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Less common but clearly identifiable causes of angioedema include drug use and alteration of complement metabolism. A recent prospective study noted that angioedema due to angiotensin-converting enzyme inhibitor (ACE-I) use occurred in 86 of 12,557 patients (0.68%) (12). ACE-I-induced angioedema was about three times more likely to occur among black patients (1.62% vs. 0.55% for white patients), and slightly more likely in women (0.84% vs. 0.54% for men). Approximately 50% of patients with ACE-I-induced angioedema experience their first episode within the first week of treatment; however, some patients may have ACE-I for months before angioedema develops.

The prevalence of hereditary angioedema (HAE), an autosomal-dominant disease, is about 1:50,000 persons (13). This disease has been reported in all races. It is due to a mutation in one copy of the inhibitor of the first component of complement. A disorder with similar pathogenesis can be acquired in patients with an unusual complement consumption profile due to lymphoma or in patients generating an IgG autoantibody to the inhibitor itself.

PATHOGENESIS

The swelling of angioedema is caused by local plasma extravasation. This occurs after a rapid increase in the permeability of submucosal and postcapillary venules.

Although angioedema may be precipitated by both immune-mediated and non-immune-mediated mechanisms, it is more easily classified into those mediated by mast cell degranulation and those mediated by bradykinin.

Immune-mediated mechanisms include those dependent on IgE (food allergy, drug allergy, hymenoptera sting, and inhaled/contact allergens) and those that are immune-complex-mediated (mononucleosis, other viral syndromes, and systemic lupus erythema-tosus). Inhibition of prostaglandin synthesis through cyclo-oxygenase (COX)-1 may cause angioedema as substrates are redirected to the lipo-oxygenase pathway, resulting in the production of cysteinyl LTs and vasoactive hydroxyl fatty acids, which presumably act on mast cells. (See also below.) Chronic angioedema (episodes that are recurrent over a greater-than-six-week period) may be idiopathic, accompany presumed mast-cell-dependent physical urticarias (cholinergic, cold, solar, and heat urticaria) or exercise anaphylaxis, or be associated with autoantibodies affecting mast-cell function. Anti-IgE and anti-FC epsilon receptor 1 (on mast cells) antibodies have been identified; these are found to occur quite commonly along with antithyroglobulin and antimicrosomal antibodies (14).

Bradykinin is the mediator responsible for ACE-I-associated angioedema and HAE. ACE inactivates bradykinin, a powerful vasoactive peptide in human skin. Inhibition of ACE results in slow bradykinin inactivation, with consequent bradykinin accumulation and vasodilatation (13).

Patients with HAE have defects in C1 inhibitor function (15). C1 is the first component of the complement cascade. Type 1 HAE patients have a quantitative defect in C1 inhibitor due to a truncating mutation that prevents synthesis, while Type 2 HAE patients have a functional defect due to an inactivating mutation that does not prevent protein secretion. In both, one normal gene is present. Recently, Type 3 HAE has been described, where both the C1 inhibitor levels and function are normal. This occurs exclusively in women and is suspected to be associated with estrogen activity. C1 inhibitor levels may be exhausted in situations of rapid complement utilization (lymphoma) or in the presence of an autoantibody to the inhibitor itself.

C1 inhibitor deficiency causes excessive formation of the enzyme kallikrein, resulting in increased production of bradykinin. C1 inhibitor is also responsible for keeping the complement cascade in check; thus, deficiency leads to increased spontaneous activation of C1 with secondary consumption of C2 and C4.

CLINICAL MANIFESTATIONS

Angioedema preferentially affects the face, hands, arms, legs, and genitalia.

Acute allergic angioedema is often (about half the time) accompanied by urticarial lesions. Mucosal or cutaneous angioedema can occur within minutes of ingestion or injection of an offending agent. Swellings typically subside within 24 to 48 hours, although relapses may occur. The areas of swelling do not leave any residual bruising unless vigorously rubbed. Some episodes of acute allergic angioedema are accompanied by symptoms of anaphylaxis, including bronchospasm and hypotension.

Angioedema due to ACE-I has a predilection for the head, neck, lips, mouth, tongue, larynx, pharynx, and subglottic areas, without urticaria (16).

Patients with HAE are usually asymptomatic until the second decade of life. Some episodes may be preceded by a nonpruritic urticarial eruption, but generally, such episodes occur in the absence of urticaria. Swellings may be precipitated by exercise, stress, alcohol consumption, hormonal factors, and even minor trauma such as dental procedures (13). In contrast to angioedema due to other factors, the swelling in HAE patients may slowly spread and persist for up to three to four days. Angioedema can also mimic an acute intestinal obstruction with associated abdominal pain and vomiting.

The most feared and potentially fatal presentation of angioedema involves the mucosae of the pharynx, larynx, and subglottic areas. Stridor and dyspnea may precede respiratory obstruction, asphyxia, and sometimes death. ACE-I angioedema is the most common cause of acute angioedema presenting to emergency departments (17-38%) (17), and up to 20% may be life threatening. In a series of 225 patients with both hereditary and acquired angioedema, 10% required intubation or tracheostomy at least once. Thus, prompt identification and management of airway angioedema is essential in preventing mortality (18).

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The differential diagnosis of angioedema includes superior vena cava syndrome, facial cellulitis, allergic contact or photodermatitis, Crohn's disease of the mouth and lips, dermato-myositis, facial lymphedema, tumid or discoid lupus erythematosus, Ascher syndrome, and Melkersson-Rosenthal syndrome (13). A complete history, including symptoms of associated urticaria, duration, location, potential precipitants, medication history (particularly of ACE-I and B-adrenergic blocking agents), and systemic manifestations, is essential. Physical exam must focus on airway evaluation and visualization of the lesion(s) and other associated disease processes. Historical factors should lead to directed blood work. Epicutaneous or radioallergosorbent testing (RAST) testing may be used for suspected allergens. Laboratory studies for evaluation of HAE include C1 inhibitor levels and function, C4 level, and C1q (if decreased, this would indicate acquired C1 inhibitor).

TREATMENT

If the respiratory tract is involved, securing the airway is the top priority. Approaches to consider include nasopharyngeal intubation, endotracheal intubation (which is often difficult), nasotracheal intubation, and cricothyrotomy. IV access should be obtained. IM epinephrine (0.3 mL of 1:1000) should be given to reduce the edema and may be repeated every 10 minutes. Admission to the hospital with careful observation for 24 hours is suggested for patients with laryngeal edema.

In cases of idiopathic angioedema, or in anaphylaxis with angioedema, use of epinephrine is critical. Diphenhydramine (50 mg) IM or IV and solumedrol IV (40 mg) may be helpful acutely, and chronic angioedema should be treated with daily anti-histaminics. In some situations, LT receptor antagonists, or even immunosuppressants, may be helpful in controlling chronic angioedema.

Patients with HAE will not respond to these measures. Intravenous fresh frozen plasma or C1 inhibitor concentrate (not yet available in the United States except in clinical trials) are effective by raising serum levels of C1 inhibitor sufficiently to prevent ongoing bradykinin and complement activation (19). In HAE, fibrinolytic inhibitors have been employed to ameliorate acute angioedema. Discontinuing any offending medication is essential. Preventive medications for patients with both Type 1 and Type 2 HAE include anabolic steroids (danazol and stanazolol) and antifibrinolytic agents. Anabolic steroids have been shown to increase the circulating levels of C1 inhibitor by decreasing consumption of the product of the normal C1-inhibitor gene (15).

COMPLICATIONS AND PROGNOSIS

Relapses can occur after an episode of ACE-I angioedema apparently resolves, despite discontinuing the offending drug. If unidentified, episodes of angioedema after repeated ACE-I exposure may lead to more severe attacks (20). A series evaluating patients with HAE noted that the average time between onset of laryngeal edema and asphyxiation was seven hours (18). The interval between onset of the laryngeal edema and asphyxiation was 20 minutes in a nine-year-old boy with no previous clinical signs of HAE. The retrospective survey of 58 patients with HAE revealed 40% of deaths by asphyxiation. A case fatality rate for anaphylaxis is difficult to determine and is not known for angioedema associated with urticaria or that which occurs independently in the absence of a known inciting cause.

The prognosis for known instances of HAE and for ACE-I-mediated angioedema is excellent with proper treatment. In cases of anaphylaxis in which the inciting agent is known, prognosis is good if the offending agent can be avoided, and if IM adrenaline (Epi-penĀ®) is available for immediate use. Such patients should avoid ACE-I and B-adrenergic inhibitory agents. In idiopathic chronic angioedema, maintenance treatment is built on use of antihistaminics, and the natural history is that many patients become free of angioedema after 5 to 20 years.

SUMMARY

Multiple mechanisms may produce the end result of angioedema. After evaluation of the airway, a thorough history may provide the necessary clues to guide the appropriate management of this disorder.

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