Transfusion-related acute lung injury a review

Transcription

1 The Intensive Care Society 2009 Transfusion-related acute lung injury a review J Thachil, J Erinjeri, TD Mahambrey Transfusion-related acute lung injury (TRALI), a type of non-cardiogenic pulmonary oedema related to blood transfusion, is gaining prominence as a common adverse event related to blood transfusions in hospitals. Various mechanisms have been postulated to cause TRALI including both antibody-related and non-immune mechanisms. Although transfusion of all types of blood components have been implicated, by far the commonest product related to TRALI was, until recently, fresh frozen plasma, especially that obtained from female donors. However the use of male-only plasma donation in the UK has resulted in an increased observance of TRALI with platelet and red cell transfusions. The diagnosis of this condition is primarily one of exclusion of other causes of pulmonary oedema, with specialist laboratory tests performed to support the diagnosis. The management of TRALI is early diagnosis and good supportive care with, occasionally, ventilatory support. An increased awareness of this complication among intensive care physicians is desirable to prevent one of the commonest and most frequently under-recognised transfusion-related adverse events of the present day. Keywords: transfusion; acute lung injury; adult respiratory distress; fresh frozen plasma; platelets; cardiac failure; blood transfusion Introduction Transfusion-related acute lung injury (TRALI) has become one of the leading causes of transfusion-related morbidity and mortality, especially since the transmission of infectious diseases through blood transmission has diminished. 1 The true incidence of TRALI is unknown partly because a standard definition is not available. A study from the United States reported only 36 cases in a two year cohort analysis of 22,292 transfused patients. 2 In the UK, however, there has been a trend towards increased reporting of TRALI, with an average of 14 cases per year from , 26 cases during and 36 in In the most recent Serious Hazards of Transfusion (SHOT) report published in 2007, 24 cases were reported, with a single patient mortality from TRALI. 3 Definition The SHOT working group defines TRALI as acute dyspnoea with hypoxia and bilateral pulmonary infiltrates occurring during or within six hours of transfusion not due to circulatory overload or other likely cause. 3 This definition does not include patients with pre-existing acute lung injury (ALI) and cases which may occur after six hours, nor does it include any laboratory diagnostic criteria. A Canadian consensus conference has also included a category of possible TRALI in which patients may have other risk factors for ALI temporally related to transfusion. 4 Pathogenesis The exact mechanism of TRALI is not fully understood, but is likely to be multifactorial and may vary from patient to patient. 5 An immune antibody-mediated mechanism is more commonly implicated in up to 85% of cases, although a nonimmune mechanism and a combination of both have also been demonstrated. 5,6 Immune and non-immune hypotheses In the immune-mediated hypothesis, antibodies in the transfused product, commonly human leukocyte antigen (HLA) or human neutrophil antigen, induce neutrophil activation in the recipient (Figure 1). 7,8 Most of these antibodies have been observed in multiparous women who became alloimmunized during pregnancy. 9 The antibody-bound neutrophils are sequestered in lung capillaries, where complement activation and release of neutrophil bioactive products result in endothelial damage and capillary leak Despite strong evidence supporting the immune mechanism, antibodies have not been found in approximately 15% of cases of TRALI. 11 The use of more sensitive assays for HLA or neutrophil antibodies, or identification of antibodies to other cell types such as monocytes or lymphocytes, may explain some of these. 11 However, the antibodies, when present, cause lung injury in only some patients and not in others, suggesting a non-antibody mediated mechanism may be possible in some cases. 13 Also, patients who have experienced TRALI reactions do not always have the cognate antigen to leukocyte antibodies found in the implicated donor. 14 This suggests a mechanism unrelated to antibodies. According to the non-antibody hypothesis, biological response modifiers, such as lipids or cytokines contained in the transfused product, may induce leukocyte priming and activation in the recipient, causing endothelial cell damage (Figure 1). 15,16 The problem with this JICS Volume 10, Number 3, July

2 Immune Antibodies in the donor transfused to the recipient Non-immune Biological substances like lipids in the transfused product First hit Activation of pulmonary endothelium Neutrophils bind to the antibodies Activate the leukocytes in the recipient Antibody-bound neutrophil sequestered in lung capillaries and inflammatory mediators Second hit Increased adhesion molecule expression on pulmonary endothelium Neutrophils attracted and attached to the endothelium primed and inflammatory mediators Complement activation Primed neutrophils activated Pulmonary endothelial damage Further release of cytokines and inflammatory mediators Capillary leak and ARDS Figure 1 Immune and non-immune hypotheses. lipid hypothesis is that it requires the transfusion of cellular blood products and will not explain the development of TRALI with blood products such as FFP that would not possess biologically active lipids, which are metabolic products arising from the breakdown of cell membranes. 12 The two-hit hypothesis TRALI has been noted to occur more often in patients in poor clinical condition at the time of the implicated transfusion. 4 This has led to the proposition of a two-hit hypothesis by Silliman and colleagues (Figure 2). 17,18 The first hit is the predisposing clinical condition, such as severe infection, and the second is the transfusion of biologically active lipids, cytokines, or leuko-agglutinating alloantibodies. 18 The first event results in activation of the pulmonary endothelium, which causes a release of cytokines and an increase in the number of adhesion molecules expressed on the endothelial cell surfaces. This results in the attraction and priming of neutrophils with their subsequent adherence to the endothelial surface. The second event then results in activation of neutrophils and release of cytokines and inflammatory mediators, leading to capillary leakage as well as pulmonary damage. 19 Although it has been suggested that a second hit affecting the lungs is necessary, there are numerous reports of TRALI in patients with no pre-existing pulmonary pathology, and reports in healthy volunteers receiving blood products. 20,21 The threshold model This model explains the spectrum of clinical severity of TRALI and the different susceptibilities of individuals to this condition. 5 Here, the recipient neutrophils are once again the Figure 2 The two-hit hypothesis. Pulmonary endothelial damage Capillary leak and ARDS key factor. Compared with a resting neutrophil, a primed neutrophil has reached a certain level of activation, still below an arbitrary threshold which leads to the condition. A broad range of substances activates the neutrophils either directly or via an activated pulmonary endothelium or both. These substances are present in the transfused blood component, but may also occur in the recipient due to, for example, surgery or infection. TRALI evolves once the neutrophil has overcome this threshold. In mild TRALI, the threshold is higher and hence the clinical picture is milder. A combination of several factors, including genetic features, the ability of the transfusion-related mediators to provoke a stronger reaction and coexisting clinical illnesses in the individual, can overcome this threshold and predispose to severe TRALI. Blood components implicated TRALI cases show a temporal relationship with the components transfused and can be seen after any transfused blood product. Fresh frozen plasma was the most frequently implicated blood product. 22 However, it may occur with no relation to the type of blood product transfused or the titre of the antibody in the transfused product. 23 In the 2007 SHOT report, there were no cases of TRALI secondary to FFP, while platelets were the main culprit and red cells contributed to the rest. 3 This shows that TRALI can follow transfusion of components containing relatively little plasma. With regard to platelet pools, replacement of the plasma contribution to the pool by male plasma or platelet additive solution has been suggested by the SHOT working group to reduce the risk of 208 Volume 10, Number 3, July 2009 JICS

3 antibody-mediated TRALI. 3 Antibodies against certain granulocyte antigens, such as human neutrophil antigen-3a may be more prone to cause severe TRALI reactions. 24 It is also more common with the administration of older units of blood, where reactive lipids may occur more commonly and activate neutrophils non-specifically to cause lung damage. 25 TRALI has also been reported following bone marrow and intravenous gamma globulin transfusions. 26,27 Clinical features The clinical manifestations of TRALI usually occur within six hours of transfusion with most cases occurring within two hours. 11 The common clinical presentation consists of rapid onset of severe hypoxia, marked systemic hypovolaemia and hypotension. 4 Fever and rigors have been reported but may be absent or relatively mild. Auscultation of the lungs may reveal diffuse crackles and decreased breath sounds, although a third heart sound suggestive of cardiogenic oedema is absent. Radiographic investigations usually reveal bilateral interstitial pulmonary infiltrates typical of ARDS. 6 Typically the heart size is not enlarged suggesting a non-cardiac aetiology. The presentation of TRALI can represent a spectrum of severity and there is increasing recognition that milder forms of TRALI do occur, with hypoxia without pulmonary oedema. 6 The central principle in diagnosing TRALI is exclusion of cardiogenic causes of pulmonary oedema. Pulmonary oedema occurring within six hours of a blood transfusion is referred to as transfusion-associated cardiac overload (TACO). 29,30 Although difficult to differentiate clinically at times, there are significant differences between the two entities. Other conditions that are considered in the differential diagnosis of TRALI include allergic/anaphylactic reactions and reactions from transfusion of contaminated blood products. Diagnosis The diagnosis of TRALI is made after the exclusion of other causes of pulmonary oedema or ARDS, which can include aspiration, pneumonia, toxic inhalation, pulmonary contusion, near drowning, sepsis, shock, multiple trauma, burns, acute pancreatitis, post-cardiopulmonary bypass and drug overdose. There are no easily available laboratory tests for confirmation of TRALI. 2 As such, a high degree of suspicion must be maintained to make a diagnosis. In cases where TRALI is suspected, blood samples should be taken after discussion with the blood transfusion service. Further tests are usually undertaken in specialised laboratories by the National Blood service. The aim of the tests is to identify leukocyte antibodies in a donor unit matching the recipient s leukocyte antigen. Occasionally, negative antibody tests may not exclude the condition, especially when a direct cross-match between suspect donor and recipient is not possible. 2 Samples of donor plasma should be tested for HLA-I and -II and granulocyte antibodies. If an antibody is found, its specificity should be determined and it should be tested for concordance with the recipient s granulocyte or lymphocyte antigens. The diagnosis of TRALI is clearly established if there is concordance. However, even without concordance, the presence of such alloantibodies is considered strong presumptive evidence of TRALI. This method of diagnosis results only in identification of donors with some of the immunologic causes of TRALI, but is negative in many cases of TRALI. 31 Management The treatment of TRALI is primarily supportive as in any other case of ARDS (see Figure 3). If TRALI is suspected during the transfusion of a blood product, that transfusion should be immediately discontinued. 32 For more severe cases, intravenous fluids, vasopressor agents, and either invasive or non-invasive mechanical ventilation may be necessary. 12 A low tidal volume lung protective strategy has been advised for patients requiring mechanical ventilation. 12 Administration of diuretics is detrimental and should generally be avoided, as the pulmonary oedema is not due to fluid overload. 33,34 Diuretics should however be considered where TACO is thought to coexist with TRALI. 33 High-dose steroids have been used, partly because of the assumption of an immunological cause, but there is no direct evidence of benefit when given after the initial insult. 34 Prostaglandin administration, extra-corporeal membrane oxygenation and plasmapheresis have been anecdotally reported but cannot be routinely recommended. 35,36 Consider alternatives to blood transfusion Inform the blood bank Suspect TRALI Stop the transfusion if still ongoing Identify the components possible for TRALI Discuss with blood bank Take appropriate blood samples TRALI confirmed Figure 3 Treatment summary for TRALI. Exclude other causes of acute lung injury Issue the patient with red alert card Patients who develop TRALI generally improve clinically within 48 to 96 hours of onset. In 80% of patients, there is resolution of the pulmonary infiltrates within 1 to 4 days with no long-term sequelae. 33 Pulmonary fibrosis or parenchymal destruction does not develop and long-term lung function in survivors who require ventilation for TRALI appears to be the same as patients who did not develop TRALI. 30,33 However, TRALI is fatal in 5 to 10% of cases. 4,37 If a TRALI case is confirmed, it is important to notify the blood bank if they have not been already informed, and to issue the patient with a red alert card for future transfusion purposes. JICS Volume 10, Number 3, July

4 Prevention TRALI is associated with serious consequences and as such, measures should be adopted to prevent it, such as the following: Transfuse blood or blood components only if absolutely necessary this is the best strategy. Protocols should be in place for the guidance of healthcare professionals for the appropriate use of blood products. 38 Donor screening for leukocyte antibodies those donors who have demonstrable antibodies and who have been implicated in TRALI reactions may be excluded from future donations, or their blood only used for blood products that do not contain significant amounts of plasma, or that are fractionated. 6 However this has drawbacks. HLA antibodies were found to be present in 22% of blood components tested and some of these antibodies may not cause TRALI. 39 It is also less clear what should be done with donors who are temporally associated with a TRALI episode but who do not have anti-hla or anti-granulocyte antibodies. 40,41 Avoidance of multiparous female FFP donors to decrease the risk of TRALI. In England, the aim is to obtain all the FFP from male donors and perform HLA pre-screening for female donors who are giving platelets. 3 Use of fresh cellular components as biologically active lipids accumulate in blood products with storage, fresh cellular components may reduce the risk by preventing exposure of recipient neutrophils to neutrophil-priming agents. 42 Use of solvent detergent plasma the pooling process decreases the titre of responsible antibodies. 43 Leukodepletion prevents complement activation. 44 Summary Clinicians should be aware of TRALI, and when pulmonary oedema is seen during or after a transfusion, they must differentiate between systemic fluid overload and ARDS. Products containing large volumes of plasma such as FFP, platelet concentrate or whole blood are more likely to cause TRALI. If TRALI is suspected, blood samples should be taken for specialised tests while respiratory support is given as in any other case of ARDS. Since TRALI is very difficult to diagnose and the management is mainly supportive, limiting blood transfusion to situations when absolutely indicated would be the best preventive method. References 1. Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Trans Med Rev 2004;18: Popovsky M, Moore S. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985;25: Serious Hazards of Transfusion Steering group, SHOT Annual Report. Published Accessed May Kleinman S, Caulfield T, Chan P et al. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion 2004;44: Bux J, Sachs UJ. The pathogenesis of TRALI. Br J Haematol 2007;136: Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005;105: Engelfriet CP, Reesink HW, Brand A, et al. Transfusion-related acute lung injury (TRALI). Vox Sang 2001;81: Lucas G, Rogers S, Evans R et al. Transfusion-related acute lung injury associated with inter donor incompatibility for the neutrophil-specific antigen HNA-1a. Vox Sang 2000;79: MacLennan S, Lucas G, Brown C et al. Prevalence of HLA and HNA antibodies in donors: correlation with pregnancy and transfusion history. Vox Sang 2004;87 (suppl 3):S2-S Webert KE, Blajchman MA. Transfusion-related acute lung injury. Curr Opin Hematol 2005;12: Triulzi DJ. Transfusion-related acute lung injury: current concepts for the clinician. Anesth Analg 2009;108: Looney M, Gropper M, Matthay M. Transfusion-related acute lung injury: a review. Chest 2004;126: Toy P, Hollis-Perry KM, Jun J, Nakagawa M. Recipients of blood from a donor with multiple HLA antibodies: a lookback study of transfusionrelated acute lung injury. Transfusion 2004;44: Kopko PM, Paglieroni TG, Popovsky MA et al. TRALI: correlation of antigen-antibody and monocyte activation in donor recipient pairs. Transfusion 2003;43: Silliman CC, Paterson AJ, Dickey WO et al. The association of biologically active lipids with the development of transfusion-related acute lung injury: a retrospective study. Transfusion 1997;37: Silliman CC, Voelkel NF, Alard JD et al. Plasma and lipids from stored red cells cause acute lung injury in an animal model. J Clint Invest 1998; 101: Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005;105: Silliman CC, Kelher M. The role of endothelial activation in the pathogenesis of transfusion-related acute lung injury. Transfusion 2005;45(suppl):S Downey GP, Doherty DE, Schwab B et al. Retention of leukocytes in capillaries: role of cell size and deformability. J Appl Physiol 1990; 69: Kopko PM, Marshall CS, Mackenzie MR et al. Transfusion-related acute lung injury: report of a clinical look-back investigation. JAMA 2002;287: Dooren MC, Ouwehand WH, Verhoeven AJ et al. Adult respiratory distress syndrome after experimental intravenous gamma-globulin concentrate and monocyte-reactive IgG antibodies. Lancet 1998;352: Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Transfus Med Rev 2004;18: Chapman CE, Stainsby D, Jones H et al. Serious Hazards of Transfusion Steering Group. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma. Transfusion 2009;49: Davoren A, Curtis BR, Shulman IA et al. TRALI due to granulocyte agglutinating human neutrophil antigen-3a (5b) alloantibodies in donor plasma: a report of 2 fatalities. Transfusion 2003;43: Silliman CC, Boshkov LK, Mehdizadehkashi Z et al. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003;101: Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41: Urahama N, Tanosaki R, Masahiro K et al. TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia. Transfusion 2003;43: Gajic O, Gropper MA, Hubmayr RD. Pulmonary edema after transfusion: how to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury. Crit Care Med 2006;34(5 suppl): S109-S Wallis J. Transfusion-related acute lung injury (TRALI) under-diagnosed and under-reported. Br J Anaesth 2003;90: Jawa RS, Anillo S, Kulaylat MN. Transfusion related acute lung injury. J Intensive Care Med 2008;23: Volume 10, Number 3, July 2009 JICS

5 31.Popovsky MA, Chaplin HC Jr, Moore SB. Transfusion-related acute lung injury: a neglected, serious complication of hemotherapy. Transfusion 1992;32: Webert K, Blajchman M. Transfusion-related acute lung injury. Curr Opin Hematol 2005;12: Moore SB. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis. Crit Care Med 2006;34(suppl 5):S114-S Kopko PM, Holland PV. Transfusion-related acute lung injury. Br J Haematol 1999;105: Shander A, Popovsky M. Understanding the consequences of transfusionrelated acute lung injury. Chest 2005;128(5 suppl 2):598S-604S. 36.Nouraei SM, Wallis JP, Bolton D, Hasan A. Management of transfusionrelated acute lung injury with extracorporeal cardiopulmonary support in a four-year-old child Br J Anaesth 2003;91: Eder AF, Herron R, Strupp A et al. Transfusion-related acute lung injury surveillance ( ) and the transfusion-related acute lung injury potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007;47: Herbert PC. Red cell transfusion strategies in the ICU. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Vox Sang 2000;78 Suppl 2: Bray RA, Harris SB, Josephson CD et al. Unappreciated risk factors for transplant patients: HLA antibodies in blood components. Hum Immunol 2004;65: Popovsky MA. Transfusion-related acute lung injury. Curr Opin Hematol 2000;7: Popovsky MA, Davenport RD. Transfusion-related acute lung injury: femme fatale? Transfusion 2001;41: Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc 2005;80: Sinnott P, Bodger S, Gupta A, Brophy M. Presence of HLA antibodies in single-donor-derived fresh frozen plasma compared with pooled, solvent detergent-treated plasma (Octaplas). Eur J Immunogenet 2004;31: Win N, Montgomery J, Sage D et al. Recurrent transfusion-related acute lung injury. Transfusion 2001;41: Jecko Thachil Specialist Registrar in Haematology, Department of Haematology, University of Liverpool Joseph F Erinjeri Specialty Doctor in Anaesthetics, Department of Anaesthetics, Fairfield General Hospital, Bury Tushar D Mahambrey Consultant Intensivist, Department of Intensive Care Medicine, St Helens and Knowsley Teaching Hospitals NHS Trust tushar.mahambrey@sthk.nhs.uk JICS Volume 10, Number 3, July