Transfusion‐associated circulatory overload and transfusion‐related acute lung injury: diagnosis, pathophysiology, management and prevention

Pulmonary oedema may be defined as the clinical manifestation of fluid accumulation in the lungs, resulting from an imbalance between fluid filtration and resorption. Pulmonary oedema leads to impaired gas exchange and may cause respiratory failure. It is considered as ‘cardiogenic’ in cases where the heart fails to remove efficiently fluid from the lung circulation, or as ‘non-cardiogenic’ in case of direct injury to the lung parenchyma [1]. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the two major complications of blood transfusion involving clinical signs of pulmonary oedema. Transfusion-associated circulatory overload had been recognized since the early times of transfusion [2]. In contrast, TRALI was identified much later, and although a few case reports were published as early as 1957 [3] and in the 1970s [4], the first comprehensive description of this adverse reaction was published in 1985 [5]. Differential diagnosis of transfusion-related pulmonary adverse reaction may include not only TACO and TRALI, but also anaphylactic reactions, and even bacteria contamination and haemolytic transfusion reaction may involve pulmonary manifestations at some point [6]. However, the major difficulty remains to differentiate TRALI from TACO. This differential diagnosis is essential in clinical practice, because the therapeutic approach of these two syndromes and the investigations in blood donors in order to confirm the diagnosis are totally different. Despite these two concerns, it is still frequent that post-transfusion pulmonary oedema is not adequately categorized. The extremely variable incidences described according to dedicated studies and haemovigilance results strongly suggests that up to now, TRALI and TACO remain both under recognized, and deserve active information of clinicians and transfusionists. This review intends to provide a description of these two adverse reactions related to blood transfusion, focusing on the following: clinical description and differential diagnosis; pathophysiology; incidence according to the different blood components; investigations necessary to confirm suspected cases; and means for prevention. Transfusion-associated circulatory overload may occur during transfusion or within 1 to 2 h after its completion, although it may begin lately. There is at present no consensus for a precise time limit to consider, which is not so surprising, as this adverse event is extremely dependent on patient's clinical status, independent of blood transfusion. Major clinical signs are dyspnoea, orthopnoea, tachypnoea and cyanosis associated with tachycardia and systolic hypertension. Rales are observed at auscultation and may be prominent initially in the lung bases, although they are present in all the lung fields once the pulmonary oedema is established. Chest radiograph shows interstitial infiltrate, and may reveal cardiomegaly, although not in all patients with heart failure [7]. Transfusion-associated circulatory overload management consists in stopping the transfusion as soon as the symptoms appear, and treating symptomatically by providing oxygen, using intravenous diuretics in order to obtain a rapid reduction of plasma volume. Although many cases can be managed outside an intensive care unit, some cases deserve a close monitoring for 1 or 2 days. As many patients will require to be transfused again in the future, a great attention should be given to avoid recurrence of TACO. Careful control of the patient's fluid balance previous to transfusion, prescription of no more than one red cell concentrate for a given day (in most medical patients), use of the recommended blood flow (2 ml/mn) and preventive diuretics injection in case of positive fluid balance are the major points to consider. Transfusion-related acute lung injury had been defined differently in three publications [5,8,9], the most internationally accepted one being the result of an international consensus conference organized in Toronto in 2004 [9]. The 2004 consensus conference definition of TRALI uses the The American-European Consensus Conference definition of ALI [10]. ALI is defined as acute onset of bilateral infiltrates on chest radiograph and pulmonary artery occlusion pressure (PAOP) < 18 mmHg obtained by pulmonary artery catheterization (if unavailable, lack of clinical evidence of left ventricular failure), and PaO2 : FiO2 < 300 mmHg. Transfusion-related acute lung injury is defined as ‘a new episode of ALI that occurs during or within 6 h of a completed transfusion, which is not temporally related to a competing aetiology for ALI. The diagnosis of TRALI is a clinical and radiographic diagnosis and is not dependent on the results of laboratory tests or any proposed pathophysiologic mechanisms. TRALI should currently be considered a clinical syndrome rather than a disease with a single aetiology’. The symptoms of TRALI include dyspnoea, cyanosis and tachycardia. After a few hours, the oedema is usually bilateral involving the whole lungs, as shown by chest radiograph. Fever (1 to 2°C increase) may be present, as well as moderate hypotension. However, in approximately 15% of cases, hypertension may be observed [5]. Another factor is that TRALI may be associated with a transient leucopenia, for usually less than 24 h [11]. Once TRALI is suspected, it is important to manage the patient according to the severity of this adverse event. If all patients require oxygen supplementation, not all deserve a transfer to an intensive care unit. Most cases improve after 2 to 4 days, but 20 to 30% of the patients require mechanical ventilation and a full intensive care monitoring. Although some factors such as a history of heart failure, a positive fluid balance and the absence of risk factor for developing an ALI make a clear orientation in favour of TACO, much more complex situations may occur where the classification is less easy. Pulmonary artery occlusion pressure has been considered as a key criterion in distinguishing cardiogenic from non-cardiogenic pulmonary oedema, values of 18 mmHg or below being in favour of a non-cardiogenic origin. However, nowadays, PAOP monitoring is far from being always performed. This invasive technique has been considered as associated with increased morbidity and mortality [12], and its utility in monitoring ALI is a matter of debate. Moreover, we should have in mind that each measurement may not be representative of the overall clinical situation, and that high values have been observed in situations considered as authentic ALI syndromes [13]. The fluid protein concentration analysis could in theory distinguish circulatory overload from ALI, the lower the protein concentration ratio of the alveolar fluid/plasma is, the more probable is the circulatory overload. A ratio < 0·65 strongly suggests a circulatory overload [14,15]. However, the technique is feasible only in intubated patients, and is subjected to technical difficulties that may alter the results [16]. Standard chest radiography may not be informative to distinguish TRALI and TACO. However, the measure of the vascular pedicle width and cardiothoracic ratio may help: it has been shown that a vascular pedicle width above 70 mm along with a cardiothoracic ratio above 0·55 may predict a PAOP above 18 mmHg [17]. B-type natriuretic peptide (BNP) is a cardiac neurohormone produced from the ventricules in case of volume expansion and pressure overload. Its dosage in plasma may be of some help: high BNP levels above 1200 pg/ml are clearly associated with circulatory overload with a specificity greater than 90%, and levels below 200 pg/ml associated with non-cardiogenic pulmonary oedema with a specificity greater than 90%[18]. In a case–control study, BNP has been shown a useful marker in confirming TACO diagnosis [19]: the post- to pre-transfusion BNP ratio was significantly high in patients with transfusion-associated volume overload as compared to matched recipients of blood transfusion without adverse reaction. The handicap of such an approach is mainly the fact that it requires to test pre- and post-transfusion samples, which means that the pre-transfusion sample may have been stored up to 2 or 3 days in poorly controlled conditions, potentially leading to false-positive results. This difficulty may be overcome by dosing the N-terminal fragment of the pro brain natriuretic peptide (NT-proBNP), a biologically inactive fragment cleaved from the proBNP along with the biologically active BNP. This marker has been shown to be more accurate than BNP to identify asymptomatic patients at risk for the development of heart failure [20]. Using this marker enables to work only on post-transfusion plasma. In a case–control study of 16 clinically defined TACO and 24 controls, post-transfusion NT-proBNP above 1000 pg/ml was found to be a good marker of TACO, with a sensitivity > 93% and a specificity > 83%[21]. Finally, it has to be stressed that, although found normal in a TRALI case report [22], this test has not actually been investigated in clinically defined TRALI at a large scale, which will be mandatory to define its definitive value for differentiating TRALI from TACO. Investigation of fluid balance is part of basic patient's care, and a clearly identified positive balance related to an intake excess is in favour of TACO. Of note, it has been indirectly shown by plasma NT-proBNP dosage that most patients with clinical TACO had a high NT-proBNP concentration, reflecting a positive fluid balance previous to the transfusion that caused TACO [21]. As already mentioned, some additional symptoms, such as the observation of fever, transient leucopenia, may add probability for the diagnosis of TRALI. Table 1 summarizes the factors contributing to differential diagnosis between TRALI and TACO. In TACO, pulmonary oedema is the result of a heart failure caused by increased hydrostatic pressure in lung due to an increased pulmonary blood volume, an increased central venous pressure. In transfusion practice, many patients are at risk for TACO. Infants are at high risk, as they may be subjected to high positive fluid balance. Elderly patients who may have a limited capacity to respond to a positive fluid balance, are also at high risk, as are patients with a history of heart failure. Finally, profoundly anaemic patients who have already tachycardia in order to compensate their anaemia, have a limited ability to adapt to blood volume variation, and are also at serious risk of TACO if not managed preventively. In the past 10 years, our knowledge in regard to the pathophysiology of TRALI increased tremendously, and it is now possible to propose a unified vision of it [23]. Neutrophils are the key trigger for TRALI, as the basic alveolar lesion leading to pulmonary oedema is the result of the release of preformed granular enzyme, and of the synthesis of highly toxic reactive oxygen species following neutrophil activation. Circulating neutrophils are required to be primed before activation. Priming is a process that potentiates the effects of an activating stimulus [24]. Therefore, it can be assumed that TRALI requires priming and activation of neutrophils to occur, and that at least priming or activation is provoked by the blood component transfused. A great number of agents have been described as being able to prime neutrophils. Among them, we can mention platelet activating factor, tumour necrosis factor-α (TNF-α), interleukin 8, granulocyte/macrophage-colony stimulating factor and interferon-γ. Most of these molecules may be released either by dying cells or by activated endothelial cells, monocytes and lymphocytes. In addition, numerous infectious agents, and bacteria-derived lipopolysaccharides may also act directly as priming agents. Transfused patients may be in clinical conditions where activation of endothelial cells, monocytes and lymphocytes may occur, such as recent surgery, cardiovascular disease and leukaemia. Moreover, they can have an active infection leading to priming of neutrophils too. Activation of pulmonary endothelial cells may be a prominent mechanism for neutrophil priming. Activated pulmonary endothelial cells express surface membrane receptors for L-selectin, P-selectin and ICAM-1 that favour neutrophil adhesion, and produce cytokines such as platelet activating factor and interleukin 8 which act as priming agents. A good clinical example of this activation of pulmonary endothelial cells as a starting event of TRALI is provided by the observation of a recipient of lung transplant who develop TRALI on the transplanted lung, after transfusion of a red cell concentrate containing an anti-HLA class I antibody recognizing an antigen present in the donor lung, but absent in the recipient [25]. Neutrophils can also be primed by a factor brought by the transfused blood component, which can be an antibody, a cytokine or bioactive lipids (see further). Whatever the way they had been primed, neutrophils exhibit a shape change, and their ability to cross the lung circulation is impaired. This results in an accumulation of primed neutrophils in the lung that can be further activated. Eventually, in case there is no further stimulus, neutrophils will go back to their initial state in at least 24 h [26]. Primed neutrophils may be activated by an exogenous factor brought by the transfused blood component, which can be an antibody, a cytokine or bioactive lipids (see further). Alternatively, neutrophils may be activated by already activated pulmonary endothelial cells. Actually, it is the interaction between neutrophils and endothelial cells that results in TRALI. Anti granulocytes antibodies. Antibodies against neutrophil antigens human neutrophil antigen (HNA)-1a, HNA-1b, HNA-1c, HNA-2a and HNA-3a have been observed in many TRALI cases [27]. An interesting observation that corroborates the ‘priming plus activation’ hypothesis is that not all the situations of incompatibility (i.e. where the recipient bears the corresponding antigen) shall lead to a clinical manifestation of TRALI. In the first description of this phenomenon, donations of a frequent plasma donor with anti-HNA-3a caused TRALI in 36% of the recipients, while the corresponding antigen is present in > 90% of Caucasians [28]. In a more recent observation, out of 10 patients receiving platelets from a donor with anti-HNA-3a, TRALI was observed on two occasions, but in a single patient [29]. Another interesting observation had been done in an ex vivo model, using an anti-HNA-2a antibody. HNA-2a expression in man is heterogeneous, some individuals having an expression on 70% or more of the neutrophils, while others express it on less than 30%. Using neutrophils from ‘highly expressed’ HNA-2a individuals, it was possible to induce neutrophil activation directly by adding the antibody, while using neutrophils from ‘weakly expressed’ HNA-2a individuals, neutrophil activation required the addition of a known priming agent to occur [30]. Anti-HLA class I antibodies. These antibodies not only are able to react with neutrophils, but also with endothelial cells. Moreover, it is clear that at least some of them are able to prime and to activate neutrophils. Indeed, anti-HLA class I antibodies are commonly found in look-back studies of TRALI cases. As these antibodies are frequently found in blood donors, it is important to test that the corresponding antigen is present in the recipient in order to confirm their immutability. Anti-HLA class II antibodies. First described as related to TRALI in 2001 [31], there is now evidence that these antibodies may play a in the onset of TRALI. However, it is that they act directly either on neutrophils or on endothelial cells, as the corresponding antigens are not on these cells. The hypothesis that these antibodies could act indirectly by first activating and that activated monocytes could the priming of neutrophils, although is still not The hypothesis that membrane lipids such as species could activate neutrophils their activating factor was proposed in in favour of such a was provided by an in In addition, the description of a TRALI case in a recipient of a red cell concentrate clearly that TRALI could in the absence of incompatibility from the already is a present in platelet as a As is not only by monocytes and but also by neutrophils, it has been that it may act as an activation means for neutrophils leading potentially to TRALI In the blood transfusion, using blood component, the of neutrophils in blood is However, some patients of neutrophils, and in cases, TRALI had been as clearly related to an incompatibility between the transfused neutrophils and the of a corresponding antibody in the recipient the for TRALI are much more Priming and activation of neutrophils is the key event produced by a great of at least one being present in the transfused blood component for TRALI. It is clear from studies to TACO that it is a frequent adverse reaction after transfusion of blood In a first study by of patient TACO, which means approximately of red cell concentrate transfused In a more recent study in intensive care unit, TACO incidence was at of red cell concentrate transfused from haemovigilance of and provide also useful In a of TACO have been between and which to an incidence of blood transfused of TACO were related to red cell concentrate Among these cases, the of is which three to In TACO have been in the 2 which to an incidence of blood transfused. In there is no that TACO is a frequent adverse event after blood transfusion, and that it to the transfusion-related morbidity and reports in incidence values from to 1000 blood transfused. may provide useful information in this from a incidence of blood component in the while the observed an incidence of 10 blood component and the 3 blood component The most to be for plasma with three major not a single case of TRALI has been observed using plasma. the of the transfused plasma provoked TRALI, while the recipients of TRALI the incidences observed in the three in the absence of any preventive measure are 16 and 16 and the of a preventive measure in in the to a reduction of TRALI to transfused. for red cell concentrate are more to the incidences from to red cell The incidence observed in may on one the fact that of requires to serious adverse reactions, and it is known that many authentic are not and on the the fact that not all in the while the provided in of blood are It is to that, provided that the cases are TRALI cases and that plasma of red cell concentrate is in the different the observed that is, red cell concentrate in is the to results for platelets actually deserve observed incidences of 8 and platelet from whole blood and while whole blood platelet and of a incidence of platelet without distinguishing between whole and platelet The results in the to provide also information during related to red cell concentrate transfusion and to platelet concentrate transfusion. Finally, one can a between the incidence of TRALI and the plasma volume from donors present in blood as identified by the control as in between the volume of plasma from donors present in the different blood and the incidence of TRALI to the from the investigations to the management of the and from the that be done in order to control the there is no to related to the blood component and the corresponding blood Once a TRALI is suspected, investigations are mandatory in order to to an the transfused blood and this information to the blood transfusion that have patient's necessary for a and it to the laboratory in of the this not that all the investigations shall be but that the laboratory in of investigations shall be able to them if and all the donors and for the way to for class I and II and use stored plasma of the corresponding if and the donors to for investigations (in case many donors are potentially to identify if positive antibodies against class I and II and antibodies against neutrophils in the blood donors In case of any positive for the of the corresponding antigen on the patient's and a that in some such as neutrophil it may be complex to these tests due to technical In most donors who have been in a TRALI case due to the of or antibody recognizing a patient's antigen are from of blood for direct therapeutic In contrast, donors found for antibodies may as well as with identified antibodies but recognized as not for the TRALI analysis of risk factors in patients and analysis of fluid balance before transfusion are the means for TACO. can be as and blood The of the in to use donors only for providing direct therapeutic plasma has been a and the incidence of TRALI related to in the with the after a reduction of TRALI in with a plasma may be from or without The is more complex for platelet on the of have of antibody in donors, but up to now, no a for these Although mentioned, one should have in mind that red cell concentrate may cause TRALI, and in the red cell TRALI may be and overall for of the However, in the present the only preventive measure that to red cell concentrate is to from further donations donors that were directly in a TRALI already that plasma can be considered as of any known TRALI Therefore, its use can be an to plasma. Moreover, at least in the of the incidence of TRALI is much with platelet concentrate than with of platelet as shown in Table This observation, along with many others in favour of the use of platelet concentrate to the management of recipients, as it is already done in some of platelet in platelet concentrate enables to the of plasma in each platelet It has been clearly as to the incidence of adverse reactions As many in favour of such a we can that information its in TRALI incidence severity will in the few Finally, one can also the fact that the of of blood before being transfused may favour the accumulation of active in blood there is pressure to the of platelet concentrate up to days. However, we can more to the present days time and to develop the of platelet concentrate in order to manage blood of a measure with and potentially for the

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