Chapter 193. Anaphylaxis, Urticaria, and Angioedema

Anaphylaxis, urticaria, and angioedema frequently share a common pathophysiology in that these conditions most commonly result from IgE-mediated mast cell activation resulting in the release of histamine, leukotrienes, and other mast cell mediators. Urticaria and angioedema are isolated to mucocutaneous symptoms whereas anaphylaxis is an acute systemic reaction that may rapidly lead to cardiopulmonary collapse.

Epidemiology

Anaphylaxis is an acute systemic type I (IgE-mediated) hypersensitivity reaction mediated by histamine, leukotrienes, and other mast cell–derived mediators.1 The estimated overall lifetime prevalence of anaphylaxis from all causes is 0.5% to 2%, and 0.7% to 2% of anaphylactic reactions are fatal. Rapid recognition, diagnosis, and therapy of anaphylaxis are imperative to prevent morbidity and mortality.

Although anaphylaxis can occur at any age, adolescents and young adults are most at risk for serious anaphylaxis. Preexisting asthma is a primary risk factor for fatal anaphylaxis, and delay in epinephrine therapy has been strongly associated with anaphylaxis mortality. Additional risk factors for poor outcomes with the occurrence of anaphylaxis include concomitant therapy with β-adrenergic or α-adrenergic antagonists, which blunts the effects of epinephrine treatment, and angiotensin-converting enzyme inhibitors, which interfere with physiologic compensatory mechanisms, thereby leading to severe or protracted anaphylaxis.

Risk factors for anaphylaxis include parenteral antigen exposure (ie, IV medications) and repeated, interrupted antigen exposure (ie, medication or food ingestion). The most common causes of anaphylaxis include (1) medications, (2) foods, (3) stinging insects, (4) latex, and (5) blood products. Of these causes, medications and foods account for the majority of serious anaphylactic reactions resulting in emergency room visits or causing anaphylaxis mortality. The most commonly implicated causative medications are β-lactam antibiotics (penicillins and cephalosporins), other antibiotics, radiocontrast agents (through direct mast cell stimulation), and neuromuscular blocking agents. Among foods, peanuts, tree nuts, cow’s milk, egg, and seafood (crustaceans, mollusks, fish) most commonly cause anaphylaxis.2 Rarely, the temporal combination of food ingestion and exercise may trigger anaphylaxis.3 This food-dependent, exercise-induced anaphylaxis is best evaluated by an allergy specialist. Other uncommon causes of anaphylaxis include physical factors such as cold, heat, or ultraviolet light exposure. Finally, idiopathic anaphylaxis occurs when no inciting allergen can be identified by considering the patient’s history or by diagnostic testing.

In the pediatric population, anaphylactic reactions to vaccines are a concern. True IgE-mediated anaphylaxis to immunizations is rare and more commonly involves IgE to vaccine components rather than the immunizing antigen itself. Gelatin, added to vaccines as a stabilizing agent, has been implicated in anaphylactic reactions to measles, mumps, and rubella (MMR), varicella, influenza, and Japanese encephalitis vaccines. Children with a history of allergy to egg should be seen by an allergy specialist prior to receiving influenza and yellow-fever vaccines, as egg protein used in these vaccines has been implicated in anaphylactic reactions to these immunizations. IgE-mediated reactions to the specific vaccine antigen is exceedingly rare, but has been reported for diphtheria and tetanus.

Generally, previous exposure to an antigen is necessary for IgE sensitization to occur in an individual. On subsequent exposure, the triggering antigen cross-links antigen-specific IgE bound to mast cells and basophils through high-affinity IgE (FcεRI) receptors. Activated mast cells and basophils release preformed mediators, including histamine, tryptase, chymase, and heparin. In addition, lipid-derived mediators such as cysteinyl leukotrienes (LTC4, LTD4, LTE4), prostaglandins, and platelet-activating factor are generated by activated mast cells and basophils. This sudden release of mediators into the circulation and tissues of the gastrointestinal and respiratory tract results in the multisystem syndrome of anaphylaxis. Less commonly, non-IgE mechanisms may lead to mast cell activation and symptoms of anaphylaxis. Such non-IgE reactions are sometimes called “anaphylactoid” reactions, as though they are clinically indistinguishable from IgE-mediated anaphylactic reactions. Direct mast cell stimulation is likely a primary mechanism responsible for immediate systemic reactions to radiocontrast media. Other non-IgE alternative mechanisms leading to anaphylactic symptoms include immune complex–mediated complement activation, as occurs with blood products.

Clinical Features and Diagnosis

Anaphylaxis is a clinical diagnosis based on presenting signs and symptoms, as well as a clinical history suggestive of allergen exposure. Symptoms of anaphylaxis typically appear within minutes of the antigen exposure, though occasionally symptom onset may be delayed for several hours after oral ingestions. In severe cases, symptoms progress rapidly and lead to fatal shock within 60 minutes of exposure. Most anaphylactic reactions are uniphasic, though up to 20% show a biphasic course with recurrent symptoms approximately 8 to 12 hours after the exposure; this may occur as late as 72 hours after the initial anaphylactic phase. The mechanism of this clinical observation has not been established, though it has historically been attributed to mast cell cytokine production resulting in recruitment of eosinophils, basophils, macrophages, and lymphocytes into tissues producing a second phase of inflammation.

The most common symptoms of anaphylaxis are cutaneous, respiratory, gastrointestinal, and cardiovascular. Skin symptoms may include urticaria, angioedema, erythema, pruritus, and diaphoresis. Respiratory symptoms of rhinitis, nasal congestion, wheezing, cough, chest tightness, and dyspnea are common. Laryngeal edema may also occur, causing stridor and airway compromise. Gastrointestinal symptoms are frequently associated with anaphylaxis, including cramping, abdominal pain, nausea, vomiting, and diarrhea. Cardiovascular features are less common in children than adults. In the most severe or advanced stages, hypotension occurs with reflex tachycardia. Syncope and shock may result from the profound hypotension associated with severe anaphylaxis. Respiratory arrest and/or cardiovascular collapse due to hypotension are the common causes of death from anaphylaxis.

A number of common conditions may be confused with anaphylaxis. These include vasovagal reactions, acute urticaria and/or angioedema, acute asthma exacerbations, vocal cord dysfunction, acute anxiety disorders, and epiglottitis or foreign body aspirations resulting in respiratory distress. In addition to these common conditions, rare disorders such as mastocytosis or basophilic leukemia may present with systemic histamine-mediated symptoms.

While anaphylaxis is a clinical diagnosis based on the history and constellation of presenting signs and symptoms, confirmatory testing with serum histamine or tryptase levels is sometimes useful to confirm systemic mast cell activation. Histamine is detectable in plasma for only 15 to 30 minutes after the anaphylactic event, making appropriate collection difficult. Tryptase, a protease specific to mast cells, reaches a serum peak 30 to 120 minutes after the event and remains elevated for approximately 6 hours making it more helpful to confirm systemic mast cell activation. Thus, an elevated serum tryptase level is useful to confirm systemic mast cell activation. A normal serum tryptase level does not necessarily exclude anaphylaxis, particularly with food-induced events, which are rarely associated with elevated serum tryptase. After treatment of the acute anaphylactic episode, additional diagnostic testing should include testing for allergen-specific IgE to confirm the causative antigen. This can be performed by allergy skin testing or serum-specific IgE testing to suspected allergens. Evaluation by an allergy-immunology specialist is appropriate.

Treatment

The approach to treating anaphylaxis should focus first on maintaining the airway, breathing, and circulation. Mortality from anaphylaxis results from asphyxiation due to upper airway angioedema, respiratory failure from severe bronchial obstruction, or cardiovascular collapse. The most important initial medical therapy is epinephrine, which is most effective when administered within 30 minutes of symptom onset.4 Anaphylaxis mortality is strongly correlated with delays in epinephrine therapy. Any ongoing exposure to the suspected antigen should be discontinued (ie, medication infusion). Hypotension requires aggressive large-volume fluid resuscitation and, if persistent, vasopressor therapy. Supplemental oxygen is recommended, and in the presence of respiratory compromise or bronchospasm, inhaled bronchodilators such as albuterol should be administered. Intubation and mechanical ventilation may be necessary. H1- and H2-receptor antagonists are adjunctive medications that should be given to reduce pruritus and urticaria, though antihistamines without epinephrine are insufficient to adequately treat anaphylaxis. Corticosteroids are frequently given to attenuate the potential late-phase inflammatory response and thereby prevent recurrence of symptoms 8 to 12 hours after the initial onset; corticosteroids are not effective for the initial acute phase. Anaphylactic reactions that occur in patients taking β-adrenergic antagonists may be particularly refractory to epinephrine. In this setting, glucagon or atropine administration should be considered. Whenever possible, patients should be observed for 8 to 12 hours after an anaphylactic reaction due to the possibility of recurrent symptoms from the late-phase response occurring several hours after the initial event.

All patients should be discharged with injectable epinephrine for home use, assuring that they receive appropriate instruction in the use of an Epipen.5 Subsequent to treatment of the acute episode, identification of the triggering antigen or exposure should be pursued through diagnostic allergy skin testing or serum IgE testing whenever possible. Patients should strongly consider wearing medical alert identification detailing their specific allergies if known.

Urticaria and angioedema are localized swelling of the skin or mucous membranes. Urticaria, commonly called hives, involves extravasation of fluid in the superficial dermis. It is characterized by well-circumscribed, pruritic, raised erythematous skin wheals, often with central pallor and blanching with applied pressure. Angioedema results from similar vasopermeability in the deeper layers of the dermis and subcutaneous tissue. Angioedema may appear associated with urticaria, but occasionally presents as an isolated symptom. Angioedema typically involves the periorbital tissues, lips, tongue, posterior oropharynx, larynx, hands, feet, or genitals. Less commonly, angioedema may involve the gastrointestinal tract, resulting in abdominal pain, nausea, vomiting, and diarrhea. Edematous swelling of angioedema may take 24 to 72 hours, or in some instances longer to fully resolve.6

Epidemiology

Urticaria and angioedema are common conditions that affect up to 25% of the population at some point during their lifetime. Over two thirds of urticaria/angioedema cases are acute, self-limited episodes resolving in less than 6 weeks. Approximately one third will persist with daily or near-daily symptoms for more than 6 weeks and are classified as chronic urticaria.7 The vast majority of urticaria and angioedema are mast cell–mediated conditions responsive to antihistamines and corticosteroids. In contrast, angioedema in the absence of urticaria may suggest a kinin-related condition. Such angioedema is much less common, but is important to recognize due to differences in therapy. Hereditary angioedema is a representative bradykinin-mediated angioedema with a prevalence of 1:10,000 to 1:100,000, affecting males and females equally.

Pathophysiology

Acute urticaria and angioedema are most often the result of mast cell activation with resultant release of histamine, leukotrienes, and other mediators into the superficial dermis (urticaria) and deep dermis (angioedema). These inflammatory mediators cause dilatation and increased permeability of capillaries and venules, leading to extravasation of fluid into (angioedema) tissues. Mast cell activation may be the result of specific IgE cross-linking from allergen exposure (foods, drugs, latex, insect venom, aeroallergens, parasitic infections, blood products), non-IgE activation (radiocontrast media, narcotics, vancomycin, muscle relaxants used in anesthesia), physical stimulation (pressure, cold, vibration), autoimmune activation, or immune complex formation and complement activation as occurs with infection.

Angioedema in the absence of urticaria may be caused by mediators other than histamine. In particular, hereditary angioedema and angioedema caused by angiotensin-converting enzyme inhibitors are classified as kinin-related angioedemas, with bradykinin recognized as the most important mediator in these conditions.6,8 Hereditary angioedema is caused by mutations in the C1-inhibitor (C1INH) gene, resulting in low C1INH protein levels and/or activity.9 The inheritance is autosomal dominant, and most affected individuals carry 1 abnormal allele. As C1INH is a primary inhibitory protein for steps leading to bradykinin production, C1INH deficiency leads to increased tissue bradykinin, which interacts with vascular bradykinin 2 receptors, resulting in vasodilation, increased vascular permeability, and angioedema. Acquired angioedema, rarely seen in the pediatric population, is associated with malignancy or autoimmune conditions and also involves dysfunctional C1INH function. Angiotensin-converting enzyme inhibitor–associated angioedema is due to increased bradykinin levels resulting from the inhibition of angiotensin-converting enzyme, which functions as a primary metabolizing enzyme for bradykinin.

Other mechanisms may be responsible for urticaria and angioedema caused by aspirin or NSAIDs. The pharmacologic properties of these drugs include inhibition of cyclooxygenase and reduced generation of prostaglandins from arachidonic acid, resulting in increased formation of cysteinyl leukotrienes.

Clinical Features and Diagnosis

In accruing the patient’s clinical history, important inquiries include food and medication ingestion, travel history, infections, atopy, and other systemic symptoms or conditions. In children, common viral or bacterial infections may account for 80% of acute urticaria. Food allergens frequently cause acute urticaria, with reactions generally occurring within 30 minutes of ingestion. Milk, egg, peanuts, tree nuts, soy, and wheat are the most frequently implicated foods causing urticaria in children. Among medication causes of urticaria, antibiotics (particularly β-lactams and sulfonamides) are most frequently implicated. Aeroallergen exposure is an uncommon cause of acute urticaria. It is important to note that in the majority of cases, no external cause of urticaria and angioedema can be identified. Therefore, it is often reasonable to defer diagnostic testing for acute urticaria and focus on symptomatic treatment, unless there is strong clinical suspicion of an allergic trigger or a systemic medical condition. Specific IgE testing for foods, medications, or insect venom may be useful if these exposures are identified. Infrequently, urticaria may be the presenting symptom of systemic diseases such as systemic lupus erythematosus, cryoglobulinemia, or autoimmune thyroid disease, so evaluation for such conditions may be appropriate if the clinical presentation is suggestive. Controlled, provocative testing may reproduce a number of physical urticarias, including those caused by pressure, cold, heat, or vibration.

Urticaria or angioedema with near daily symptoms lasting more than 6 weeks is deemed chronic, and a more thorough diagnostic evaluation may be indicated, though in the majority of cases no systemic underlying cause is identified. Evaluation for thyroid autoantibodies, autoimmune conditions, and chronic viral infections may be considered, depending on the clinical presentation. Thirty to fifty percent of patients with chronic urticaria demonstrate mast cell–stimulating autoantibodies, suggesting an autoimmune mechanism for some cases of chronic idiopathic urticaria.

Approximately 90% of mast cell–mediated angioedema is associated with urticaria and/or pruritus, so absence of these concomitant symptoms suggests a different underlying pathway. Thus, the evaluation of isolated angioedema (ie, angioedema occurring in the absence of urticaria) should include consideration of kinin-related angioedemas such as hereditary or angiotensin-converting enzyme inhibitor-associated angioedema. Hereditary angioedema (HAE) or C1-inhibitor (C1INH) deficiency often presents during the first or second decade of life, with recurrent angioedema episodes affecting the face, throat, extremities, genitals, or gastrointestinal tract. Seventy-five percent of patients with HAE experience their first attack by the age of 15. Triggers for HAE attacks may include tissue trauma, infections, dental procedures, or emotional stress, though frequently angioedema occurs spontaneously without an identifiable trigger. Angioedema episodes typically last for 48 to 72 hours before spontaneous resolution. Twenty-five percent of new HAE diagnoses are attributed to de novo mutations, as no family history of HAE exists. Frequently, patients with HAE have been previously diagnosed with “recurrent allergic reactions,” and surgical and/or gastrointestinal consultations are frequently obtained for recurrent, unexplained episodic abdominal pain that occurs in the absence of visible cutaneous angioedema. Screening for hereditary angioedema is performed by testing serum C4 level, which is typically low due to complement consumption. More comprehensive testing with quantitative and functional C1INH levels is recommended.10 Both quantitative and functional C1INH assays are required as approximately 15% of HAE occurs due to abnormal protein function (HAE type II) rather than reduced quantitative C1INH levels (HAE type I). In children less than 1 year of age, CINH levels are 30% to 50% lower than adult levels, and C4 levels are variable, making interpretation of lab results difficult. In these cases, testing should be repeated after 1 year of age or, alternatively, genetic testing for HAE may be pursued, though this is complicated by over 150 described C1INH gene mutations associated with HAE.

Treatment

Treatment of acute urticaria and angioedema should focus on (1) identification and discontinuation of any triggering underlying process and (2) symptom suppression until resolution of the acute episode. If an allergic trigger or physical urticaria is identified, avoidance of the allergen or physical stimulation is vital to terminating the reaction and preventing future episodes of urticaria. Symptom suppression can often be achieved with the administration of H1-receptor antagonists that are most effective at relieving pruritus associated with urticaria, but may also reduce visible skin wheals. The use of first-generation H1-receptor antagonists (ie, diphenhydramine, hydroxyzine) is limited by their sedating and anticholinergic side effects, but these agents may be particularly useful for nocturnal urticarial symptoms that interfere with sleep. Regular use of longer-acting nonsedating antihistamines (ie, cetirizine, fexofenadine, loratadine) is generally preferable for controlling urticarial symptoms that persist for more than a few days. H2-receptor antagonists are useful adjuvant medications, but it is most efficient to maximize the H1-receptor antagonist therapy prior to adding additional medications.11 Likewise, leukotriene inhibitors (eg, montelukast, zafirlukast, zileuton) may benefit some patients with chronic urticaria, particularly those with the autoimmune form of the condition.12 Short courses of oral corticosteroids can be used to control severe urticaria that is refractory to high-dose antihistamines. Long-term systemic corticosteroid use for chronic urticaria is associated with significant adverse side effects. In rare patients with severe chronic urticaria requiring frequent corticosteroids, a variety of “steroid-sparing” medications have been employed. These include cyclosporine, dapsone, hydroxychloroquine, and sulfasalazine. Other approaches for refractory urticaria include the use of omalizumab, nifedipine, and intravenous immunoglobulin.

Treatment of kinin-related angioedema is distinct because these conditions typically do not respond to antihistamines and corticosteroids. Angiotensin-converting enzyme inhibitor-associated angioedema is primarily treated by withdrawal of the offending drug. Generally, symptoms resolve within 48 to 72 hours of drug discontinuation. Treatment of hereditary angioedema in the United States is currently limited by the lack of FDA-approved medications for the condition.13 At present, acute episodes of angioedema from hereditary angioedema (HAE) are managed with supportive care. Epinephrine may be useful as a temporizing measure for laryngeal attacks with airway obstruction; however, epinephrine is not a substitute for proper airway management, as intubation is occasionally necessary for significant laryngeal edema associated with HAE. The use of fresh frozen plasma, which provides a level of C1INH replacement, is complicated by reports of it worsening HAE attacks due to the additional substrate proteins contained in the product and the risk of transmissible blood-borne pathogens. Thus, any use of fresh frozen plasma in the therapy of HAE attacks should be undertaken with great caution.

Several investigational drugs are in development for the treatment of acute hereditary angioedema (HAE) attacks.13 Plasma-derived C1INH has been used safely and effectively for HAE in other parts of the world and is currently being reviewed by the FDA for approved use in the United States. Preventative therapy for HAE attacks should be considered in patients experiencing frequent or severe attacks.14 The attenuated androgens (ie, danazol) are the most effective available prophylactic medications at present; however, use in the pediatric population is complicated by concern for side effects, including epiphyseal closure and decreased growth.15 Antifibrinolytic agents such as tranexamic acid and aminocaproic acid are less effective at preventing HAE attacks, but may be useful in the pediatric population when androgen use is contraindicated. At present in the United States, aminocaproic acid is the only available agent of this class that is potentially useful for long-term preventative therapy in HAE.16 Specialist consultation is advised if such therapy is considered.