An overview of angioedema: Clinical features, diagnosis, and management

INTRODUCTION — Angioedema is self-limited, localized subcutaneous (or submucosal) swelling, which results from extravasation of fluid into interstitial tissues. Angioedema may occur in isolation, accompanied by urticaria, or as a component of anaphylaxis.

The clinical features, diagnosis, differential diagnosis, and management of angioedema will be reviewed here. The pathogenesis and causes of angioedema are discussed separately. (See "An overview of angioedema: Pathogenesis and causes".)

CLINICAL FEATURES — Angioedema typically affects areas with loose connective tissue, such as the face, lips, mouth, and throat, larynx, uvula, extremities, and genitalia. Bowel wall angioedema presents as colicky abdominal pain.

Angioedema can be distinguished clinically from other forms of edema by the following characteristics:

●Onset in minutes to hours and spontaneous resolution in hours to a few days

●Asymmetric distribution

●Tendency not to involve gravitationally dependent areas

●Involvement of face, lips, larynx, and bowels

●Association of some forms of angioedema with other signs and symptoms of allergic reactions or anaphylaxis

Types of angioedema — Two types of angioedema can be distinguished: mast cell-mediated, also called histaminergic angioedema, and bradykinin-mediated angioedema. However, for many of the known triggers of angioedema, the mechanism is unclear. (See "An overview of angioedema: Pathogenesis and causes".)

●In mast cell-mediated angioedema, such as allergic reactions to foods or insect stings, there are often (not always) other signs and symptoms of mast cell mediator release. Histamine is a prominent mediator, and this type of angioedema is also called histaminergic. Other signs and symptoms of mast cell-mediated reactions include urticaria, flushing, generalized pruritus, bronchospasm, throat tightness, and/or hypotension. Patients with additional symptoms affecting organ systems other than the skin may be experiencing anaphylaxis and should be treated immediately with epinephrine (figure 1 and table 1). Mast cell-mediated angioedema usually begins within minutes of exposure to the allergen, builds over a few hours, and resolves in 24 to 48 hours. (See "An overview of angioedema: Pathogenesis and causes", section on 'Mast cell-mediated etiologies'.)

Angioedema may also be histamine mediated (histaminergic) without clear evidence of mast cell degranulation. This is typically seen for idiopathic (also known as spontaneous) angioedema. In these cases, angioedema typically occurs alone or with urticaria but is not accompanied by respiratory or circulatory symptoms. (See 'Recurrent, idiopathic angioedema' below.)

●Bradykinin-induced angioedema is not associated with urticaria, bronchospasm, or other symptoms of allergic reactions. It has a somewhat more prolonged time course, usually developing over 24 to 36 hours and resolving within two to four days [1-7]. In this type of angioedema, the relationship between the trigger and the onset of symptoms is often not apparent. As an example, in angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, swelling may appear within a week of starting or increasing the medications or after years of use. (See "An overview of angioedema: Pathogenesis and causes", section on 'Bradykinin-mediated etiologies'.)

Anatomic sites

Larynx — Laryngeal edema can develop rapidly (over minutes) or more slowly over several hours. Early symptoms include hoarse voice, throat tightness, and difficulty swallowing. Assessment and treatment are discussed below. (See 'Angioedema in or near the airway' below.)

Lips, tongue, and uvula — The lips, tongue, and uvula are other structures that can be affected by angioedema and result in airway compromise. ACE inhibitor-induced angioedema most commonly presents with swelling of the lips, tongue, or face, although other causes of angioedema affect these structures as well [8]. In contrast, swelling of the floor of the mouth is more likely to be caused by tumors, infections, or lithiasis [9]. Orolingual angioedema is infrequently seen after intravenous thrombolysis with tissue-type plasminogen activator [10].

Skin and mucous membranes — Angioedema affects the subcutaneous and submucosal tissues (picture 1 and picture 2 and picture 3). Pruritus is absent, unless the angioedema is associated with urticarial lesions, which are intensely pruritic (picture 4). The skin is either normal in color or mildly erythematous. Mild pain and warmth may be present but are much less prominent than the pain and warmth of cellulitis. Some patients describe the discomfort of angioedema as burning in nature. Angioedema resolves without leaving residual markings on the skin, unless there has been trauma induced by rubbing or scratching.

Bowel wall — Angioedema affecting the bowel wall presents as colicky abdominal pain, sometimes accompanied by nausea, vomiting, and/or diarrhea. Bowel wall edema can often be visualized by abdominal computed tomography (CT) or ultrasound. Bowel wall angioedema is occasionally seen in patients on ACE inhibitors and frequently in those with hereditary or acquired C1 inhibitor deficiency:

●ACE inhibitors should be suspected in an older adult taking these medications and should be stopped [11-15]. (See 'Imaging for suspected bowel wall edema' below.)

●Acquired C1 inhibitor deficiency also typically presents in older patients. Many patients are found to have an underlying lymphoproliferative disorder. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

●Hereditary angioedema (HAE) should be considered in an adolescent or adult, particularly if there is a family history of episodic swelling or recurrent abdominal pain. A more detailed discussion of the evaluation of abdominal pain in patients with HAE is found separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Gastrointestinal attacks'.)

Life-threatening situations — Angioedema is usually a benign and transient condition, although it can be life threatening when severe angioedema of the larynx, upper airway, or tongue results in airway obstruction. This characteristically happens in anaphylaxis and in bradykinin-mediated forms of angioedema (ie, ACE inhibitor-induced angioedema or hereditary or acquired C1 inhibitor deficiency) (see "Anaphylaxis: Emergency treatment", section on 'Airway management'). Angioedema of the bowel wall can cause severe symptoms mimicking an intraabdominal catastrophe and, when not recognized, may lead to unnecessary abdominal surgery.

EVALUATION — In patients presenting with angioedema affecting the airway, airway protection must be given priority over a comprehensive diagnostic evaluation. (See 'Angioedema in or near the airway' below.)

Clinical history — The history should be directed at identifying possible causes, as well as determining if the patient has had previous episodes of angioedema. Causes are reviewed elsewhere (table 2). (See "An overview of angioedema: Pathogenesis and causes".)

●Characteristics of the swelling, especially duration, concomitant hives, locations, and response to treatment, should be carefully documented.

●The patient should be questioned about any unusual exposures (eg, insect stings), activities (eg, exercise), foods, or other ingestions in the 24 hours before the onset of symptoms.

●A review of the patient's medications is important, with particular attention to the following:

•Nonsteroidal antiinflammatory drugs. (See "An overview of angioedema: Pathogenesis and causes", section on 'Aspirin and NSAIDs'.)

•Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The literature concerning angioedema related to each of these medications is reviewed in detail separately. (See "ACE inhibitor-induced angioedema".)

•Estrogens, as these can increase the frequency of attacks in patients with hereditary angioedema (HAE), although estrogens are not a cause of angioedema in patients without this disorder. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Medications'.)

•Any new medications or significant increases in doses of medications [1].

•Patients with previous episodes of angioedema (cutaneous swelling or abdominal pain) should be asked about activities and exposures surrounding those episodes to see if any pattern is apparent. Individuals with ACE inhibitor-induced angioedema may have several episodes of swelling before the drug is recognized as the culprit and discontinued [16]. Patients with recurrent orofacial angioedema after dental work or episodes of unexplained abdominal pain may have hereditary or acquired C1 inhibitor deficiency.

•Patients should be asked about family members with similar episodes of cutaneous or laryngeal angioedema or with recurrent abdominal pain to identify families with HAE. However, approximately 25 percent of patients with HAE have a new mutation and so do not have a positive family history. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

Physical examination — Angioedema is localized swelling of the skin or of the mucous membranes of the upper respiratory or gastrointestinal tracts. It is not gravitationally dependent, and it is usually asymmetrical and nonpitting. The margins of the affected areas are often diffuse, and the skin may be normal colored or slightly erythematous.

The presence of other signs and symptoms of an allergic reaction (or, more precisely, of mast cell activation) is helpful in narrowing the list of possible causes to those that are mast cell mediated. These signs and symptoms include urticaria, flushing, generalized pruritus, bronchospasm, throat tightness, and/or hypotension. If one or more of these other signs or symptoms is present, the history should be directed toward mast cell-mediated etiologies, such as allergic reactions to foods, drugs, and stinging insects (table 3) [17]. (See "An overview of angioedema: Pathogenesis and causes", section on 'Mast cell-mediated etiologies'.)

If signs and symptoms of mast cell activation are absent and if the angioedema is unaccompanied by urticaria and nonresponsive to antihistamines, then bradykinin-mediated angioedema, such as that caused by ACE inhibitors and the rare disorder hereditary or acquired C1 inhibitor deficiency, should be considered. (See "An overview of angioedema: Pathogenesis and causes", section on 'Bradykinin-mediated etiologies'.)

Laboratory tests — The laboratory tests that are indicated in a patient presenting with angioedema are influenced by the presence of other signs and symptoms and by the suspected cause, as described below.

Isolated angioedema — We suggest that the following laboratories be performed in all patients with isolated angioedema: complete blood count with differential, basic chemistry panel with liver function tests, C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and levels of the complement protein C4.

●Depressed C4 levels should prompt further evaluation for hereditary or acquired C1 inhibitor deficiency. In cases in which the history suggests a possible diagnosis of HAE or acquired C1 inhibitor deficiency (ie, lack of response to antihistamines or positive family history), C1 inhibitor antigen and functional levels should also be measured.

●CRP and ESR may be markedly elevated during infections (particularly bacterial) and in the setting of malignancies and elevated to a lesser degree in a variety of inflammatory diseases. These disorders are occasionally associated with angioedema. Elevations in these tests indicate the need for further evaluation based upon the clinical history. CRP may also be elevated in ACE inhibitor-induced angioedema [18]. (See "Acute phase reactants".)

Angioedema with prominent urticaria — Guidelines for the evaluation of urticaria (with or without angioedema) suggest that testing is generally of low yield if a specific cause or underlying condition is not apparent from the history or physical examination. This evaluation is reviewed separately. A specific cause can sometimes be identified in patients with new-onset urticaria/angioedema. (See "New-onset urticaria".)

Urticaria/angioedema is considered chronic when it has been present on most days of the week for a period of six weeks or more. The evaluation of chronic urticaria/angioedema differs from that of new-onset symptoms since a specific external trigger or allergy is not found in most patients and laboratory studies are most often normal. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

Angioedema with anaphylaxis — A serum total tryptase level drawn shortly after the onset of anaphylaxis may be useful in confirming that the episode was a mast cell-mediated event. Serum tryptase is a mast cell-specific protease that is released upon mast cell activation. Any elevation in serum tryptase suggests an anaphylactic event. However, a normal level does not exclude anaphylaxis, because tryptase elevations are variable and transient. Tryptase elevations are most consistently found in patients with hypotension during anaphylaxis. Instructions for proper sample collection are provided in the table (table 4). (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Angioedema due to a suspect allergen — In cases in which an allergic reaction to an identifiable substance is suspected, there may be commercially available tests for immunoglobulin E (IgE) antibodies to the substance in question. Allergen-specific IgE immunoassays are available for a variety of foods, insect venoms, inhaled allergens, and latex. These tests vary in sensitivity and specificity, but a positive result can be helpful. IgE immunoassays are not altered by recent allergic reactions, so they can be obtained at any time. Allergy skin testing provides similar information and is more sensitive in many cases, but it requires referral to an allergy specialist and should be deferred until the patient has fully recovered from the angioedema event (one month is generally sufficient). (See "Overview of in vitro allergy tests", section on 'Immunoassays for allergen-specific IgE' and "Overview of skin testing for IgE-mediated allergic disease".)

Imaging for suspected bowel wall edema — Bowel wall edema may be imaged by ultrasound or abdominal computed tomography (CT). Multidetector CT (MDCT) has been suggested as particularly helpful for diagnosis of ACE inhibitor-induced angioedema. Most reported cases of ACE inhibitor-induced intestinal angioedema involved the small bowel, with abdominal CT demonstrating circumferential thickening of the small bowel wall with ascites or incomplete obstruction [12,14,19]. The thickened area of bowel wall may have a stratified appearance, and mesenteric lymphadenopathy has not been reported [19]. Recognition of this complication of ACE inhibitor therapy can spare the patient unnecessary surgical intervention.

DIAGNOSIS — The diagnosis of angioedema is made clinically based on a suggestive history and physical findings. It presents as localized, subcutaneous (or submucosal), nondependent swelling that typically affects the face, lips, throat, larynx, extremities, genitalia, or the bowel wall. It develops within minutes to hours and resolves in hours to days. Laboratory tests may be helpful in confirming an underlying allergy or a complement disorder. However, routine laboratories are normal in many cases of angioedema.

An algorithmic approach to the evaluation and management of angioedema in an emergency setting is presented (algorithm 1).

The utility of extensive empiric testing — Extensive testing beyond the laboratory tests already mentioned is of relatively low yield. (See 'Laboratory tests' above.)

The utility of extensive testing was evaluated in a large series of 776 patients with recurrent angioedema, without major urticaria, who presented to a referral center over a 10-year period [20]. In the majority of these patients, neither the patient nor the referring clinician could detect an association between the episodes of angioedema and an obvious trigger. All patients underwent a careful history and physical examination, sinus and dental radiographs, complete blood count, serum protein electrophoresis, complement studies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hepatic enzymes, kidney function, thyroid function and anti-tissue antibodies, stool examination for ova and parasites, urinalysis, pharyngeal cultures, and urine cultures. Further studies, including allergy testing or medication withdrawal and challenge, were performed only if allergy was suggested by the clinical history. A condition or trigger was considered causative only if the angioedema improved after treatment/discontinuation.

The following potentially causative conditions were identified (figure 2):

●Hereditary or acquired angioedema due to C1 inhibitor deficiency was identified in 23 and 2 percent, respectively.

●Angiotensin-converting enzyme (ACE) inhibitors were implicated in 11 percent, with a median duration of treatment of one year before symptoms began.

●A specific causative factor (a food, drug, insect bite, environmental allergen, or physical stimulus) was identified in 16 percent.

●Other disorders, most commonly chronic infection or autoimmune disease, were identified in 7 percent. Within this group, chronic infections were identified in 27 patients, 19 of whom had resolution of the angioedema following treatment of the infection.

●Three percent did not have angioedema, but rather other types of peripheral or generalized edema. (See 'Differential diagnosis' below.)

No trigger could be identified in 38 percent, and these patients were deemed to have idiopathic angioedema. Thus, if the initial approach suggested above (ie, obtaining complete blood count with differential; basic chemistry panel with liver function tests, CRP, ESR, and C4 levels; and stopping any ACE inhibitors) were applied to this referral group, patients with hereditary or acquired angioedema and those with ACE inhibitor-related angioedema would have been reliably detected. A detailed clinical history and review of systems would likely have identified many of the remaining patients (those with a specific causative factor or an underlying infection or autoimmune disease) as requiring further evaluation.

Idiopathic angioedema — Idiopathic angioedema is the term applied to recurrent episodes of angioedema without urticaria for which no explanation can be found after a thorough evaluation (as previously described) to exclude allergic disorders, drug reactions, and defects in complement pathways [20]. Idiopathic angioedema may be mast cell mediated or bradykinin mediated, with very different risk and therapeutic implications. The possibility of hereditary angioedema (HAE) with normal C1 inhibitor or nonhistaminergic idiopathic angioedema should be considered in all patients with recurrent idiopathic angioedema without hives.

DIFFERENTIAL DIAGNOSIS — There are several conditions that may be mistaken for angioedema [21,22].

Disorders resembling cutaneous edema — Cutaneous edema mimicking angioedema can result from contact dermatitis, cellulitis, autoimmune diseases, superior vena cava syndrome, and other disorders.

●Contact dermatitis – Contact dermatitis is a common mimic of facial angioedema and can cause dramatic swelling of the facial and periorbital skin when it develops in response to cosmetics or topical pharmaceuticals (picture 5 and picture 6). Microvesiculation and/or deep erythema of the skin can help distinguish contact dermatitis from complement-mediated angioedema. Poison ivy can cause severe facial swelling, although linear patterns of vesiculations are often present.

Patients with contact dermatitis often report prominent pain, pruritus, and burning of the skin. Resolution of contact dermatitis is typically prolonged compared with angioedema and may be followed by peeling, which does not occur in angioedema. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Allergic contact dermatitis in children".)

●Cellulitis and erysipelas – Cellulitis and erysipelas are infections of various layers of the dermis, which present as areas of skin erythema, edema, and warmth in the absence of an underlying suppurative focus. Cellulitis involves the deeper dermis and subcutaneous fat and has relatively smooth, flat borders. In contrast, erysipelas involves the upper dermis and superficial lymphatics and is characteristically raised above the level of surrounding skin, with a clear line of demarcation between involved and uninvolved tissue (picture 7 and picture 8).

Compared with angioedema, cellulitis and erysipelas are deeply erythematous, painful, and may be accompanied by fever. The involved areas of skin are more clearly demarcated than angioedematous skin. Resolution may be followed by peeling, whereas angioedema resolves without peeling.

●Facial lymphedema – Facial lymphedema can be associated with rosacea, although there are other characteristic skin changes in rosacea. Patients may also experience prominent flushing and warmth of the face, and the combination of flushing, heat, and swelling is interpreted by some patients as a possible allergic reaction. However, lymphedema does not develop or resolve rapidly, in contrast to angioedema. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)

●Autoimmune conditions – Edema of the face, periorbital areas, and sometimes the hands can be seen in systemic lupus, polymyositis, dermatomyositis, and Sjögren's disease. Early stages of both scleredema and systemic sclerosis can present as swelling. Scleredema often involves the posterior neck, and systemic sclerosis often affects the hands and is accompanied by Raynaud phenomenon [23]. These disorders can be distinguished from angioedema by their persistence and by the presence of associated systemic rheumatologic findings. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●Eyelid edema – Blepharochalasis is an uncommon disorder in which recurrent and episodic eyelid edema leads to atrophic eyelid skin with fine wrinkling and bronze discoloration (picture 9) [24-27]. This is seen predominantly in children and young adults. The etiology is unknown, although immunoglobulin A (IgA) deposits have been described in the periorbital tissues, suggesting an immunologic pathogenesis [28].

●Parasitic infections – In areas of the world where parasitic infections are prevalent, certain infections can cause periorbital edema that is persistent rather than episodic. Specific infections that can present with this finding include trichinosis and American trypanosomiasis (ie, Romana's sign) [29]. (See "Trichinellosis" and "Chagas disease: Acute and congenital Trypanosoma cruzi infection".)

●Hypothyroidism – Severe hypothyroidism can cause a puffiness of the face and lips that can be mistaken for angioedema but is not transient. Nonpitting edema (myxedema) may be generalized. Myxedema results from infiltration of the skin by glycosaminoglycans with associated water retention. (See "Clinical manifestations of hypothyroidism".)

●Superior vena cava syndrome and tumors – Occasionally, edema of the face, neck, or upper extremities, accompanied by venous engorgement, is observed with superior vena cava syndrome [29] (see "Malignancy-related superior vena cava syndrome"). Tumors of the head and neck, lymphoma, and superior (pulmonary) sulcus (Pancoast) tumors can also cause localized edema. With these entities, protracted or progressive swelling would be expected, in contrast to the transient swelling of angioedema.

●Cheilitis granulomatosa (Miescher's cheilitis) and Melkersson-Rosenthal syndrome – These are rare disorders of recurrent angioedema involving the lips and face that lead to eventual permanent enlargement of the affected areas (picture 10 and picture 11) [30,31].

●Idiopathic edema – Idiopathic edema (as opposed to idiopathic angioedema) is a syndrome of persistent and recurrent fluid retention, typically occurring in young, menstruating females in the absence of cardiac, hepatic, or kidney disease. (See "Idiopathic edema".)

●Factitious angioedema – Factitious angioedema involving the tongue has been reported and appears to be a type of somatoform disorder in which patients gain satisfaction from assuming the sick role. Laboratory evaluation is normal, and the "angioedema" typically resolves rapidly (within minutes) once the patient has been evaluated [32].

Disorders resembling laryngeal edema — The differential diagnosis of laryngeal edema includes tonsillitis, peritonsillar abscess, and pharyngeal foreign body [21]. Historical information should differentiate these entities from angioedema as infectious causes should have accompanying fever and other signs of illness. The diagnosis of a pharyngeal foreign body can be difficult, however, particularly in the preverbal infant. (See "Emergency evaluation of acute upper airway obstruction in children".)

Other causes of bowel wall edema — Thickening of the wall of the small bowel can be seen in multiple disorders, including mesenteric infarction, vasculitis, intramural hemorrhage, inflammatory bowel disease, acute ileitis (Yersinia, Campylobacter infections), peritoneal carcinomatosis, inflammatory conditions adjacent to the bowel wall, and other disorders [19,33-35].

TREATMENT — The treatment of angioedema depends upon the acuity, severity, and proposed mechanism (algorithm 1).

Angioedema in or near the airway — The patient with angioedema near or involving the tongue, uvula, soft palate, or larynx must be immediately assessed for signs of airway compromise. If intubation is necessary, the airway should be managed by the most experienced person available because intubation in the presence of laryngeal angioedema can be difficult due to distortion of the normal anatomy. Angioedema of the lips or mouth sometimes spreads to involve the throat, and frequent monitoring of airway patency is critical throughout treatment. (See "Approach to the difficult airway in adults for emergency medicine and critical care" and "The difficult pediatric airway for emergency medicine".)

If no airway compromise is detected, then the patient should be treated (depending upon the presumed cause, as described below) and observed until there are clear signs of improvement to ensure that the angioedema is not the beginning of a more generalized allergic reaction that is still in evolution. When eventually discharged, the patient should have clear instructions on what to do if symptoms recur.

Angioedema with anaphylaxis — Anaphylaxis should be treated with intramuscular epinephrine, intravenous fluids, and oxygen. Rapid overview tables are provided for treatment of anaphylaxis in adults (table 5) and children (table 6). The treatment of anaphylaxis is reviewed in greater detail elsewhere. (See "Anaphylaxis: Emergency treatment".)

All patients who have experienced anaphylaxis should be equipped with an anaphylaxis emergency action plan, one or more epinephrine autoinjectors, a plan for arranging further evaluation, and printed information about anaphylaxis and its treatment. These materials can be found separately. (See "Anaphylaxis: Emergency treatment", section on 'Discharge care'.)

Acute allergic angioedema (less severe than anaphylaxis) — Antihistamines and glucocorticoids are the main therapies for isolated angioedema that appears to be allergic (ie, mast cell-mediated) but is not part of a larger anaphylactic reaction. In contrast, anaphylaxis should be treated with intramuscular epinephrine because antihistamines are not sufficient. Angioedema that is accelerating and could affect the airway would also be appropriately treated with intramuscular epinephrine, although this is unlikely to help if the angioedema is bradykinin mediated (as in hereditary angioedema [HAE]).

Suggested treatment for allergic angioedema includes the following:

●H1 antihistamines (eg, cetirizine up to 20 mg twice daily)

●Glucocorticoids (the dosing in acute angioedema has not been specifically studied):

•Methylprednisolone, 60 to 80 mg intravenously initially, replaced with oral preparations and tapered over five to seven days, in adults requiring hospitalization for severe angioedema

•Prednisone, 20 to 40 mg orally daily, in adults or prednisolone, 0.5 to 1 mg/kg/day, in children, tapered over five to seven days in patients discharged to home

The use of antihistamines for angioedema is extrapolated from the treatment of acute urticaria/angioedema as the data on isolated allergic angioedema are scant [21]. (See "New-onset urticaria", section on 'Treatment'.)

ACE inhibitor-induced angioedema — Treatment of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema primarily involves discontinuation of the drug and monitoring for resolution. The airway must be protected if swelling involves the mouth or throat as several deaths have been attributed to asphyxiation from massive tongue swelling [36].

The utility of other medications for severe or refractory symptoms is reviewed elsewhere. (See "ACE inhibitor-induced angioedema", section on 'Management'.)

Future use of related medications, particularly angiotensin receptor blockers (ARBs), is discussed separately. (See "ACE inhibitor-induced angioedema", section on 'Future use of related drugs'.)

C1 inhibitor deficiency (hereditary angioedema) — The treatment of acute attacks of hereditary and acquired C1 inhibitor disorders is outlined here and discussed in detail separately.

The treatment of laryngeal attacks, which are the leading cause of mortality in patients with HAE, must always begin with immediate and meticulous attention to airway patency regardless of the therapies available (see 'Angioedema in or near the airway' above). Those with respiratory distress or stridor may require intubation because even the first-line therapies take approximately 30 minutes or more to begin working.

Briefly, treatment options include:

●Purified C1 inhibitor concentrate (Cinryze, Berinert, or Ruconest).

●Ecallantide (Kalbitor) (a kallikrein inhibitor available in the United States).

●Icatibant (Firazyr), a bradykinin-B₂-receptor antagonist.

●Fresh frozen plasma (FFP) or solvent-detergent treated plasma, which should only be used if other therapies are not available. Note that FFP has the occasional paradoxical effect of making the angioedema acutely worse, and the clinician must be prepared to intubate the patient if this happens.

The dosing and administration of each of these therapies is reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions' and "Acquired C1 inhibitor deficiency: Management and prognosis".)

Recurrent, idiopathic angioedema — A trial of nonsedating antihistamines administered twice daily is suggested as an initial intervention to prevent additional angioedema episodes in patients with idiopathic recurrent angioedema without urticaria. Such patients should be referred to an allergy specialist for further evaluation.

●In the largest series available, 294 patients with idiopathic recurrent angioedema without urticaria were treated with nonsedating antihistamines initially (ie, either cetirizine 10 mg twice daily or desloratadine 5 mg twice daily) for at least one month [20]. With this intervention, 86 percent experienced significant improvement or resolution of the angioedema. In those that did not improve significantly, the addition of hydroxyzine (eg, 25 mg three times daily) did not result in additional symptom control. Responsiveness to antihistamines suggests that mast cell- or basophil-mediated processes were underlying the symptoms of these patients despite the lack of identifiable triggers.

●One consensus report suggests increasing the dose of nonsedating antihistamine up to fourfold (eg, cetirizine 20 mg twice daily) before concluding that the patient's angioedema is not responsive to antihistamine therapy [37].

●Other experts describe less success in preventing recurrence with antihistamines, with no response in up to 30 percent of patients, even with high doses (ie, up to 200 mg of hydroxyzine or diphenhydramine) [21,38].

The addition of montelukast, a leukotriene receptor antagonist, at the standard dose of 10 mg before bed may help some patients for whom antihistamines alone were not adequate [39].

In severe and refractory cases, successful treatment with dapsone, icatibant (bradykinin-B₂-receptor antagonist), and rituximab (B cell-depleting anti-CD20 monoclonal antibody) has been reported [40-42].

Treatment of acute episodes — For adult patients with idiopathic angioedema who have infrequent attacks (ie, a few attacks per year) and do not wish to take regular medications for prevention, or for those with less frequent breakthrough episodes despite daily antihistamines, we (the authors and editors of UpToDate) have found the following to be helpful. We instruct patients to take 40 mg of prednisone and 25 to 50 mg of diphenhydramine, all at once, at the first sign of swelling, with no further doses. Some patients have identifiable sensations in the skin just before the onset of angioedema, and the medications should be taken when these sensations appear. This approach has not been formally studied.

DISPOSITION AND REFERRAL — In patients who do not require admission to the hospital for ongoing management, we suggest observation until there are unequivocal signs of improvement to ensure that the angioedema is not the beginning of a more generalized allergic reaction that is still evolving. Episodes of isolated angioedema characteristically peak and then gradually resolve over the course of either hours (if mild) or three to five days (if severe). It is unusual for angioedema to follow a fluctuating course within a single episode. Therefore, when an episode of angioedema is clearly resolving, the patient can generally be discharged with clear instructions on how to proceed if another episode occurs and preferably with an epinephrine autoinjector if the etiology is known or suspected to be histaminergic. In contrast to idiopathic or bradykinin-mediated angioedema, patients with severe acute allergic angioedema, including anaphylaxis, may experience a late-phase reaction and may need longer observation. The prevalence of biphasic and protracted anaphylaxis is reviewed separately. (See "Anaphylaxis: Acute diagnosis", section on 'Biphasic anaphylaxis'.)

Patients with severe or recurrent angioedema or angioedema/urticaria, for which no cause is readily apparent, should be referred to a specialist for further evaluation. An allergy specialist is most appropriate in most situations. Dermatology specialists also manage mast cell-mediated urticaria/angioedema.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Angioedema (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Angioedema typically affects the skin and mucosal tissues of the face, lips, mouth, and throat, larynx, extremities, and genitalia, often in an asymmetric pattern (picture 1). Angioedema can also affect the bowel wall and present as colicky abdominal pain. Episodes of isolated angioedema characteristically peak and then gradually resolve over the course of either hours (if mild) or three to five days (if severe). (See 'Clinical features' above.)

●Pathogenesis – Two types of angioedema can be distinguished: mast cell-mediated angioedema (eg, allergic reactions) and bradykinin-mediated angioedema (eg, angiotensin-converting enzyme [ACE] inhibitor-induced angioedema, hereditary angioedema [HAE]) (table 2). However, there are other causes of angioedema for which the mechanism is unknown. (See "An overview of angioedema: Pathogenesis and causes".)

●Life-threatening presentations – Angioedema may be life threatening if it causes airway obstruction or when it represents a component of anaphylaxis. (See 'Life-threatening situations' above.)

●Evaluation – If the clinical history or physical examination reveals a possible external cause or concomitant condition, then these findings should guide further testing (algorithm 1). The presence of urticaria means that a mast cell-mediated process is present. If there is no information to suggest an external cause and the patient has isolated angioedema (without pruritus or urticaria), then a C4 and a C1 inhibitor antigenic level should be obtained. (See 'Evaluation' above.)

●Management – The management of angioedema depends upon the location, acuity, severity, and the mechanism believed responsible (mast cell or bradykinin mediated) (algorithm 1). (See 'Treatment' above.)

•Immediate assessment and ongoing protection of the airway is critical in any patient with angioedema near or affecting the larynx, mouth, soft palate, or tongue. (See 'Angioedema in or near the airway' above.)

•Mast cell-mediated angioedema responds to epinephrine (if severe), glucocorticoids, and antihistamines. (See 'Angioedema with anaphylaxis' above and 'Acute allergic angioedema (less severe than anaphylaxis)' above.)

•Bradykinin-mediated angioedema responds to C1 inhibitor concentrate, icatibant, fresh frozen plasma (FFP), and other agents that interfere with the production or action of bradykinin (algorithm 1). (See 'ACE inhibitor-induced angioedema' above and 'C1 inhibitor deficiency (hereditary angioedema)' above.)

●Disposition – Patients who do not require admission to the hospital for ongoing management should be observed until there are unequivocal signs of improvement to ensure that the angioedema is not the beginning of a more generalized allergic reaction in evolution. Once symptoms are improving, the patient can be discharged with clear instructions on how to proceed if another episode occurs and preferably with an epinephrine autoinjector if the etiology is known or suspected to be histaminergic. (See 'Disposition and referral' above.)