TRANSFUSION-RELATED ACUTE LUNG INJURY (“TRALI”)

Marcus B. Simpson, M.D.
Medical Director, Centralized Transfusion Service

INTRODUCTION

Acute pulmonary edema has been recognized for many years as a complication of transfusion therapy. Over the past two decades, however, a growing body of evidence has demonstrated that many of these cases are due, not to fluid overloading, but to an inflammatory insult to the pulmonary microvasculature. Known as “Transfusion-Related Acute Lung Injury” or “TRALI”, this syndrome of acute respiratory distress was formerly dubbed “non-cardiogenic pulmonary edema” – a descriptive term that succinctly notes the more apparent clinical features.  TRALI has been increasingly recognized in recent years as a significant cause of morbidity and mortality in transfusion therapy. Reports to the Food and Drug Administration from 1976 to 1998 reveal acute pulmonary edema as the third most common cause of transfusion-related fatality, representing about 13 % of such cases and ranking behind hemolysis and bacterial contamination in frequency. Due to their clinical similarities, TRALI can easily be confused with volume-related pulmonary edema. This diagnostic error could adversely affect the patient’s clinical management, because the therapeutic strategies are quite different for the two entities.

CLINICAL FEATURES

TRALI is a clinical constellation of symptoms that includes severe dyspnea, hypotension, tachycardia, and fever, usually with accompanying rigors. The reaction typically begins by 1 to 2 hours after starting the transfusion and becomes fully manifest within 6 hours. Patients may show cyanosis and severe hypoxemia, with arterial oxygen tensions as low as 30 torr, and clinical findings initially indistinguishable from adult respiratory distress syndrome (ARDS). Classic radiologic features include bilateral pulmonary “white out” due to interstitial and alveolar infiltrates, but with no evidence of cardiac decompensation or fluid overload. In the early stages, CXRs may show patchy infiltrates involving the lower lung fields, but the edema soon spreads to the entire lung.

Most TRALI patients have no previous history of transfusion reactions and no particular disease association. The male:female ratio is 1:1, and the age of reported patients ranges from 1 month to 90 years. The frequency of TRALI is estimated at 0.014 percent to 0.02 percent of units transfused and from 0.04 percent to 0.16 percent of patients transfused.

IMPLICATED PRODUCTS

Fresh Frozen Plasma (FFP) is the most commonly implicated component in TRALI reactions. Other cases have involved whole blood, red blood cells, platelet concentrates, apheresis platelets, granulocyte concentrates, cryoprecipitate, and IVIG. To date there are no reports involving washed red cells, deglycerolized frozen red cells, albumin, or plasma protein fraction. Although TRALI cases have typically been seen with components having plasma volumes greater than 50 mL, reactions may also occur with smaller volumes of transfused blood, as with cryoprecipitate, where less than 15 to 20 mL are involved.

DIFFERENTIAL DIAGNOSIS

At the time of the reaction, the diagnosis is mostly a process of exclusion. Lab findings are generally not helpful until later, when serologic testing of the implicated donors may reveal anti-leukocyte antibodies. Three diagnoses are most often considered: 

Pulmonary edema (volume overload or CHF):

TRALI is most frequently mistaken for pulmonary edema attributed to congestive heart failure or to intravascular volume overloading. In contrast to TRALI, congestive heart failure and fluid overload are more likely to show arterial hypertension, elevated central venous pressure, elevated pulmonary capillary wedge pressure, a vascular pattern of pulmonary edema, and an enlarged cardiac shadow on CXR. Classic TRALI cases demonstrate normal to decreased pulmonary capillary wedge pressure, normal pulmonary artery pressure, absence of jugular venous distention, absence of murmurs or gallops, a normal cardiac silhouette on CXR, and systemic hypotension. Fever and chills are more frequently present in TRALI than in volume overloading.

 

Bacterial contamination:

The clinical onset is usually much more rapid and dramatic, with high fever, severe rigors, and profound hypotension, while respiratory symptoms are usually less prominent.  Gram stain of the bag contents may provide rapid diagnosis.

Allergic/anaphylactic reactions:

Fever and chills are usually absent or minimal in anaphylactic reactions, which are often characterized by sudden and profound hypotension. The radiographic picture typically shows little or no pulmonary edema, and clinically the respiratory distress is due to bronchospasm and laryngeal edema.

 

CLINICAL MANAGEMENT
 

Clinical management is largely supportive. Prompt and aggressive attention to oxygenation and to maintenance of blood volume is critical. In most series, 100 % of patients received oxygen administration, usually for at least two days following onset of symptoms. Approximately three out of four patients also require mechanical ventilation support to ensure adequate respiratory function. Because TRALI is due to microvascular pulmonary injury and not to volume overload, diuretics are not indicated. Inducing diuresis may, in fact, be harmful due to exacerbating volume depletion and thereby worsening the hypotension that commonly occurs in TRALI. Steroids have generally been considered ineffective.

PROGNOSIS

The overwhelming majority of TRALI cases survive with oxygen support and mechanical ventilation. Unlike ARDS, which has mortality rates of 40 to 50 % and permanent sequellae in many who recover, TRALI is classically associated with mortality rates ranging from 5 % to 13 % and with no residual pulmonary damage in survivors. Complete resolution typically occurs in 48 to 96 hours, although about one case in five may have pulmonary infiltrates that persist for up to a week after the reaction.

PATHOPHYSIOLOGIC MECHANISMS

The etiology of TRALI has not been unequivocally delineated, but most cases are attributed to anti-leukocyte antibodies in the donor plasma of infused units. These donor antibodies react with the patient’s leukocytes, which become sequestered in the pulmonary microvasculature. Subsequent complement activation and cytokine production cause local damage to the alveolar endothelium. The increased vascular permeability permits fluid leakage into the interstitium and alveolar sacs, leading to severe pulmonary edema. Donor anti-leukocyte antibodies have been reported in 65 to 85 % of reported cases; in the remainder, the antibodies are found in the recipient or cannot be demonstrated in either the donor or the patient. Rare cases have been attributed to interdonor reactions. Most reports implicate multiparous donors, who are more likely than other donor groups to have anti-leukocyte antibodies. Antibody specificities may involve HLA class I or class II antigens and/or granulocyte-specific antigens, such as NA2, NB2, or 5b.

TRALI does not occur in all patients who receive transfusions containing anti-leukocyte antibodies against the corresponding antigen in the recipient, indicating that additional factors may be important. Underlying inflammatory conditions in the patient (e.g.: infection, trauma, or surgery) and biologically active lipids in the infused units may play a role in priming the patient’s leukocytes, thereby making them susceptible to activation when exposed to anti-leukocyte antibodies.

PREVENTION

TRALI is most widely attributed to anti-leukocyte antibodies in donor plasma; proposed strategies to prevent this complication have focused on eliminating high-risk donors or restricting components from such donors to plasma-free products, such as washed red cells. Recognized high-risk donor groups include multiparous women in particular, as well as transfused donors and those implicated in previous TRALI reactions. Currently accepted strategies involve reporting TRALI cases to the blood donor center for evaluation and follow-up testing of donors. Additional considerations are to avoid using the biological mother as the donor for one of her children. Leukoreduction of blood components may be appropriate for patients whose reactions appear to be due to recipient anti-leukocyte antibodies.

REPORTING

Patients in whom TRALI is suspected should be reported to the hospital blood bank after evaluation by the transfusion medicine physician, the details of any suspected TRALI event should be reported to the donor center or manufacturer that supplied the implicated units or products. Associated components should be recalled.  Fatalities must be reported to the FDA within 24 hours, with the final report due in 7 days. Non-fatal reactions should be reported to MedWatch:

REFERENCES

1.  Kopko PM, Popovsky MA, MacKenzie MR, et al. Transfusion 2001; 41:1244-1248.

2.  Popovsky MA. Transfusion Reactions. Bethesda: AABB Press, 2001; 155-70.

3.  Popovsky MA, Davenport RD. Transfusion 2001; 41:312-5.

4.  Rizk A, Gorson K, Kenny L, et al. Transfusion 2001; 41:264-268.

5.  Silliman, CC. Transf Med Rvws 1999; 13:177-86.

           Copyright © 2001, The Institute For Transfusion Medicine