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.
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Photographic documentation of swelling.
Signs and symptoms
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.
Diagnosis
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.
Management
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)
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).
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Photographic documentation of swelling.
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.
Histamine- and bradykinin-mediated 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 spontaneous mast cell activation and histamine release. Another example of non–IgE-mediated mast-cell activation is the reaction induced by intravenous (IV) contrast material.
Plasma and tissue factors, such as bradykinin, and certain components in the contact system or the fibrinolytic system are also found to play an important role in certain forms of angioedema.[20, 21] For angioedema without evidence of histamine involvement, bradykinin is likely the most important mediator.[11]
Hereditary angioedema (HAE), angiotensin-converting enzyme (ACE) inhibitor–induced angioedema, and certain idiopathic angioedemas are examples of bradykinin-mediated angioedema; bradykinin levels are elevated during an episode of angioedema.[13] Accumulation of bradykinin, either from overproduction or from decreased breakdown, accounts for the pathogenesis of these types of angioedema.[20]
C1-INH is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease (either hereditary or acquired) results in unchecked activation of the kallikrein-kinin system, which leads to the overproduction of bradykinin (see the image below).[22] (See Hereditary Angioedema.)
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Bradykinin production and metabolism.
Other mediators
Besides mast cells, many other cellular components (eg, macrophages, dendritic cells, lymphocytes, monocytes, eosinophils, and endothelial cells) are involved in the pathogenesis of angioedema.[3, 23] These contribute to the generation, maturation, and activation of mast cells and basophils and thereby exert an influence on histamine release.[24] Release of vasoactive substances causes vasodilatation of endothelial cells, as well as smooth muscle bowel contraction,[25] ultimately manifesting in the common clinical presentation of the disease.
Urticaria and angioedema
Urticaria is often discussed together with angioedema. In many cases, the 2 conditions are remarkably similar, both in their underlying etiologies and in the clinical management strategies employed to treat them. However, angioedema is also quite different from urticaria, in that 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 mid-dermis). In fact, mucosal involvement is observed only in angioedema but not in urticaria.
In addition, pruritus is the most prominent complaint in urticaria, but it is less troublesome or absent in angioedema. Furthermore, pain or tenderness is uncommon in urticaria but frequent or even severe in angioedema. Addressing these differences is necessary for successful treatment of angioedema.
Angioedema with and without urticaria
Angioedema associated with urticaria may represent hypersensitivity to an offending agent. Histamine is released into the bloodstream, resulting in increased endothelial cell permeability. Angioedema, generalized urticaria, and, in severe cases, anaphylaxis will occur.[26] The allergen binds to the mast cell, causing degranulation and histamine and tryptase release. Degranulations of mast cells have also been shown to be a direct result of anesthetics, contrast media, and opiates.[26]
Autoantibodies against the mast cell IgE receptor or mast cell−bound IgE (or basophils) are another common cause of histamine release. Additionally, proteases may activate the complement cascade associated with C3a, C4a, and C5a, which are considered anaphylactoids, and result in increased capillary permeability and extravasation of fluid.[25]
With respect to pathophysiology, angioedema without urticaria may differ substantially from angioedema with urticaria. In many cases, histamine is not involved or only minimally involved. Bradykinin is known to be the major mediator for HAE, acquired angioedema (AAE), ACE inhibitor–induced angioedema, and certain idiopathic angioedemas.
HAE and AAE
The following 3 types of HAE have been identified:
Type I – C1-INH deficiency
Type II – Believed to be a dysfunction of C1-INH, with normal-to-high circulating levels of the molecule[27, 28] ; types I and II are not distinguishable clinically,[28] and with both types, the result is unchecked bradykinin production[29, 30]
Type III – Normal C1-INH concentration and function with C1-esterase dysfunction[31] ; often seen in women with factor XII gene mutations.[20, 32, 33]
There are no reliable diagnostic tests to establish the diagnosis of type III HAE; rather the patient’s family history and clinical presentation are key diagnostic components. Originally described as affecting women only, type III HAE was subsequently reported in a few men as well.[34] Orofacial involvement seems to be the most common presentation for type III HAE, but abdominal attacks are seen less frequently in this variant. The new classification has proposed to combine HAE Type I and II and name it as C1-IHN HAE, whereas HAE Type III is to be differentiated into FXII-HAE and U-HAE.[16]
AAE (now preferred to be named as C1-INH-AAE) is classified as either type I or type II.[13]
C1-INH-AAE Type I is associated with B-cell proliferative disorders and is characterized by hypercatabolization of C1-INH. Immune complexes are formed between antibodies and abnormal immunoglobulins on the cell surface of B cells. The complement cascade hyperreacts, producing large amounts of C1. C1-INH is then consumed in attempts to prevent the activation of the continuously activated C1. As a result, levels of serum C1q are decreased in patients with C1-INH-AAE, but not in those with C1-INH-HAE (see Laboratory Studies).
The relative deficiency of C1-INH causes increased activation of the kallikrein-kinin system.[35, 25] Enzymatic cleavage by kallikrein is increased with consumption of kininogen, and subsequently, the production of bradykinin increases. The end result of this intricate molecular cascade is vasodilation meditated by the interaction of kinins with the endothelial cell receptors B1R and B2R.[36]
Type II AAE is associated with autoantibodies (IgG, and less often, IgM) directed against the C1-INH molecule.[25] Depletion of C1-INH results in the production of large amounts of bradykinin and other vasoactive substances, which causes the signs and symptoms of angioedema.
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 angioedema
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
“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
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.)
Idiopathic angioedema
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.
Other causes
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 statistics
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.
Age-related demographics
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]
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. 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.
Race-related demographics
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])
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:
Family history and prior personal experience of angioedema
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)
Potential triggering or exacerbating factors
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.
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.
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Angioedema secondary to angiotensin-converting enzyme (ACE) inhibitors.
Documentation of swelling by means of physician notes, photographs (see the image below), or both is important.
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:
Acute (< 6 weeks) or chronic (>6 weeks)
Allergic (eg, food, drug, insect sting venom, or latex)
Pseudoallergic (eg, induced by NSAIDs)
Physical (eg, from cold, vibration, pressure, or physical exercise)
Autoimmune disease
Idiopathic
Angioedema without urticaria is characterized by the following based on the new international work group recommendation:[16]
Acquired Angioedema (AAE)
Idiopathic (no identifiable causes)
Idiopathic histaminergic (IH-AAE): Responds to antihistamines
Idiopathic nonhistaminergic angioedema (InH-AAE): No response to antihistamines
Acquired angioedema related to ACEI (ACEI-AAE): On ACEI therapy, no other identifiable causes
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)
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).
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]
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Classification of angioedema without urticaria based on clinical or etiopathologic features. AAE = acquired angioedema; ACEI = angiotensin-converting ....
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.
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.
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
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] :
C1 INH-HAE Type I – Low levels of C1-INH protein and function, low C4, but normal C1q;
C1 INH-HAE Type II – Normal levels of C1-INH protein, but low levels of C4 and C1-INH function, normal C1q;
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;
C1 INH-AAE (previously known as AAE) – Low levels of C1-INH protein and function, low C4 and low C1q;
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:
Complete blood count (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
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:
Stool analysis for ova and parasites
H pylori workup
Hepatitis B and C workup
Rheumatoid factor
Cryoglobulin levels
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).
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.
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:
Plain abdominal radiography – Plain films may show a “stacked coin” or “thumbprint” appearance of the intestines[4]
Abdominal ultrasonography – Sonograms may show ascites
CT of the abdomen – Scans may show severe edema of the bowel wall[1]
Radiography of the chest – Chest x-rays may show pleural effusion
Radiography of cervical soft tissue – Neck films may show soft-tissue swelling[5]
Patients with moderate to severe angioedema often present to the emergency department (ED). Epinephrine should be used when laryngeal angioedema is suspected. Supportive care (eg, pain control) should also be provided, regardless of the etiology.
Inpatient care for angioedema is usually not necessary when timely treatment is administered. For patients with a known history of hereditary angioedema (HAE), a treatment option approved by the US Food and Drug Administration (FDA) (eg, C1 esterase inhibitor [C1-INH] concentrate, ecallantide, or icatibant) should be administered as soon as an angioedema attack is recognized.[53]
Airway protection is the most important consideration with laryngeal angioedema. It is helpful to include anesthesiologists, critical care specialists or pulmonologists, otolaryngologists, and respiratory therapists in the management team. In cases of possible airway compromise, early intubation may be preferred.
When intubation is required, admission to an intensive care unit (ICU) is often needed; the procedure may be exceedingly difficult, and advanced techniques (eg, fiberoptic intubation) may be necessary. In severe cases of laryngeal edema, a surgeon should be consulted, because a surgical airway will have to be created via cricothyrotomy or tracheotomy.
Clinicians should attempt to identify and patients should attempt to avoid triggers such as the following:
Food allergies
Drugs
Physical factors (eg, vibrations, cold or heat, or pressure)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Angiotensin-converting enzyme (ACE) inhibitors
For patients who have angioedema without urticaria, clinicians must rule out HAE, acquired C1-INH deficiency (C1-INH-AAE), and ACE inhibitor−induced angioedema (ACEI-AAE).
Depending on the etiology of the angioedema, management can vary dramatically. To guide therapy, angioedema with unidentifiable causes can be regarded as histaminergic or nonhistaminergic.
Guidelines
The 2015 guidelines from the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) provide guidance for the management of patients with chronic urticaria/angioedema.[54]
For adult patients with weals
Check that symptomatic episodes have not followed ingestion of a nonsteroidal anti-inflammatory drug such as aspirin or ibuprofen.
Give a once-daily dose of a long-acting, nonsedating antihistamine (prn if symptoms are infrequent).
If necessary, double the dose of antihistamine (usually given at night), and/or add a second antihistamine.
Consider further increase in dose of antihistamine up to 4 times the recommended dose.
In addition to the instructions above for adult patients with weals, the following steps should be considered:
If the patient is taking an ACE inhibitor, this drug should be stopped.
Even if the patient is not taking an ACE inhibitor, these drugs should be avoided in the future.
Consider addition of tranexamic acid for higher-dose antihistamine-resistant angioedema.
An adrenaline autoinjector is rarely required and should only be considered if there is a history of significant angioedema affecting the upper airway (rare in angioedema with urticaria). The patient should then be shown how to use the device and provided with a written self-management protocol.
Exclude C1 inhibitor deficiency; a normal plasma C4 during an attack—or normal C4, C1 inhibitor, and C1 inhibitor function between attacks—will typically exclude this.
If the patient is taking an ACE inhibitor, this drug should be stopped.
Even if the patient is not taking an ACE inhibitor, such drugs should be avoided in the future.
Give a once-daily dose of a long-acting, nonsedating antihistamine (prn if symptoms are infrequent) and consider higher doses of antihistamines.
Consider tranexamic acid in antihistamine-resistant angioedema.
An adrenaline autoinjector and short-term oral corticosteroids are unlikely to be beneficial unless an underlying histaminergic mechanism is considered to be responsible for the angioedema.
In 2013, the World Allergy Organization (WAO) issued the following recommendations for the management of HAE types 1 and 2[14] :
Assess all patients suspected of having HAE-1/2 for blood levels of C4, C1 esterase inhibitor (C1-INH) protein, and C1-INH function
Consider on-demand treatment for all HAE attacks that (1) result in debilitation or dysfunction or (2) involve the face, the neck, or the abdomen; attacks affecting the upper airways must be treated
Treat all HAE attacks as early as possible with C1-INH, ecallantide, or icatibant; do not use oral antifibrinolytics as on-demand treatment
Consider intubation or tracheotomy early in progressive upper airway edema
Administer adjuvant therapy in HAE attacks when indicated, but use specific therapies without delay when indicated
All HAE-1/2 patients should (1) have on-demand treatment for 2 attacks and (2) carry their on-demand treatment at all times
Plasma-derived (pd) C1-INH is the preferred on-demand therapy for HAE-1/2 attacks in children and in pregnant or breast-feeding women
All patients should have an action plan, product available to treat HAE attacks, and an HAE identification card
Instruct all patients given on-demand treatment licensed for self-administration on how to self-administer
All patients should have at least 1 annual assessment by an HAE specialist
The WAO’s 2013 recommendations regarding prophylaxis and screening in HAE are as follows[55] :
Consider administering short-term preprocedural prophylaxis, particularly in cases involving dental or intraoral surgery and bronchoscopy or endoscopy; endotracheal intubation; and manipulation of the upper airway or pharynx
Before beginning long-term prophylaxis with androgens, obtain a complete blood count (CBC), urinalysis, liver function tests (LFTs), lipid profile, and liver ultrasonography, as well as assess the patient for cardiac risk factors; during use of androgens for long-term prophylaxis and for 6 months after cessation of therapy, monitor the patient’s CBC, urinalysis, lipid profile, LFTs, and blood pressure every 6 months; perform annual ultrasonography of the liver
Defer screening children for HAE-1/2 until the age of 12 months; test all offspring of an affected parent
Family members of HAE-1/2 patients should be screened so that appropriate therapy can be available for treatment
Administer HAV and HBV vaccinations to HAE-1/2 patients receiving blood products, including pdC1-INH; administer influenza vaccine to all HAE-1/2 patients
Histaminergic angioedema (IH-AAE) is either immunoglobulin E (IgE)-dependent (eg, an allergic reaction to a food or drug) or IgE-independent (eg, a reaction to radiocontrast medium). NSAID-related angioedema and most cases of idiopathic angioedema are treated with the same measures.
Most cases of angioedema can be managed well with outpatient treatment alone. Antihistamines, usually second-generation agents (eg, cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine), are often used as first-line treatment. These agents are also given to help reduce the severity or frequency of attacks, in dosages often as high as 4 times the standard dosage.[56]
Current urticaria and angioedema treatment guidelines support the use of higher dosages of second-generation antihistamines as a treatment of choice in preference to the use of corticosteroids or other immune modulators.[38] However, this recommendation for updosing is primarily based on expert opinion,[57] and there is only limited clinical evidence to support it.[56]
Although the relative efficacy and safety of the various second-generation antihistamines have not been adequately studied, some data indicate that cetirizine 10 mg is more effective than fexofenadine 180 mg[58] and that levocetirizine 5 mg is more effective than desloratadine.[59] However, although some studies found the sedative effects of cetirizine to be greater than those of fexofenadine or loratadine,[60] another study found no such differences among cetirizine, levocetirizine, and loratadine.[61]
For moderate-to-severe cases of angioedema, close monitoring is often necessary. Diphenhydramine 50 mg intramuscularly (IM) or intravenously (IV) is helpful. Hydrocortisone 200 mg IV or methylprednisolone 40-60 mg IV may reduce the possibility of relapse.
For laryngeal swelling and airway obstruction, close monitoring of the airway is mandatory. Epinephrine (1:1000) should be administered IM at a dose of 0.01 mg/kg or 0.3 mg, repeated every 10-15 minutes if necessary. Occasionally, intubation, or even tracheostomy, may be necessary. These patients should be admitted for at least 24 hours of observation.
Other pharmacologic options
Theoretical considerations suggest that leukotriene antagonists might be helpful; however, clinical observation has not confirmed the benefits of these agents in either urticaria or angioedema.
Because of their sedative side effects, first-generation antihistamines are usually recommended as add-on therapy when a second-generation antihistamine fails to relieve symptoms adequately. Thus, H1 antihistamines may be given in combination with H2 antihistamines. Most often, the initial dose is given at bedtime or late in the evening. Many patients may become more tolerant to the sedative effects of the first-generation antihistamine after a few days of treatment. The dosage can be gradually titrated toward better symptom control as tolerated.
Doxepin is a tricyclic antidepressant (TCA) that has potent H1-blocking activity. For this reason, it has been used off label to treat so-called recalcitrant angioedema—that is, angioedema that does not respond adequately to antihistamine treatment.
A number of well-controlled studies have shown cyclosporine and various other immunomodulatory drugs, including omalizumab,[62, 63] to be effective for many recalcitrant cases of chronic idiopathic urticaria and angioedema.[64, 47] However, a major limitation of omalizumab treatment is high cost. The beneift of these immunomodulators has not been well studied in angioedema without urticaria.[65]
Corticosteroid use in histamine-mediated angioedema should be limited to severe cases. Outpatient treatment should avoid long-term corticosteroid use.
Angioedema caused by ACE inhibitors is a classic example of bradykinin-mediated angioedema. HAE, AAE, estrogen-dependent angioedema, and certain forms of idiopathic angioedema are also bradykinin-mediated. Antihistamines do not work for these patients, and corticosteroids have limited or no value. In C1-INH-AAE, treatment of the underlying disorder usually results in correction of the abnormality.
Administration of 2 units of fresh frozen plasma (FFP), which contains C1-INH, has been shown to be helpful in certain patients. However, FFP also contains substrates that may worsen angioedema attacks. If this treatment is used, be ready to intubate or perform a tracheostomy, if necessary.
Antifibrinolytic agents (eg, aminocaproic acid or tranexamic acid) may be helpful in treating HAE, C1-INH-AAE, and certain cases of InH-IAE. However, they are not indicated in the treatment of IH-AAE. The exact mechanism by which these agents act against angioedema is uncertain, but it is probably related to inhibition of plasmin and a subsequent effect on bradykinin metabolism.
Acute HAE attacks can be treated with infusion of C1-INH 20 U/kg. This agent is also reportedly used to treat other types of angioedema attacks, though its clinical efficacy against those other types has not been fully studied.
Administration of nanofiltered C1-INH concentrate can shorten the duration of acute HAE attacks. In randomized trials by Zuraw et al, the median time to onset of unequivocal relief was 2 hours with nanofiltered C1-INH concentrate versus more than 4 hours with placebo.[66] When used for prophylaxis, nanofiltered C1-INH concentrate reduced the number of acute attacks over a 12-week period from 12.73 to 6.26.
Subsequently, Riedl et al showed that 68% of patients achieved unequivocal relief within 1 hour after receiving nanofiltered C1-INH concentrate, and 87% achieved relief within 4 hours.[67] The median time to onset of relief was 0.75 hour. Currently, however, purified C1-INH is approved by the FDA only for prophylaxis.
In 2009, ecallantide, a potent, selective, reversible inhibitor of plasma kallikrein that suppresses bradykinin generation, was approved by the FDA for treatment of acute HAE attacks. During such attacks, unregulated plasma kallikrein activity leads to excessive bradykinin generation, resulting in swelling, inflammation, and pain. The inhibition of plasma kallikrein reduces the conversion of kininogen to bradykinin.[68]
In 2011, icatibant, a bradykinin B2 receptor antagonist, was approved by the FDA for the treatment of acute HAE attacks.[69] This agent is administered subcutaneously via prefilled syringes that can be can be carried and stored at room temperature. Icatibant can be self-injected by the patient.[70]
A 2012 guideline from the Hereditary Angioedema International Working Group includes the following management recommendations for individuals with HAE[71] :
For treatment of acute attacks, provide all HAE patients with access to at least 1 specific medication, such as C1 inhibitors (plasma-derived or recombinant), icatibant, or ecallantide, even if asymptomatic
Whenever possible, have patients keep medication on hand to treat acute attacks at home, and train patients to self-administer these medications
Advise patients to treat any attack, regardless of location, as soon as it is clearly recognized and to report to the hospital if laryngeal symptoms persist after initial treatment
An international panel has proposed guidelines for management of gynecologic and obstetric issues in women with C1INH-HAE. Recommendations of this panel include the following[72] :
For contraception, estrogens should be avoided; barrier methods, intrauterine devices, and progestins can be used
Attenuated androgens are contraindicated during pregnancy and should be discontinued before attempting conception
During pregnancy, plasma-derived human C1-INH is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis
During pregnancy, tranexamic acid or virally inactivated FFP can be used for long-term prophylaxis if human plasma-derived C1-INH is not available
No pregnancy safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH)
During delivery, plasma-derived human C1-INH prophylaxis is advised before forceps or vacuum extraction or cesarean section
Regional anesthesia is preferred to endotracheal intubation for cesarean section
The FDA has approved various agents including C1-INHs, the kallikrein inhibitor ecallantide, lanadelumab, a monoclonal antibody that targets kallikrein, and the bradykinin-receptor antagonist icatibant for use in patients with HAE, either as prophylaxis or to treat acute attacks. (See Hereditary Angioedema.)
In August 2018, the FDA approved lanadelumab, a monoclonal antibody that targets kallikrein, for prophylaxis of HAE. Approval was based on the HELP clinical trial which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in hereditary angioedema (HAE). Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared to placebo (P < 0.001) over the 26-week duration of the study. The 300 mg SC every 2 week regimen reduced attacks by 92.8% from baseline in patient with < 2 attacks per month and by 88.2% in patients whose baseline was 2 to < 3 attacks per month.[78]
FFP has been used for short-term prophylaxis of C1-INH–related angioedema. In patients with C1-INH-AAE, treatment of the underlying disorder usually results in elimination of angioedema.
The Hereditary Angioedema International Working Group guidelines consider long-term prophylaxis to be appropriate for C1-INH-HAE patients in whom on-demand acute treatment is inadequate to minimize disease.[71] The Working Group found high levels of evidence for the efficacy of both attenuated androgens and plasma-derived C1-INH, but not for the efficacy of antifibrinolytic agents.[71]
Androgen derivatives (eg, danazol, oxandrolone) have been used in patients with HAE as a prophylactic option. These agents can be considered for nonpregnant, nonlactating patients older than 16 years, and they may also help for certain cases of C1-INH-AAE. However, androgen derivatives are not recommended if the patient cannot tolerate them or if the effective danazol dosage exceeds 200 mg/day. There is no clear benefit to the use of androgen derivatives in treating other types of angioedema.[14]
Plasma-derived C1-INH can also be considered for all patients with C1-INH-HAE. Because a dosage of 1000 units twice weekly reduces attack rates only by 50%, some patients may need higher dosages for better control.[71]
If a patient taking an ACE inhibitor experiences an attack of angioedema, the medication should be withdrawn. Most of these patients can tolerate an angiotensin II receptor blocker (ARB); however, in a very few patients, even an ARB will trigger angioedema and must therefore be avoided. Similarly, patients with a history of episodes possibly triggered by estrogen-based oral contraceptives should avoid such agents.
For patients with an established food allergy or food additive hypersensitivity, avoidance of the identified allergen is indicated. Most patients do not need activity restriction. However, physical trauma may trigger certain types of angioedema; therefore, patients should exercise caution when engaging in contact sports.
For IH-AAE, the response to treatment varies tremendously among individuals. Many patients may need multiple attempts to find the right combination of medicine to control their symptoms. Antihistamines and H2 antagonists are still the agents most commonly prescribed for this condition. Leukotriene antagonists (eg, montelukast and zafirlukast), a 5-lipoxygenase inhibitor (zileuton), and immunomodulators (eg, cyclosporine) have been used.
Corticosteroid treatment is reserved for very recalcitrant cases. Antifibrinolytics have been tried in some patients with success (those with IH-AAE, C1-INH-AAE, and HAE). Androgen derivatives and progesterone-only oral contraceptives may also be considered.
When symptoms of angioedema are moderate or severe and the offending factors are not easily identifiable, referral to allergy and immunology specialists should be considered. In cases of laryngeal attacks, consultations with ear, nose, and throat (ENT) and intensive care specialists are advisable. Allergy and immunology specialists should also be consulted (eg, to identify potential allergies, medication reactions, or changes in certain body enzymes).
The primary goal of medical therapy for angioedema is to reduce and prevent swelling. Reducing discomfort and minimizing complications are also extremely important goals. Most of the drugs used for urticaria and anaphylaxis are also used for many types of angioedema.
In histamine-mediated angioedema, second-generation antihistamines are often first-line treatment. Corticosteroids can be used in severe cases of this form of the disease, but long-term use of these agents should be avoided in outpatient treatment.
Antihistamines do not work for patients with bradykinin-mediated angioedema, and corticosteroids have limited or no value in this type of angioedema. However, fresh frozen plasma (FFP), antifibrinolytics, C1 esterase inhibitor (C1-INH), ecallantide, and icatibant can be used to manage bradykinin-mediated angioedema.
Limited small studies of anti-inflammatory agents have shown dapsone, sulfasalazine, hydroxychloroquine, and colchicine to provide clinical benefit in patients with chronic urticaria or angioedema.[7] This group of medications is associated with higher risk than antihistamines or H2 antagonists and leukotriene receptor antagonists. However, for those requiring corticosteroids, selecting one of these drugs may offer better side effect profile. Special safety monitoring is recommended for each individual medication.
Recalcitrant angioedema
Immunosuppressants such as calcineurin inhibitors (cyclosporine and tacrolimus), methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, and sirolimus have been tried in treating antihistamine-resistant chronic urticaria or angioedema. Of these, cyclosporine has been most thoroughly studied in this setting.[62] Although clear benefit has been shown with cyclosporine, concerns for its side effects (which may outweigh the benefit) still pose a challenge for clinicians.
Intravenous immunoglobulin (IVIg) has also shown to be effective for some patients who are antihistamine-unresponsive. Evidence of its efficacy is limited to a few open-label case studies, and the appropriate dosage, dosing interval, and treatment duration have not been well established. At this time, IVIg use is limited to a carefully selected group of patients who do not have an adequate treatment response or do not tolerate alternative treatment.
Clinical Context:
Use epinephrine in case of laryngeal edema. It has alpha-agonist effects that include increased peripheral vascular resistance and reduced vascular permeability.
Adrenergic agonist agents cause vasoconstriction and bronchodilation and reduce vascular permeability. They are vitally important in treating acute angioedema associated with an allergic reaction affecting the upper airways. Their benefit in other types of laryngeal edema (eg, acute hereditary angioedema [HAE]) is less certain.
Clinical Context:
Diphenhydramine is used for the relief of symptoms caused by the release of histamine. It is the most commonly used first-generation antihistamine and is available without a prescription in the United States.
Clinical Context:
Chlorpheniramine is a first-generation agent. It competes with histamine for H1-receptor sites on effector cells in blood vessels and the respiratory tract. Chlorpheniramine is one of the safest antihistamines to use during pregnancy.
Clinical Context:
Cyproheptadine is a first-generation agent. It is used for the symptomatic relief of allergic symptoms caused by histamine release. Cyproheptadine prevents histamine release in blood vessels and is more effective in preventing histamine response than in reversing it. It may be useful in patients with syndromes sustained by histamine-producing tumors.
Clinical Context:
Hydroxyzine hydrochloride antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the central nervous system (CNS).
Antihistamines (H1 and H2) generally work well for urticaria. However, the great majority of angioedema cases, especially when not accompanied by urticaria, do not respond adequately to antihistamine treatment. In certain types of angioedema, such as hereditary angioedema (HAE), angiotensin-converting enzyme (ACE) inhibitor–acquired angioedema (AIIA), and acquired angioedema (AAE), antihistamines are ineffective and are not recommended for treatment.
The first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine, doxepin, chlorpheniramine, and cyproheptadine) are inexpensive and effective in reducing pruritus, but drowsiness and anticholinergic effects can be troublesome. Because of the potential sedative effects, patients should be cautioned about driving and operating heavy machinery.
Clinical Context:
Fexofenadine is a nonsedating second-generation antihistamine. It is tolerated very well, with a rate of sedation that does not differ significantly from that of placebo.
Clinical Context:
Cetirizine selectively inhibits histamine H1 receptor sites in blood vessels and in the gastrointestinal (GI) and respiratory tracts, and this action, in turn, inhibits the physiologic effects that histamine normally induces at H1 receptor sites. The once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.
Clinical Context:
Desloratadine is a long-acting, tricyclic histamine antagonist that is selective for the H1 receptor. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.
Clinical Context:
Loratadine selectively inhibits peripheral histamine H1 receptors. It is tolerated very well, with a rate of sedation that does not differ significantly from that of placebo. The once-daily dosing makes it convenient.
Clinical Context:
Levocetirizine is an H1-receptor antagonist that is an active enantiomer of cetirizine. This agent is available as a 5-mg breakable (scored) tab and a 0.5 mg/mL oral solution.
The second-generation antihistamines have much lower sedative effects. Nevertheless, any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery.
Clinical Context:
Cimetidine is a nonprescription antihistamine H2-receptor antagonist. Its use can increase the serum concentration of hydroxyzine but not of cetirizine.[73]
Clinical Context:
Ranitidine is a nonprescription antihistamine H2-receptor antagonist. It has a better safety profile, a longer duration of action, and considerably (10 times) stronger H2-receptor binding than cimetidine does, and it does not suppress cytochrome P450 isoenzymes. Its clinical efficacy as add-on therapy to antihistamine in urticaria has not been conclusively determined.[74, 75, 76]
These drugs are usually used to decrease gastric acid secretion. When used as a single agent for urticaria and angioedema, they are not effective. However, the combination of an H1 antagonist with an H2 antagonist has been shown to be more effective than an H1 antagonist alone. Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.
Leukotriene receptor antagonists may be used as add-on therapy for histamine-mediated angioedema with or without urticaria. A subset of patients, especially those with sensitivity to aspirin or nonsteroidal anti-inflammatory agents (NSAIDs) or food additive intolerance, may benefit more from this treatment; however, this is not supported by strong clinical evidence.[77]
Clinical Context:
Prednisone, a commonly used oral agent, may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. To have an effect, it must be metabolized to the active metabolite prednisolone. Conversion may be impaired in liver disease.
Despite the paucity of well controlled clinical studies, the efficacy of corticosteroids in histamine-mediated angioedema and some forms of idiopathic angioedema (IAE) appears to be evident. However, because of their well-recognized side effects, long-term use of corticosteroids is generally not advisable.
The optimal dosage and duration of treatment are not well established. Most experts are in favor of their short-term use, preferably with the lowest effective dosage over a limited time period (eg, 15 mg/day, reduced by 1 mg weekly). Corticosteroids should only be used when other treatments cannot provide adequate clinical benefits or symptom control.{[14]
Corticosteroids may be used when antihistamines are inadequate or ineffective at controlling an acute episode of angioedema. These agents usually reduce inflammation and reduce vascular permeability in allergic angioedema and in some cases of idiopathic angioedema. However, they usually have very limited or no benefit in ACE inhibitor ̶ induced angioedema (AIIA), hereditary angioedema (HAE), and acquired angioedema (AAE).
Corticosteroids can be given as a short course of an oral agent (administered daily for 5-7 days, with or without a taper) or as a single dose of a long-acting, injectable agent. Such regimens are not usually associated with long-term sequelae.
Long-term corticosteroid use should be avoided in chronic angioedema, when possible. If angioedema is severe and cannot be safely controlled with other medications, low-dose therapy and/or alternate-day therapy can be considered.
Androgens are particularly useful in patients with HAE and perhaps in some patients with AAE. They are not useful in angioedema due to allergy or to drug sensitivity or intolerance. There is limited experience with these drugs in IAE. They may induce the synthesis of messenger ribonucleic acid (mRNA) in the liver and directly increase C1-INH.
Clinical Context:
Aminocaproic acid inhibits fibrinolysis through inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It may be used in HAE and AAE as prophylaxis and to relieve acute attacks. The clinical benefit is marginal.
Clinical Context:
Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. In Europe, it is used primarily for HAE prophylaxis, though some authors believe that it is also helpful for treating acute HAE attacks.
The exact mechanism by which hemostatic agents act against angioedema is uncertain, but it is most likely related to the inhibition of plasmin, with subsequent effects on bradykinin metabolism. Hemostatic agents have shown benefit in treating HAE, AAE, and certain forms of IAE. They are not indicated in the treatment of allergic angioedema.
Clinical Context:
Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein. It treats acute, episodic attacks of HAE by binding to plasma kallikrein and blocking its binding site, thus inhibiting the conversion of high-molecular-weight kininogen to bradykinin.
Clinical Context:
Icatibant inhibits the binding of bradykinin to the B2 receptor and thereby treats the clinical symptoms of an acute attack of angioedema. The recommended dose is 30 mg subcutaneously in the abdominal area. The drug is available in a single-use prefilled syringe, which delivers a dose of 30 mg (10 mg/mL). Syringes can be carried and stored at room temperature, and the medication can be self-injected by the patient.
Clinical Context:
C1-INH is a serine protease inhibitor (serpin) and a normal constituent of human blood that regulates activation of the complement pathway, the intrinsic coagulation system, and the fibrinolytic system. It binds to and neutralizes substrates that activate these systems, suppressing conversion of tissue high- molecular-weight kininogen to bradykinin and thereby reducing bradykinin-mediated angioedema. Pharmacologic preparations of C1-INH are pasteurized, lyophilized products derived from purified human plasma.
Cinryze is approved by the US Food and Drug Administration (FDA) for prophylaxis of HAE attacks in adolescents and adults. It is available as a freeze-dried powder that is reconstituted for IV administration. Haegarda is indicated for routine prophylaxis in adults and adolescents and is administered as a twice weekly SC injection. Berinert is indicated for the treatment of acute laryngeal, abdominal, and facial angioedema attacks in children and adults with HAE. It is approved for patient self-administration after proper training by a healthcare professional.
Clinical Context:
Recombinant C1 esterase inhibitor is from the milk of genetically modified (transgenic) rabbits. It restores the level of functional C1 esterase inhibitor in a patient's plasma, thereby treating the acute attack of swelling. It is indicated for adolescents and adults to treat acute attacks of hereditary angioedema (HAE). Efficacy for treatment of laryngeal attack was not established.
Clinical Context:
Omalizumab has been reported to be an effective treatment option for patients with angioedema who are unresponsive to high doses of antihistamine treatment. It binds to free IgE and thereby prevents IgE from binding to mast cells and basophils. As the binding of IgE decreases, the activation and release of mediators in an allergic response is minimized.
What is angioedema?What are the signs and symptoms of angioedema?What is included in the physical exam of suspected angioedema?What can result from angioedema?What is the role of aeroallergen screening in suspected angioedema?Which lab tests are performed in the workup of angioedema with urticaria?Which lab tests may be considered for the workup of chronic or recurrent angioedema?What tests may be helpful for the diagnosis of angioedema when a specific condition is suspected?What is the role of imaging studies in the diagnosis of angioedema?What is the primary goal of medical treatment for angioedema?When is epinephrine indicated for the treatment of angioedema?Which medications are used in the management of angioedema?When is surgery indicated for angioedema?What is angioedema?Which areas of the body are most commonly affected by angioedema?When is angioedema of greater concern?What is the most common symptom of angioedema?What are the signs and symptoms of angioedema?What are the manifestations of angioedema?How does etiology affect the treatment strategy for angioedema?What causes the onset of angioedema?What is the role of vasoactive mediators in the pathogenesis of angioedema?What is the pathophysiology of histamine-mediated angioedema?What is the pathophysiology of bradykinin-mediated angioedema?Which cellular components are involved in the pathogenesis of angioedema?How do the pathophysiology of urticaria and angioedema differ?How can urticarial and angioedema be differentiated?What is the pathophysiology of angioedema with urticaria?What is the pathophysiology of angioedema without urticaria?What types of hereditary angioedema (HAE) have been identified?What is characteristic of type III angioedema?How are the different types of angioedema named under the new classification system?What is characteristic of type I angioedema?What is characteristic of type II angioedema?What is pseudoallergic angioedema (PAE)?What are the types of nonallergic angioedema?What are the causes of physically induced angioedema?What are some common triggers of angioedema attacks?What causes angioedemas?What types of angioedemas have unidentifiable etiologies?Which conditions are associated with angioedemas?What is hypersensitivity (allergic) angioedema?What are the causes of hereditary angioedema (HAE)?What are the causes of acquired angioedema (C1-INH-AAE)?What is ACE inhibitor–induced angioedema (ACEI-AAE or AIIA)?What are the causes of idiopathic angioedema (IAE)?What is the role of Helicobacter pylori infection in the etiology of hereditary angioedema (HAE)?What is the biological mechanism of hereditary angioedema (HAE) type III?What is the role of Gleich syndrome in the etiology of angioedema?What is the prevalence of autoantibodies in angioedema?What is the prevalence of angioedema in the US?What is the prevalence of angioedema with urticaria in the US?What is the prevalence of hereditary angioedema (HAE) in the US?What is the global prevalence of angioedema?How does the prevalence of angioedema vary by age?How does the prevalence of angioedema vary by sex?How does the prevalence of angioedema vary by race?What is the prognosis of angioedema?What information about angioedema should patients be given?Where can patients with angioedema get information regarding their condition?What should be the focus of clinical history in suspected angioedema?How should the focus of history vary for different types of angioedema?Where in the body can edema occur during angioedema?What are symptoms of angioedema?What are the clinical symptoms of hereditary angioedema (HAE), idiopathic angioedema (IAE), and drug-induced angioedema?What are triggers of an angioedema attack?What is the purpose of skin exam for angioedema?Which physical findings are characteristic of abdominal (intestinal mucosal) angioedema?How should swelling due to angioedema be documented?How is angioedema classified?What are features of angioedema with urticaria?What are the characteristics of acquired angioedema (AAE) without urticaria?What are the characteristics of hereditary angioedema (HAE) without urticaria?What is the prevalence of each subtype of angioedema?What are complications of angioedema?How are the different types of angioedema differentiated?What are the differential diagnoses for Angioedema?How is angioedema diagnosed?Which diagnostic tests should be performed in suspected angioedema without urticaria?What is the role of lab tests in the diagnosis of angioedema?Which lab findings suggest C1-INH-hereditary angioedema (HAE) types I and II?Which diagnostic tests are performed for recurrent angioedema without a clear trigger?Which lab tests may be helpful in the diagnosis of angioedema?Which histologic findings are characteristic of angioedema?What is the role of allergy testing in the diagnosis of angioedema?Which radiologic findings are characteristic of angioedema?What is the role of imaging studies for the diagnosis of angioedema?What are the World Allergy Organization (WAO) recommendations regarding prophylaxis and screening in hereditary angioedema (HAE)?What is the emergency department treatment of angioedema?When is inpatient care indicated for the treatment of angioedema?What is the most important consideration with laryngeal angioedema?When is admission to the ICU indicated for angioedema?What are triggers for angioedema?Which types of angioedema must be differentiated when urticaria is absent?How is angioedema managed?Which organization has published treatment guidelines for chronic urticaria/angioedema?What are BSAC treatment guidelines for adults with urticaria?What are BSAC treatment guidelines for adults with angioedema and urticaria?What are BSAC treatment guidelines for adults with angioedema without urticaria?What are the World Allergy Organization (WAO) recommendations for the management of hereditary angioedema (HAE)?What is histaminergic angioedema (IH-AAE)?What are the treatment options for histaminergic angioedema (IH-AAE)?What are the dosing recommendations for treating histaminergic angioedema (IH-AAE)?Which medications are used to treat histaminergic angioedema (IH-AAE)?What are treatment options for moderate-to-severe histaminergic angioedema (IH-AAE)?How is laryngeal swelling and airway obstruction caused by angioedema treated?What is the role of leukotriene antagonists in the treatment of histaminergic angioedema (IH-AAE)?What is the role of doxepin in the treatment of histaminergic angioedema (IH-AAE)?What is the role of immunomodulatory drugs in the treatment of histaminergic angioedema (IH-AAE)?What is the role of corticosteroids in the treatment of histaminergic angioedema (IH-AAE)?What are treatment options for nonhistaminergic angioedema (InH-AAE)?What is the role of fresh frozen plasma (FFP) in the treatment of nonhistaminergic angioedema (InH-AAE)?What are treatment options for hereditary angioedema (HAE)?What are treatment options for acute hereditary angioedema (HAE)?What are the Hereditary Angioedema International Working Group recommendations treatment of hereditary angioedema (HAE)?What are the treatment guidelines for gynecologic and obstetric issues in patients with C1-INH-hereditary angioedema (HAE)?What are the FDA approved medications for management of hereditary angioedema (HAE)?What is the role of fresh frozen plasma (FFP) in the prevention of angioedema?When is long-term prophylaxis indicated in patients with angioedema?Which medications are used to prevent angioedema?Which drugs may provoke an attack of angioedema?How is angioedema prevented in patients with food allergies?What medications are used in the treatment of idiopathic histaminergic angioedema (IH-AAE)?When is corticosteroid treatment indicated for the treatment of angioedema?What specialist consultations are needed for the management of angioedema?What is the primary goal of medical therapy for angioedema?Which medications are used to treat histamine-mediated angioedema?Which medications are used to treat bradykinin-mediated angioedema?Which anti-inflammatory drugs are used to treat angioedema?What are treatment options for recalcitrant angioedema?Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Angioedema?Which medications in the drug class Immunomodulators are used in the treatment of Angioedema?Which medications in the drug class Antifibrinolytic Agents are used in the treatment of Angioedema?Which medications in the drug class Androgens are used in the treatment of Angioedema?Which medications in the drug class Corticosteroids are used in the treatment of Angioedema?Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Angioedema?Which medications in the drug class Leukotriene Receptor Antagonists are used in the treatment of Angioedema?Which medications in the drug class Histamine H2 Antagonists are used in the treatment of Angioedema?Which medications in the drug class Antihistamines, 2nd Generation are used in the treatment of Angioedema?Which medications in the drug class Antihistamines, 1st-Generation are used in the treatment of Angioedema?Which medications in the drug class Alpha/Beta-Adrenergic Agonists are used in the treatment of Angioedema?
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
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.
Specialty Editors
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.
Chief Editor
Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy
Disclosure: Nothing to disclose.
Acknowledgements
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
US Food and Drug Administration. FDA approves Firazyr to treat acute attacks of hereditary angioedema. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269616.htm. Accessed: January 3, 2013.
Riedl M, Tachdjian R, Schranz J, Nurse C, Bernstein JA. Consistent lanadelumab treatment effect in patients with hereditary angioedema (HAE) regardless of baseline attack frequency in the phase 3 HELP study. Presented at the 2018 AAAAI/WAO Joint Congress annual meeting, March 2-5, 2018 Orlando, FL. J of Aller Clin Immunol. 2018 Feb. 141(2; suppl):AB47:
Photographic documentation of swelling.
Photographic documentation of swelling.
Bradykinin production and metabolism.
Angioedema secondary to angiotensin-converting enzyme (ACE) inhibitors.
Photographic documentation of swelling.
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.
Photographic documentation of swelling.
Bradykinin production and metabolism.
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.
Angioedema secondary to angiotensin-converting enzyme (ACE) inhibitors.
Types of angioedema.
Pathways for production of prostaglandins and leukotrine from mobilized arachidonic acid.
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