Allergic Transfusion Reactions

Clinical Features

ATRs occur in 0.03%–0.61% of red blood cell (RBC) transfusions, 0.3%–6% of platelet transfusions, and 1%–3% of plasma transfusions. About 90% of these reactions are mild. Anaphylactic reactions occur in approximately 1 in 20,000–47,000 components transfused. The incidence of any allergic reaction to factor VIII, factor IX, and von Willebrand factor concentrates is approximately 1 in 5000 doses, with a roughly similar incidence for concentrates and recombinant factors. Anaphylaxis accounts for 5% of transfusion-related mortality reported to the FDA (eight cases reported from 2011 to 2015). Leukoreduction does not reduce the incidence of ATRs. Atopic disease in blood donors does not contribute to ATRs in most cases; the rare exception is passively transfused IgE that has specificity to an allergen exposure in the transfusion recipient, e.g., peanuts. Atopic disease in the recipient, particularly hay fever, is associated with a risk of ATRs.

Symptom onset of anaphylactic reactions is between seconds and 45 minutes after the start of transfusion, while symptom onset for mild ATRs occurs up to 2–3 hours after completing transfusion. Generalized pruritus may precede urticarial eruptions. There may be generalized erythema (flushing) of the skin or angioedema. Symptoms of severe reactions evolve quickly. Upper and/or lower airway obstruction is caused by angioedema and results in hoarseness, stridor, and/or the complaint of a “lump” in the throat. Lower airway obstruction results in audible wheezing, feeling of chest tightness, substernal pain, dyspnea, or cyanosis. There may be profound hypotension, possibly leading to loss of consciousness, tachycardia, cardiac arrhythmias, or cardiac arrest. Severe gastrointestinal symptoms (abdominal cramps/pain, nausea, vomiting, diarrhea) may also be present.

Diagnosis

Some symptoms that are consistent with ATRs overlap with other types of reactions, particularly dyspnea and shock. Immediate hemolytic transfusion reactions can be differentiated by the presence of fever and absence of cutaneous manifestations. Hypotensive reactions have marked drops in blood pressure without cutaneous symptoms or other signs of anaphylaxis. Transfusion-related acute lung injury can be differentiated from ATRs by the presence of fever, chest X-ray findings of pulmonary edema, and absence of cutaneous symptoms. Bacterial contamination is associated with hypotension and shock, but the presence of rigors and fever and the absence of urticaria and angioedema differentiate it from ATRs. Flushing and hypotension may be seen in patients taking angiotensin-converting enzyme inhibitors but can be differentiated from ATRs by the absence of pruritus or pulmonary findings. Other causes of the patient’s allergic reaction should be ruled out, such as coincidental administration of a drug or food.

Patients with a severe ATR may be tested for IgA deficiency and the presence of anti-IgA, although the prevalence of IgA deficiency among patients with severe reactions is low. Screening for IgA deficiency can be performed with routine IgA testing. Reference laboratories can perform IgA tests that are more sensitive and can distinguish severe IgA deficiency from IgA concentrations that are present, but below the limit of detection of routine assays. Anti-IgA testing is currently only performed in reference laboratories, and a common diagnostic approach is to screen for anti-IgA antibodies only after severe IgA deficiency is diagnosed.

Pathophysiology

ATRs manifest clinically as type I hypersensitivity responses, and biomarkers of immediate hypersensitivity reactions, e.g., tryptase, are elevated after severe ATRs. In IgE-mediated hypersensitivity responses, IgE binds to mast cells and basophils by means of IgE Fc receptors, causing activation and release of mediators (such as histamine, heparin, leukotrienes, platelet-activating factor, cytokines, and chemokines). These mediators instigate changes in smooth muscle tone and extravasation of cells and fluid into the tissues, resulting in signs and symptoms of the skin, respiratory tract, and cardiovascular and gastrointestinal systems. In addition, IgG may also mediate ATRs through complement fixation, one of the results of which is the formation of C3a and C5a anaphylatoxins.