailed imaging of pulmonary infiltrates, aiding in the assessment of TRALI severity.^7,8 Moreover, point-of-care ultrasound (POCUS) has emerged as a valuable bedside tool, allowing for rapid detection of pulmonary edema and B-lines, thereby facilitating prompt diagnosis and management of TRALI.^9-12

The pathophysiology of TRALI is complicated and varied. Often, it is described as a two-hit model. Typically, the first hit is a predisposing condition in the patient that involves either systemic inflammation or activation of the pulmonary endothelium.^13,14 The first hit refers to underlying conditions that prime the pulmonary endothelium, making it more vulnerable to damage when transfusion-related factors come into play. These predisposing conditions include systemic inflammation, sepsis, major trauma, hematologic malignancies, liver dysfunction, and recent surgery requiring mechanical ventilation.⁵ Each of these conditions sets off a cascade of inflammatory signals that activate the endothelial cells lining the lungs, triggering an increase in adhesion molecules such as ICAM-1 and VCAM-1.¹³ As a result, neutrophils—the body’s first re-sponders to infection and injury—become trapped in the lung’s microvasculature, further intensifying the inflammatory response.¹⁴ Once confined to the lungs, these primed neutrophils are further stimulated by inflammatory messengers like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), shifting them into a hyper-reactive state.¹³ At this stage, the body is teetering on the edge—the first hit alone does not necessarily cause lung injury, but it creates a fragile environment where even a minor additional trigger can tip the balance.² That trigger—the second hit—often comes from transfused blood products carrying HLA or granulocyte-specific antibodies, biologically active lipids, or pro-inflammatory cytokines.⁶ When these factors interact with the already primed neutrophils, it unleashes a storm of oxidative stress, triggering rapid endothelial damage, vascular leakiness, and pulmonary edema—the hallmark features of TRALI.^5,14,15 These interactions result in the activation and sequestration of neutrophils within the pulmonary vasculature, leading to endothelial damage, increased capillary permeability, and pulmonary edema.^4,5 Several recent studies have also suggested that the complement cascade may have an important role in TRALI, although conflicting results suggest a need for further investigation.^2,13,16,17

Whilst TRALI was initially defined as a clinical entity in the mid-twentieth century, its recognition as a distinct syndrome changed dramatically by the 1980s, with reports on cases associated with specific donor antibodies.^1,2 Over time, increased awareness and improved diagnostic criteria have made TRALI more identifiable. However, diagnosing this disease remains difficult especially for patients with risk factors concurrent with acute lung injury (ALI) such as sepsis or multiple transfusions. Moreover, underdiagnosis and underreporting conceal the true incidence figures and the impact of TRALI on patients.^16,18 Worldwide, work has been performed towards creating regular specifications and diagnostic models to identify cases of TRALI.^19-21 Nevertheless, there still exists some unsteadiness that interferes with comparative studies and epidemiological analysis. Consequently, questions remain regarding its pathogenesis and best management approaches as well as prevention methods. This paper summarizes the existing information about TRALI, explains its worldwide implications at the regional level, and discusses how it can be prevented in the future.¹⁶ One thing is clear: the burden of TRALI necessitates immediate action for enhanced awareness, systematic reporting, and targeted intervention for better transfusion safety that can save patients’ lives.

Epidemiology

Transfusion-related acute lung injury (TRALI) has a variable incidence in different studies and geographical areas, ranging from 0.08 to 15 per 10,000 transfusions.^22,23 The diagnostic criteria, reporting practices, and transfusion protocols used are responsible for the variations between these different reports. The first descriptions of what is now known as TRALI appeared in the 1950s, in which cases exhibited fever, hypotension, respiratory distress, and transient leukopenia after receiving a blood donation with leukocyte-reactive antibodies.^2,3 These insights provided a foundation for the conception of TRALI as a distinct clinical entity.

In high-income countries, however, targeted preventive measures including male-only plasma donation and universal leukoreduction in blood products have greatly reduced TRALI rates. For instance, plasma-containing products in the Unites States (US) and Canada have an associated TRALI incidence rate of roughly one out of every five thousand transfusions.^24,25 In the US, the Food and Drug Administration (FDA) recognized TRALI as a leading cause of death associated with blood transfusion in the early 2000s.^24-26 This recognition has been made possible through increased awareness and reporting; nevertheless, it still remains underdiagnosed and underreported.

On the contrary, there are limited data from low- and middle-income countries (LMICs). This emphasizes the need for epidemiologic studies aimed at finding out the real burden of TRALI in these regions. Factors like cultural and logistical issues may influence LMICs’ rates of TRALI because of their dependence on family/replacement donations and variations in blood product processing standards. Furthermore, robust hemovigilance systems do not exist in many of these areas, leading to problems concerning the accurate assessment of TRALI incidence.^27,28

Some historical analyses have suggested that some occurrences of acute chest syndrome or acute respiratory distress syndrome may be unknowingly misdiagnosed as TRALI.²⁹ Similarly, there is overlap between lung injury associated with granulocyte transfusion in leukopenic stem cell transplant recipients and TRALI.³⁰ This overlap underscores the importance of differentiating TRALI from other transfusion-related lung injuries for better diagnostic accuracy and patient outcomes.

Even in developed countries, TRALI is underreported despite its increased recognition.^31–33 For example, the FDA reports only about 8–21 fatal cases annually, which is an underestimate, since approximately 25 million units of blood are administered each year in the US. Using a conservative incidence rate of 1 per 5,000 transfusions and a mortality rate of 6%, one would expect around three hundred fatalities due to TRALI each year in the US alone.^24,32,34,35 This discrepancy underscores that there should be standard diagnostic criteria, greater awareness of TRALI in medical staff, and more systematic reporting mechanisms available to manufacturing agencies.

Transfusion-related acute lung injury often strikes when least expected, making it even more critical to understand where and why it happens.⁵ While TRALI can occur in anyone receiving a transfusion, certain patients are at significantly higher risk.^13,17 Those in intensive care, especially individuals with sepsis, major trauma, or those undergoing complex surgeries like cardiac bypass or liver transplantation, are particularly vulnerable.¹⁴ Their bodies are already in a heightened inflammatory state, which can set the stage for a severe reaction to transfused blood products. Similarly, cancer patients requiring frequent transfusions, especially those with hematologic malignancies or undergoing bone marrow transplants, face an increased likelihood of developing TRALI due to cumulative exposure to donor antibodies.^5,13,16,18

Some risk factors come directly from the donor. For example, plasma from women who have had multiple pregnancies is more likely to contain anti-leukocyte antibodies which have been strongly linked to TRALI cases.^13,20,31 While donor screening measures in some countries have significantly reduced this risk, not all transfusion systems have the same level of precaution in place. Additionally, the way blood products are stored and handled plays a role.^5,31 Older stored blood, particularly plasma-rich components like fresh frozen plasma and apheresis platelets, can accumulate bioactive lipids and inflammatory mediators, which may exacerbate an already vulnerable recipient’s condition. The speed and volume of transfusion also matter—rapid or massive transfusions can overwhelm the body’s ability to cope, increasing the chances of a reaction.^16,17,32

Nevertheless, the actual prevalence of TRALI is still unknown worldwide.^36,37 The significant regional differences are largely due to variability in transfusion practices, donor selection protocols, and diagnostic frameworks. For instance, high-income countries have stringent donor screening and advanced blood product handling processes; in contrast, LMICs often encounter problems such as poor infrastructure, limited healthcare personnel training, and the absence of hemovigilance systems.³⁶ Global collaboration is crucial in narrowing these gaps so that a holistic view of TRALI can be realized, enabling effective prevention and management strategies worldwide.

Pathophysiology

Transfusion-related acute lung injury is a complex clinical syndrome that arises from increased pulmonary microvascular permeability, leading to non-cardiogenic pulmonary edema. Its pathogenesis involves two primary pathways: immune-mediated (antibody-dependent) TRALI and non-immune-mediated (antibody-independent) TRALI (Figure 1). While each mechanism can independently cause TRALI, they often overlap, making it challenging to pinpoint a single causative factor in many cases.^26,34,38

Figure 1.

- The pathophysiology of TRALI: alveolar–capillary changes. This figure illustrates the pathophysiology of TRALI, comparing a healthy alveolus (left) with a TRALI-affected alveolus (right). Key features include endothelial damage, interstitial edema, and activated neutrophils releasing ROS, proteolytic enzymes, and forming NETs. Bioactive lipids and cytokines drive inflammation, causing a cytokine storm. Alveolar–capillary barrier disruption leads to pulmonary edema and acute respiratory distress, highlighting the interplay between immune and non-immune mechanisms.

These 2 paths ultimately reach the alveolar–capillary barrier, resulting in acute lung injury or pulmonary edema, as well as acute respiratory distress syndrome. Newly proposed mechanisms (like NETosis (“neutrophil extracellular trap formation”) and cytokine storms) and interactions between donors and recipients are considered major contributors to triggering TRALI.

Immune-mediated pathway

In this mechanism, TRALI occurs when donor-derived leukocyte antibodies bind to recipient antigens, triggering an inflammatory cascade (Figure 1).³⁹ It’s well established that pregnancy increases the likelihood of alloimmunization, making multiparous women more likely to develop antibodies against HLA and granulocyte antigens. This has significant implications in transfusion medicine, as studies have consistently shown that plasma from multiparous women carries a higher risk of triggering TRALI. A large case-control study by Middelburg et al⁴⁰ found that the majority (85%) of donors implicated in TRALI cases were female, with many having had multiple pregnancies. In response to these findings, the U.S. and several other countries implemented male-only plasma donation policies, which had a measurable impact reported a significant drop in TRALI cases following the policy change.⁶

Figure 1.

- Pathophysiology of transfusion-related acute lung injury (TRALI). The illustration emphasizes the mechanisms of TRALI involving immune and non-immune systems. The immune pathway in-volves antibodies in donor leukocytes that stimulate a process involving neutrophil activation followed by ROS (“reactive oxygen species”) release and complement activation, leading to endo-thelial damage and capillary leakage. The non-immune pathway includes bioactive lipids and cytokines stored in blood products, priming neutrophils ahead of inflammation process escalation. These two paths ultimately reach the alveolar–capillary barrier, resulting in acute lung injury or pulmonary edema, as well as acute respiratory distress syndrome. Newly proposed mechanisms (like NETosis [“neutrophil extracellular trap formation”] and cytokine storms) and interactions between donors and recipients are considered major contributors to triggering TRALI.

Upon transfusion, these antibodies interact with recipient leukocytes, particularly neutrophils, in the pulmonary capillaries. This interaction triggers complement activation, leading to the release of reactive oxygen species (ROS), proteolytic enzymes, and inflammatory cytokines. As a result, the alveolar-capillary membrane becomes damaged, causing fluid leakage into the alveoli, which results in pulmonary edema and acute respiratory distress.^26,38,39 Studies have shown that many TRALI cases involve an-ti-human leukocyte antigen (HLA) antibodies, particularly those directed against Class I (such as HLA-A2, HLA-B44) and Class II (such as HLA-DRB1, HLA-DQ) alleles, or an-ti-granulocyte antibodies.^18,19,25,41 The involvement of HLA class II antibodies has recently been confirmed in clinical cases where transfusion-induced lung injury was directly traced to donor anti-HLA-DR antibodies, highlighting their pathological role.^13,41–44 As a result, these patients often have elevated levels of HLA class I and II antibodies, which could increase their susceptibility to TRALI following transfusion.^16,41 Recent studies have identified HLA class II antibodies in multiple TRALI cases, suggesting that underlying immune dysregulation may amplify transfusion-related inflammatory responses. This raises the question of whether individuals with autoimmune diseases such as systemic lupus erythematosus (SLE) may be at heightened risk.⁴² These patients often exhibit chronic immune activation, elevated levels of autoantibodies including HLA class I and II, and increased circulating immune complexes.^18,41 Such factors can prime neutrophils and sensitize pulmonary endothelium, creating a fertile environment for TRALI upon exposure to triggering transfused antibodies.¹⁷ Moreover, complement activation may be exaggerated in this group, compounding endothelial damage. While large-scale epidemiological evidence remains limited, biologically and mechanistically, patients with autoimmune disorders may represent a higher-risk population for TRALI.^19,35 Future studies should investigate risk-reduction strategies such as leukoreduction, use of male-predominant plasma, and pre-screening of donors or high-risk recipients for HLA antibodies.²⁶

Non-immune pathway

While antibodies play a critical role in many TRALI cases, they are not always present. In non-immune TRALI, lung injury is instead triggered by biological response modifiers (BRMs) a group of biologically active substances that accumulate in stored blood components. These include lipid mediators (such as lysophosphatidylcholines, sphingosine-1-phosphate [S1P]) and pro-inflammatory cytokines that can prime neutrophils upon transfusion. During storage, blood products undergo metabolic and structural changes that lead to the release of these BRMs. When transfused, they enter the recipient’s circulation and contribute to a neutrophil-mediated inflammatory response, even in the absence of donor antibodies. For example, stored packed red cells may contain elevated levels of S1P, a lipid mediator associated with neutrophil activation and endothelial dysfunction (Figure 2).^1,18,41 Priming occurs when neutrophils are exposed to these BRMs, making them more responsive to additional stimuli. Once primed, neutrophils adhere to the pulmonary microvasculature, become activated, and release cytotoxic mediators that damage the alveolar endothelium. This results in capillary leakage and pulmonary edema—the hallmark of TRALI.^4,13,14,39

The 2-hit hypothesis

The 2-hit model is widely accepted in explaining TRALI. It accounts for both immune and non-immune mechanisms that contribute to lung injury following trans-fusion. The first hit refers to a predisposing condition that primes the pulmonary endothelium, making it more susceptible to damage. This could be due to factors such as infection, major surgery, trauma, sepsis, or mechanical ventilation.^16,17,26 These conditions promote endothelial activation and neutrophil sequestration within the pulmonary microvasculature, setting the stage for TRALI. The neutrophils, though not yet fully activated, remain in a “primed” state, awaiting a second trigger.

The second hit occurs when transfused blood products introduce HLA or granulocyte-specific antibodies, bioactive lipids, or pro-inflammatory cytokines that interact with these primed neutrophils.^25,39 Upon activation, neutrophils release ROS, proteases, and inflammatory mediators, leading to endothelial damage, vascular leakiness, and pulmonary edema—hallmark features of TRALI (Figure 2). This 2-step process explains why not every transfusion results in TRALI, as a primed environment is often necessary for full-blown lung injury to occur. However, TRALI can also develop in individuals with no apparent predisposing conditions. Cases have been reported where patients without active infection, trauma, or underlying illness still developed TRALI following transfusion. One possible explanation is that certain transfused components, such as strong HLA antibodies, can directly activate neutrophils and trigger TRALI without the need for a pre-existing inflammatory state.^26,31,33 Additionally, genetic factors may play a role, as variations in immune response genes could make some individuals inherently more vulnerable to neutrophil activation and endothelial damage, even in the absence of traditional risk factors.

Recognizing the 2-hit model helps explain TRALI’s complexity and why prevention strategies remain crucial. Approaches such as leukoreduction, preferentially using male donor plasma, and screening for HLA antibodies in high-risk donors have significantly reduced TRALI incidence.^24,35,36 Nonetheless, further research is needed to better understand why some cases occur spontaneously and whether specific biomarkers could help identify at-risk individuals before transfusion.

Emerging concepts and animal models

Recent research has broadened our understanding of TRALI by identifying additional mechanisms that amplify lung injury.⁴⁵ Among these, NETosis and cytokine storms have emerged as significant contributors. NETosis refers to the release of web-like DNA structures (neutrophil extracellular traps, or NETs) by activated neutrophils, which trap pathogens but also damage pulmonary endothelial and alveolar structures. Transfusion-related acute lung injury induces an acute inflammatory cascade, leading to rapid neutrophil recruitment and activation in the pulmonary microvasculature. These neutrophils undergo NETosis, resulting in further tissue injury. Concurrently, an excessive release of pro-inflammatory cytokines exacerbates the inflammatory response and worsens lung dysfunction.^13,16,45 Elevated levels of interleukins (IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), and interferon-gamma have been linked to increased endothelial permeability and enhanced neutrophil priming, creating a vicious cycle of inflammation and lung damage.^13,16,45 The interplay between NETosis and cytokine storms not only amplifies TRALI severity but also presents promising targets for future therapeutic interventions.^16,45

Although immune and non-immune pathways are the major components of TRALI pathogenesis, other causes had been proposed, especially in unique patients like those who are neutropenic.^46,47 In these cases, it is believed that TRALI may be caused by infusion with blood containing vascular endothelial growth factor (VEGF) or anti-HLA class II antibodies on pulmonary endothelial cells. Such interactions induce fenestration and permeability changes in the endothelium, leading to mild pulmonary edema.^17,47,48

Despite the progress made in understanding TRALI, there remain several questions unanswered. For example, not all antibody-containing transfused recipients develop TRALI, indicating the involvement of additional factors in the recipient, such as a genetic predisposition or pre-existing health problems.^39,49 Moreover, while some studies have demonstrated its significance, others have noted discrepant results, thereby causing controversy surrounding complement activation’s exact role in TRALI.²

Another mechanism increasingly recognized is reverse TRALI, in which the immunologic roles are inverted compared to classical TRALI.^50,51 Rather than antibodies in donor plasma, reverse TRALI results from pre-existing anti-HLA or anti-HNA anti-bodies in the recipient, which react with leukocyte antigens present in the transfused donor product.⁵¹ This is particularly relevant in patients who are heavily transfused, such as those with hematologic malignancies, and those previously exposed to non-leukoreduced blood components.⁵²

These recipient antibodies may activate donor leukocytes in vivo, leading to neutrophil activation, endothelial injury, and the typical presentation of TRALI.⁵² Several case reports and small studies have identified reverse TRALI as a likely cause of acute pulmonary deterioration post-transfusion, with radiographic findings identical to classical TRALI.^50,51 Although underdiagnosed due to limited availability of immunodiagnostic testing, reverse TRALI may be more frequent than previously recognized, especially in high-risk or immunologically sensitized patients.^50,51 Recognition of this entity is essential to refine transfusion practices and guide future preventive strategies.

Prevention

Reducing the incidence of TRALI relies on proactive prevention strategies, which have been shown to significantly decrease morbidity and mortality.^1,6,33 Globally, these strategies focus on both donor- and recipient-related risk factors, with strong evidence supporting their effectiveness.^21,40,41 The importance of such measures becomes even clearer when examining real-world cases. These real-world findings reinforce the idea that TRALI is not an unavoidable complication but rather a risk that can be mitigated through thoughtful transfusion practices.

One such case involved a 25-year-old woman who developed acute respiratory distress, fever, and hypotension within hours of receiving a fresh frozen plasma transfusion.¹² Another case featured an 84-year-old man with atrial fibrillation and a recent femur fracture, who suffered severe respiratory failure following multiple plasma transfusions, ultimately requiring intubation.⁵³ These cases underscore the unpredictable nature of TRALI and highlight the need for more robust preventive strategies to minimize risk.

Donor screening

One of the most influential prevention approaches involves donor screening for the minimization of antibody-mediated TRALI.³⁵ Due to their high chances of having anti-HLA and anti-HNA antibodies in their blood, multiparous women are considered high-risk donors.^35,54,55 The United Kingdom together with the Netherlands has put gender-specific donation measures into effect that permit only males to donate plasma, thereby resulting in a noticeable decrease in TRALI occurrences.^41,45,57,58 Further improvements can be achieved with leukocyte antibody screening in women who have tested positive for them and who have had previous pregnancies. Nevertheless, these methods also pose some obstacles, including a decreased donation pool and costs incurred from antibody testing.^25,26,35

Leukoreduction

Leukoreduction, the process of removing white blood cells from transfused blood products, has become a standard practice aimed at reducing transfusion-related complications, including TRALI.⁵⁸ By eliminating leukocytes, this method significantly lowers the accumulation of pro-inflammatory cytokines and biologically active lipids that develop during blood storage, both of which have been implicated in TRALI pathogenesis.^58,59 Numerous studies have demonstrated that the implementation of universal leukoreduction correlates with a decreased incidence of TRALI, along with reductions in alloimmunization and febrile non-hemolytic transfusion reactions.^35,45,58,59 However, while leukoreduction plays an essential role in minimizing the inflammatory burden of transfused blood, its effectiveness in preventing TRALI is nuanced. Since antibody-mediated TRALI is primarily driven by donor-derived HLA or granulocyte antibodies—rather than recipient leukocytes—leukoreduction alone does not fully eliminate TRALI risk.⁶⁰ In contrast, non-antibody-mediated TRALI, which involves the accumulation of bioactive lipids and cytokines, may be more directly impacted by leukoreduction.^45,55

To maximize TRALI prevention, leukoreduction is often combined with selective donor screening strategies. For instance, male-predominant plasma donation policies and screening multiparous female donors for HLA antibodies have been effective in further reducing TRALI incidence.^24,35,36,59 While evidence strongly supports leukoreduction as a critical component of TRALI risk mitigation, further research is needed to evaluate whether universal leukoreduction should be complemented with additional preventive strategies, such as pathogen reduction technologies and advanced donor screening protocols.

Blood product handling and management

Another measure that has reduced the risk of TRALI development is the improved handling of blood products, particularly through the application of pathogen reduction technologies (PRTs). These technologies chemically or photochemically inactivate nucleic acids, thereby neutralizing donor leukocytes and pathogens present in blood components.¹⁶ This process prevents leukocyte proliferation and reduces the risk of alloimmunization and immune-mediated pulmonary injury. For example, the INTERCEPT system uses amotosalen combined with UVA light, while the Mirasol system employs riboflavin with UVB light to achieve nucleic acid crosslinking.¹⁶

Although PRTs do not neutralize donor-derived antibodies, they effectively eliminate viable white blood cells and potential inflammatory triggers such as residual microbes, pro-inflammatory cytokines, and leukocyte-derived mediators. By removing these upstream activators, PRT-treated blood components may reduce the risk of neutrophil priming and limit complement activation-2 central mechanisms in TRALI pathogenesis.

Additionally, limiting the storage duration of red blood cells and platelets helps minimize the accumulation of biologically active lipids and inflammatory cytokines, which can act as second-hit mediators in susceptible recipients.³⁵ Techniques such as using fresher blood units and washing cellular components to remove residual plasma and antibodies are particularly beneficial for high-risk patients.^61–63 While most studies report outcomes such as ARDS rather than TRALI specifically, the overlap in clinical presentation suggests that reductions in ARDS may indirectly reflect enhanced pulmonary safety in transfusion practice.⁶⁴

Restricted transfusion practices

Minimizing unnecessary exposure to transfusion-related risks, including TRALI, necessitates promoting the judicious use of blood products.^59,60 Restrictive transfusion protocols, which limit blood product administration to only when absolutely necessary, have been widely adopted to enhance patient safety while preserving blood supplies. These guidelines are particularly beneficial in critically ill patients, where studies have demonstrated that lower transfusion thresholds not only reduce TRALI risk but also improve overall patient outcomes.^16,19 Additionally, specialized transfusion algorithms have been integrated into hospital protocols to guide clinical decision-making. These include individualized risk assessments, point-of-care testing, and evidence-based transfusion thresholds, ensuring that transfusions are only administered when necessary.^33,35 This approach not only reduces TRALI incidence but also aligns with broader goals of patient blood management (PBM), which focus on optimizing red cell mass and minimizing unnecessary transfusions.^35,45 Through these, valuable blood reserves are maintained whilst achieving greater alignment with broader patient safety objectives.^48,49

Recent and prospective advancements

In addition, there are a range of new technologies that can be used to prevent TRALI such as solvent/detergent-treated plasma.^65,66 This dilutes the leukocyte antibody concentration by pooling and treating plasma from various donors and thus significantly reduces the risk of TRALI. Moreover, platelet additive solutions (PASs) have attracted interest for their ability to replace plasma in stored platelets, thereby reducing the relevant antibodies and lipids.^66,67

Nevertheless, clinically diagnosed TRALI can still occur following SDP transfusion.⁶⁸ This is due to remaining antibodies as well as non-immune factors, such as active lipids or cytokines, and patient-specific reasons like previous inflammation, which puts patients at risk of TRALI.

Roles of health professionals and hemovigilance systems

Effective TRALI prevention involves more than laboratory practices alone; it involves the active participation of healthcare professionals.^6,19,35,69 Education and awareness programs are important for the early identification of TRALI cases as well as its correct reporting. Strong hemovigilance systems allow for the continuous monitoring and analysis of transfusion-related events, leading to timely interventions and policy revisions.^70-74

Obstacles to worldwide implementation

TRALI prevention has definitely advanced in high-income countries, but it is still a difficult challenge for low- and middle-income countries.⁷⁵ A key issue is the Inadequate access to much-needed technologies like leukoreduction, antibody testing, and pathogen reduction, which are widely implemented in HICs but often unavailable or unaffordable in LMICs.^75,76 The lack of universal leukoreduction in these regions increases the risk of transfusion-related complications, including TRALI, as blood products may contain high levels of bioactive substances that contribute to pulmonary inflammation and endothelial injury. These challenges are further compounded by financial constraints, resource shortages, and underdeveloped healthcare infrastructure, which weaken the capacity of blood transfusion services in LMICs.^75,76 The other problem is that these regions do not have strong hemovigilance systems, which would otherwise ensure effective monitoring and response to adverse events associated with transfusions.^33,75 Many LMICs lack the infrastructure and trained personnel needed for systematic reporting, leading to underdiagnosis of TRALI.⁴⁰ Strengthening hemovigilance requires investment in healthcare worker training, integration of electronic surveillance systems, and the establishment of national reporting frameworks. Cost-effective digital reporting platforms and collaborations with international blood safety programs could enhance transfusion monitoring in resource-limited settings.²¹

Screening blood donors for anti-HLA and anti-HNA antibodies is another critical but costly TRALI prevention strategy. Since large-scale antibody testing is often unfeasible in LMICs, a male-predominant plasma donation policy—which excludes multiparous women from plasma donation—has been adopted in high-income countries to mitigate TRALI risk.^6,57 LMICs could implement similar policies as a low-cost alternative while selectively screening donors with previous transfusion reactions to optimize resource allocation.⁵⁷

Lack of standardized national transfusion policies further complicates TRALI prevention efforts. Many LMICs lack clear guidelines that prioritize TRALI risk reduction, often due to competing healthcare challenges.³⁶ Developing country-specific transfusion policies and fostering regional blood banking collaborations could optimize limited resources. Public-private partnerships involving governmental and non-governmental organizations (NGOs) may further support training programs and infrastructure development.¹⁸

To address these differences, international collaboration is needed, which includes finance, technology, and knowledge-sharing campaigns such as those described here led by global health organizations. The activities of the WHO, IFRC, and other international initiatives have revealed how coordinated work can improve the transfusion safety.^36,75,76 Long-term sustainability is, however, still a major challenge. Diverse funding models and public–private partnership promotion as well as local capacity building through training and education must be developed to fill this gap.^75–78 This will help foster worldwide cooperation and ensure equal access to sophisticated transfusion technologies, thereby improving transfusion safety and reducing preventable complications globally.

Managing transfusion-related acute lung injury (TRALI): A practical approach

Dealing with TRALI is challenging, mainly because there is no targeted treatment—care is entirely supportive.⁶ The key to managing TRALI lies in early recognition, stopping the transfusion immediately, and providing the right level of respiratory and circulatory support. Given how suddenly TRALI can develop, healthcare teams must be vigilant, especially when a transfusion recipient unexpectedly develops breathing difficulties.¹⁶

Once TRALI is suspected, stopping the transfusion is the first and most important step. This prevents further exposure to harmful antibodies or bioactive substances that may have triggered the reaction.⁶ However, stopping the transfusion alone is not enough. Oxygen support is crucial because hypoxia is a hallmark of TRALI. In milder cases, oxygen via a nasal cannula or simple face mask may suffice, but for patients struggling to breathe, more advanced measures such as high-flow nasal oxygen or non-invasive ventilation (NIV) may be necessary.^16,55 In severe cases, intubation and mechanical ventilation become unavoidable. When mechanical ventilation is needed, lung-protective strategies—such as using low tidal volume and keeping airway pressures low—help prevent further lung injury. Fluid management in TRALI is another delicate balance. Unlike heart failure or transfusion-associated circulatory overload (TACO), TRALI does not result from excess fluid retention but rather from leaky lung blood vessels due to inflammation.^6,16 This means that diuretics, which are commonly used for fluid overload, are often ineffective in TRALI and could even worsen low blood pressure (hypotension). Instead, carefully adjusting fluids to maintain circulation while avoiding further lung congestion is essential. If blood pressure drops significantly, vasopressors like norepinephrine may be needed to help stabilize the patient.⁵⁵

Despite TRALI’s inflammatory nature, steroids are not routinely recommended. While they are sometimes used for other types of lung injury, there is no strong evidence that they improve outcomes in TRALI patients. However, in cases where patients have other inflammatory conditions, a careful, case-by-case decision on steroid use may be appropriate. Another critical step in TRALI management is ensuring that similar cases do not happen again.⁵⁷ Once a case of TRALI is suspected or confirmed, the hospital’s blood bank must be notified immediately. The goal is to investigate whether do-nor-derived antibodies (such as anti-HLA or anti-HNA antibodies) played a role. If the same donor is linked to multiple TRALI cases, they may be permanently deferred from plasma or platelet donations to protect future recipients. Hospitals that participate in hemovigilance programs can use data from TRALI cases to strengthen transfusion safety policies and prevent future incidents.^6,55,57,73 Most patients with TRALI recover within 48–72 hours, but for those requiring prolonged mechanical ventilation, the road to recovery can be longer. The mortality rate ranges from 5% to 25%, depending on factors like underlying health conditions and the severity of the reaction. Ultimately, the best way to tackle TRALI is to prevent it from happening in the first place, but when it does occur, timely recognition and proper management can be lifesaving.⁷¹

Pharmacologic strategies for TRALI prevention

The use of antihistamines and corticosteroids as prophylactic measures to prevent TRALI remains a debated topic in transfusion medicine. While some clinicians administer these agents preemptively, assuming TRALI shares mechanistic similarities with allergic or anaphylactic transfusion reactions, current evidence suggests otherwise. Unlike anaphylaxis, which is driven primarily by mast cell degranulation and histamine release, TRALI is predominantly mediated by neutrophil activation, endothelial damage, and an inflammatory cascade triggered by transfusion-related factors.^14,72,73 Given this distinction, the theoretical benefit of antihistamines in TRALI prevention appears minimal, as they primarily block histamine receptors rather than interrupting the underlying neutrophil-mediated inflammatory response.⁷⁴

Corticosteroids, known for their broad immunosuppressive and anti-inflammatory effects, have also been explored as potential protective agents against TRALI. Some studies suggest that pre-treatment with corticosteroids could dampen inflammatory re-sponses by reducing cytokine release and stabilizing endothelial integrity.^18,72,75 However, clinical trials assessing their efficacy in TRALI prevention have yielded conflicting results, and there is no consensus on their routine use.^16,18,72 Additionally, concerns regarding immunosuppression in critically ill patients raise further questions about their safety, as they may increase the risk of secondary infections or impair immune responses post-transfusion.⁷⁹

Currently, no strong clinical evidence supports the routine prophylactic use of antihistamines or corticosteroids for TRALI prevention.^45,72,74 Instead, preventative strategies such as leukoreduction, donor screening, and improved transfusion practices remain the gold standard for mitigating TRALI risk. Further well-designed clinical trials are necessary to evaluate whether targeted pharmacologic interventions could play a role in improving transfusion safety while avoiding unnecessary risks.

Challenges, limitations, and future directions

Although progress has been made towards understanding and mitigating TRALI, it is still difficult to ensure that all cases of TRALI are prevented and managed properly.^67,76,79 A major concern is underreporting, as many cases go unrecognized due to low clinical awareness or misdiagnosis, often being mistaken for other transfusion-related complications such as Transfusion-Associated Circulatory Overload (TACO).^35,45,57 Transfusion-related acute lung injury and TACO are among the leading causes of acute respiratory distress following transfusion, yet their pathophysiology and management strategies differ significantly.^14,34 Transfusion-related acute lung injury results from immune- or non-immune-mediated mechanisms, leading to non-cardiogenic pulmonary edema, while TACO is driven by fluid overload, resulting in hydrostatic pulmonary edema.³⁴ Distinguishing between these conditions is crucial, as misdiagnosing TRALI as TACO can lead to inappropriate fluid management, worsening hypoxemia, and underestimating transfusion-related risks.³⁴ While TACO responds well to diuretics and fluid restriction, TRALI requires supportive care, including oxygen therapy and mechanical ventilation in severe cases.^16,34,75,79 Furthermore, differentiating these diseases is hampered by a lack of universally accepted diagnostic guidelines, thus leading to inconsistent reporting and an underestimation of the actual incidence of TRALI.³⁵

Data gaps also pose a significant hurdle in some areas such as developing countries with poor hemovigilance systems.^24,71 Inadequate global efforts on transfusion safety are due to the absence of comprehensive epidemiological studies from these regions. To this end, addressing this knowledge gap requires improved diagnosis methods incorporating biomarkers as well as harmonization among health systems involved in reporting.^71,78

Given these limitations, further research should concentrate on both prevention and treatment options. One possible alternative route is the development of early detection biomarkers. Biomarkers such as cytokine profiles or neutrophil extracellular traps (NETs) could help identify patients at risk at an earlier stage, thereby permitting more targeted interventions as needed.^35,49,60 Another future prospect might include considering people’s genetic predispositions to conditions such as TRALI so that personalized transfusion strategies can be implemented among such individuals.^17,25

Immune-modulatory approaches on the therapeutic front are promising. In recent animal studies, it has been shown that regulatory T cell and IL-10 administration could be used to reduce TRALI incidence.^17,27,67 These findings might suggest that there are new ways to treat both non-antibody-mediated and antibody-mediated TRALI in the clinical setting. In addition, targeted anti-inflammatory interventions of specific cytokines, NETs, or reactive oxygen species can improve patient outcomes as well.

At a systems level, leveraging electronic health records (EHRs) and machine learning algorithms could revolutionize TRALI prevention.¹⁵ Predictive models built into EHRs could identify patients who are at a higher risk for pulmonary transfusion reactions, thereby allowing for proactive measures such as diuretic administration or allocation of low-risk blood products.²¹ Additionally, improved surveillance systems with natural language processing capabilities can enhance adverse event reporting and clarify diagnostic criteria.

Conclusion

Transfusion-related acute lung injury remains one of the most challenging complications in transfusion medicine, requiring continued awareness, prevention, and collaboration. The key to reducing its impact lies in strengthening hemovigilance systems, refining donor selection, and expanding research into new diagnostic and treatment approaches. As our understanding evolves, translating these insights into real-world clinical practice will be essential for making transfusion medicine safer and more effective for patients worldwide.