In light of increased reports of transfusion-related acute lung injury (TRALI) deaths over the last several years, members of the blood community and the Food and Drug Administration (FDA) have been working to establish a uniform definition for the diagnosis of TRALI. Adoption of a uniform definition would facilitate more meaningful research and clinical understanding of the condition.

The need to improve identification and prevention strategies for TRALI is becoming more important as reports of fatalities from TRALI have dramatically increased since 1992, when the syndrome was first identified. In 2003, TRALI was the single most commonly reported cause of transfusion deaths, according to Leslie Holness, MD, a medical officer in the Division of Drug Applications, Center for Biologics Evaluation and Research, FDA. Speaking before FDA's Blood Products Advisory Committee (BPAC), Holness said the majority of TRALI deaths have been associated with transfusion of Fresh Frozen Plasma (FFP), followed by Red Blood Cells (RBCs) and apheresis Platelets.

Part of the difficulty in crafting a uniform definition is that, according to FDA, TRALI comprises a "clinical constellation" of symptoms, including dyspnea, fever and hypotension occurring within six hours of transfusion. There is no consensus in the literature on the exact cause of the syndrome, its triggering mechanisms, or clinical or laboratory diagnosis. However, at a recent Canadian Consensus Conference on TRALI, experts generally agreed that there appears to be good evidence for at least two major pathophysiological mechanisms leading to the condition. One involves antibodies to leukocytes and the other involves biologically active mediators.

Other statements from the conference's 11-member consensus panel were:

The magnitude of the risk of TRALI to recipients of blood products is unknown at this time. Estimates range from 1 in 5,000 to 1 in 100,000 transfused components. The panel will look at possible processes to help define the magnitude of the TRALI risk. There is insufficient evidence at this time to recommend implementation of any specific laboratory screening test and/or other deferral measure be implemented to exclude groups of donors in order to reduce the risk of TRALI. However, the panel is considering various options that could be used for the management of donors associated with a TRALI episode. A suggested definition for TRALI will be published in early 2005, which may serve as a basis for an internationally accepted consensus definition. (For more information on the conference, see the May 21, 2004, issue of Weekly Report).

In general, the panel recommended that TRALI should be diagnosed in patients with no acute lung injury (ALI) prior to transfusion who, during or within six hours after transfusion, experienced certain specific criteria. The panel distinguished "possible TRALI" cases, which would involve patients with the same criteria who also had one or more temporally associated ALI risk factors. AABB endorsed the proposed definition (which is now under modification) and urged FDA to adopt the panel's definition as well.

Donor management strategies

Holness said FDA is considering three possible regulatory actions if supported by adequate scientific data:

1. Diversion of plasma from female donors to components other than FFP. Female donors, especially those who have been pregnant, may be implicated in TRALI. Such women are more likely than men to have anti-human leukocyte antigen (HLA) and/or anti-granulocyte antibodies in their plasma. This strategy has been implemented in the United Kingdom, according to FDA, with an estimated 7 percent loss of donated plasma. FDA noted that in addition to the problem of shortages in some areas, this approach would only reduce TRALI in FFP and would ignore the volumes of plasma in other components.

2. Preventative HLA and granulocyte antibody testing, and/or questioning of female donors on parity (number of pregnancies) followed by plasma product diversion and washing of RBCs from donors at increased risk. FDA pointed out several issues with this strategy:

• Sample preparation and testing has not been standardized;
• Antibodies may not be found in 15 percent of cases;
• It is not known whether all antibodies to white blood cell antigens are equally likely to cause TRALI; and
• Antibody positive donors may not cause TRALI in every recipient.

3. Deferral of donors involved in a single unit or more than one multiple unit case of TRALI regardless of antibody status. However, this strategy would allow the first case of TRALI to occur before preventative measures are taken, and would be dependent on accurate case reporting.

AABB and other members of the blood community rejected these methods until further study can establish donor deferral criteria for TRALI. "It is important to understand what proportion of the donor population would be affected by proposed deferral criteria, so that the potential impact on the blood supply can be evaluated," said AABB Director of Regulatory Affairs Kay Gregory MS, MT(ASCP)SBB. "These data are especially critical, as we already too frequently face blood shortages in regions across the country."

Gregory's statement (July 22, 2004) to BPAC on behalf of AABB can be found by visiting the AABB Web site, under "Members_Area/Regulatory/Patient Safety." (Access limited to AABB members).