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Transfusion Related Acute Lung Injury (TRALI)

Transfusion-related acute lung injury (TRALI) is a clinical syndrome that presents as acute hypoxemia and noncardiogenic pulmonary edema within 6 hours after completion of a transfusion of one or more plasma containing blood components, which is not temporally related to another cause of acute lung injury such as pneumonia, gastric aspiration, toxic inhalation, sepsis, shock, and cardio-pulmonary bypass. Today, TRALI is the most frequent cause of transfusion-related death reported to the FDA.

Etiology: Substantial circumstantial evidence indicates that the majority of cases of TRALI are caused by transfusion of plasma containing leukocyte antibodies. Many recipients who develop TRALI have received a donor unit containing antibodies directed against an antigen present on their leukocytes. Anti-HLA Class II antibodies are most commonly found in blood from female multiparous donors and are most commonly associated with TRALI cases. Anti-HNA, especially anti-HNA-3a, antibodies have been detected in severe TRALI cases but are less common overall. Anti-HLA Class I antibodies are generally not associated with TRALI.

A transfusion of as little as 10 to 20 mL of plasma containing high titer multispecific antibodies has been associated with TRALI. The highest frequency of leukocyte antibodies is found in female donors who have previously been pregnant. Overall, about 15 to 20% of female donors have HLA antibodies compared to <1% of male donors. No one has determined why the incidence of TRALI has been so much lower than the prevalence of antibody in transfused blood.

Several years ago, investigators from the United Kingdom (UK) Serious Hazards of Transfusion (SHOT) system determined that the rate of TRALI occurrence was 5 to 7-fold greater for blood components that contained high volumes of plasma such as FFP and platelets than for packed red blood cells. This data also showed that the majority of TRALI cases involved a leukocyte antibody-positive female donor. On the basis of the SHOT analysis, the UK adopted a policy to minimize the transfusion of FFP and platelets from female donors. Since the implementation of this policy in October 2003, the number of TRALI cases has decreased from 20 per year to 3.

American Red Cross analyzed cases of fatal TRALI reported between 2003 and 2005. Retrospective review of fatalities revealed 38 cases of probable TRALI, the majority of which (24 of 38) followed plasma transfusion. A female leukocyte antibody-positive donor was involved in 75% of cases involving plasma and in 60% of cases involving apheresis platelets.

Patients at greatest risk of developing TRALI include those who have undergone recent surgery, induction chemotherapy, cardiopulmonary bypass, massive transfusion, plasma exchange for TTP, or have recently aspirated gastric contents or developed sepsis.

All blood components containing plasma have been implicated in TRALI cases, but the greatest risk is associated with those components containing the largest volume of plasma such as plasma, platelets and cryoprecipitate.

The National Healthcare Safety Network (NHSN) hemovigilance protocol defines TRALI as:

• No evidence of acute lung injury prior to transfusion AND
• Acute lung injury onset during or within 6 hours of cessation of transfusion AND
• Hypoxemia defined by any of these methods:
  • PaO2/FiO2 les than or equal to 300 mm Hg
  • Oxygen saturation less than 90% on room air
  • Other clinical evidence AND
• Radiographic evidence of bilateral infiltrates AND
• No evidence of circulatory overload

Other causes of acute lung injurt include:

 

The most frequently observed findings in TRALI cases include dyspnea, tachypnea, cyanosis, fever, tachycardia, hypotension or hypertension, froth in endotracheal tube, and mechanical ventilation required to support oxygenation. TRALI in thrombocytopenic stem cell transplant patients with recovering neutrophils may be diagnosed as diffuse alveolar hemorrhage.

Consequences: Between 6 and 10% of cases are fatal. TRALI must be recognized promptly and treated appropriately. The patient’s physician should be notified immediately.

Prevention: AABB has recommended that all blood collecting facilities take steps to minimize the preparation of high plasma-volume components from donors known to be at increased risk of leukocyte alloimmunization. Accordingly, blood centers have begun supplying FFP from only male donors. They also had to implement a plan to reduce the risk from apheresis platelets from female donors by November 2008. This plan may include collecting platelet pheresis from male donors only or male donors and nulliparous female donors. Alternatively, donors may be tested for HLA and granulocyte antibodies.

The blood center supplying a unit implicated in a TRALI case should be notified so that the donor plasma can be tested for leukocyte antibody. Donors testing positive will be permanently deferred from future donations. Patients who develop TRALI are unlikely to have another reaction because it is most often donor specific.

Lab Data: Investigation of a suspected TRALI case

1. Adverse reaction is reported to hospital Transfusion Service
2. Medical Director of Transfusion Service determines if the adverse reaction meets the criteria for diagnosis of TRALI. Other adverse reactions to transfusion may produce similar signs and symptoms. The differential diagnosis includes:

• Transfusion associated circulatory overload (TACO)
• Severe allergic or anaphylactic reactions
• Bacterial contamination
• Acute hemolytic reaction, usually secondary to ABO incompatibility
• Acute event unrelated to transfusion; myocardial infarction, pulmonary embolism, sepsis, pneumonia

3. Transfusion service will retrieve a sample of blood from the patient as close as possible to the onset of TRALI.
4. Hospital transfusion service notifies the blood center. Testing for antibodies to HLA class I & II and human neutrophil antigens (HNA) should be confined to donors whose components were transfused within 6 hours preceding the onset of TRALI. The most likely candidates include:
   1. Donors whose components were administered closest to TRALI onset
   2. Donors of plasma>platelets>cryoprecipitate>red blood cells
   3. Donors who are multiparous females>other females>male donors
5. If antibody is detected, its specificity for the recipients’ WBC antigens can be determined by either determining the HLA and HNA type of the recipient or performing a crossmatch of donor serum with recipient’s WBCs.
6. A donor that is implicated in TRALI will be permanently deferred from future donation.
7. When ALI is temporally related to both transfusion and at least one of these other risk factors, the reaction should be classified as possible TRALI.
8. Fatal cases of TRALI must be reported to FDA and nonfatal cases to MedWatch.
9. Patients with TRALI usually have a normal BNP and may have transient leucopenia.

TRALI cases associated with antibody in the recipient reacting with donor WBCs are rare and usually occur after transfusion of nonleukocyte reduced units. Because of their low frequency and the frequent use of universal leukocyte reduction, these cases do not require laboratory confirmation. Testing would not influence donor management.

Treatment: The transfusion should be stopped. Symptomatic support includes oxygen administration and possibly intubation with mechanical ventilation. Diuretics are not useful in treatment of TRALI because the underlying pathology involves microvascular injury, rather than fluid overload. Corticosteroids are often used empirically but their effectiveness has not been proven.