History
An important part of diagnosis of angioedema is the clinical history. The presence or absence of urticaria should always be considered and determined. When angioedema is associated with urticaria, the diagnosis and treatment approach will follow the intervention for urticaria. This chapter will primarily concentrate on those cases of angioedema without urticaria.
Important clinical information should include the following:
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Family history and prior personal experience of angioedema
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New food or medicine and any relation with the onset of angioedema – Question patients carefully regarding the use of medications with a higher risk of causing angioedema (eg, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory agents [NSAIDs], and antibiotics)
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Potential triggering or exacerbating factors
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Concurrent medical conditions
For acute and new-onset angioedema, special attention should be directed to the potential relation with food or drug intake, insect stings, or other unusual exposures. For chronic and recurrent cases, ask the patient about potential triggers, medication use and associated medical history, and past evaluation. A thorough family history is also important. Hereditary angioedema (HAE) types I and II are inherited in an autosomal dominant manner, though approximately 20-25% of cases are the result of spontaneous mutations.
During episodes, edema may occur in the subcutaneous tissue, the wall of the intestine, and the larynx. Patients usually describe swelling of the face (eg, eyelids, lips), tongue, hands, and feet; the genitalia can be affected, and rarely, edema of the soft palate may occur.
Angioedema can be acute or chronic, and each episode may last a few hours to a few days. A local burning sensation and pain can be observed without pronounced itchiness or local erythema. Abdominal pain occurs from intestinal involvement. It is sometimes accompanied by nausea, vomiting, and ascites; and can sometimes be the only presenting symptom of angioedema. Throat tightness, voice changes, and trouble breathing may indicate airway involvement.
In HAE, idiopathic angioedema (IAE), and drug-induced angioedema, episodes consist of relapsing, self-limiting edema. Episodes last for 1-7 days and are followed by a disease-free interval. The frequency and severity of the clinical symptoms are highly variable from patient to patient and even from episode to episode in the same patient. [36, 13]
The history may reveal triggers of the attack, such as local trauma (eg, a dental procedure or tonsillectomy) or stress. However, most episodes do not have a recognizable external trigger. The medication history may identify use of ACEIs or NSAIDs.
Physical Examination
In angioedema patients with skin involvement, examination can easily identify affected areas, which will exhibit edema of distensible tissues, often with ill-defined margins. The face, extremities, and genitalia are most commonly affected. [13] Urticaria may also be present.
Physical examination findings in patients with abdominal (intestinal mucosal) angioedema can vary widely. Massive edema of the submucosal tissue in the abdominal region may produce abdominal distention and signs consistent with bowel obstruction. In many cases, there may be no specific findings, even in severe cases of angioedema, and patients may have only changes in bowel sounds and diffuse or localized tenderness.
Uvula or tongue swelling can be visualized directly (see the image below). However, laryngoscopy is indicated to assess laryngeal or vocal cord involvement. Determining airway patency is the first step in airway assessment. In severe attacks, dyspnea can herald the onset of systemic anaphylaxis.
Documentation of swelling by means of physician notes, photographs (see the image below), or both is important.
Classification and Subtypes of Angioedema
Angioedema is a highly heterogeneous group of conditions. Because of its frequent coexistence with urticaria, it is often classified in the same manner as urticaria (eg, acute/chronic, allergic/pseudoallergic, physical, autoimmune, and idiopathic/spontaneous). However, it also includes categories not associated with urticaria, such as ACE inhibitor−induced and C1 esterase inhibitor (C1-INH) deficiency (hereditary or acquired). Thus, revising the classification to include angioedema with urticaria and angioedema without urticaria has been considered. [14, 15, 11]
Angioedema with urticaria has the following features:
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Acute (< 6 weeks) or chronic (>6 weeks)
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Allergic (eg, food, drug, insect sting venom, or latex)
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Pseudoallergic (eg, induced by NSAIDs)
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Physical (eg, from cold, vibration, pressure, or physical exercise)
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Autoimmune disease
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Idiopathic
Angioedema without urticaria is characterized by the following based on the new international work group recommendation: [16]
Acquired Angioedema (AAE)
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Idiopathic (no identifiable causes)
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Idiopathic histaminergic (IH-AAE): Responds to antihistamines
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Idiopathic nonhistaminergic angioedema (InH-AAE): No response to antihistamines
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Acquired angioedema related to ACEI (ACEI-AAE): On ACEI therapy, no other identifiable causes
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C1 INH deficiency (C1-INH-AAE): C1 INH Deficiency, no family history of angioedema, onset older than 40 years of age, low C1q. No genetic mutation in C1 INH gene. Secondary reduction of C1 INH function.
Hereditary Angioedema (HAE)
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Hereditary angioedema with C1 INH deficiency (C1-INH-HAE): C1 INH deficiency, impaired normal C1 INH production and/or function (de novo mutation may account for 25% of cases, therefore, negative family history may not rule out C1-INH-HAE).
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Normal C1 INH: Hereditary angioedema with FXII mutations (FXII-HAE) and hereditary angioedema of unknown origin (U-HAE). [16]
An Italian study of 1,058 consecutive angioedema patients without urticaria showed idiopathic histaminergic angioedema (IH-AAE) accounts for 56% of AAE, whereas ACEI-AAE represents 27% of AAE, InH-AAE is about 10% of AAE, and the rest, 7%, is C1-INH-AAE. [15]
Classification of angioedema without urticaria based on clinical or etiopathologic features. AAE = acquired angioedema; ACEI = angiotensin-converting enzyme inhibitors; HAE = hereditary angioedema; Specific triggers = food, drug, insect bite, environmental allergen, or other physical stimulus. Based on data from Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: a large clinical survey. CMAJ. Oct 24 2006; 175(9): 1065–70.
Complications
Angioedema can be life-threatening when it involves the larynx and upper airway. It can cause 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. [25]
Airway swelling can make intubation difficult. This may increase the risk of vocal cord damage during intubation. In patients with angioedema who present to the emergency department, 10-25% of such cases are considered to be life-threatening. [40, 42]
Angioedema is commonly associated with severe pain and disfiguration. These can interfere with daily function and adversely affect patient quality of life.
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Photographic documentation of swelling.
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Bradykinin production and metabolism.
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Classification of angioedema without urticaria based on clinical or etiopathologic features. AAE = acquired angioedema; ACEI = angiotensin-converting enzyme inhibitors; HAE = hereditary angioedema; Specific triggers = food, drug, insect bite, environmental allergen, or other physical stimulus. Based on data from Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: a large clinical survey. CMAJ. Oct 24 2006; 175(9): 1065–70.
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Angioedema secondary to angiotensin-converting enzyme (ACE) inhibitors.
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Types of angioedema.
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Pathways for production of prostaglandins and leukotrine from mobilized arachidonic acid.
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