(See also Overview of Allergic and Atopic Disorders Overview of Allergic and Atopic Disorders Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more .)
Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. Known mediators of increased vascular permeability include the following:
Mast cell–derived mediators (eg, histamine, leukotrienes, prostaglandins)
Bradykinin and complement-derived mediators
Mast cell–derived mediators tend to also affect layers superficial to subcutaneous tissue, including the dermal-epidermal junction. There, these mediators cause urticaria and pruritus, which thus usually accompany mast cell–mediated angioedema.
In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent.
In some cases, the mechanism and cause of angioedema are unknown. Several causes (eg, calcium channel blockers, fibrinolytic drugs) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically.
Angioedema can be acute or chronic (> 6 weeks). There are hereditary and acquired forms Hereditary and Acquired Angioedema Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation... read more characterized by an abnormal complement response.
Acute angioedema is mast cell–mediated in > 90% of cases. Mast cell–mediated mechanisms include acute allergic, typically IgE-mediated reactions. IgE-mediated angioedema is usually accompanied by acute urticaria Urticaria Urticaria consists of migratory, well-circumscribed, erythematous, pruritic plaques on the skin. Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation... read more (local wheals and erythema in the skin). It may often be caused by the same allergens (eg, drug, venom, dietary, extracted allergens) that are responsible for acute IgE-mediated urticaria.
Acute angioedema can also result from agents that directly stimulate mast cells without involving IgE. Causes can include opiates, radiopaque contrast agents, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Angiotensin-converting enzyme (ACE) inhibitors cause up to 30% of cases of acute angioedema seen in emergency departments. ACE inhibitors can directly increase levels of bradykinin. The face and upper airways are most commonly affected, but the intestine may be affected. Urticaria does not occur. Angioedema may occur soon or years after therapy begins.
The cause of chronic (> 6 weeks) angioedema is usually unknown. IgE-mediated mechanisms are rare, but chronic ingestion of an unsuspected drug or chemical (eg, penicillin in milk, a nonprescription drug, preservatives, other food additives) is sometimes the cause. A few cases are due to hereditary or acquired C1 inhibitor deficiency.
Idiopathic angioedema is angioedema that occurs without urticaria, is chronic and recurrent, and has no identifiable cause.
Hereditary and acquired angioedema
Hereditary angioedema and acquired angioedema Hereditary and Acquired Angioedema Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation... read more are disorders that are characterized by abnormal complement responses and caused by deficiency or dysfunction of C1 inhibitor. Symptoms are those of bradykinin-mediated angioedema.
Symptoms and Signs of Angioedema
In angioedema, edema is often asymmetric and mildly painful. It often involves the face, lips, and/or tongue and may also occur on the back of hands or feet or on the genitals. Edema of the upper airways may cause respiratory distress and stridor; the stridor may be mistaken for asthma. The airways may be completely obstructed. Edema of the intestine may cause nausea, vomiting, colicky abdominal pain, and/or diarrhea.
Other manifestations of angioedema depend on the mediator.
Mast cell–mediated angioedema
Tends to develop over minutes to several hours
May be accompanied by other manifestations of acute allergic reactions (eg, pruritus, urticaria, flushing, bronchospasm, anaphylactic shock)
Tends to develop over hours to a few days
Is not accompanied by other manifestations of allergic reactions
Diagnosis of Angioedema
For diagnosis of urticaria, see Urticaria: Evaluation Evaluation Urticaria consists of migratory, well-circumscribed, erythematous, pruritic plaques on the skin. Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation... read more .
Patients with localized swelling but no urticaria are asked specifically about use of ACE inhibitors.
The cause of angioedema is often obvious, and diagnostic tests are seldom required because most reactions are self-limited and do not recur. When angioedema is acute, no test is particularly useful. When it is chronic, thorough drug and dietary evaluation are warranted.
If no cause is obvious or if family members have urticaria, clinicians should consider measuring C1 inhibitor levels to check for C1 inhibitor deficiency Diagnosis Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation... read more and C4 levels to check for hereditary or acquired angioedema. Low levels of C4 help confirm a diagnosis of hereditary angioedema (types 1 and 2) or acquired C1 inhibitor deficiency.
Erythropoietic protoporphyria Diagnosis Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more may mimic allergic forms of angioedema; both can cause edema and erythema after exposure to sunlight. The two can be distinguished by measuring blood and fecal porphyrins.
Pearls & Pitfalls
Treatment of Angioedema
For mast cell-mediated angioedema, an antihistamine and sometimes a systemic corticosteroid and epinephrine
For ACE inhibitor–related angioedema, occasionally fresh frozen plasma and C1 inhibitor concentrate
For recurrent idiopathic angioedema, an oral antihistamine given twice a day
Securing an airway is the highest priority. If angioedema involves the airways, epinephrine Epinephrine Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more is given subcutaneously or IM as for anaphylaxis unless the mechanism is obviously bradykinin-mediated (eg, due to use of an ACE inhibitor or to known hereditary or acquired angioedema). In mast cell–mediated angioedema, treatment usually rapidly reduces airway edema; however, in bradykinin-mediated angioedema, edema usually takes > 30 minutes to decrease after treatment begins. Thus, endotracheal intubation is more likely to be needed in bradykinin-mediated angioedema.
Treatment of angioedema also includes removing or avoiding the allergen and using drugs that relieve symptoms. If a cause is not obvious, all nonessential drugs should be stopped.
For mast cell–mediated angioedema, drugs that may relieve symptoms include H1 blockers H1 blockers Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more . Prednisone 30 to 40 mg orally once a day is indicated for more severe reactions. Topical corticosteroids are useless. If symptoms are severe, a corticosteroid and antihistamine can be given IV (eg, methylprednisolone 125 mg and diphenhydramine 50 mg). Long-term treatment may involve H1 and H2 blockers and occasionally corticosteroids.
Patients who have severe mast-cell mediated reactions should be advised to always carry a prefilled, self-injecting syringe of epinephrine and oral antihistamines and, if a severe reaction occurs, to use these treatments as quickly as possible and then go to the emergency department. There, they can be closely monitored and treatment can be repeated or adjusted as needed.
For bradykinin-mediated angioedema, epinephrine, corticosteroids, and antihistamines have not been shown to be effective. Angioedema due to ACE inhibitor use usually resolves about 24 to 48 hours after stopping the drug. If symptoms are severe, progressing, or refractory, treatments used for hereditary or acquired angioedema Treatment Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation... read more can be tried. They include fresh frozen plasma, C1 inhibitor concentrate, and possibly ecallantide (which inhibits plasma kallikrein, required for the generation of bradykinin) and icatibant (which blocks bradykinin).
For idiopathic angioedema, a high dose of a nonsedating oral antihistamine can be tried.
In the emergency department, up to 30% of cases of acute angioedema are caused by ACE inhibitors (bradykinin-mediated), although overall, > 90% of cases are mast cell–mediated.
The cause of chronic angioedema is usually unknown.
Swelling always develops; bradykinin-mediated angioedema tends to develop more slowly and to cause fewer symptoms of an acute allergic reaction (eg, pruritus, urticaria, anaphylactic shock) than does mast cell–mediated angioedema.
For chronic angioedema, take a thorough drug and dietary history, and consider testing for C1 inhibitor deficiency and measuring C4 levels; testing is rarely necessary for acute angioedema.
First, make sure the airway is secure; if the airway is affected, give epinephrine subcutaneously or IM unless the cause is obviously bradykinin-mediated angioedema, which is more likely to require endotracheal intubation.
Eliminating or avoiding the allergen is key.
For symptomatic and adjunctive treatment, an antihistamine (eg, H1 blocker) and a systemic corticosteroid can relieve symptoms of mast cell–mediated angioedema; frozen plasma, C1 inhibitor concentrate, and/or ecallantide or icatibant may be tried if bradykinin-mediated angioedema is severe or refractory.