Angioedema

Angioedema is edema of the deep dermis and subcutaneous tissues. It is usually an acute mast cell–mediated reaction caused by exposure to drug, venom, dietary, pollen or animal dander allergens. Angioedema can also be an acute reaction to ACE inhibitors, a chronic reaction, or a hereditary or an acquired disorder characterized by an abnormal complement response. The main symptom is swelling, which can be severe. Diagnosis is by examination. Treatment is with airway management as needed, elimination or avoidance of the allergen, and drugs to minimize swelling (eg, H₁ blockers).

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, Ca channel blockers, fibrinolytic drugs) have no identified mechanism; sometimes a cause with a known mechanism is overlooked clinically.

Angioedema can be acute or chronic (> 6 wk). There is a hereditary form (see Hereditary and Acquired Angioedema).

Acute angioedema: 

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 (local wheals and erythema in the skin—see Urticaria). 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 dyes, aspirin



, and NSAIDs.

 

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. Angioedema may occur soon or years after therapy begins.

Chronic angioedema: 

The cause of chronic (> 6 wk) 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 (acquired C1 deficiency—see Hereditary and Acquired Angioedema) 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

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 intestines may cause nausea, vomiting, colicky abdominal pain, and/or diarrhea.

Other manifestations 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)

Bradykinin-mediated angioedema

• Tends to develop over hours to a few days
• Is not accompanied by other manifestations of allergic reactions

Angioedema

Diagnosis

• Clinical evaluation

For diagnosis of urticaria, see Evaluation.  

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 it, testing for C1 inhibitor deficiency should be considered to check for hereditary or acquired angioedema (see Diagnosis).

Erythropoietic protoporphyria 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 (see Erythropoietic Protoporphyria).

Pearls & Pitfalls If angioedema is not accompanied by urticaria and recurs without clear cause or is present in family members, consider hereditary or acquired angioedema.

Treatment

• Airway management
• 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 bid

Securing an airway is the highest priority. In mast cell–mediated angioedema, treatment usually rapidly reduces airway edema; however, in bradykinin-mediated angioedema, edema usually takes > 30 min to decrease after treatment begins. Thus, endotracheal intubation see Tracheal Intubation is more likely to be needed in bradykinin-mediated angioedema. If angioedema involves the airways, epinephrine


 sc or IM is given as for anaphylaxis (see Treatment) unless the mechanism is obviously bradykinin-mediated (eg, due to use of an ACE inhibitor or to known hereditary or acquired angioedema).

Treatment 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 (see H blockers). Prednisone

 30 to 40 mg po once/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.

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 h after stopping the drug. If symptoms are severe, progressing, or refractory, treatments used for hereditary or acquired angioedema can be tried (see Treatment). They include fresh frozen plasma, C1 inhibitor concentrate, and possibly ecallantide and icatibant (not available in the US). 

For idiopathic angioedema, a high dose of a nonsedating oral antihistamine can be tried.

Key Points

• 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 possibly test for C1 inhibitor deficiency; testing is rarely necessary for acute angioedema.
• First, make sure the airway is secure; if the airway is affected, give epinephrine
  
  
   sc 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 may be tried if bradykinin-mediated angioedema is severe or refractory.