Angioedema 

Angioedema is the swelling of deep dermis, subcutaneous, or submucosal tissue due to vascular leakage.^{[1, 2]} It was first described in 1586.^[3] Other terms, such as giant urticaria,^[4] Quincke edema,^[5] and angioneurotic edema,^[6] have also been used in the past to describe this condition. Clinically, angioedema is usually nonpitting and nonpruritic. The area of involvement is often skin-colored or slightly erythematous. Depending on the area of swelling, pain can be absent or mild, as in most peripheral or facial swelling, or it can be very severe, as in gastrointestinal angioedema. (See Clinical.)

Acute episodes may involve the skin, larynx, and buccal and gastrointestinal (GI) mucosa.^[7] Laryngeal swelling is life-threatening and should be treated as a medical emergency (see the image below). (See Treatment and Medications.)

Angioedema is often associated with urticaria. In fact, almost 50% of patients who present with urticaria also have angioedema.^[8] In many cases, urticaria and angioedema are remarkably similar in underlying etiology and in clinical management strategies. (See Etiology, Treatment, and Medications.)

On the other hand, angioedema is also quite different from urticaria. It usually involves a deeper layer of skin (reticular dermis) or subcutaneous or submucosal tissue, whereas urticaria affects a more superficial layer of skin (papillary dermis and middermis). In fact, mucosal involvement is observed in angioedema but not in urticaria. In addition, pruritus is the most prominent complaint in urticaria but is less troublesome or absent in angioedema. Furthermore, pain or tenderness is uncommon in urticaria but frequent and sometimes severe in angioedema. Addressing these differences is necessary for the successful treatment of angioedema. (See Clinical.)

Angioedema, with or without concurrent urticaria, has a variety of etiologies. This article concentrates on angioedema without urticaria. For angioedema associated with urticaria, the treatment strategies are essentially the same as discussed those found in Acute Urticaria. (See Etiology.)

The swelling of the affected area of angioedema is a result of the fast onset of increase of local vascular permeability in submucosal and subcutaneous tissue. Immunoglobulin E (IgE) ̶ mediated mast cell activation and degranulation, key elements of an allergic reaction, often manifest as urticaria and angioedema. Non–IgE-mediated mast cell activation/mediator release may explain certain autoimmune-mediated and idiopathic angioedema.^[9]

In addition to mast cells, many other cells, such as macrophages, dendritic cells, lymphocytes, monocytes, eosinophils, and endothelial cells, have been shown to be involved in the pathogenesis of angioedema.^{[1, 10]} Plasma and tissue factors, such as bradykinin, and certain components in contact system or fibrinolytic systems are also found to play an important role in certain forms of angioedema.^{[11, 12]}

Angioedema can be categorized as allergic, pseudoallergic, nonallergic, or idiopathic. More than 40% of chronic angioedema is idiopathic. All cases of angioedema pose significant diagnostic and treatment challenges. Trauma, surgical procedure, and stress are common nonspecific triggers for angioedema attacks.

Allergic angioedema

Allergic angioedema is often associated with urticaria. It is typically observed within 30 minutes to 2 hours after exposure to the allergen (eg, food, drug, venom, latex). Brown et al, reporting on 142 patients with anaphylaxis who presented in the emergency department found that angioedema was present in 40% of the cases (49.3% of those with urticaria).^[13]

Pseudoallergic angioedema

Pseudoallergic angioedema is not IgE-mediated. However, its clinical course and presentation is very similar to allergic angioedema. Typical examples are angioedema induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and intravenous contrast material; aspirin is the most common culprit.

True IgE-mediated reactions to aspirin or other NSAIDs are uncommon. The angioedema (with or without urticaria) reflects the pharmacologic properties of the drugs. By inhibiting cyclooxygenase (COX), aspirin and NSAIDs lead to overproduction of proinflammatory and vasoactive leukotrienes. COX-2 inhibitors and acetaminophen do not usually cause angioedema.

Nonallergic angioedema

Nonallergic angioedema does not involve IgE or histamine; urticaria is generally not associated with this type of angioedema.

Hereditary angioedema (HAE) is perhaps the prototype of this type of angioedema. Decreased functional C1-inhibitor (C1-INH) production leading to unchecked bradykinin production is believed to be the fundamental change in HAE types I and II.^{[14, 15]} Acquired angioedema (AAE) also has decreased C1-INH function due to autoantibody production or accelerated consumption of C1-INH.

Angiotensin-converting enzyme (ACE) inhibitor–induced angioedema (AIIA) is bradykinin-mediated, as in cases of HAE and AAE. Most AIIA is observed in the first week after starting the medicine; however, up to 30% of AIIA starts months, or even years, after starting the medicine.^{[16, 17]} Therefore, it can easily be overlooked as a cause for angioedema. AIIA is not drug-specific. ACE inhibitors interfere with the degradation of bradykinin, a potent vasoactive nonapeptide. (See the diagram below.)

The most common sites of ACE-induced angioedema are the face, lip, and tongue. However, abdominal involvement has been reported.^[1] It usually starts with severe abdominal pain. Abdominal CT scans can be informative.

Genetic screening for ACE polymorphism may help identify at risk population for AIIA. Patients with AIIA may have a risk of developing angioedema when switching to an angiotensin II receptor blocker (ARB) in 0-9.2% of cases.^[14]

Idiopathic angioedema

The causes of idiopathic angioedema are, by definition, not identifiable. Furthermore, the exact mechanisms are unclear.^{[18, 19]} Some may be associated with urticaria. Based on responses to medication, some cases are thought to be mediated by mast cell activation, albeit IgE-independent.

Common triggers include heat, cold, emotional stress, and exercise. Nonspecific mast cell activation and degranulation are suspected causes.

Thyroid autoantibodies are found in 14-28% of patients with chronic urticaria/angioedema, and IgG autoantibodies to either the high affinity receptor for IgE (FceRI) or to IgE are found in 30-50% of patients with chronic urticaria/angioedema.^{[18, 20]} In affected individuals, autoantibody (IgG) has been found to crosslink FceRI on mast cells, resulting in mast cell activation and release of histamine, cytokines, and other proinflammatory mediators. Immunomodulatory drugs may be beneficial for this type of angioedema.^[21]

The link between infection and angioedema is vague at best. Helicobacter pylori infection has been found to be associated with HAE exacerbation. Treatment of H pylori infection has led to clinical improvement of chronic urticaria and angioedema.^[22] Systemic viral, bacterial, or parasitic infection may stimulate the immune system and cause improper activation or inflammatory changes.

C1-INH functions normally in estrogen-dependent angioedema.^[23] This has been proposed as HAE type III. The exact mechanism of angioedema in these patients is still unclear.^[24] In some of the affected patients, FXII point mutation results in a gain of function that can potentially affect the metabolism of bradykinin.^[25]

Patients with Gleich syndrome exhibit elevated eosinophils with angioedema. Gleich syndrome, which responds well to corticosteroids, is thought to be related to hypereosinophilic syndrome.^[26] In addition to the elevated eosinophil count, IgG autoantibody against endothelial cells has been identified. The image below compares types of angioedema.

Occurrence

In the United States, angioedema (excluding hereditary angioedema [HAE] and acquired angioedema [AAE]) may affect 10-20% of the population at some time in their lives.^{[18, 19]} The great majority of chronic angioedema is idiopathic.^[18] HAE is an autosomal dominant genetic disorder with an estimated prevalence of 1 per 10,000-150,000 persons.^[27] AAE is even less common. Until 2006, about 136 cases had been reported in the literature.^[28] The reported incidence of ACE inhibitor ̶ induced angioedema varies from 0.1% to 6%.^[16]

International occurrence rates for angioedema are believed to be similar to those reported in the United States.

Race-related demographics

African Americans are more susceptible to angioedema induced by ACE inhibitors. Compared with white persons, the adjusted relative risk is about 3.0 to 4.5.^[16] Other forms of angioedema have no clear association between race and the disease frequency or severity.

Sex-related demographics

Estrogen may exacerbate certain forms of angioedema. In HAE, affected women tend to have more frequent attacks and run more severe clinical courses. HAE type III is found predominantly in women. In these patients, taking oral contraceptives that contain estrogen is often a triggering factor for angioedema.^[24] Chronic idiopathic angioedema is more common in females than in males. Other types of angioedema do not show a strong sex predilection.

Age-related demographics

Angioedema can affect patient of all ages. Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Allergic reactions to food are more common in children. For patients with HAE, the onset of symptoms is often around puberty. The average age for angioedema induced by ACE inhibitors is 60 years. Idiopathic angioedema is more common among persons aged 30-50 years than among other age groups.

The prognoses for angioedema include the following:

• Angioedema induced by allergies or medications - Usually resolves once the triggers are identified and avoided
• Chronic idiopathic angioedema - Runs a variable course, which may be a few weeks to a few years; in a small percentage of patients, symptoms may persist for more than 10 years.
• Hereditary angioedema (HAE) - Often requires lifelong treatment
• Acquired angioedema (AAE) - The outcome of depends on the treatment of underlying lymphoproliferative or autoimmune disorders

Complications

Angioedema can be life threatening when it involves the larynx and upper airway, leading to trouble breathing, asphyxia, and even death. (Throat pain or discomfort, dysphonia, and dysphasia may indicate laryngeal involvement.) Asphyxiation due to laryngeal edema yields a 3-40% mortality rate.^[29]

Airway swelling can make intubation difficult; the risk is increased for vocal cord damage during intubation. Of angioedema presented in the emergency room, 10-25% of cases are considered to be life threatening.^{[30, 31]}

Other complications, such as severe abdominal pain, bowel obstruction, acute pancreatitis, and skin rupture, have been described.

Angioedema is one of the most troubling complications of an acute allergic reaction. In one study, 69.4% of 138 patients who had anaphylaxis were found to have angioedema.^[30] In addition to the disfiguring appearance, patients often report local pain and discomfort. When angioedema affects the hands and feet, walking and many other daily activities are impaired. Abdominal pain is common when the GI tract is involved; it can be severe and disabling.

Individuals with allergies to food, venom, or medications need to be educated regarding allergen avoidance. For patient education information, see the Allergies Center and the Skin Conditions and Beauty Center, as well as Hives and Angioedema, Severe Allergic Reaction (Anaphylactic Shock), Food Allergy, and Drug Allergy.

Patients must be educated regarding the indications for and proper technique of epinephrine autoinjector administration and the need to seek further medical assistance following administration.

Other recommended Web sites include the following:

• World Allergy Organization (WAO)
• American Academy of Allergy, Asthma, and Immunology (AAAAI)
• American College of Allergy, Asthma, and Immunology
• Joint Council of Allergy, Asthma, and Immunology
• Food Allergy and Anaphylaxis Network (FAAN)
• Hereditary Angioedema Association