Angioedema
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Angioedema is the swelling of deep dermis, subcutaneous, or submucosal tissue due to vascular leakage. [1, 2] Acute episodes often involve the lip, eyes, and face (see the image below); however, angioedema may affect other parts of body, including respiratory and gastrointestinal (GI) mucosa. Laryngeal swelling can be life-threatening.
Angioedema may affect many organ systems. Visible swelling is common in peripheral angioedema. It is often associated with local burning sensation and pain without pronounced itchiness or local erythema. The most commonly involved areas are:
Peripheral swelling: skin and urogenital area (e.g., eyelids or lips, tongue, hands, feet, scrotum, etc.)
Abdomen: Abdominal pain (sometimes it can be the only presenting symptom of angioedema)
Larynx: Throat tightness, voice changes, and breathing trouble (indicators of possible airway involvement), potentially life-threatening.
See Presentation for more detail.
Examination in patients with suspected angioedema includes the following:
Dermatologic – Areas of swelling with or without erythematous skin, often with ill-defined margins; the face, extremities, and genitalia are most commonly affected [3]
GI – No specific findings may be present, even in severe cases of angioedema, or there may be abdominal distention and signs consistent with bowel obstruction; changes in bowel sounds and diffuse or localized tenderness may be present; the clinical picture may resemble that of an acute abdomen
Upper airway – Direct visualization of the uvula or tongue swelling; laryngoscopy is needed to assess laryngeal or vocal cord involvement; document swelling by means of physician notes, photographs, or both
Severe attacks of angioedema can herald the onset of systemic anaphylaxis, characterized initially by dyspnea. Many cases of angioedema occur in patients with urticaria.
Testing
Most mild cases of angioedema do not require laboratory testing. Suspected allergies to food, stinging insects, latex, and antibiotics can be screened and diagnosed. The value of aeroallergen screening for patients with angioedema is limited, except with regard to establishing atopic status.
For angioedema without urticaria (especially those with recurrent episodes), diagnostic tests should include the following:
C4 level
C1 esterase inhibitor (C1-INH) quantitative and functional measurements
C1q level
Screening laboratory studies have limited value in most cases. For chronic or recurrent angioedema without a clear trigger, clinicians may consider the following tests:
CBC with differential
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level
D-dimer level
Urinalysis
Comprehensive metabolic profile
Antinuclear antibody (ANA) testing
CH50 level
Thyroid studies, including levels of thyroid stimulating hormone, free T4, and thyroid autoantibodies (antimicrosomal and antithyroglobulin), particularly in women or in patients with a family history of thyroid disease or other autoimmune diseases
If the history and physical examination findings suggest specific problems, other tests that may be helpful include the following:
Stool analysis for ova and parasites
Helicobacter pylori workup
Hepatitis B and C virus workup
Rheumatoid factor
Cryoglobulin levels
Imaging studies
Imaging studies
Most angioedema patients do not need any imaging studies. However, when internal organ involvement is suspected, during acute attacks, the following studies can be performed:
Plain abdominal films – These may show a “stacked coin” or “thumbprint” appearance of the intestines [4]
Abdominal ultrasonography – This may show ascites.
Abdominal computed tomography – This may show severe edema of the bowel wall [1]
Chest radiography – This may show pleural effusion
Soft-tissue neck radiography – This may show soft-tissue swelling [5]
See Workup for more detail.
The primary goal of medical treatment for angioedema is to reduce and prevent swelling, as well as to reduce discomfort and complication.
Most medications used in treating urticaria and anaphylaxis are also used in the management of many types of angioedema. Epinephrine should be used when laryngeal angioedema is suspected. In addition, supportive care should be provided, regardless of the etiology.
Pharmacotherapy
Medications used in the management of angioedema include the following:
Alpha- and beta-adrenergic agonist agents (eg, epinephrine)
First-generation antihistamines (eg, diphenhydramine, chlorpheniramine, cyproheptadine, hydroxyzine hydrochloride)
Second-generation antihistamines (eg, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine)
Histamine H2 antagonists (eg, ranitidine, cimetidine)
Leukotriene receptor antagonists (eg, montelukast, zafirlukast)
Tricyclic antidepressants (eg, doxepin)
Corticosteroids (eg, prednisone, methylprednisolone, prednisolone)
Androgen derivatives (eg, danazol, oxandrolone), progesterone-based birth control pills.
Antifibrinolytic agents (eg, aminocaproic acid, tranexamic acid)
Immunomodulators (eg, cyclosporine, mycophenolate, methotrexate, )
Agents for treatment or prophylaxis: C1 INH concentrates, ecallantide, lanadelumab, and icatibant.
Surgical option
In severe cases of laryngeal edema, a surgical airway must be created via cricothyrotomy or tracheotomy.
See Treatment and Medication for more detail.
Angioedema, first described in 1586, [6] is usually defined by pronounced swelling of the deep dermis, subcutaneous or submucosal tissue, or mucous membranes as a result of vascular leakage. [3] Other terms, such as giant urticaria, [7] Quincke edema, [8] and angioneurotic edema, [9] have also been used in the past to describe this condition. Clinically, angioedema is usually nonpitting and nonpruritic. Involved skin often shows no change in color or may be slightly erythematous (see the image below).
Angioedema is most commonly observed affecting the lips and eyes (periorbital). Other commonly involved areas may include the face, hands, feet, and genitalia. However, this condition is not always visible, as in cases involving the gastrointestinal (GI) tract. [10] 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 GI angioedema. (See Presentation.)
Swelling that involves the tongue and upper airways is cause for greater concern than swelling involving other areas, owing to the potential of airway compromise. [11, 12] Laryngeal swelling is life-threatening and should be treated as a medical emergency.
Disfiguration, pain, and reduced function are common complaints in patients with angioedema, but this condition is also commonly associated with urticaria. When both angioedema and urticaria are evident during clinical presentation, the episode is primarily mast cell−mediated. [13] Affected patients describe subjective pruritus, sometimes associated with hypersensitivity to an offending agent (eg, a food or drug). However, the underlying triggers are often unidentifiable.
There are also a significant number of angioedema cases that present with angioedema alone. In such cases, the clinical presentation, trigger, cause, and response to treatment may be quite different from those in cases that present with both angioedema and urticaria; therefore, some experts believe that these patients may (at least in part) have different pathophysiologic mechanisms. [11] Many such cases do not respond to antihistamines. Vasoactive mediators other than histamine (eg, bradykinin) may be involved in the swelling. [11] (See Pathophysiology.)
Although angioedema can manifest as an episodic or self-limiting event, it can often be described as recurrent or chronic. Thus, classification is not always straightforward. Because most cases of angioedema are found to be associated with urticaria, those cases usually follow the classification of urticaria (ie, acute vs chronic or induced vs spontaneous). [14] For angioedema that is not associated with urticaria, other classifications have been suggested. [15, 11] (See Classification and Subtypes of Angioedema.) The most recent classification for recurrent angioedema without the presence of urticaria has also been proposed by an international angioedema work group. [16]
This article concentrates on angioedema without urticaria. For angioedema associated with urticaria, the treatment strategies are essentially the same as those for acute urticaria (see Acute Urticaria). Angioedema caused by decreased functional C1-esterase inhibitor (C1-INH) is covered elsewhere as well (see Hereditary Angioedema [HAE] and Acquired Angioedema [AAE]).
Angioedema is a result of the fast onset of an increase in local vascular permeability in subcutaneous or submucosal tissue. Histamine and bradykinin are the most recognized vasoactive mediators known to be critical in the pathologic process of angioedema; most cases of angioedema are primarily mediated by 1 of these 2 mediators, though some investigators indicate the possibility that both may be involved in certain cases. [17] (See Classification and Subtypes of Angioedema.)
Other vasoactive mediators are, at least in part, involved in the pathogenesis of various types of angioedema. Leukotrienes, for example, may play an important role in the onset of angioedema that is induced by nonsteroidal anti-inflammatory drugs (NSAIDs). [18] Thus, factors influencing histamine release, bradykinin metabolism, and endothelial cell function or permeability may directly or indirectly regulate the process of angioedema.
For histamine-mediated angioedema (histaminergic angioedema), mast cells and basophils are the primary sources of histamine. The activation of mast cells or basophils with subsequent histamine release may be either mediated or unmediated by immunoglobulin E (IgE). IgE-mediated mast cell activation and degranulation, key elements of an allergic reaction, often manifest as urticaria and angioedema. Type I hypersensitivity reactions, such as food or drug allergies, are typically IgE-mediated.
Non–IgE-mediated mast cell activation or mediator release may explain certain autoimmune-mediated and idiopathic angioedema. [19] Numerous inflammatory mediators and cytokines and chemokines are known to influence histamine release and activation of mast cells and basophils. In addition, C3a and C5a are known to activate mast cells or basophils via an IgE-independent pathway.
Mast cells can also be activated by other non–IgE-mediated processes, such as the binding of IgG antibodies to IgE receptors on mast cells or basophils, leading to spontan
More than 40% of chronic angioedema is idiopathic. Trauma, surgical procedures, and stress are common nonspecific triggers for angioedema attacks.
Angioedemas with identifiable etiologies include those caused by the following:
Hypersensitivity (eg, food, drugs, or insect stings)
Physical stimuli (eg, cold or vibrations)
Autoimmune disease or infection
ACE inhibitors
NSAIDs
C1-INH deficiency (hereditary and acquired)
Angioedemas with unidentifiable etiologies include idiopathic angioedema (histaminergic or nonhistaminergic).
Angioedema has also been associated with certain conditions or syndromes, such as the following:
Cytokine-associated angioedema syndrome (ie, Gleich syndrome or episodic angioedema with eosinophilia) [37]
Well syndrome or eosinophilic cellulitis (ie, granulomatous dermatitis with eosinophilia) [38]
Hypersensitivity (allergic) angioedema is often associated with urticaria. It is typically observed within 30 minutes to 2 hours after exposure to the allergen. Mast cell–mediated angioedema or urticaria may be triggered by food, drugs, animal bites, stings (eg, from Hymenoptera), preservatives, or food coloring. [13] Food coloring and preservatives may cause angioedema with or without urticaria. [25]
Allergic angioedema may be associated with urticaria and anaphylaxis. In an Australian study of all anaphylaxis presentations to an adult emergency department (ED) in a single year, angioedema was present in 40% of the 142 cases (49.3% of those with urticaria). [39] In a Korean study, 69.4% of 138 patients who had anaphylaxis were found to have angioedema. [40]
“Pseudoallergic” angioedema (PAE) is not mediated by IgE; that is, the angioedema is caused by a nonallergic or nonimmunologic reaction. However, its clinical course and presentation are very similar to those of allergic angioedema. Typical examples are angioedema induced by NSAIDs and that induced by intravenous (IV) contrast material; aspirin (ASA) is the most common culprit.
True IgE-mediated reactions to ASA or other NSAIDs are uncommon. The angioedema (with or without urticaria) reflects the pharmacologic properties of the drugs. By inhibiting cyclooxygenase (COX), ASA and NSAIDs cause overproduction of proinflammatory and vasoactive leukotrienes. COX-2 inhibitors and acetaminophen (APAP) do not usually cause angioedema.
Nonallergic angioedema does not involve IgE or histamine and is generally not associated with urticaria. The 5 types of nonallergic angioedema are as follows [20] :
HAE
AAE
Renin-angiotensin-aldosterone system (RAAS)-blocker-induced angioedema (RAE)
PAE
IAE
Hereditary angioedema
HAE, a rare autosomal dominant disorder, is perhaps the prototype of nonallergic angioedema. [27] Most patients report a family history of disease, but approximately 20–25% of cases are the result of spontaneous mutations. More than 150 mutations in the C1 INH gene on the long arm of chromosome 11 have been associated with HAE. [41] As noted (see Pathophysiology), 3 types of HAE have been identified.
Acquired angioedema
Acquired angioedema, now known as C1-INH-AAE is a rare disorder caused by accelerated consumption of C1-INH or the production of autoantibodies to C1-INH. Onset is usually in the fourth decade of life. C1-INH-AAE is often associated with autoimmune diseases and lymphoproliferative disorders. [25]
ACE inhibitor–induced angioedema (ACEI-AAE or AIIA)
ACE inhibitors can precipitate attacks of angioedema by directly interfering with the degradation of bradykinin, thereby potentiating its vasoactive effect. ACE inhibitor–induced angioedema (AIIA or ACEI-AAE) is bradykinin-mediated, as in cases of HAE and AAE. ACEI-AAE occurs when ACE inhibitors interfere with the degradation of bradykinin, a potent vasoactive nonapeptide.
In a multicenter study, ACEI-AAE accounted for almost one-third of angioedema cases treated in the ED; however, it remains a rare ED presentation. [42] Most ACEI-AAE is observed in the first week after starting the medicine; in as many as 30% of cases, however, onset occurs after months, or even years, of taking the medicine. [30, 42] In later-onset cases, the ACE inhibitor can easily be overlooked as a cause of angioedema.
The most common sites of ACEI-AAE are the face, lip, and tongue, but abdominal involvement has been reported as well. [3] Abdominal computed tomography (CT) can be informative in cases with GI involvement. [2]
Genetic screening for ACE polymorphism may help identify the population at risk for ACEI-AAE. In 0-9.2% of cases, patients with ACEI-AAE may develop angioedema when switching to an angiotensin II receptor blocker (ARB). [30]
Physically induced angioedema
Physically induced angioedema is caused by physical agents, such as cold, heat pressure, vibration, and ultraviolet radiation. [25] This manifestation may occur with or without urticaria. Cold-induced angioedema and urticaria have been reported in association with cryoglobulins, cold agglutinin disease, cryofibrinogenemia, and paroxysmal cold hemoglobinuria. (See Anaphylaxis, Urticaria, and Acute Urticaria.)
The causes of IAE are, by definition, not identifiable. Furthermore, the exact mechanisms are unclear, though nonspecific mast cell activation and degranulation are suspected. [43, 26] On the basis of responses to medication, some cases are thought to be mediated by mast cell activation, albeit independent of IgE. Some cases may be associated with urticaria. Common triggers include heat, cold, emotional stress, and exercise.
The link between infection and angioedema is vague at best. Helicobacter pylori infection has been found to be associated with HAE exacerbation, and treatment of H pylori infection has led to clinical improvement of chronic urticaria and angioedema. [28] 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. [44] This has been proposed as HAE type III. The exact mechanism of angioedema in these patients is still unclear. [31] In some of the affected patients, factor XII (FXII) point mutation results in a gain of function that can potentially affect the metabolism of bradykinin. [45]
Patients with Gleich syndrome exhibit elevated eosinophil levels with angioedema. Gleich syndrome, which responds well to corticosteroids, is thought to be related to hypereosinophilic syndrome. [46] In addition to the elevated eosinophil count, immunoglobulin G (IgG) autoantibody against endothelial cells has been identified.
Thyroid autoantibodies are found in 14-28% of patients with chronic urticaria or angioedema, and IgG autoantibodies to either the high-affinity receptor for IgE (FceRI) or to IgE are found in 30-50% of these patients. [43, 28] 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. [47]
The reported incidence or prevalence of angioedema varies depends on the study population and the method of study (eg, patient reported vs physician diagnosed). The World Allergy Organization (WAO) notes that urticaria and angioedema affects up to 20% of the population. [14] It is estimated that approximately 10-20% of population may experience at least 1 episode of angioedema during their lifetime. [43, 26]
Approximately 40-50% of patients with chronic spontaneous urticaria have angioedema, and about 10% have angioedema alone. [13, 14] Up to 1% of the population has chronic urticaria. [43] With these data in mind, up to 0.5% of the population is estimated to have chronic or recurrent angioedema.
It is likely that the great majority of cases of chronic or recurrent angioedema are idiopathic. [43, 26] HAE has an estimated prevalence of 1:10,000 to 1:50,000. [48] The prevalence of AAE is very low; until 2006, only about 136 cases had been reported in the literature. [29] The reported incidence of ACE inhibitor–induced angioedema ranges from 0.1% to 6%. [30]
International occurrence rates are believed to be similar to those reported in the United States. However, in a Danish population survey, the lifetime prevalence of angioedema was 7.4%, and approximately 50% of cases were chronic angioedema (non-HAE). [35] In this study, 35.5% of angioedema patients had urticaria. The basis for the inconsistency between these findings and those of other studies is not clear.
Angioedema can affect people of all ages. Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence in the third decade of life. There is a continuous increase in the rate of hospital admissions for angioedema (3.0% per year). [14] The rate of hospitalization is highest in persons aged 65 years and older. [14]
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. IAE is more common among persons aged 30-50 years than among other age groups. [43]
Estrogen may exacerbate certain forms of angioedema. In HAE, affected women tend to have more frequent attacks and run more severe clinical courses. Oral contraceptives containing estrogen are often linked to exacerbation of swelling attacks. Chronic idiopathic angioedema is more common in females than in males. [43] Other types of angioedema do not show a strong sex preponderance.
No specific racial predilection exists for angioedema. However, black individuals are more susceptible to angioedema induced by ACE inhibitors. Compared with white persons, the adjusted relative risk for black persons is about 3.0 to 4.5. [30] Other forms of angioedema have no clear association between race and the disease frequency or severity.
The prognosis for patients with angioedema depends on the etiology and varies as follows:
Angioedema with identifiable causes – If the trigger(s) can be identified and avoided, angioedema can be prevented
Angioedema without identifiable causes – There is a tremendously variable clinical course, ranging from mild to severe and a few days to many years; the response to conventional treatment is less unpredictable
HAE – Lifelong treatment is often required
AAE – Outcome depends on the treatment of underlying lymphoproliferative or autoimmune disorders
Individuals with allergies to food, venom, or medications need to be educated regarding allergen avoidance. Patients must also be educated regarding the indications for and proper technique of epinephrine autoinjector use and the need to seek further medical assistance afterward.
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.
Other recommended Websites 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 (JCAAI)
Food Allergy Research and Education (FARE) (formerly Food Allergy and Anaphylaxis Network [FAAN])
US Hereditary Angioedema Association (HAEA)
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Huamin Henry Li, MD, PhD, CPI Director of Chevy Chase Clinical Research, Institute for Asthma and Allergy; Assistant Professor, George Washington University Hospital; Clinical Faculty, Johns Hopkins Asthma and Allergy Center, Johns Hopkins Hospital
Huamin Henry Li, MD, PhD, CPI is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology, MedChi The Maryland State Medical Society
Disclosure: Received consulting fee from Dyax for consulting; Received consulting fee from Pharming/Salix for consulting; Received consulting fee from CSL Behring for consulting; Received honoraria from Viropharma/Shire for speaking and teaching; Received consulting fee from Viropharma/Shire for consulting; Received honoraria from Dyax for speaking and teaching.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians
Disclosure: Nothing to disclose.
Stephen C Dreskin, MD, PhD Professor of Medicine, Departments of Internal Medicine, Director of Allergy, Asthma, and Immunology Practice, University of Colorado Health Sciences Center
Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting; American Health Insurance Plans Consulting fee Consulting; Johns Hopkins School of Public Health Consulting fee Consulting; Array BioPharma Consulting fee Consulting
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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