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* From the Departments of Pathology (Drs. Stowell and Sepehr) and Medicine (Dr. Abdel-Wahab), Massachusetts General Hospital, Boston, MA; and Division of Hematology and Medical Oncology (Dr. Darabi), Our Lady of Mercy Medical Center, Bronx, NY.
Correspondence to: Kamran Darabi, MD, Our Lady of Mercy Medical Center, Cancer Center, 600 East 233rd St, Bronx, NY 10466; e-mail: kamrandarabi{at}yahoo.com
An 87-year-old woman was taken to the emergency department of a nearby hospital for evaluation of confusion. The patient’s medical history was notable for hypertension, hyperlipidemia, COPD, and coronary artery bypass grafting. Echocardiography performed 2 weeks prior to hospital admission revealed an estimated ejection fraction of 59%, right ventricular dilation, diastolic and systolic interventricular septal flattening, stable severe tricuspid regurgitation, and no obvious ventricular wall motion abnormalities. In addition to coronary artery disease, the patient had a history of sick sinus syndrome for which a dual-chamber pacemaker had been placed 4 months prior. She was maintained on anticoagulation with warfarin, 3 mg/d, but had variable international normalized ratio values ranging from 1.0 to 3.3. The patient was a former smoker, and recent pulmonary function tests demonstrated FEV1 of 52% of predicted; FVC, 61% of predicted; FEV1/FVC ratio, 86% of predicted; total lung capacity, 113% of predicted; and residual volume, 180% of predicted.
Physical Examination
On initial physical examination in the emergency department, the patient was afebrile with a BP of 188/58 mm Hg and pulse rate of 64 beats/min. She had a respiratory rate of 12 breaths/min with an oxygen saturation of 98% as measured by pulse oximetry while breathing room air. She appeared well and was sitting up in bed, and was in no acute distress. She was alert, oriented, and able to answer questions meaningfully, and was no longer confused. The remainder of her neurologic examination was unremarkable. Her oral mucosa was dry, and her neck veins appeared flat. Her lungs were clear to auscultation bilaterally in the anterior and posterior dimensions. Her cardiac examination revealed a regular rate and rhythm with a II/VI holosystolic murmur along the lower-left sternal border. Her abdomen was soft and nontender without any organomegaly. She had no edema, and her extremities were warm with readily palpable pulses.
Laboratory Data and Radiographic Findings
The patient had a WBC count of 10.8 x 103/µL and a hematocrit of 27.4%, which was slightly decreased from her usual range of 29 to 33%. Her coagulation test results at hospital admission revealed a prothrombin time of 44.6 s and an international normalized ratio (INR) of 13.1. Her initial chest radiograph revealed no infiltrates or pleural effusions. Noncontrast head CT revealed no acute intracranial process.
Hospital Course
The patient was hydrated and empirically started on levofloxacin for cystitis. Her evening warfarin dose was withheld, and she was administered vitamin K, 10 mg subcutaneously, for an elevated INR of 13.1.
On the morning after hospital admission, a decision was made to transfuse the patient with 1 U of packed RBCs for a hematocrit of 25.8%. Before transfusion, her temperature was 98°C; BP, 132/60 mm Hg; pulse rate, 72 beats/min, and oxygen saturation, 97% (room air). After receiving approximately 200 mL of the unit of blood over 40 min, she became short of breath, confused, and agitated, and was initially found to be hypertensive to 200/100 mm Hg, with an oxygen saturation of 77% (3 L/min). On further examination, her lungs were clear but her oxygen saturation subsequently fell to approximately 65% despite breathing 100% oxygen. She was administered nitropaste to reduce her BP and 120 mg of furosemide to treat what was presumed to be flash pulmonary edema even though the initial posttransfusion chest radiograph (Fig 1 , top) was not consistent with pulmonary edema, nor were there crackles on physical examination. She was placed on continuous positive airway pressure, but shortly afterwards hemoptysis developed and she was intubated. A chest radiograph obtained just before intubation and 1.5 h after the initiation of the transfusion revealed the development of new patchy infiltrates (Fig 1, bottom). Given the elevated INR of 13.1 from her hospital admission laboratory work and the development of hemoptysis, she received transfusion with the first of 4 U of fresh frozen plasma. A CBC count performed at this time revealed a stable hematocrit but development of leukopenia, with WBC count of 2.0 x 103/µL (down from 10.8 x 103/µL earlier). The BP was 100/44 mm Hg without vasopressors; however, within minutes after transfer to the ICU, cardiac arrest developed and resuscitation was unsuccessful.
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Diagnosis: In the absence of other mechanisms to explain acute lung injury, a diagnosis of transfusion-related acute lung injury complicated by alveolar hemorrhage was made in a patient who was excessively anticoagulated.
Discussion
Transfusion-related acute lung injury (TRALI) is an uncommon, although probably underrecognized, complication of transfusion that is characterized by acute respiratory distress. It is a clinical diagnosis and as such has suffered from the application of varying definitions. Recently, however, an international consensus conference (Kleinman et al) and a National Heart, Lung, and Blood Institute Working Group (Toy et al) have established definitions of TRALI that should aid the clinician as well as bring some consistency to the literature. TRALI may be diagnosed when acute lung injury occurs during or within 6 h of transfusion in a patient without preexisting acute lung injury and in the absence of a temporally related alternative risk factor for acute lung injury (eg, sepsis, shock, cardiac failure). The international consensus definition of possible TRALI includes any event meeting the criteria for TRALI but in the presence of a temporally associated alternative risk factor for acute lung injury, whereas the National Heart, Lung, and Blood Institute criteria permit the clinician to make the determination whether the transfusion was mechanistically related to acute lung injury (hence, TRALI) or is merely coincidental (hence, not TRALI).
TRALI may present with a variety of symptoms including dyspnea, hypotension (or, less commonly, hypertension), fever, or a frothy endotracheal aspirate. Tachycardia and cyanosis are common symptoms as well. This constellation of findings usually occurs within 1 to 2 h of transfusion but may be delayed up to 6 h.
Diagnostic difficulties frequently lead to misdiagnosis and consequently underreporting of TRALI. The differential diagnosis of transfusion-associated respiratory distress also includes circulatory overload and hypersensitivity reactions with bronchospasm. Transfusion-associated circulatory overload usually occurs in the setting of preexisting cardiac pathology and may be signaled by jugular-venous distension or a prominent S3. If measured invasively, an elevated central venous pressure or pulmonary capillary wedge pressure may be present. Direct lung injury can also mimic TRALI and may be caused by aspiration, pneumonia, lung contusion, inhalation of toxins, or near-drowning. Indirect lung injury, which may be a byproduct of sepsis, shock, trauma, burns, cardiopulmonary bypass, or drug overdose, also must be differentiated from TRALI. Unfortunately, there are no laboratory tests that are very helpful in making the diagnosis. Transient leukopenia, which was noted in this patient, is occasionally observed and is believed to be due to sequestration of leukocytes in the pulmonary circulation.
Most patients with TRALI need supplemental oxygen, and many require mechanical ventilation. Although the process is usually completely reversible in 2 to 7 days, TRALI is sometimes fatal. Data from the Serious Hazards of Transfusion initiative in the United Kingdom showed that 18 of 70 confirmed cases (26%) of TRALI resulted in death (Williamson et al), although a mortality rate of 5 to 10% is usually cited based on a single study (Popovsky et al). In fatal cases, autopsy findings include histologic evidence of pulmonary edema, the presence of proteinaceous material within alveolar air spaces and interstitial tissues and, in severe cases, frank hemorrhage. Other microscopic findings include intravascular leukoagglutination in lung capillaries and widespread degranulation of granulocytes on ultrastructural analysis.
The estimates of the incidence of TRALI vary considerably, probably reflecting different clinical case definitions and underreporting. The Serious Hazards of Transfusion data from the United Kingdom showed an incidence of 70 confirmed cases per 16 to 17 million blood components transfused (Williamson et al). Others have reported an incidence of 1:1,000 to 1:20,000 blood components transfused or 1:625 patients transfused.
The pathophysiology of TRALI has not been completely elucidated. There are two hypotheses that are supported, at least in part, by clinical observations and studies in animal model systems. The antibody hypothesis postulates that TRALI is triggered by an antibody-antigen interaction. In many cases of TRALI, the donor unit has been found to contain antibodies against human leukocyte antigens (HLAs) that are believed to injure pulmonary endothelial cells either directly, or indirectly, by binding to circulating leukocytes, particularly neutrophils, causing their activation. Evidence for a direct effect of antibodies against HLA comes from a case of TRALI that occurred in a single transplanted lung with sparing of the patient’s native lung following the transfusion of blood with antibodies directed at HLA epitopes borne by the transplanted lung (Dykes et al). In the indirect injury model, activated neutrophils either adhere to the pulmonary endothelium or are agglutinated and trapped in the pulmonary microvasculature, where they release vasoactive and cytotoxic substances that induce endothelial leakage and damage. The antibody hypothesis is also supported by the observation that antibodies to class I or class II HLAs or human neutrophil antigens borne by the transfusion recipient are found in many donor units implicated in TRALI, although in approximately 10% of cases, they are present in the transfusion recipient and are presumed to react with passenger leukocytes in the transfused unit. However, a number of cases of apparent TRALI have been reported in which HLA or human neutrophil antigen antibodies could not be demonstrated. Conversely, not all recipients of plasma containing such antibodies acquire TRALI (Kopko et al). In addition, a randomized, double-blind, crossover study of 105 patients showed that the plasma from multiparous female donors produced small but statistically significant decreases in the PaO2/fraction of inspired oxygen ratio compared to control plasma (Palfi et al). However, only one patient had evidence of TRALI. These data, plus the discrepancy between the high prevalence of anti-leukocyte antibodies in multiparous donors and the low incidence of TRALI, suggest that the presence of anti-leukocyte antibodies alone is not sufficient to produce this pulmonary complication.
The second hypothesis for the pathophysiology of TRALI is based on a two-event, or neutrophil priming, model. The first event primes neutrophils, while the second event activates the already primed neutrophils that are sequestered in the lung and trigger the cascade of events that eventuate in clinically apparent TRALI. One of the events is thought to relate to comorbid conditions such as surgery, massive transfusion, infection, or inflammation, which may increase the susceptibility of the recipient’s WBCs to the priming stimulus. The second event is thought to be related to transfusion. Although anti-leukocyte antibodies in the donor unit may be responsible for the second event, it has also been suggested that other biologically active substances that accumulate in the donor unit during storage, such a cytokines or lipids, may play a role. Current strategies for reducing the risk of TRALI include screening antibody testing and/or questioning of donors on parity, followed by plasma diversion for high-risk donors or deferral of donors implicated in a case of TRALI (Holness).
Autopsy and Blood Bank Evaluation
An autopsy was performed at the request of the family. The autopsy was most remarkable for diffusely edematous lungs, weighing two to three times normal (combined lung weight, 2,084 g; expected weight, 685 to 1,150 g), with sanguineous fluid oozing from the airspaces. Pulmonary emboli were not grossly identified. On microscopic examination, the alveolar airspaces were filled with proteinaceous and hemorrhagic exudates (Fig 2
). There was no evidence of pneumonia, hyaline membrane formation, or emboli. Severe atherosclerotic coronary artery disease and cardiomegaly with biventricular hypertrophy and four-chamber dilatation were observed (heart weight, 482 g). Bilateral nephrosclerosis and acute tubular necrosis were present.
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Clinical Pearls
Received for publication October 25, 2005. Accepted for publication January 27, 2006.
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