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Brief Report |

Transfusion-Related Acute Lung Injury:  Report of a Clinical Look-Back Investigation FREE

Patricia M. Kopko, MD; Carol S. Marshall, MD; Malcolm R. MacKenzie, MD; Paul V. Holland, MD; Mark A. Popovsky, MD
[+] Author Affiliations

Author Affiliations: Sacramento Blood Centers, Sacramento, Calif (Drs Kopko, MacKenzie, and Holland); Department of Pathology, University of California at Davis Medical Center, Sacramento (Dr Marshall); and Haemonetics Corp, Braintree, Mass (Dr Popovsky).


JAMA. 2002;287(15):1968-1971. doi:10.1001/jama.287.15.1968.
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Context Transfusion-related acute lung injury (TRALI) is a syndrome that includes dyspnea, hypotension, bilateral pulmonary edema, and fever. TRALI is the third leading cause of transfusion-related mortality, but it is probably underdiagnosed and underreported.

Objective To determine if blood products from a frequent plasma donor, whose blood product was implicated in a fatal case of TRALI, caused symptoms of TRALI in other recipients of her plasma.

Design, Setting, and Participants Retrospective chart review (conducted from November 2000 through April 2001) of 50 patients who received blood components within 2 years (October 1998 through October 2000) from a donor linked to a transfusion-related fatality.

Main Outcome Measure Occurrence of mild/moderate (dyspnea with fever, chills, hypotension, and/or hypoxemia) or severe (acute pulmonary edema or need for mechanical ventilation) reaction associated with transfusion.

Results Superimposed illness prevented assessment of TRALI in 14 patients. Of the 36 patient charts that could be reviewed, 7 mild/moderate reactions were reported in 6 patients (16.7%) and 8 severe reactions were reported in 8 patients (22.2%). Of 5 patients who received multiple transfusions from the same donor, 2 experienced 2 reactions: one had 2 mild/moderate reactions and the other had both a mild/moderate and a severe reaction. While 5 of the 7 mild/moderate reactions were reported to the hospital transfusion service, only 2 of the 8 severe reactions were reported. Only 2 reactions (1 mild/moderate and 1 severe) were reported to the regional blood collection facility.

Conclusions TRALI was frequently underdiagnosed and underreported in recipients of blood products from a donor whose blood products may have caused TRALI in several transfusion recipients. Clinical education and awareness of this often-overlooked diagnosis are imperative for appropriate prevention and treatment.

Figures in this Article

Transfusion-related acute lung injury (TRALI) is a clinical syndrome associated with transfusion that typically includes dyspnea, hypoxemia, hypotension, bilateral pulmonary edema, and fever.1 Symptoms may occur during the period between the beginning of transfusion and 4 hours afterward. The severity of symptoms can range from mild to severe. However, in a large series of TRALI cases, 100% required oxygen support, and 72% also required mechanical ventilation.2 In this same series, symptoms resolved within 96 hours in 80% of patients. The other 20% of patients required longer support, which was associated with persistence of pulmonary infiltrates on chest radiograph.

TRALI has been associated with the presence of granulocyte antibodies, HLA class I antibodies,2 HLA class II antibodies,3 and biologically active lipids4 in donor plasma. All plasma-containing blood components, including red blood cells, platelets, fresh frozen plasma (FFP), and cryoprecipitate, have been implicated in TRALI.1 Infusion of even small volumes of plasma can trigger the reaction.5 Intravenous immunoglobulin prepared from a large pool of plasma has also been reported to cause TRALI,6 but pooled solvent detergent–treated plasma has not.

Severity of TRALI does not appear to be related to the volume of plasma infused, but may be correlated with the degree of hypoxemia.2 Infusion of white blood cell antibodies alone is probably not sufficient to induce TRALI.7 Approximately 20% of women who have had 2 pregnancies have antibodies to leukocytes.8 Therefore, if infusion of antibodies alone were sufficient to cause TRALI, the reaction would be relatively common. Although it seems natural to assume that the transfusion recipient must possess the corresponding leukocyte antigen for an antibody to cause TRALI, such an association has not been demonstrated. Little is known regarding the effect of antibody titer, antibody avidity, or leukocyte-antigen density on the severity or frequency of TRALI reactions.1

Other recipient factors, however, may play a role in TRALI. A 2-event hypothesis of TRALI has been advanced as a possible way of explaining why some recipients experience the reaction while others do not.1,4 It has been theorized that a transfusion recipient must first have a predisposing condition and then receive plasma that contains leukocyte antibody or biologically active lipid.4 Conditions thought to predispose transfusion recipients to develop TRALI include infection, cytokine administration, recent surgery, and/or transfusion of large volumes of blood products.4

Leukocytes coated with antibodies localize to the pulmonary microvasculature.9 The release of cytokines by these antibody-coated leukocytes in the vascular space is thought to lead to an increase in vascular permeability and exudation of fluid and protein into the alveolar spaces.1,10 The degree of fluid exudation likely determines the severity of the pulmonary reaction and whether oxygen administration or mechanical ventilation is required.

TRALI is fatal in 5% to 10% of cases,2,11 and is the third leading cause of transfusion-related mortality.12 Unfortunately, the signs and symptoms associated with TRALI can easily be attributed to other causes, including fluid overload, pneumonia, and acute respiratory distress syndrome (ARDS).1,13 Pulmonary edema, with bilateral "white out" on chest radiograph (Figure 1), similar to that seen in ARDS, is generally present along with fever and hypotension. The key to distinguishing TRALI from other forms of pulmonary edema is recognition that the pulmonary edema is noncardiogenic and that affected patients do not have volume overload.1 This distinction is important because treating patients with TRALI with aggressive diuresis can result in further hypotension, shock, and death.14,15 Treatment should consist of maintenance of hemodynamic status and ventilatory assistance. An extensive review of TRALI, including diagnostic criteria, has recently been published.1

Figure. Posttransfusion Chest Radiograph of Bilateral "White Out" Consistent With Pulmonary Edema
Graphic Jump Location

Although TRALI is often discussed in the transfusion literature, it has received little attention among clinicians. Therefore, it is likely to be underrecognized as a clinical entity. We report a fatal case of TRALI following an FFP transfusion from a frequent plasma donor. Prior transfusions from this frequent plasma donor had not been reported to the regional blood center as causing any transfusion reactions.

A 54-year-old man was given FFP for reversal of coumadin effect prior to elective knee surgery. Approximately 45 minutes after initiation of the FFP transfusion, the patient experienced respiratory arrest. He died 6 hours later despite aggressive attempts at cardiopulmonary resuscitation.

The blood donor, whose blood component was implicated in this reaction, was a 54-year-old woman who had made 290 previous donations. She had had 3 pregnancies, resulting in 2 births and 1 abortion. The donor's plasma was found to be strongly positive for granulocyte 5b antibody. Although the granulocyte-specific 5b antigen is present in more than 90% of whites,16 this was the first time this donor was implicated in a case of TRALI, despite more than 15 years of frequent donation. The donor was permanently deferred from future donations. During the transfusion-related fatality investigation, the Food and Drug Administration (FDA) investigator requested that we perform a look-back study to determine if previous recipients of this donor's blood components had experienced TRALI or other transfusion reactions.

All donations made by the implicated donor in the 2 years prior to the fatality were investigated. Transfusion service medical directors at the facilities that transfused the donor's FFP units were asked to perform chart reviews, including review of both physicians' and nurses' notes, to determine if any other recipients had an adverse reaction to this donor's blood components. They were asked to determine and report if the recipients experienced fever, chills, hypotension, dyspnea, pulmonary edema, ARDS, or any other untoward event within 6 hours of transfusion.

Reactions were classified as either mild/moderate or severe. Mild/moderate reactions consisted of dyspnea with fever, chills, hypotension and/or oxygen desaturation, but without documented evidence of acute pulmonary edema or need for mechanical ventilation. Severe reactions were defined as any reaction with clinical or radiographic evidence of acute pulmonary edema and/or need for mechanical ventilation within 6 hours of transfusion. Recipients were excluded from the analysis if their underlying clinical condition prevented the reviewer's ability to determine if a symptomatic reaction was related to the transfusion. These preexisting conditions included pulmonary edema, ARDS, or rapidly deteriorating clinical status resulting in efforts of cardiopulmonary resuscitation prior to transfusion of the blood component.

The donor made 73 donations (72 plasmaphereses and 1 whole blood) in the 2 years prior to her deferral. A total of 54 patients received 63 blood products from this donor. The remaining components were either quarantined when the donor was deferred or not transfused for other reasons. Underlying illness prevented evaluation for evidence of TRALI following transfusion in 14 patients. Charts were unavailable for review in 4 patients.

Of the 36 patient charts that could be evaluated, 13 (36.1%) indicated a transfusion reaction. The clinical scenarios of the patients identified as having had a transfusion reaction are presented in Table 1. All reactions were temporally associated with an infusion of FFP. Seven mild/moderate reactions were identified in 6 (16.7%) recipients. Severe reactions were reported in 8 (22.2%) recipients. Of the 5 patients who received multiple transfusions from this donor, 2 experienced 2 reactions each: 1 had 2 mild/moderate reactions, and the other had both a mild/moderate and a severe reaction. Seven (46.7%) of the 15 reactions (5 of 7 mild/moderate, 2 of 8 severe) were reported to the hospital's transfusion service. Only 2 reactions (13.3%) were reported to the blood collection facility: one was the fatality and the other was a mild/moderate reaction that occurred while the fatality was under investigation.

Table Graphic Jump LocationTable. Clinical Scenarios of 15 Transfusion-Related Acute Lung Injuries Among 13 Patients*

Our findings suggest that TRALI is frequently not diagnosed. Lack of recognition of this syndrome can result in inappropriate treatment, as well as failure to report the reaction to the transfusion service and the blood collection facility. Lack of recognition of TRALI and its reporting in this series of cases led to numerous reactions and, ultimately, a fatality that might have been prevented.

TRALI should be included in the differential diagnosis of respiratory distress (with or without pulmonary edema or ARDS) in the setting of blood and component transfusions. To underscore this point, the FDA recently issued an advisory to alert physicians to the characteristics and morbidity of TRALI.17 We recommend that respiratory symptoms occurring within 2 hours of a transfusion, particularly when combined with fever or hypotension, should be reported to the transfusion service as a possible case of TRALI. An evaluation may then be undertaken and advice regarding treatment provided. Additionally, all confirmed cases of TRALI (both fatal and nonfatal) should be reported to the FDA.17

Our investigation was performed at the request of the FDA and was not designed as a prospective clinical study. Therefore, we did not assemble a matched control group for comparison of rates. However, the general rate of transfusion reactions is approximately 1%.18 The hospital that received the most components involved in our study had transfused 51 792 blood components, which resulted in 229 documented transfusion reactions (0.44%) during the selected 2-year period. The reaction rate in our series of FFP transfusions is much higher. We are unable to determine if plasma transfusions from the implicated donor had a negative impact on the clinical course of the patients who were excluded from the analysis because of the complexity of their underlying illness. We may have thus underestimated the rate of TRALI, since severely ill patients may be especially predisposed to develop it.4

Although donor antibodies to white blood cells may be found in about 70% of cases of TRALI,2 they are of uncertain significance when infused to recipients who do not display signs of TRALI. It is not clear whether a case of TRALI represents an isolated event, or whether an implicated donor (with white blood cell antibodies) can cause multiple cases of TRALI. Our study suggests that donors with leukocyte antibodies who are implicated in a case of TRALI may represent a future transfusion hazard. These findings also support performing a routine look-back investigation if a donor's blood components are implicated in a TRALI case. The results of a look-back investigation can be used to learn more about this disorder and to determine if reactions are being underdiagnosed and unreported.

TRALI appears to have a spectrum of clinical presentation. Although more than 90% of recipients would be expected to be capable of reacting to granulocyte 5b antibody due to presence of the antigen on their leukocytes, we found only 36% had clinical evidence of a reaction. Prior authors made the diagnosis of TRALI only if there was evidence of pulmonary edema.2 Our look-back investigation at recipients of blood components from a donor with a granulocyte antibody suggests that TRALI may also present with symptoms that are more subtle. Approximately half of the cases we identified were less severe and involved dyspnea and oxygen desaturation but no pulmonary edema or ARDS.

TRALI has been estimated to occur about once in 5000 transfusions.2,19 A recent report suggests it may be higher.20 The only way to obtain the true frequency of TRALI is to both recognize and report cases to transfusion services and blood collection facilities. Diagnosis and reporting of this syndrome would allow for appropriate treatment and prevent additional reactions in other recipients. Permanent deferral of all future donations may sometimes be warranted. Look-back investigations may provide insight into why some recipients experience severe TRALI with pulmonary edema while others have less severe reactions.

Kopko PM, Holland PV. Transfusion-related acute lung injury.  Br J Haematol.1999;105:322-329.
Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury.  Transfusion.1985;25:573-577.
Kopko PM, Popovsky MA, MacKenzie MR.  et al.  Human leukocyte antigen class II antibodies in transfusion-related acute lung injury.  Transfusion.2001;41:1244-1248.
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;37:719-726.
Brittingham TE. Immunologic studies on leukocytes.  Vox Sang.1957;2:242-248.
Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG.  Transfusion.2001;41:264-268.
Boshkov LK, Mehdizadehkashi Z, Alcorn J.  et al.  Failure to implicate anti-granulocyte or anti-HLA class I or class II antibodies as the major pathogenetic mechanism in a series of transfusion-associated acute lung injury cases (TRALI).  Blood.2001;98:828A.
Payne R. The development and persistence of leukoagglutinins in parous women.  Blood.1962;19:411-424.
McCullough J, Clay M, Hurd D.  et al.  Effect of leukocyte antibodies and HLA matching on the intravascular recovery, survival, and tissue localization of 111-indium granuloctyes.  Blood.1986;67:522-528.
Seeger W, Schneider U, Kreusler B.  et al.  Reproduction of transfusion-related acute lung injury in an ex vivo lung model.  Blood.1990;76:1438-1444.
Popovsky MA, Haley NR. Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity.  Immunohematology.2000;16:157-159.
Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985.  Transfusion.1990;30:583-590.
Levy GJ, Shabot MM, Hart ME, Mya WW, Goldfinger D. Transfusion-associated non-cardiogenic pulmonary edema.  Transfusion.1986;26:278-281.
O'Connor PC, Erskine JG, Pringle TH. Pulmonary oedema after transfusion with fresh frozen plasma.  Br Med J (Clin Res Ed).1981;282:379-380.
Hashim SW, Kay HR, Hammond GL, Kopf GS, Geha AS. Non-cardiogenic pulmonary edema after cardiopulmonary bypass: an anaphylactic reaction to fresh frozen plasma.  Am J Surg.1984;147:560-564.
Van Leeuwen A, Eernise JG, Van Rood JJ. A new leukocyte group with two alleles: leukocyte group five.  Vox Sang.1964;9:431-437.
 Transfusion-related Acute Lung Injury.  Rockville, Md: Food and Drug Administration, Center for Biologics Evaluation and Research; 2001. Available at: http://www.fda.gov/cber/ltr/trali101901.htm. Accessibility verified March 22, 2002.
Menitove J. Complications of blood transfusion. In: McClatchey KD, ed. Clinical Laboratory Medicine. Baltimore, Md: Williams & Wilkins; 1994:1783-1799.
Ausley MB. Fatal transfusion reactions caused by donor antibodies to recipient leukocytes.  Am J Forensic Med Pathol.1987;8:287-290.
Clarke G, Podiosky L, Petrie L.  et al.  Severe respiratory reactions to random donor platelets: an incidence and nested case-control study.  Blood.1994;84(S1):465.

Figures

Figure. Posttransfusion Chest Radiograph of Bilateral "White Out" Consistent With Pulmonary Edema
Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Clinical Scenarios of 15 Transfusion-Related Acute Lung Injuries Among 13 Patients*

References

Kopko PM, Holland PV. Transfusion-related acute lung injury.  Br J Haematol.1999;105:322-329.
Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury.  Transfusion.1985;25:573-577.
Kopko PM, Popovsky MA, MacKenzie MR.  et al.  Human leukocyte antigen class II antibodies in transfusion-related acute lung injury.  Transfusion.2001;41:1244-1248.
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;37:719-726.
Brittingham TE. Immunologic studies on leukocytes.  Vox Sang.1957;2:242-248.
Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG.  Transfusion.2001;41:264-268.
Boshkov LK, Mehdizadehkashi Z, Alcorn J.  et al.  Failure to implicate anti-granulocyte or anti-HLA class I or class II antibodies as the major pathogenetic mechanism in a series of transfusion-associated acute lung injury cases (TRALI).  Blood.2001;98:828A.
Payne R. The development and persistence of leukoagglutinins in parous women.  Blood.1962;19:411-424.
McCullough J, Clay M, Hurd D.  et al.  Effect of leukocyte antibodies and HLA matching on the intravascular recovery, survival, and tissue localization of 111-indium granuloctyes.  Blood.1986;67:522-528.
Seeger W, Schneider U, Kreusler B.  et al.  Reproduction of transfusion-related acute lung injury in an ex vivo lung model.  Blood.1990;76:1438-1444.
Popovsky MA, Haley NR. Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity.  Immunohematology.2000;16:157-159.
Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985.  Transfusion.1990;30:583-590.
Levy GJ, Shabot MM, Hart ME, Mya WW, Goldfinger D. Transfusion-associated non-cardiogenic pulmonary edema.  Transfusion.1986;26:278-281.
O'Connor PC, Erskine JG, Pringle TH. Pulmonary oedema after transfusion with fresh frozen plasma.  Br Med J (Clin Res Ed).1981;282:379-380.
Hashim SW, Kay HR, Hammond GL, Kopf GS, Geha AS. Non-cardiogenic pulmonary edema after cardiopulmonary bypass: an anaphylactic reaction to fresh frozen plasma.  Am J Surg.1984;147:560-564.
Van Leeuwen A, Eernise JG, Van Rood JJ. A new leukocyte group with two alleles: leukocyte group five.  Vox Sang.1964;9:431-437.
 Transfusion-related Acute Lung Injury.  Rockville, Md: Food and Drug Administration, Center for Biologics Evaluation and Research; 2001. Available at: http://www.fda.gov/cber/ltr/trali101901.htm. Accessibility verified March 22, 2002.
Menitove J. Complications of blood transfusion. In: McClatchey KD, ed. Clinical Laboratory Medicine. Baltimore, Md: Williams & Wilkins; 1994:1783-1799.
Ausley MB. Fatal transfusion reactions caused by donor antibodies to recipient leukocytes.  Am J Forensic Med Pathol.1987;8:287-290.
Clarke G, Podiosky L, Petrie L.  et al.  Severe respiratory reactions to random donor platelets: an incidence and nested case-control study.  Blood.1994;84(S1):465.
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