Approach Considerations
The great majority of cases of angioedema can be diagnosed on the basis of the history and physical examination alone; extensive diagnostic workup and laboratory testing are rarely indicated. As in acute urticaria, upper respiratory tract and viral infections are considered as a common etiology, especially in children (see Differential Diagnosis). [14]
Most mild cases of angioedema do not require any laboratory tests. Screening for suspected allergies to food, stinging insects, latex, and antibiotics can be performed. Aeroallergen screening for patients with angioedema has limited value, except to establish atopic status. Special consideration should be given to those who present with recurrent angioedema without urticaria. In these cases, C1 INH deficiency should be evaluated.
Laboratory Studies
For angioedema without urticaria (especially those with recurrent episodes), diagnostic tests should include the following:
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C4 level
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C1 esterase inhibitor (C1-INH) quantitative and functional measurements
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C1q level
These studies will help to establish or rule out C1-INH deficiency–associated angioedema, either hereditary or acquired. The Joint Taskforce on Practice Parameters’ 2013 update of the 2000 angioedema practice parameters include diagnostic testing to differentiate among subtypes of angioedema without urticaria. [50] Such tests include measurements of C1-INH, C4, and C1q levels, as well as of C1-INH function, with the following results [50, 51] :
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C1 INH-HAE Type I – Low levels of C1-INH protein and function, low C4, but normal C1q;
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C1 INH-HAE Type II – Normal levels of C1-INH protein, but low levels of C4 and C1-INH function, normal C1q;
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FXII-HAE and U-HAE (previously known as HAE Type III, or HAE with normal C1 INH) – Normal levels of C1-INH protein and function, normal C4 and C1q;
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C1 INH-AAE (previously known as AAE) – Low levels of C1-INH protein and function, low C4 and low C1q;
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ACEI-AAE, IH-AAE and InH-AAE – Normal levels of C1-INH protein and function, normal C4 and C1q;
C1-INH-HAE types I and II are characterized by low levels of C1-INH or elevated levels of dysfunctional C1-INH, as detected by an immune assay. Between attacks, low levels of C4 are noted. Elevated prothrombin fragment F1 + 2 and D-dimer are associated with acute attacks in HAE. [52] Whether these markers have value in monitoring other types of angioedema requires additional research.
Screening tests
Screening laboratory studies have limited value in most cases. For recurrent angioedema without a clear trigger, clinicians may consider the following tests:
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Complete blood count (CBC) with differential
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Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level
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D-dimer level
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Urinalysis
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Comprehensive metabolic profile
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Antinuclear antibody (ANA) testing
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CH50 level
Consider thyroid studies, including levels of thyroid-stimulating hormone, free T4, and thyroid autoantibody (antimicrosomal or antithyroglobulin), particularly in women or in patients with a family history of thyroid disease or other autoimmune diseases.
Other studies
If the initial laboratory tests yield abnormal results or if a specific medical condition is suspected, additional tests may be needed. Evaluation for possible occult infection can be considered.
Chronic infection is a potential cause of unexplained angioedema (with or without urticaria). With this consideration, the diagnostic approach for detecting potential chronic infection may be considered.
Other tests to consider if the history and physical examination findings suggest specific problems include the following:
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Stool analysis for ova and parasites
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H pylori workup
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Hepatitis B and C workup
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Rheumatoid factor
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Cryoglobulin levels
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Imaging studies (see Radiologic Studies)
Assays for serum histamine–releasing factors and evaluation for specific autoantibodies (anti-immunoglobulin E [IgE] receptor and anti-IgE) are performed by some research centers. These tests are not approved by the US Food and Drug Administration (FDA) and currently are available from only a few laboratories (eg, National Jewish Health, Denver, CO; IBT Reference Lab, Lenexa, KS).
When the CH50 or C4 level is low, additional tests for C1-INH function and C1q level should be considered. Patients with a low C1q level may require additional hematologic evaluation.
Histologic findings
Histologic findings in angioedema are nonspecific. Significant inflammation is usually absent; skin morphology is usually intact. Eosinophil infiltration is not a common feature of angioedema (except in Gleich syndrome).
Allergy Testing
The diagnosis of IgE-mediated angioedema is usually made on the basis of the history. However, epicutaneous skin testing or radioallergosorbent tests (RASTs) for foods may be confirmatory. Identifying the potential triggers is a critical step of successful control of angioedema with or without urticaria. When food or drug hypersensitivity is suspected, allergy testing will be advisable, especially those with a history resembling type I hypersensitivity.
Skin tests for penicillin and local anesthetics have high sensitivity and specificity. Skin tests for other drugs have greater variability; accordingly, greater expertise is required for their interpretation. Allergy skin tests are not useful in diagnosing angioedema related to nonsteroidal anti-inflammatory drugs (NSAIDs) or ACE inhibitors.
Radiologic Studies
Most angioedema patients do not need any imaging studies. Findings from abdominal radiography and computed tomography (CT) are reported to be consistent with small bowel wall edema during angioedema attacks. [4, 5, 2] Other findings during such attacks may include soft-tissue swelling in the neck. [1] However, the sensitivity and specificity of these studies for angioedema have not been adequately studied. At present, therefore, routine use of such studies to confirm or rule out angioedema is not advisable.
When internal organ involvement is suspected, during acute attacks, the following studies can be performed:
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Plain abdominal radiography – Plain films may show a “stacked coin” or “thumbprint” appearance of the intestines [4]
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Abdominal ultrasonography – Sonograms may show ascites
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CT of the abdomen – Scans may show severe edema of the bowel wall [1]
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Radiography of the chest – Chest x-rays may show pleural effusion
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Radiography of cervical soft tissue – Neck films may show soft-tissue swelling [5]
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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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