Though there are multiple inducing agents, AE most commonly is idiopathic. Etiologic agents include the following: foods (eggs, peanuts, shellfish, and cow's milk), medications (trimethoprim/sulfamethoxazole, other sulfa derivatives, penicillins, NSAIDs, and cephalosporins), certain insects such as fire ants, latex in children with myelomeningocele, and physical factors (i.e., heat, cold, pressure). Viral infections (i.e., HSV, Epstein–Barr virus, and coxsackievirus) can trigger AE and urticaria. Bacterial infections such as otitis media, sinusitis, and urinary tract infections are associated with AE. In hereditary angioneurotic edema (HAE), which is transmitted as an autosomal dominant condition, there is a mutation in the C1 esterase inhibitor (C1-INH) gene. In acquired AE, there is increased destruction or metabolism of C1-INH, which becomes clinically apparent after 40 to 50 years of age and is associated with lymphomas and rheumatologic conditions.
AE is a common allergic disease that leads to hospitalization, though its exact incidence is not known. It has a higher prevalence in children with atopic dermatitis, asthma, allergic rhinitis, and food allergies. The prevalence of HAE is estimated between 1 in 10,000 and 1 in 150,000 worldwide, with an estimated 6000 to 10,000 people with HAE in the United States.41
AE, similar to urticaria, may occur through IgE-mediated or non–IgE-mediated pathways. In the former, IgE-antigen complexes cross-link mast cells leading to histamine release, which increases vascular permeability and leakage of fluid into the skin. In the latter, nonIgE mediated release of kinin, a potent vasodilator, leads to vascular permeability and edema. AE caused by angiotensin-converting enzyme inhibitors exemplifies the kinin mediated pathway.42 Also similar to urticaria, certain agents such as radio contrast dye, physical stimuli, medications (i.e., vancomycin), and foods such as strawberries directly cause AE. In HAE, a mutation in the C1-INH gene triggers kinin pathway activation.43 In type I HAE (85%), there is a quantitative deficiency in C1-INH.43 In type II HAE (15%), dysfunctional C1-INH is released.43
AE presents as nonpitting edema involving the deeper layers of the dermis and subcutaneous tissues. Compared to other forms of edema, AE is asymmetric, has a rapid onset, and occurs in nondependent areas of the body. It can present in the face, lips, hands, feet, and gastrointestinal tract with edema that has ill-defined margins. Gastrointestinal tract edema can present with acute vomiting, abdominal pain, and nausea with or without cutaneous features. Throat AE can cause rapid airway obstruction. There are three clinical forms of HAE: subcutaneous, abdominal, and laryngeal edema. In the subcutaneous form, edema is circumscribed, nonerythematous, nonpruritic, and not associated with urticaria. In the abdominal form, edema may manifest itself as vomiting, diarrhea, ileus, and diffuse abdominal pain, at times mimicking a surgical abdomen. In the laryngeal form, edema is life threatening and presents as stridor, dyspnea, hoarseness, and dysphagia.
Immediate airway assessment and intervention (as needed) along with administration of epinephrine (0.01 ml/kg intramuscular of 1:1000 solution) is of paramount importance in laryngeal angioedema. Epinephrine can be repeated at 5- to 15-minute intervals. Antihistamines, both H1 (diphenhydramine 1 mg/kg divided q6h) and H2 (famotidine 0.5 mg/kg IV with maximum dose of 40 mg), are also used in the treatment of AE. Steroids are indicated for airway involvement or extensive cutaneous involvement (dexamethasone 0.2 mg/kg). Any identified triggers should be removed and not used in any confirmatory allergy testing. For HAE, epinephrine, antihistamines, and steroids are ineffective and not recommended.44 In laryngeal HAE, the most important aspect is early, aggressive support of the airway. Pharmacologic interventions for acute attacks of HAE include plasma derived C1-INH concentrate or kallikrein inhibitor. Recombinant C1-INH is used in Europe, and recently, a bradykinin-receptor antagonist was approved for use in the United States for patients 18 years of age and older.44 Pharmacologic options are available for HAE prophylaxis, though there is no indication for their use by the emergency physician.
There is no routinely recommended laboratory test for AE. An elevated tryptase level may reflect mast cell degranulation, but normal levels do not exclude AE. In patients with recurrent AE, one may have to pursue an underlying autoimmune etiology. In HAE, complement C4 levels are usually low during acute attacks as well as between episodes. C1-INH levels help distinguish between type I and II HAE. Routine imaging is also not indicated, though abdominal ultrasound may help differentiate abdominal AE that mimics a surgical abdomen. In abdominal AE, 80% have ascites and edema of the intestinal wall.45