Anaphylaxis, Urticaria, and Angioedema

After completing this article, readers should be able to:Anaphylaxis is an acute, life-threatening systemic reaction that results from the sudden release of mediators from mast cells and basophils. Prompt recognition of the signs and symptoms of anaphylaxis is critical to providing rapid and effective treatment. Epinephrine is the most important medication for treating anaphylaxis, and earlier administration portends better prognosis.The potential causes of anaphylaxis are numerous and include foods, medications, stinging insects, vaccinations, latex, and less common causes, such as exercise and immunotherapy (Table 1). The prevalence of life-threatening anaphylaxis is estimated to be 10 per 100,000 persons, but this number may be an underestimate because of poor recognition of signs and symptoms.The most common cause of anaphylaxis in the outpatient setting is food. Current estimates suggest that the prevalence of food allergy in North America is 6% of young children. Food allergens account for 30% of fatal cases of anaphylaxis, with approximately 200 deaths in the United States per year. The foods most commonly implicated in food-induced anaphylaxis are peanuts, tree nuts, fish, shellfish, cow milk, soy, and egg. In addition, sesame seeds have become increasingly important as a cause of anaphylaxis. Reactions can occur after the first known exposure or with any subsequent exposure. Prior tolerance to a food does not exclude the development of allergy. Children who have an allergy to peanuts or tree nuts, who have a history of food allergy or asthma, or who experience a delay in administration of epinephrine when symptoms warrant use of that drug are at the highest risk for severe food-induced anaphylaxis.It is important to counsel families that food allergy in children can have varying prognoses. Food allergies to milk, egg, soy, and wheat usually are outgrown during the first decade of life. Food allergies to peanut, tree nuts, fish, and shellfish most commonly are life-long. Still, peanut allergy can be outgrown in 20% of children, so yearly evaluation by an allergist is important to identify these children, who may be candidates for oral food challenge and consequent reintroduction of an item into the diet.Medications are the second most common cause of anaphylaxis in children. The 2 most frequent culprits are antibiotics, particularly β-lactam antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Anaphylaxis also can be caused by chemotherapy drugs, especially cisplatinum and carboplatinum, and biologic agents and monoclonal antibodies, such as omalizumab, which is used for refractory asthma.Anaphylactoid reactions associated with radiographic contrast material occur in approximately 1% of patients. The reactions are considered anaphylactoid because they present identically to immediate hypersensitivity reactions with urticaria, angioedema, severe vomiting, and respiratory symptoms, but they do not appear to be mediated by IgE or other immunologic mechanisms. Pretreatment with oral corticosteroids and antihistamines can reduce the risk of anaphylactoid reactions from radiographic contrast material.Hymenoptera stings by bees, vespids (yellow jacket, hornet, and wasps), and stinging fire ants can cause anaphylaxis. Approximately 0.4% to 0.8% of children report systemic allergic reactions to insect stings. At least 50 cases of fatal anaphylaxis to insect stings occur annually in the United States.Cutaneous symptoms alone occur in 60% of children with stinging insect hypersensitivity, and these cases do not warrant venom testing or consideration of venom immunotherapy for children younger than 16 years. Cutaneous symptoms can be treated symptomatically with cold compresses, oral antihistamines, and oral analgesics.The additional presence of any respiratory or gastrointestinal symptoms or signs or symptoms of hypotension, including dizziness or syncope, should prompt immediate administration of epinephrine and immediate evaluation in a local emergency department. After stabilization of the patient, referral to an allergist should be made for venom skin testing and consideration of immunotherapy.For venom allergic children, the risk of a systemic reaction to an insect sting, even into adulthood, is approximately 30%. Venom immunotherapy has been shown to be effective. The risk of a subsequent systemic reaction after a completed course of venom immunotherapy, typically administered over 3 to 5 years, is reduced to less than 5%, and if a reaction occurs, it is usually mild.Natural rubber latex is an emerging cause of anaphylaxis, especially in the health-care setting and in certain patient populations. Latex allergy is caused by sensitization to any of the antigens from the Hevea brasiliensis tree. In certain patient subsets, such as children born with spina bifida, those with bladder extrophy, and those requiring frequent bladder catheterizations, the prevalence of latex allergy is as high as 75%. In these specific patients, latex avoidance from birth has helped to decrease the risk of sensitization. Latex-induced anaphylaxis is also a common cause of intraoperative anaphylaxis and is responsible for up to 17% of cases of intraoperative anaphylaxis.The most common mode of sensitization is direct contact with latex products, including medical gloves, catheters, and dental instruments; however, patients also can develop severe symptoms on inhalation of the latex antigen aerosolized by cornstarch powder that occurs when donning gloves. Patients with latex allergy should be educated to avoid any possible latex-containing product. A comprehensive list of these products, with additional valuable patient information on latex allergy, can be found at American Latex Allergy Association website (http://www.latexallergyresources.org/).Anaphylaxis to vaccines is an exceedingly rare but important cause of a life-threatening allergic reaction. The rate of anaphylaxis to vaccines is estimated to be 0.65 per 1 million doses. Immediate hypersensitivity reactions are usually caused by components of the vaccine rather than the immunizing agent itself. Examples of vaccine components that are known to cause anaphylaxis are gelatin, egg, chicken, yeast, and neomycin. In suspected cases of anaphylaxis to a vaccine, patients can undergo skin testing to the components of the vaccine, such as gelatin, and to the vaccine itself. This information can then be used to determine the safety of future vaccinations with the same agent.Exercise and physical exertion can lead to systemic mast cell mediator release, resulting in anaphylaxis. The symptoms usually start within a few minutes of exercise and consist of flushing, pruritus, diffuse warmth, urticaria, and fatigue. These early symptoms may progress to angioedema, laryngeal edema, gastrointestinal symptoms, hypotension, or collapse if exercise is continued. Typically, high levels of exertion, such as jogging or doing aerobics, are most risky for these patients; however, some patients can have symptoms with low-impact exercise, such as walking.In many cases, there must be a cotrigger or cofactor before any symptoms occur. Examples of cotriggers are ingestion of specific foods, use of NSAIDs, drinking alcoholic beverages, menstruation, or high pollen exposure. The most commonly implicated foods are wheat, grains, nuts, and seafood. In situations that involve food cotriggers, having eaten the specific food 4 to 6 hours before exercise is common. When the ingestion of NSAIDs is a factor, taking the medication may have preceded exercise by up to 24 hours. This type of anaphylaxis is termed food-exercise–induced anaphylaxis or medication-exercise–induced anaphylaxis.Subcutaneous allergen immunotherapy (allergy shots) is another potential cause of anaphylaxis. The rate of systemic reactions to immunotherapy is estimated to be less than 1%. Fatal reactions are estimated to occur in 1 in 2.5 million injections, making this outcome exceedingly rare. However, in children with poorly controlled asthma, the risk of a systemic reaction is increased. Therefore, it is critical that asthma control be optimized before starting immunotherapy and that immunotherapy be held during asthma exacerbations. Furthermore, immunotherapy should be given only in a health-care setting in which clinicians are trained in the recognition and treatment of anaphylaxis. In addition, it is imperative that patients wait the recommended 30 minutes after an injection because most systemic reactions related to immunotherapy occur within the first 30 minutes.When a causative allergen or inciting physical factor is not found, the diagnosis of idiopathic anaphylaxis is made. This is a poorly understood disease and should be considered only after a thorough detailed history has been completed, appropriate allergy testing has been performed, and other mimickers of anaphylaxis have been excluded. Idiopathic anaphylaxis is considerably rare in adults and adolescents and even less frequent in children. If the cause is truly idiopathic, it is important to screen for underlying systemic mastocytosis by obtaining a baseline serum tryptase level.The diagnosis of anaphylaxis is based on prompt recognition of its signs and symptoms, which may include but are not limited to flushing, urticaria, pruritus, angioedema, cough, wheezing, stridor, dyspnea, abdominal cramping, vomiting, diarrhea, dizziness, and syncope. The absence of cutaneous symptoms argues against anaphylaxis but cannot completely rule it out. Other conditions that should be considered in the differential diagnosis are vasovagal or neurogenic syncope, vocal cord dysfunction, asthma exacerbation, panic attack, isolated angioedema, food poisoning, and other causes of shock, such as sepsis or cardiogenic shock.It can be difficult to distinguish food poisoning from anaphylaxis because both can present with nausea, vomiting, diarrhea, and abdominal cramping; however, there are several important differences to consider. Allergic reactions that are IgE mediated typically occur rapidly and usually within 1 hour of ingesting the food. Non–IgE-mediated reactions, such as food poisoning, occur more slowly and may be delayed by as much as 24 hours from ingestion. In addition, 80% to 90% of cases of food-induced anaphylaxis present with cutaneous findings of hives, angioedema, or both, whereas cutaneous findings are uncommon in food poisoning.A careful history from the patient, parent, caregiver, or other witnesses is helpful in determining a potential trigger. A serum tryptase level taken within 6 hours of a suspected anaphylactic reaction may help to confirm the diagnosis, but the tryptase level may not be elevated in some cases of food-induced anaphylaxis. The causative agent may be obvious in most cases; still, referral to an allergist is warranted so that skin tests, specific IgE in vitro testing, or challenge tests may be considered for more definitive diagnosis, especially in difficult cases.The mainstay of short-term treatment for anaphylaxis is epinephrine in the form of aqueous epinephrine in a 1:1000 dilution (0.01 mg/kg in children; maximum, 0.3 mg). Epinephrine should be administered intramuscularly in the outer aspect of the thigh every 5 minutes as needed to control symptoms. The child should be placed in the recumbent position to slow hemodynamic compromise. Second-line therapy includes diphenhydramine, 1 to 2 mg/kg every 6 hours as needed, ranitidine, 1 to 2 mg/kg every 12 hours as needed, or other histamine2 (H2)-receptor antagonists. In addition, inhaled β-agonists may be used to treat bronchospasm or wheezing. Glucocorticosteroids may not be helpful for short-term treatment but can be considered for prevention of recurrent or protracted anaphylaxis. Oxygen therapy and intravenous fluid replacement should be given if needed for severe signs, such as hypoxia or hypotension.Long-term management involves identifying the causative agent if possible and providing education regarding avoidance of the offending agent. Patients with food-induced anaphylaxis and their families should be instructed on reading food labels and must learn to identify foods to avoid. They should be provided a Food Allergy Action Plan, which lists the patient’s allergies and gives instructions for the administration of medications should there be an unintentional exposure or an allergic reaction. An example of such a plan can be found on the Food Allergy and Anaphylaxis Network website (http://www.foodallergy.org/).The plan should be implemented at the patient’s school or childcare center, and all caregivers should be educated on the correct technique for the administration of epinephrine. Parents, pediatricians, and allergists can work together as a team with the child’s teachers and school administrators on prevention strategies, so that unintentional exposures of the allergenic food are minimized and a treatment plan is in place in the event of an allergic reaction.The presence or absence of IgE-mediated medication-induced anaphylaxis must be determined carefully to educate appropriately patients about medications that may cross-react with the offending agent. For example, penicillin allergy is reported in up to 10% of children; however, studies report that only 0.3% to 3% of these patients who have a history of penicillin allergy have evidence of IgE-mediated type 1 hypersensitivity when skin testing or radioallergosorbent testing is performed. In most cases, the reaction is non–IgE-mediated, manifesting as vomiting, diarrhea, headache, or a nonurticarial, nonpruritic rash.Each class of cephalosporins has a different rate of cross-reactivity with penicillin, which is based on the presence or absence of the 7-position side chain on the β-lactam For example, the in risk of an allergic reaction to cephalosporins in patients is whereas the risk is for it is recommended that cephalosporins be used with in patients who have a history of anaphylaxis or other IgE-mediated reactions to cephalosporins may be given with who have reactions to penicillin, such as a may cephalosporins with risk of allergy. 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