Transfusion-Associated Lung Injury (TRALI)

What is TRALI?

TRALI is a syndrome characterized by the development of non-cardiogenic pulmonary edema with hypoxia during or up to 6 hours after a blood transfusion.

Table 1. Recommended Criteria for TRALI and Possible TRALI 1. TRALI criteria a. ALI (Acute lung injury) i. Acute onset ii. Hypoxemia Research Setting: PaO2/FiO2 < 300 or SPO2 90% on RA Nonresearch setting: PzO2/FiO2 < 300 or SPO2 < 90% on RA or other clinical evidence of hypoxemia iii. Bilateral infiltrates on frontal CXR iv. No evidence of left atrial hypertension (i.e., circulatory overload) b. No preexisting ALI before transfusion c. During or within 6 hrs of transfusion d. No temporal relationship to an alternative risk factor for ALI 2. Possible TRALI a. ALI b. No preexisting ALI before transfusion c. During or within 6 hrs of transfusion d. Clear temporal relationship to an alternative risk factor for ALI *See Reference 1.

Based on recommendations from the Consensus Conference held in Toronto Canada in April 2004 the definition and criteria for TRALI are presented in Table 1. 

What are the clinical features of TRALI?

The diagnosis of TRALI should be based on clinical and radiologic findings. Frequent presenting signs and symptoms include: dyspnea, hypoxemia, bilateral pulmonary edema, and fever (1-2ºC rise). Other reported findings have been hypotension and tachycardia. Characteristic chest X-rays show pulmonary infiltrates, usually bilateral with alveolar and/or interstitial patterns without evidence of cardiac enlargement or other evidence of fluid overload. 

TRALI should be diagnosed with caution when pulmonary edema can be explained by an alternative etiology (e.g., myocardial damage, valvular heart disease, or volume overload) or when there is a co-existing risk factor for acute lung injury (ALI). Risk factors for ALI may include septic shock, aspiration, pneumonia, inhalation injury, lung contusion, multiple trauma, burn injuries, cardiopulmonary bypass, and acute pancreatitis. Other causes of dyspnea (pulmonary embolus, severe allergic reaction) should also be excluded.

How soon after transfusion do the symptoms occur?

Symptoms typically begin within 1 to 2 hours of the transfusion, but can occur up to 6 hours after transfusion. 

What is the management and outcome in patients with TRALI?

The management of a patient with suspected TRALI is supportive: oxygen and ventilation support for the degree of hypoxia present and fluid administration for hypotension may be beneficial in some patients. Diuretics are not effective in treating TRALI, as the edema is from microvascular injury, not volume overload. 

Most cases begin to show clinical improvement within the first few hours of onset and generally resolve completely within 24-96 hours. Infiltrates resolve within 96 hours in about 80% of affected patients but may persist for 7 days or more. Mortality has been reported to be 6-23%, highlighting the importance of early recognition. 

What blood components are implicated in TRALI?

All blood products have been associated with TRALI. Plasma content appears to be associated with increased risk. As such, FFP is the most frequently implicated blood product, followed by platelets and RBCs. 

What is the incidence of TRALI?

The incidence of TRALI is not well delineated. It is believed that a number of cases are underreported or misdiaganosed, since many physicians are unfamiliar with the entity. The estimated risk ranges from 1 in 2,000 to 1 in 25,000 transfusions. In the most recent data on FDA reported deaths following blood transfusion, TRALI is now the most common cause, representing 16.3% of all such deaths. Approximately 16 fatal cases of TRALI have been reported each year to FDA for years 2001-2004. 

What are the possible causes of TRALI?

The causes of TRALI are not well understood. Two mechanisms: (1) antibodies to white blood cell antigens (HLA, granulocyte and monocyte) and (2) biologically active lipids are thought to be involved in the pathogenesis of TRALI. In the first mechanism it is theorized that white blood cell antibodies present in the donor’s plasma bind to the white cells of the recipient, resulting in activation and aggregation of the white cells and adhesion to the capillary endothelium of the lung. Complement activation and release of biologic response modifiers results in capillary leak and noncardiogenic pulmonary edema.

In the second mechanism blood products produce bioactive lipids during storage. These biologically active lipids either prime neutrophils that are then activated by a second factor (sepsis, trauma, MOF) causing release of harmful biologic response modifiers resulting in endothelial damage and pulmonary edema, or act as a secondary factor causing activation of already primed neutrophils, the so-called “two-hit” model of TRALI pathogenesis. Further studies are required to clearly elucidate the exact mechanism of TRALI. 

What should I do if I suspect TRALI in one of my patients?

After your patient is stabilized, immediately notify the hospital Transfusion Service. Because the diagnosis of ALI can be difficult and may be due to an alternative cause, it is important that there be communication between the patient’s physician and Transfusion Service physician. After discussion and review of the patient’s chart, if TRALI or possible TRALI is suspected, the Transfusion Service Medical Director will begin the process for suspected TRALI investigation and notify BloodCenter of Wisconsin. The investigation is not considered diagnostic but rather assists in identifying and deferring implicated donors involved in TRALI reactions, possibly preventing TRALI in future recipients. If your patient has suffered a fatal reaction thought to be TRALI, federal regulations require Transfusion Services to notify the FDA within 24 hours. Therefore such cases should be reported to the Transfusion Service as soon as possible after they occur. 

What testing will typically be done for a suspected TRALI investigation?

Samples from the patient will be collected for HLA typing and a serum sample set aside for possible HLA antibody testing. Ordering and collection of patient samples will be done under the direction of the Transfusion Service physician. Testing will be performed at BloodCenter of Wisconsin. 

The associated donors are interviewed and those with a history of pregnancy and/or transfusion will be tested for HLA and granulocyte antibodies. If HLA or granulocyte antibody is identified, correlation with the typing of the recipient is done to help determine if a donor is implicated in the suspected TRALI. Since donors are asked to return for collection of blood samples, testing and interpretation of results may take up to 10 weeks to complete. The results of the findings will be forwarded to the Transfusion Service physician and copies sent to the attending physician(s). 

Does the patient who has had TRALI require any special blood products for future transfusions?

Since TRALI is thought to be due to factors in a particular donor’s plasma, the patient may be transfused as necessary without change in transfusion practice or need for modification of the blood products. 

References:

1. Kleinman S et al. Toward an understanding of transfusion-related acute lung in injury: statement of a consensus panel. Transfusion 2004;44:1774-1789.
2. Goldman M et al. Proceedings from a consensus conference: towards an understanding of TRALI. Transfusion Med Rev 2005;19:2-31.
3. AABB Association Bulletin #05-09, Issued August 11, 2005.