1 Consultant Haematologist, Department of Haematology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK. E-mail: jonathan.wallis@tfh.nuth.northy.nhs.uk
Transfusion-related acute lung injury (TRALI) is almost certainly under-diagnosed. Though first described in 1957,1 many clinicians are unaware of the condition or may not recognize transfusion as the cause when it occurs. TRALI describes a particular form of acute respiratory distress syndrome (ARDS) that occurs after transfusion and which is caused by antibodies in plasma of a single donor unit reacting with leucocyte antigens in the recipient.
The condition is characterized by the sudden onset of non-cardiogenic pulmonary oedema, often with marked systemic hypovolaemia and hypotension, occurring during or within a few hours of transfusion.2 Fever and rigours are reported, but may be absent or relatively mild. There is rapid onset of severe hypoxia, a chest radiograph typical of ARDS, and copious frothy yellow or pink fluid in the trachea.3 Diagnosis of TRALI depends on the exclusion of other causes of pulmonary oedema or ARDS. Laboratory findings may include unexpected haemoconcentration and a sudden fall in serum albumin.4 5 As in other causes of acute alveolar capillary leak, the pulmonary exudate in TRALI has a high albumin content. Peripheral blood neutropenia has been reported but neutrophilia is more common.6 7 We have observed marked monocytopenia in many cases, but this finding is not specific to TRALI.5
The reaction is secondary to antibodies in donor plasma against antigens present on the recipients leucocytes. These may be antibodies to epitopes of the human leucocyte antigen (HLA) system, or to other leucocyte antigens.2 610 HLA antibodies may be directed against either HLA class I (A, B, C) antigens, which are found on all leucocytes and many other tissues, or HLA class II (DR) antigens, which are found chiefly on B lymphocytes and monocytes, and on some cell types, including endothelial cells, when they are activated. Experimental evidence from an animal model suggests that complement may also be necessary.11 The antibodies are postulated to bind and activate leucocytes in peripheral blood, which are then sequestered in the lungs where they cause endothelial cell damage that allows a profound fluid leak into the alveoli.4 The relative importance of blood monocytes and neutrophils is uncertain, and it is possible that alveolar macrophages may be involved in the reaction.12 It has also been suggested that a second hit affecting the lungs is necessary, but there are numerous reports of TRALI in patients with no pre-existing pulmonary pathology, and two reports in healthy volunteers receiving blood products.9 13 Pre-existing lung damage will almost certainly increase the severity of TRALI and may worsen the outcome, but is clearly not required for TRALI to occur. Silliman and colleagues14 have suggested an alternative aetiology for TRALI, by which reactive lipids in aged cellular blood components may activate neutrophils non-specifically to cause lung damage. The condition of transient respiratory impairment not necessarily associated with donor antibodies that they describe for some of their cases may be better considered as separate from classic TRALI, although it may be relevant to development of ARDS in recipients of massive transfusion.
TRALI occurs with 1 in 510 000 units of plasma-containing products transfused.2 5 15 TRALI is most commonly seen, and appears to be more severe, with products containing larger amounts of plasma, such as whole blood or fresh frozen plasma (FFP). However, it has been reported after transfusion of plasma-reduced red cells containing approximately 70 ml plasma, cryoprecipitate or as little as 50 ml whole blood.1 2 16 More than 90% of packed red cells transfused in the UK are now in the form of red cells in optimal additive solution, which retain only 1020 ml plasma. There are no published cases of TRALI specifically implicating this product, but there is no reason why TRALI should not occur with optimal additive red cells if the antibody titre in the remaining plasma is high enough. The serious hazards of transfusion (SHOT) voluntary reporting scheme in the UK receives about 15 reports each year of TRALI, for which red cells have been implicated as the causative unit in about one third, and FFP and platelets in just under half; the causative unit in the remainder is uncertain. Details of the precise form of red cell product involved have not been recorded.17
No specific laboratory tests are available for TRALI and initial diagnosis depends on a high degree of suspicion. The subsequent finding of leucocyte antibodies in a donor unit, matching a recipient leucocyte antigen, may be taken as strongly supportive evidence in a suspected case. These tests may take several months to complete. Occasional negative antibody tests may not exclude the condition, especially when a direct cross-match between suspect donor and recipient is not possible. Where feasible, it is worthwhile salvaging any remaining plasma from blood bags for antibody testing, although this is often insufficient in volume, and sending a sample of EDTA anticoagulated peripheral blood from the patient for preparation of DNA for later HLA and neutrophil antigen typing (Fig. 1). If the patient survives, HLA and neutrophil antigen typing may be done later.
|
Mortality is quoted as 5% in the largest observational study, from the Mayo clinic in 1985.2 In that study, most cases were associated with transfusion of whole blood units that contain a volume of plasma equivalent to that in a unit of FFP. With the greater use of optimal additive red cells, relatively more cases are now being reported as being caused by FFP or platelet concentrates. Patients receiving these products are likely to be more seriously ill. SHOT has recorded an overall mortality of 25%, if cases in which TRALI was possibly, probably or definitely implicated in the patients death are included. Furthermore, death was more common where the implicated unit was a plasma product (12 of 31 cases) than when red cells were implicated (2 of 23 cases).17 The higher mortality with TRALI resulting from FFP has also been noted in North America.22
It is of interest that an alveolar leak syndrome is common after cardiac surgery when large amounts of whole blood, plasma and platelet concentrates are used. Although the role of blood transfusion has been considered, it has not been studied systematically and many other possible causes have been suggested.18 Two studies in the 1980s reported an incidence of post-bypass ARDS or post-pump lung of 1.41.7%, with a 50% mortality.23 24 In the 1990s, the condition became less common as use of blood products decreased. It seems likely that some cases of this condition, with such high mortality, were unrecognized cases of TRALI.
That TRALI suffers from under diagnosis was recently emphasized in a report of a look-back exercise.25 A case was recognized and shown to be caused by a regular plasma donor with a strong antibody against the leucocyte antigen 5b, found on the cells of 90% of individuals. Thirty-six previous recipients of donations were traced and the recipients records examined. Seven mild or moderate and eight severe reactions in keeping with TRALI were documented. While seven of these cases were reported to the hospital transfusion service, none was reported to the supplying blood centre before the index case. If a clinician is suspicious that he has seen a case of TRALI, it is important that he informs the local blood centre (Fig. 1) via his local haematologist, so that donors of potentially dangerous plasma can be retired from the donor list and the case can be reported to SHOT.
Women who have been immunized against leucocyte antigens during pregnancy2 10 15 account for the majority of implicated donors, to such an extent that many blood services initially only investigate female donors. As many as 20% of parous female donors have anti-leucocyte antibodies in their plasma.26 27 It has been repeatedly suggested that donations from parous females should not be used for products containing large amounts of plasma, and this strategy has been implemented by some blood services.2 10 25 28 29 Screening of donors for leucocyte antibodies may seem an obvious step. However, uncertainty about which antibodies to look for and the possible effect of significant loss of donors have hampered its introduction.27 Screening is currently under active consideration and may become a practical possibility in the future, particularly for regular donors of apheresis platelets or plasma.
Avoiding TRALI can be partly achieved by avoiding unnecessary transfusion, particularly of plasma and platelets. Alternatively, use of pooled plasma preparations rather than the standard single-donor FFP may prevent the condition because relevant antibodies are diluted. To date, no definite cases have been reported associated with the use of such commercially available and viricidally treated pooled plasma. The increased use of optimal additive red cells containing less plasma is likely to reduce the clinical incidence and severity of the condition resulting from red cell transfusion. Use of red cells containing safe plasma is particularly important in small children where the dose per kg plasma from a single unit of red cells may be relatively large.
Clinicians should be aware of TRALI, and where pulmonary oedema is seen during or after a transfusion they must differentiate between systemic fluid overload and ARDS. If TRALI is suspected, they should seek help from both intensivists and haematologists for diagnosis and treatment. Products containing large volumes of plasma such as FFP, platelet concentrate or whole blood are more likely to cause TRALI, but it may occur after transfusion of a product containing small volumes of plasma. There is good evidence that the condition is under-diagnosed and under-reported.25 All suspected cases should be reported to the local blood centre for investigation and to SHOT. TRALI is now probably the most common cause of mortality and serious morbidity resulting from blood transfusion in the UK.17
References
1 Brittingham TE. Immunological studies of leucocytes. Vox Sang 1957; 2: 242
2 Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985; 25: 5737[CrossRef][ISI][Medline]
3 Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann Intern Med 1970; 73: 68994[ISI][Medline]
4 Dry SM, Bechard KM, Milford EL, Churchill WH, Benjamin RJ. The pathology of transfusion-related acute lung injury. Am J Clin Pathol 1999; 112: 21621[ISI][Medline]
5 Wallis JP. Transfusion related acute lung injury. Experience in a single institution. Vox Sang 2002; 83 (suppl 2): 219
6 Yomtovian R, Kline W, Press C, et al. Severe pulmonary hypersensitivity associated with passive transfusion of a neutrophil-specific antibody. Lancet 1984; 1: 2446[ISI][Medline]
7 VanBuren NL, Stroncek DF, Clay ME, McCullough JM, Dalmasso AP. Transfusion related acute lung injury caused by an NB2 granulocyte specific antibody in a patient with thrombotic thrombocytopenic purpura. Transfusion 1990; 30: 425[CrossRef][ISI][Medline]
8 Kopko PM, Popovsky MA, MacKenzie MR, Pagliaroni TG, Muto KN, Holland PV. Human leucocyte antigen class II antibodies in transfusion related acute lung injury. Transfusion 2001; 41: 31722[CrossRef][ISI][Medline]
9 Flesch BK, Neppert J. Transfusion-related acute lung injury caused by human leucocyte antigen class II antibody. Br J Haematol 2002; 116: 6736[CrossRef]
10 Nordhagen R, Conradi M, Dromtorp SM. Pulmonary reaction associated with transfusion of plasma containing Anti-5b. Vox Sang 1986; 51: 1027
11 Seeger W, Schneider U, Kreusler B, et al. Reproduction of transfusion-related acute lung injury in an ex vivo lung model. Blood 1990; 76: 143844[Abstract]
12 Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (TRALI) in a patient with a single lung transplant. Br J Haematol 2000; 109: 6745
13 Dooren MC, Ouwehand WH, Verhoeven AJ, von dem Borne AEGKr, Kuijpers RW. Adult respiratory distress syndrome after experimental intravenous gamma-globulin concentrate and monocyte-reactive IgG antibodies. Lancet 1998; 352: 16012[ISI][Medline]
14 Silliman CC, Paterson AJ, Dicket WO, et al. The association of biologically active lipids with the development of transfusion-related acute lung injury: a retrospective study. Transfusion 1997; 37: 71926[CrossRef][ISI][Medline]
15 Popovsky MA, Davenport RD. Transfusion related acute lung injury: femme fatale? Transfusion 2001; 41: 3125[CrossRef][ISI][Medline]
16 Reese EP, McCullough JJ, Craddock PR. An adverse pulmonary reaction to cryoprecipitate in a hemophiliac. Transfusion 1975; 15: 5838[ISI][Medline]
17 SHOT Annual report 2000/2001. Available at http//www.shot@ demon.co.uk (accessed 6/11/2002)
18 Maggart M, Stewart S. The mechanisms and management of noncardiogenic pulmonary edema following cardiopulmonary bypass. Ann Thorac Surg 1987; 43: 2316[Abstract]
19 Culliford AT, Thomas S, Spencer FC. Fulminating noncardiogenic pulmonary edema: a newly recognised hazard during cardiac operations. J Thorac Cardiovasc Surg 1980; 80: 86875[Abstract]
20 Hashim SW, Kay HR, Hammond GL, Kopf GS, Geha AS. Noncardiogenic pulmonary edema after cardiopulmonary bypass: an anaphylactic reaction to fresh frozen plasma. Am J Surg 1984; 147: 5604[ISI][Medline]
21 Nouraei SM, Wallis JP, Bolton DT, Hasan A. Management of transfusion related acute lung injury with extracorporeal cardiopulmonary support in a four year old child. Br J Anaesth 2003; 91: (in press)
22 FDA. Transfusion Related Acute Lung Injury. Rockville, MD: Food and Drug Administration, Center for Biologics Evaluation and Research; 2001. Available at: http: //www.fd.gov./cber/ltr/trali101901.htm (accessed 10/10/2002)
23 Messent M, Sullivan K, Keogh BF, Morgan CJ, Evans TW. Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction. Anaesthesia 1992; 47: 2678[ISI][Medline]
24 Fowler AA, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 98: 5937[ISI][Medline]
25 Kopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MA. Transfusion related acute lung injury; report of a clinical look-back investigation. JAMA 2002; 287: 196871
26 Densmore TL, Goodnough LT, Ali S, Dynis M, Chaplin H. Prevalence of HLA sensitization in female apheresis donors. Transfusion 1999; 39: 1036[CrossRef][ISI][Medline]
27 Payne R. The development and persistence of leukoagglutinins in parous women. Blood 1962; 19: 41124[ISI]
28 Wallis JP. Transfusion-related acute lung injury. Transfusion Med 1999; 9: 175[CrossRef][ISI][Medline]
29 Wallis JP, Haynes S, Stark G, Lucas GE, Green FA, Chapman CE. Transfusion related alloimmune neutropenia: an undescribed complication of blood transfusion. Lancet 2002; 360: 10734[CrossRef][ISI][Medline]