How I diagnose and treat cardiorespiratory complications of transfusion Free

Among all transfusion-related adverse reactions, cardiorespiratory reactions are the leading cause of severe transfusion-related morbidity and mortality.^1-3 In prospective studies incidences range between 0.08% and 15% of patients transfused with mortality rates up to 40%.^4-7 The most important cardiorespiratory side effects that can be discriminated are transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO); as different pathophysiologic entities they both cause cardiorespiratory side effects during or soon after transfusion with objectivated dyspnea.^5,7,8 A third category, transfusion-associated dyspnea (TAD) has also been defined internationally; its position will be discussed briefly in this work. Fever leading to an increased respiratory rate should in this sense be set apart and is not considered as a primary cardiorespiratory side effect in the current overview. Anaphylaxis will be mentioned as a potential cause of dyspnea with bronchospasm in the context of a transfusion, but we will not review respiratory compromise as a component of hemolysis or of sepsis from bacterial contamination. For management of these complications, we refer to other publications.⁸ 

The diagnostic procedures and supportive treatment of these side effects need to be immediate and should precede pinpointing of the precise transfusion reaction. The challenge is that, on the one hand, a deterioration of a patient’s medical condition can suggest a transfusion reaction and delay the treatment of an underlying cause such as pneumonia. On the other hand, which is more often the case, signs of a transfusion reaction can be taken for deterioration of the underlying condition of the patient.

The present article hence aims to provide:

1. Guidance for bedside diagnosis, practical management, and effective treatment of presumed transfusion-related cardiorespiratory reactions, with a focus on TRALI and TACO.

2. Insight into the pathophysiology and definition updates of these cardiorespiratory transfusion reactions.

3. Guidance for the field of hemovigilance toward effectively dealing with the complexity of case mix, given the often incomplete and/or conflicting data in clinical practice.

A 45-year-old male patient is admitted to the intensive care unit (ICU) after major abdominal trauma. Due to ongoing diffuse bleeding and coagulopathy (prothrombin time 32 seconds), the patient is transfused with 10 mL/kg plasma (pooled solvent-detergent treated). Three hours after receiving the plasma products, the patient experiences a rapid onset of hypoxia with signs of bilateral consolidations on the lung ultrasound (normal lung sliding) and fever. A quick look cardiac ultrasound shows normal cardiac function and no tamponade. The patient is treated with diuretics, which have some effect on respiratory distress; however, he ultimately needs intubation and mechanical ventilator support. Forty-eight hours later the patient’s condition is improving. He is weaned from the ventilator 60 hours after symptom onset and discharged to the ward. Within 72 hours, he has fully recovered.

TRALI, which is part of the acute respiratory distress syndrome (ARDS) spectrum, is defined using the updated international 2019 TRALI consensus definition (Table 1).⁹ The main updates compared with the 2004 definition are that TRALI is categorized into TRALI type I and TRALI type II. TRALI type I is the onset of acute lung injury within 6 hours after a blood transfusion in the absence of a risk factor for acute lung injury. TRALI type II is the onset of lung injury within 6 hours of a blood transfusion in the presence of a risk factor for acute lung injury. Based on the new insights, patients with moderate ARDS developing severe ARDS within 6 hours after a blood transfusion can also be classified as TRALI. Furthermore, the diagnostic approach of TRALI is aligned with the updated ARDS Berlin definition, which now allows for the use of computed tomography scan and lung ultrasound alongside conventional chest radiograph to diagnose bilateral infiltrates.¹⁰ Also, the presence of mild volume overload is allowed as long as it is not the main cause of respiratory distress. Last but not least the use of SpO2 can be used to calculate the ratio of arterial pO2 to an inspired fraction of oxygen which is essential to determine the severity of hypoxia in a ward setting (supplemental Conversion Tables, available on the Blood website). The updated TRALI definition is applied in clinical practice and has been successfully adopted in a number of hemovigilance systems.^11-13 

TRALI is regarded as a 2-hit syndrome in which the first hit is the underlying condition of the patient, resulting in priming of the endothelium and neutrophils (eg, sepsis), and the second hit is blood transfusion, causing activation of the neutrophils and damage to the endothelium.^7,14-16 Damage to the endothelium results in leakage of proteins into the alveolar compartment with subsequent fluid extravasation (Figure 1A). The transfusion risk factors can be divided into antibody- and nonantibody–mediated TRALI. Antibody-mediated TRALI is caused by donor leukocyte antibodies reacting with the cognate antigen of the recipient. Antibodies include but are not limited to HLA class I, II and human neutrophil antigen (HNA) antibodies.¹⁷ Reverse TRALI is the occurrence of TRALI due to a reaction of recipient antibodies with a cognate antigen in the transfused blood product. Nonantibody–mediated TRALI may be caused by the accumulation of proinflammatory mediators in cell-containing blood products as well as the aging of the erythrocytes and platelets themselves.¹⁸ Universal leuko-reduction was thought to have mitigated reverse TRALI however recent reports show it is still present and underreported.^12,13 

There is no biomarker to diagnose TRALI, and TRALI remains a clinical diagnosis. TRALI was suspected clinically in case 1 as it was a patient with respiratory compromise within 6 hours of transfusion. Further suggestive features are the presence of pink frothy sputum, drop in blood pressure, and absence of signs suggesting TACO (detailed further below). The patient might have had risk factors for TRALI, and less so or none for TACO. Imaging showing bilateral infiltrates is needed to confirm the diagnosis; however, even experienced radiologists often cannot distinguish between TRALI and TACO on (sometimes low-quality bedside) chest radiograph or other imaging.¹⁹ Furthermore, bilateral infiltrates may be subtle and overlooked.²⁰ In case 1, ultrasound imaging demonstrated normal cardiac function, and the suspicion of TRALI was strengthened by insufficient response to diuretic therapy.

For hemovigilance classification, it should be noted that TRALI has been classically associated with plasma-rich blood components owing to the potential presence of donor leukocyte antibodies. Our case occurred after the administration of a pooled plasma product in which donor antibodies or other mediators would be diluted, lowering the risk of TRALI. However, recent studies have shown that TRALI may still occur after transfusion of pooled plasma products.¹² One hypothesis is that in the presence of a strong first hit, such as in critically ill patients, a low titer of antibodies still may induce TRALI. This is in line with the threshold approach for TRALI.²¹ However, as described above, TRALI can also be triggered by nonimmunological mechanisms. Anti-HLA antibody incompatibility testing has a high specificity if confirmed. In contrast, not finding or not investigating the latter does not rule out TRALI as diagnosis. Indeed, leukocyte antibody testing of all involved donors (ie, donors whose components were transfused within the 6-hour time window before the onset of symptoms), and even more so proving their incompatibility with the patient, are time-consuming and costly investigations that only have potential consequences for the donor end of the transfusion chain and future recipients of these specific donors.^22,23 The results will not be available in time to make a difference for the current patient. In practice, these investigations are often reserved for clear-cut cases with high imputability, in which alternative diagnoses are less likely, and in situations in which 1 or a small number of donors of plasma-containing components are involved. Whether this is too conservative is questionable when the risk of TRALI is considered alongside the risk of viral transmission and the huge screening costs for infectious diseases. Most blood services will have a policy of deferral of an “implicated” donor in whom HLA antibodies are found that are cognate with the HLA antigens of patients with TRALI. The broadness of the detected donor HLA antibodies can also be taken into consideration for donor deferral because broad antibodies (ie, reactive with a wide spectrum of HLA types), if present, can lead to more TRALI cases instead of only being specific for a small number of patients.

An 80-year-old female patient on daily diuretics because of left ventricular dysfunction subsequent to a previous acute myocardial infarction and stenting of the left coronary artery is admitted with chronic myeloid leukemia with 200 × 10⁹/L leukocytes and hemoglobin (Hb) 6 mmol/L (9.7 g/dL), creatinine 200 μmol/L, and low blood pressure; there are no signs of infection or inflammation. Her Hb drops gradually during admission to 5 mmol/L (8 g/dL), for which 2 units of packed red blood cells (1 h/unit) are prescribed. After 1 unit, acute dyspnea develops with hypoxia (83% oxygen saturation by pulse oximetry), and a chest radiograph shows features of circulatory overload (CO) with an enlarged heart contour and prominent Kerley B (interlobular) lines. Diuretics (200 mg furosemide IV) and O₂ (nasal prongs) rapidly (within a few hours) reverse the dyspnea. The patient is started on hydroxyurea and later tyrosine kinase inhibitor treatment. Moreover, a pretransfusion sample is retrieved in the laboratory and yields an N- terminal prohormone of brain natriuretic peptide (NT-proBNP) level of 6000 ng/L which increased to 10 000 ng/L a few hours after the transfusion. The patient recovers to a stable cardiorespiratory status and is discharged home in 7 days.

TACO is defined using the criteria of the updated international TACO case definition (Table 2). The updated definition has been validated in the hemovigilance setting and is applied in clinical practice.²⁴ Compared with the previous TACO definition, the time frame allows for the onset of TACO symptoms within 6 hours or beyond, up to 12 hours after blood transfusion. Furthermore, respiratory and cardiovascular criteria are more clearly defined, including the application of biomarkers, such as pre- and posttransfusion NT-proBNP.

TACO is also considered a 2-hit syndrome.^5,25 The first hit is the underlying condition of the patient, leading to volume incompliance (eg, cardiac or renal failure), and the second hit is transfusion causing hydrostatic pulmonary edema (Figure 1B). The classic TACO theory is that it is a syndrome of pure hydrostatic pulmonary edema. However, recent studies have shed some different light on the pathophysiologic mechanisms in place. A case-control study of patients developing TACO or CO in the absence of transfusion showed that patients developing CO in the absence of transfusion need a more positive fluid balance to develop CO compared with transfused patients.⁴ Hence, something else in addition to pure volume overload seems to play a role.²⁶ In line with this approximately one-third of patients develop fever during TACO.²⁷ Recently the first animal models of TACO have been published which will help to understand the pathophysiology of TACO in more depth.^28-31 

As in case 2, a patient with TACO often has typical individual risk factors, such as a previous episode of TACO, old age and/or renal failure, and/or cardiac dysfunction and/or a raised and further increasing NT-proBNP before and after transfusion, respectively, as signs of a pre-existing positive fluid balance and cardiac dysfunction.³² The diagnosis of TACO may be supported by chest radiography showing an increased cardiothoracic ratio, widened vascular pedicle, circulatory redistribution to the upper lung fields, interstitial pulmonary edema with septal thickening, peri-bronchial cuffing, Kerley B lines, and sometimes some pleural fluid, and possible progression to alveolar edema with bilateral infiltrates. Radiographic signs, particularly in more severe cases and in sitting, recumbent, or poorly inspired views, may be indistinguishable from TRALI. Other imaging techniques may show equivalent findings or demonstrate impaired ventricular function. Conversely, an unchanged chest radiograph does not exclude TACO, because typical clinical signs can occur before radiographically visible changes. The mainstay of TACO treatment is diuretics at proper doses (increased dose in reduced renal function), with typically fast recovery as a result. Prevention of TACO, however, is even more important; this is done by first following current evidence-based restrictive transfusion guidelines, that is, transfusing 1 unit at a time as opposed to the case 2 patient, and adhering to cardiopulmonary function dependent Hb thresholds.^33,34 Second, applying additional measures in patients with the mentioned higher risk to develop TACO, for example, treatment of pre-existent fluid overload, slower infusion rates, and more intensive monitoring should be strongly considered.^35,36 

A 53-year-old man without recent previous IV fluid therapy receives a red cell unit in 2 hours for anemia (Hb 3.4 mmol/L, 5.5 g/dL) due to prostate cancer with bony metastases. Between 5 and 6 hours after the transfusion, he develops respiratory distress, oxygen desaturation to 80%, raised blood pressure to 205/119 mm Hg, a 1.9°C rise in body temperature, and tachycardia. He is transferred to the ICU and treated with diuretics, morphine, noninvasive ventilation, nitroglycerine, and 3× hydrocortisone 100 mg. An hour later, noninvasive ventilation is no longer necessary, and the next morning, after a total diuresis of >1000 mL, he has recovered and all additional medication is stopped. The poor-quality anteroposterior chest radiograph at the time of the reaction shows bilateral infiltrates, some increased vascular markings, and thickened fissures, but no change in the cardiomediastinal contour. High NT-proBNP levels were measured in the ICU but pretransfusion testing (eg, from transfusion laboratory samples) was not thought of. The treating physician’s primary diagnosis was TRALI; however, vital parameters and favorable response to diuretic therapy are also supportive for TACO.

In clinical practice, TRALI and TACO cases are often initially atypical and are only partly supported by the absence or presence of risk features suggesting TRALI, TACO, or an alternative diagnosis (Table 3). However, in hindsight with additional diagnostics and knowing the response to therapy, for example, a slower and clearly nondiuretic–dependent recovery vs the opposite, TRALI or TACO differentiation and classification can remain problematic.

Indeed, a patient with suspected TRALI may be an older patient with cardiac dysfunction instead of a younger previously healthy trauma patient (as in case 1). Similarly, suspected TACO cases may be young, instead of an older patient, likely to have pre-existing cardiac or renal dysfunction. Additionally, identifying parameters both for TACO and TRALI may be missing or discrepant; for example, no or poor-quality chest radiograph, no NT-proBNP, or a sky-high pretransfusion NT-proBNP in suspected TRALI cases or a slow response to diuretics in suspected TACO cases. Such findings, or especially a late onset of dyspnea between 6 to 24 hours (Tables 1 and 2), might lead us to consider a case mix with both TRALI and TACO characteristics.

The revised TRALI case definition specifically recognizes that TRALI and TACO may co-occur. It can be presumed that the pathophysiology is a combination of hydrostatic and inflammatory edema. The observations that on one hand, ∼30% of patients developing ARDS have some form of CO and, on the other hand, the presence of HLA class II antibodies can be associated with TACO, suggest an overlap between the 2 entities.^10,37 In line with this, it has previously been suggested that TRALI may still occur 72 hours after transfusion, the so-called delayed TRALI.³⁸ Clinical cohort studies and preclinical confirmative studies are needed to elucidate the gray zone and the probable synergistic mechanisms that play a role in TRALI as well as in TACO.

In case 3, the initial management consists of respiratory support and diuretic treatment combined with morphine and nitroglycerine, which reduce the cardiac afterload. Case 3 very importantly illustrates a 2-stage clinical management (Figure 2). First, immediate stopping of the transfusion (not forgetting to exclude transfusion errors) and cardiorespiratory support can be combined with diuretic therapy unless the patient is hypotensive. A restrictive fluid strategy with testing the effect of diuretics as mainstay of TACO treatment, however, also improves outcomes in patients with ARDS/TRALI as some degree of fluid overload may coexist with ARDS so it makes sense to administer diuretics in both TRALI and TACO.³⁹ Often IV antihistamine is administered, although this would only be of benefit for an allergic (anaphylactic) reaction; the latter diagnosis should be considered in a patient with bronchospasm and hypotension. Their routine (and preventive) use, however, is inappropriate. Furthermore, the use of hydrocortisone does not have an early effect in reducing inflammation and is not regarded as evidence-based for TACO or TRALI. On the contrary, corticosteroids have well-known unwanted side effects themselves. Although the response to the initial treatment is observed, imaging and further workup are instituted and will guide a second phase with the continuation or adjustment of clinical management.

In case 3, as in many cases of cardiorespiratory transfusion reactions, both TRALI and TACO are possible initially but as said both may remain possible even in hindsight with all available data at hand. Hence, we have to acknowledge that not only at first sight but also mechanistically and for hemovigilance there is a continuous spectrum from circulatory (volume) overload (purely hydrostatic) to inflammatory vasculogenic pulmonary edema and that a combination therapy targeting them both is justified. At least mechanistically, it seems better to explicitly acknowledge these mix/overlap cases instead of merely calling them TAD. The appropriate meaning and use of TAD will now be briefly discussed.

Many cases do not fit all the criteria for pure TRALI or pure TACO as described above, and TAD as a third category was proposed as early as the 2000s.⁴⁰ TAD is the hemovigilance label for respiratory reactions that cannot be ascribed to the “standard” types of reactions but consist of respiratory distress occurring within 24 hours of transfusion that does not meet the criteria of TRALI, TACO, or allergic reaction and cannot be explained by the patient’s underlying condition or any other known cause (Table 4). Therefore, this category’s definition seems not to be meant as a label for cases that meet criteria for and/or are explained by a combination of TRALI and TACO mechanisms.

Although TAD as a definition cannot be used for cases that are an overlap between or a combination of TRALI and TACO, the pathophysiology of TAD remains unclear. Thus, TAD is clinically and mechanistically difficult to envision as a separate entity, as opposed to an overlap between TRALI and TACO. At the same time, within the broad group of cardiorespiratory transfusion reactions, the absence of diagnostic information is frequently an impediment to rigorous classification for hemovigilance purposes. Hemovigilance systems have hence adopted different practices for their labeling of incompletely investigated cases, but also for including reactions that clinically have clear TRALI and TACO features. This has led to a current lack of harmonization in the use of the TAD “bucket,” hampering meaningful cross-border comparisons. We would strongly recommend that mixed TRALI/TACO cases should be reported separately and not as TAD.

In the setting of a cardiorespiratory complication after blood transfusion, a possible allergic reaction (or anaphylactic) should be considered, especially if there is an accompanying skin rash, stridor, hypotension, or bronchospasm, and absence of pulmonary crackles and other findings of pulmonary edema (Figures 2 and 3). This could be transfusion related but other iatrogenic causes should be borne in mind. Dyspnea and hypotension (or hypertension) could also be a more or less prominent part of a hemolytic transfusion reaction, febrile nonhemolytic reaction, sepsis from a contaminated unit, or other causes. Appropriate additional tests, such as biochemical hemolysis parameters and blood cultures, should be included in the follow-up assessment, and the patient should be adequately monitored even after initial improvement.

Physicians first and foremost need to be aware of and prepared for cardiorespiratory complications after and due to transfusions. Second, they need to treat patients with cardiorespiratory symptoms in a timely fashion and determine the most likely diagnosis to optimize current clinical management as well as future transfusions. For this, we suggest a 2-step approach (Figure 3). First, one should determine if the cardiorespiratory deterioration can be considered as a clear-cut TRALI or TACO (or anaphylaxis) case (see definitions in Tables 1, 2, and 4) and institute specific management. If the initial weighing of positive and negative risk factors, along with confirmatory or excluding features, does not lead to a clear TRALI or TACO diagnosis, the clinician should obtain more data to narrow down the diagnosis but start pragmatic treatment anyway.

Interestingly, the direct clinical management of apparent but not yet clear TACO and TRALI cases overlaps for a large part, namely, stop the transfusion, objectivate the hypoxia and breathing pattern, consider and exclude alternative causes of dyspnea (such as acute hemolysis (possible ABO-incompatible transfusion), glottis edema, aspiration, pulmonary embolism, pneumonia, infection), and provide O₂ supplementation, bed rest, close monitoring of the patient until recovery from the reaction, and additional cardiorespiratory support as indicated. Even in patients who are hypotensive, as in some TRALI cases but also in patients with TACO who have additional forward failure, the use of diuretics to assess their fast effect should not be a problem in these mostly closely monitored patients. If available, a cardiac ultrasound before starting therapy could be helpful to exclude any other causes. Meanwhile, we advise to be cautious and restrictive with often pragmatically administered corticosteroids, given their known and often unavoidable side effects, as well as with antihistamines.

The second phase, later in time, leads to the best possible diagnosis and hemovigilance classification and integrates all available data, including follow-up, response to initial treatment, and later diagnostic data.

The chief biomarker that, in the second-step assessment, can be of relevance in respiratory transfusion reactions is (the before and after transfusion change in) NT-proBNP. Its utility in the acute situation is limited.³⁷ A pretransfusion sample can be tested as part of the workup of the transfusion reaction. Increased NT-proBNP in this sample can occur in patients whose reactions are diagnosed as “transfused ARDS” or as TACO.⁴¹ Although a result around the time of the reaction which is similar or somewhat higher, could also be found in a patient with TRALI, a normal result in the hours after the reaction effectively excludes TACO. Given the strong association between elevated pretransfusion NT-proBNP and the subsequent development of TACO, this finding could even be considered an alternative to imaging in resource-poor settings and indicative of a need for mitigating measures before transfusion. Pretransfusion assessment of NT-proBNP in specific patient populations to better recognize patients at increased risk of developing TACO might also be considered. Finally, advanced imaging and/or ICU-specific hemodynamic assessment can change the diagnosis (in hindsight) to a more likely TACO or TRALI case.

For a case that still combines features of both TACO and TRALI, the treatment, if successful, can be continued, whereas adjustment of treatment might be needed for an alternative diagnosis or in the case of a poor response. Importantly, our proposed 2-step assessment and treatment strategy acknowledges the TACO/TRALI mix as an initial clinical and final hemovigilance diagnosis, even in the face of missing data or conflicting findings. In this context, the use and incidence of TAD as a classification might decline, but time will tell.

Early case reports of both TRALI and TACO predate the development of formal hemovigilance systems.^42,43 The latter aim first to systematically monitor adverse reactions in blood donors and transfusion recipients, as well as adverse events such as errors and incidents in the transfusion chain. The second objective of hemovigilance is to analyze and learn from the reported cases and to improve the safety of the clinical use of blood components. The emergence of formal hemovigilance in the mid-1990s and the early 2000s at regional and national levels led to an acceleration of research and awareness of the cardiorespiratory complications of blood transfusion. There was some delay because initially many national-level hemovigilance systems did not recognize TACO as a transfusion complication; “it’s just part of fluid management.” The growing awareness of TRALI led to increasing reports of cardiorespiratory transfusion reactions in the mid-2000s and careful assessment of patients with suspected TRALI, as well as the reclassification of some reports as TACO. The latter clearly showed the need for hemovigilance systems to better classify reported cases according to agreed case definitions based on parameters that can be objectively determined. Indeed, the recognition and rigorous assessment of transfusion reactions according to hemovigilance procedures and definitions can also support clinicians in managing their patients. Along with advances in intensive care medicine, the desire for improved hemovigilance reporting led to (separate) updates of the hemovigilance definitions of the TACO and TRALI definitions, as described above.^9,24 International partnerships are needed to have more large-scale validations of the updated TRALI and TACO definitions and pave the way for their wider adoption. If the partnership takes a broader scope, including TAD and less clear-cut cases, as well as the TACO/TRALI mixed cases, this will guide the harmonization of the hemovigilance approach. This is essential to strengthen transparency and trend recognition, and to open new roads for prevention and better treatment.

A hemovigilance case report starts with a clear minimal data set. More thorough and ideal assessment, however, will need a more extensive data set, including the patient’s pretransfusion risk factors, as discussed above, as well as comorbidities, clinical situation, medication, fluid balance etc. An international model reporting form for cardiorespiratory transfusion reactions has been published and should support data comparing and harmonization of classification by hemovigilance systems.⁴⁴ For the final hemovigilance classification assessment of the causal association (=imputability) between symptoms and the transfusion remains essential and should be graded as probable or stronger (definite) based on the appropriate temporal association, contributory data and imaging and absence of other potential causes (that could need another treatment; see also definition tables).⁴⁵ 

Moreover, hemovigilance systems have developed pretransfusion assessment tools to guide mitigation measures to reduce the likelihood of TACO occurring.³ To date, these are based on recognition of patient risk factors (including age, renal, cardiac, positive fluid balance, and pretransfusion raised NT-proBNP levels) and expert clinical opinion. The suggested pretransfusion/peritransfusion mitigating measures, including proper indication and restrictive and slow transfusions together with pretransfusion diuretics, are well endorsed by clinical experience but not yet confirmed for their effectiveness for prevention.⁴⁶ Regarding patients with TACO, SHOT (Serious Hazards of Transfusion, United Kingdom hemovigilance agency) has furthermore proposed that there should be an incident investigation: was the patient appropriately assessed before transfusion and were TACO mitigation measures applied? We do not go so far as to propose this as a formal requirement but recommend an active clinical review of risk factors in patients with TACO and a prescription of mitigation measures for future transfusions of the individual patients.

On the side of TRALI, preventive product-based measures were adopted in the mid-2000s: the use of plasma from (never-transfused) male donors only, or from female donors tested and negative for HLA antibodies. This led to an ∼30% reduction in the incidence of TRALI, which has been well-documented in hemovigilance systems.^47-50 However, the mechanism responsible for nonimmunologically mediated TRALI (no antibodies found or antibodies without an incompatible recipient cognate) has not yet been elucidated, and these reactions cannot yet be effectively prevented.

The strict definitions of TRALI and TACO (and TAD) have helped to increase understanding of the pathophysiologic mechanisms and patient risk factors and to design preventive strategies for these life-threatening syndromes. It is becoming clear that the entities TACO and TRALI can occur together or may in some cases be the explanation for what is designated as TAD. Hemovigilance and international definitions should allow the classification of transfusion reactions as a combination of TRALI and TACO.

At present, hemovigilance systems worldwide differ in their classifications of TRALI, TACO, and TAD. Future efforts should aim to align systems, apply universal reporting forms, and harmonize data collection. This will facilitate research and provide more insight into the risk factors and incidence of these entities.

A.P.J.V. is supported by a Landsteiner Foundation for Blood Research fellowship grant (number 1931F) from the Landsteiner Foundation for Blood Transfusion Research, Haarlem, the Netherlands and by a personal grant from the Netherlands Organization for Scientific Research (VIDI grant number 09150172010047).

Contribution: A.P.J.V., J.J.Z., and J.C.W.-O. designed and wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: A. P. J. Vlaar, Laboratory of Experimental Intensive Care and Anesthesiology and Department of Intensive Care Medicine, Amsterdam UMC, Room C3-415 Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; email: a.p.vlaar@amsterdamumc.nl.