Anaphylaxis

Phil Lieberman

Debendra Pattanaik

I. DEFINITION

The classic definition of anaphylaxis is “An acute, systemic, immediate hypersensitivity reaction caused by IgE-mediated immunologic release of mediators from mast cells and basophils.”

Clinically similar events not mediated through IgE have been called anaphylactoid reactions. More recently, it has been suggested that the term “anaphylactoid” be abandoned, and all events, regardless of the mechanism of production, be called anaphylactic episodes. Thus, the new definition of anaphylaxis would include events that are IgE mediated plus those that are non-IgE mediated.

II. INCIDENCE

The exact incidence of anaphylaxis is unknown, but based on data gleaned from real-time prescriptions for automatic epinephrine injectors, as much as 1% of the population may be at risk for anaphylaxis. Anaphylactic episodes appear to be increasing in frequency. The risk factors that predispose an individual to anaphylaxis are the presence of atopy, asthma, and, in adults, prior to menarche, female gender. In addition, geographic location seems to play some role in that episodes have been reported to be more frequent in higher latitudes in the upper hemisphere and lower latitudes in the lower hemisphere (thus increasing in frequency with diminishing exposure to sunlight).

III. PATHOPHYSIOLOGY

The degranulation of mast cells and basophils is the primary event underlying anaphylactic episodes. The mediators released from mast cells and basophils include histamine, neutral proteases, proteoglycans, chemoattractants, nitric oxide, interleukins, and other cytokines. For a detailed discussion of these mediators, please see the chapter on Immediate Hypersensitivity. The sum total of the effects of these mediators is to produce vasodilatation, increased vascular permeability, smooth muscle constriction, irritation of afferent sensory nerves, and chemotaxis.

IV. CLINICAL MANIFESTATIONS

A. Symptoms

The clinical manifestations of anaphylactic events are seen in Table 13-1, which lists them by incidence. Cutaneous and subcutaneous manifestations are the most common. In adults, 90% or more of patients experience
cutaneous manifestations characterized by urticaria, pruritus, or flush. The incidence of these in children appears to be slightly lower. Respiratory complaints occur next most commonly. They consist of wheeze, shortness of breath, stridor, and cough. They occur in about 40% to 60% of cases. They are a risk factor for mortality. Cardiovascular symptoms are the next most frequent manifestation. They consist of hypotension, arrhythmia, dizziness, syncope, angina, and myocardial infarction. They appear in 30% to 35% of events overall. They are more common in adults. Gastrointestinal symptoms appear at about the same frequency as cardiovascular manifestations. They include nausea, vomiting, cramping abdominal pain, and diarrhea. They seem to be more frequent if the antigen has been ingested versus injected. Symptoms of anaphylaxis usually begin 5 to 30 minutes after antigen injection and within 2 hours after antigen ingestion. However, there can be a delay of several hours after ingestion in some instances. It is felt that the more rapid the onset of symptoms after exposure to allergen, the more severe the event.

Table 13-1 Signs and Symptoms of Anaphylaxis

Cutaneous, subcutaneous
	Urticaria and angioedema
	Flush
	Pruritus without rash
Respiratory
	Wheeze
	Dyspnea
	Upper respiratory obstruction (angioedema)
	Rhinitis
Cardiovascular
	Dizziness
	Syncope
	Hypotension
	Arrhythmia
	Angina
	Myocardial infarction
Gastrointestinal
	Nausea
	Vomiting
	Diarrhea
	Cramping abdominal pain
Miscellaneous
	Headache
	Substernal pain
	Seizure
	Disseminated intravascular coagulation

It should be noted that some patients do not present with “classical” manifestations as described above. Perhaps the most common atypical presentation is cardiovascular collapse with shock in the absence of other symptoms or signs. A significant percent of such patients express neurologic
manifestations including seizures and muscle spasms. Asthmatic children with food allergies can have episodes that begin initially with only asthma. Of course, respiratory reactions and cardiovascular reactions are responsible for the majority of fatalities. Upper airway obstruction as well as asthma can result in fatal events. Shock and myocardial infarction due to coronary artery vasospasm are also causes of fatal reactions.

B. Duration of anaphylaxis

Anaphylactic episodes can be uniphasic, biphasic, or protracted. Uniphasic events usually have a rapid onset, and symptoms subside within an hour or two and do not return. Biphasic events are characterized by a recurrence of symptoms after resolution of the initial episode. Protracted events can last hours and, in rare instances, even days. The exact incidence of each type of event is unknown. Uniphasic events are clearly the most common however. Biphasic events have been estimated to occur from 1% to 20% of episodes. The majority of these appear within 8 hours after resolution of the initial symptoms, but such events can be delayed as long as 24 hours and rarely even longer. Because of the clinical significance of biphasic reactions in terms of the suggested length of patient observation after an initial resolution of symptoms, it is important to be aware of the risk factors for biphasic events. Factors that have been cited that increase the risk of a biphasic event are the presence of hypotension during the first phase, the failure to administer epinephrine or a delay in its administration, and an event due to an ingested (vs. injected) antigen, especially food.

V. SUBSTANCES CAUSING ANAPHYLACTIC EPISODES

The most common causes of anaphylactic events are seen in Table 13-2. Foods are probably the most common cause of anaphylaxis overall and are certainly the most common cause in children. Of these, milk, egg, wheat, soy, peanut, and tree nut produce the majority of reactions in children, and shellfish, fish, and peanut are the most common food offenders in adults. However, overall, in adults, medications rival food as the most common cause of anaphylactic events. The most common of these are beta-lactam antibiotics, and the next most common are nonsteroidal anti-inflammatory drugs (NSAIDs). It is important to note that in published series of adults experiencing anaphylaxis, the majority of events are idiopathic.

VI. COMMON TYPES OF ANAPHYLAXIS

A. Natural rubber latex-induced anaphylaxis

Three groups of individuals are at high risk of developing sensitivity to latex. These include children with spina bifida and genitourinary abnormalities, workers with occupational exposure to latex, and health care workers. Latex-induced anaphylaxis can occur in a variety of situations including direct contact with latex (this is usually via gloves and also condoms) or by aerosolization of latex antigen adhered to corn starch from the powder of latex gloves. Thus, one of the most common settings for latex reactions is in surgery. Latex reactions in this setting have also been reported due to the administration of a drug through a latex port. Latex anaphylaxis has become
less common as the use of powdered latex gloves in health care settings has declined. It still, however, remains a problem in the other two groups of at risk individuals. Unfortunately, there is no standardized skin test for latex available in the United States today. However, there is a test for serum-specific IgE to latex. If the in vitro test is positive, there is a high clinical likelihood that latex sensitivity is present. In contrast, a negative test does not rule out latex sensitivity. Patients with a diagnosis of latex allergy should wear a medical identification bracelet. If there is any chance of exposure, they should also carry an automatic epinephrine injector. Patients with latex sensitivity should be instructed to notify all their health care providers including dentists of their sensitivity. Surgical procedures should be done in latex-free operating rooms, and precautions should also be taken during dental visits.

Table 13-2 Frequently Reported Causes of Immediate Generalized Reactions

Causative Agent	Mechanism
Foods	IgE mediated
Nuts
Legumes (peanuts)
Shellfish
Egg whites
Milk
Pistachios, cashews
Seeds (mustard)
Insect venoms	IgE mediated
Wasps
Hornets
Honey bees
Yellow jackets
Fire ants
Proteins or peptides
Streptokinase	IgE mediated
Insulin	IgE mediated
Seminal plasma	Some IgE mediated
Allergen immunotherapy vaccines	IgE mediated
Latex	IgE mediated
Muscle relaxants	Mast cell activation (some IgE mediated)
Antibiotics
Penicillins	IgE mediated
Cephalosporins	IgE mediated
Sulfamethoxazole	Some IgE mediated
Trimethoprim	Some IgE mediated
Fluoroquinolones	Unknown
Vancomycin	Mast cell activation
Diagnostic agents
Radiocontrast media	Unknown
Gadolinium	Unknown
Fluorescein dye	Unknown
Procedure related
Dialyzer membranes	Complement activation
Plasma (including platelet infusions)	Complement activation (some IgE mediated)
Intravenous immunoglobulin	Complement activation, IgG or IgE mediated
Miscellaneous
Monoclonal or chimeric antibody	Likely IgE mediated
Aspirin, nonselective NSAIDs	Leukotriene D₄ production; suppression of prostaglandin E; mast cell activation
Angiotensin-converting enzyme inhibitors	Bradykinin potentiation
Exercise-induced anaphylaxis	Unknown
Exercise plus food-induced anaphylaxis	Unknown
Idiopathic anaphylaxis	Unknown
IgE, immunoglobulin E; NSAIDs, nonsteroidal anti-inflammatory drugs.

B. Exercise-induced anaphylaxis

Exercise-induced anaphylaxis has been reported due to almost any form of exercise including jogging, racket sports, aerobics, dancing, brisk walking, and weight lifting. Cessation of the exercise usually rapidly improves symptoms, but if exercise is continued, symptoms will progress. Fatal reactions to exercise-induced episodes are probably rare, but there has been at least one death. Many patients with exercise-induced anaphylaxis require cofactors. That is, exercise alone is insufficient to produce the reaction. The most common cofactor is the ingestion of a specific food to which the patient is allergic. In some patients, eating itself, regardless of the food, can be a cofactor. Other cofactors include drugs, especially NSAIDs, alcoholic beverages, menstruation, and seasonal pollen exposure. Neither the exercise nor the specific cofactor alone will produce an event, but if exposure is associated with exercise, the reaction will occur.

The diagnosis of exercise-induced anaphylaxis is made by history. An exercise challenge can be performed, but for reasons unknown, responses can be inconsistent. When a patient does have exercise-induced anaphylaxis, it is important to identify cofactors on the basis of history, and allergy skin testing is also recommended when the history is suggestive. Exercise-induced anaphylaxis should be distinguished from cholinergic urticaria. In the latter condition, the event is induced by elevation of body temperature sufficient to cause sweating. Exercise therefore is one of the triggers. However, other triggers that raise body temperature such as a hot shower can also produce an event. In addition, the appearance of the urticaria differs between these two entities. Cholinergic urticaria is characterized by pinpoint wheals that can progress and coalesce to giant hives. In exercise-induced anaphylaxis, giant hives usually appear as one of the first signs.

Strategies to prevent exercise-induced anaphylaxis must be individualized. The patient should always have immediate access to autoinjectable epinephrine whenever they exercise. Patients should be advised to exercise with a partner. In those patients where a cofactor has been identified, exposure to this cofactor should be avoided when the patient is exercising. At the first sign of symptoms, the patient should stop exercising immediately. Pharmacologic therapy for prevention has produced inconsistent results. There is no definite evidence that oral antihistamines or corticosteroids will have a beneficial effect.

C. Idiopathic anaphylaxis

A group of patients (in fact as many as 60% of cases in adults) will experience repeated episodes of anaphylaxis without any identifiable cause. Regardless of how intensively such patients are evaluated, no cause can be determined. The symptoms are identical to those that are found in other causes of anaphylaxis. Mast cell degranulation is certainly involved, since patients do exhibit elevated tryptase and also increases in urinary histamine metabolites.

The diagnosis of idiopathic anaphylaxis is clinical and relies upon the exclusion of other causes. Therefore, patients should receive a careful evaluation with emphasis on the history and events surrounding the episodes. Selective skin testing to foods (sometimes employing fresh foods rather than commercial extracts) and/or tests for serum-specific IgE to foods are indicated. Systemic mastocytosis should be ruled out. Patients with episodes of idiopathic anaphylaxis should be evaluated with a baseline serum tryptase, and if the tryptase level is elevated, a bone marrow biopsy should be considered.

Many daily preventive regimens have been suggested. Patients have been treated with daily oral corticosteroids, H1 antagonists, and a combination of H1 and H2 antagonists. The studies have for the most part shown that such daily treatment can be helpful but most often does not control the episodes completely. Particular care must be taken with chronic administration of oral corticosteroids because of side effects. Fortunately, the prognosis is usually good for such patients. The majority experience a diminished frequency of episodes as time progresses.

D. Radiocontrast media

The vast majority of radiocontrast media reactions are probably due to the direct effect of radiocontrast on mast cells and basophils and do not appear to be IgE mediated. Anaphylactic episodes to radiocontrast media have declined markedly since the advent of agents that are iso-osmolar. Atopic patients are predisposed to such reactions. It was originally hypothesized that patients allergic to shellfish were predisposed, incorrectly attributing the reaction to “iodine” present both in shellfish and radiocontrast. However, iodine is not involved in the pathogenesis of these events. It does happen, however, that atopic individuals are more prone to these events, not patients with shellfish allergy in particular, but those with atopy in general. The reason for this has not been completely established, but it is hypothesized that atopic individuals have a lower threshold for degranulation (not only to radiocontrast but to other direct-acting mast cell secretagogues as well).

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