Anaphylaxis: Implications of Monoclonal Antibody Use in Oncology
Anaphylaxis: Implications of Monoclonal Antibody Use in Oncology
Anaphylaxis is currently classified as an immunologically triggered response with reactions that are IgE-mediated and reactions that are not IgE-mediated. This immunologically mediated phenomenon can result in various clinical manifestations, including decreased blood pressure, generalized skin infl ammation, such as hives and pruritus, and respiratory symptoms, such as wheezing or bronchospasm. The severity of anaphylaxis can range from a mild allergic reaction to a potentially fatal anaphylactic shock. Numerous causative agents trigger anaphylactic reactions, and some of the best described include food and bee sting allergens. Monoclonal antibodies, which are increasingly used in the treatment of various malignances, also can cause anaphylaxis. In this review, the mechanisms governing anaphylaxis along with treatment strategies are reviewed. Diagnostic aids for anaphylaxis are also discussed. Increased awareness of the mechanisms, symptoms, and treatment of anaphylaxis can aid caregivers to make informed decisions when new agents, such as monoclonal antibodies, are introduced into the clinic.
The phenomenon of anaphylaxis was discovered by Portier and Richet in 1903.[1,2] They injected dogs with toxins from sea anemone with the intent of generating protective antibodies. Unexpectedly, they found that certain dogs became ill with a rapid heartbeat and collapse. Because this syndrome was the precise opposite of protection or prophylaxis, they termed it anaphylaxis.
Subsequent investigations have shown that anaphylaxis is an immunologically mediated event, most commonly associated with production of IgE antibodies in humans. Animal models have shown that both IgE and IgG antibody classes can trigger anaphylaxis. Mast cells and basophils possess the high affinity IgE receptor, FcεR1, and release mediators of anaphylaxis, including histamine, tryptase, carboxypeptidase A, prostaglandin D2, leukotrienes, and platelet-activating factor (PAF) following activation.
Anaphylaxis is a serious and impressive immunologic reaction with an abrupt, and often unexpected, onset and potentially rapid, fatal outcome if untreated.
Characteristics of Anaphylaxis
A review of 1,865 patients compiled the approximate frequency of the symptoms and signs characteristic of anaphylaxis (Table 1). Cutaneous findings were most frequent, and 90% of patients undergoing an anaphylactic reaction showed skin changes such as urticaria, angioedema, flushing, and pruritus. Circulatory symptoms, such as dizziness, syncope, and hypotension, were experienced by 30% to 35% of patients, and these were clearly the most alarming, since they signaled impending circulatory collapse.
Diagnosis of Anaphylaxis
An expert panel of clinicians and investigators concerned with immediate hypersensitivity reactions proposed criteria for the diagnosis of anaphylaxis (Table 2). These criteria include an acute onset of illness, within minutes to hours, associated skin or mucosal involvement with hives, pruritus, or fl ushing, and either respiratory symptoms, such as dyspnea, wheezing, or bronchospasm, or a circulatory component with reduced blood pressure. Specifically, a systolic blood pressure of 90 mm Hg or less, or a 30% decrease in systolic blood pressure, qualifies as a criterion for the diagnosis of anaphylaxis.
Criteria for Grading the Severity of Anaphylaxis
Recently, criteria for grading the severity of anaphylaxis have also been utilized.[7,8] These criteria specify three categories:
• Grade 1: acute allergic reaction
• Grade 2: mild to moderate anaphylaxis
• Grade 3: severe anaphylaxis
Patients with an acute allergic reaction (grade 1 anaphylaxis) only have cutaneous and upper respiratory tract findings, such as generalized skin lesions, pruritus, rhinitis/conjunctivitis, urticaria, local edema, and angioedema, without any systemic symptoms or signs or evidence of other organ involvement.
Patients with mild to moderate anaphylaxis (grade 2) have evidence of grade 1 anaphylaxis and respiratory, cardiovascular, gastrointestinal, or neurologic features. The additional features include shortness of breath or dyspnea, wheeze, hoarseness, and nausea or vomiting with associated physical findings, such as bronchospasm, but with systolic blood pressure greater than 90 mm Hg, respiratory rate less than 25/min, and a normal Glasgow Coma Scale score.
Patients with severe anaphylaxis (grade 3) present with the findings listed for grade 2 and potentially life-threatening symptoms or signs. These include one or more of the following:
•Loss of consciousness, syncope, dizziness, or lightheadedness at any time
• Systolic blood pressure less than 90 mm Hg, Glasgow Coma Scale score less than 15 (related to cardiovascular system collapse and/or neurologic dysfunction from hypoperfusion, hypoxia)
•Dyspnea, wheeze, hoarseness, or bronchospasm
•Stridor, cyanosis, laryngeal edema, or a respiratory rate ≥ 25/min
Manifestations of anaphylaxis involving the cutaneous, gastrointestinal, and respiratory organs tend to worsen with each grade and have implications for treatment and life support. Thus, grade 1 anaphylaxis is characterized by involvement of only the skin, mucous membranes, and/or upper airway, whereas grade 2 or mild to moderate anaphylaxis is characterized by the same findings as grade 1 plus involvement of another organ system. Grade 3 or severe anaphylaxis is defined as the same features for grade 2 plus severe life-threatening respiratory or cardiovascular signs.
Classification and Causes of Anaphylaxis
Previously, anaphylaxis had been separated into categories such as true anaphylaxis and anaphylactoid reactions.[ 6] Anaphylactoid reactions were defined as similar to those of anaphylaxis, but triggered by non-IgE mechanisms, such as reactions to nonsteroidal anti-infl ammatory drugs, including aspirin and ibuprofen, reactions to radiocontrast dye exposure, and exercise. More recently, anaphylaxis has been classified as immunologically mediated with subcategories of those reactions that are IgE-mediated and those that are not.
Various agents stimulate IgE antibodies and cause IgE-mediated anaphylaxis. These include exposures primarily through ingestion, injection, or sting. Foods are common anaphylaxis-inducing agents, including peanuts, tree nuts, shellfish, milk, eggs, fish, soy, sesame seeds, and wheat in children, and shellfish in adults. Approximately 3% of young children are allergic to milk and approximately 2% of adults are sensitive to shellfish.
Virtually any oral or injection medication may provoke an anaphylactic reaction, including injections of allergen employed in immunotherapy for the treatment of allergic respiratory disease. An example of anaphylaxis mediated by IgG antibodies are transfusion reactions in patients deficient in IgA who have IgG antibodies to IgA. Although the mechanism of anaphylaxis in IgA-deficient patients has not been thoroughly studied, it seems most likely that formation of immune complexes with fixation of complement and generation of anaphylatoxin are important.