Angioedema

What is angioedema?

Angioedema is a skin reaction similar to hives or urticaria. It is most often characterised by an abrupt and short-lived swelling of the skin and mucous membranes. All parts of the body may be affected but swelling most often occurs around the eyes and lips. In severe cases, the internal lining of the upper respiratory tract and intestines may also be affected.

Image provided by Dr Janjua

What's the difference between angioedema and urticaria?

Angioedema and urticaria are very similar in many ways and can co-exist and overlap. Urticaria occurs more commonly and is less severe than angioedema as it only affects the skin layers whereas angioedema affects the tissues beneath the skin (subcutaneous tissue). The main differences between urticaria and angioedema are shown in the following table.

What causes angioedema?

The causes of angioedema depend on the type of angioedema a patient has. Angioedema can be classified into at least four types, acute allergic angioedema, non-allergic drug reactions, idiopathic angioedema, hereditary angioedema (HAE) and acquired C1 inhibitor deficiency.

Whatever the cause of angioedema, the actual mechanism behind the swelling is the same in all cases. Small blood vessels in the subcutaneous and/or submucosal tissues leak watery liquid through their walls and cause swelling. This same mechanism occurs in urticaria but just closer to the skin surface.

What are the clinical features of angioedema?

Symptoms and signs of angioedema may vary slightly between the different types of angioedema but in general, some or all of the following occur.

• Marked swelling, usually around the eyes and mouth
• Throat, tongue, hands, feet and/or genitals may be affected too
• The skin may appear normal, i.e. no hives or another rash
• Swellings may or may not be itchy
• Swellings may be painful, tender or burning
• In severe angioedema swelling of the throat and/or tongue may make it difficult to breath
• Swelling of the lining of the intestinal tracts may cause gastrointestinal pain and cramps

Some features specific to the different types of angioedema are listed below.

How is the diagnosis made?

A detailed medical history is invaluable in diagnosing angioedema.

• Keep a diary of exposure to possible irritants
• Tell your doctor about all medications you take, including over-the-counter (OTC) drugs and herbal remedies (even if taking them irregularly)
• Any family history of skin rash, allergies

Skin prick testing may be performed to try and identify any allergens. If hereditary angioedema is suspected, blood tests to check for levels and function of specific complement blood proteins may be done.

What is the treatment for angioedema?

Treatment of angioedema depends on the severity of the condition. In cases where the respiratory tract is involved the first priority is to secure the airway. Patients may need emergency hospital care and require intubation (placement of a tube in the throat to keep the airway open).

Angioedema associated with urticaria

Patients with mild acute angioedema can usually be treated in the same way as acute urticaria. In many cases, the swelling is self-limiting and resolves spontaneously after a few hours or days. In more severe cases where there is persistent swelling, itchiness or pain the following medications may be used.

• Subcutaneous adrenaline (epinephrine)
• Oral or intravenous corticosteroids
• Oral or injected antihistamines

Chronic angioedema with chronic autoimmune or chronic idiopathic urticaria is often difficult to treat and response to medication variable. The following treatment steps are recommended. Each step is added to the previous one if an inadequate response is obtained.

Omalizumab, an anti-IgE monoclonal antibody, has been reported to be effective in some refractory cases of angioedema.

The goal of treatment for chronic angioedema is to reduce itch, swelling, tenderness and pain to a tolerable level to maintain function (eg, at work, school, and during sleep).

Hereditary angioedema

Acute episodes of hereditary angioedema do not respond to adrenaline, antihistamine and corticosteroids. Most acute episodes of Type I and II hereditary angioedema are not life-threatening.

• The mainstay of emergency medical treatment is intravenous C1 inhibitor concentrate (a blood product).
• If this is unavailable, fresh frozen plasma can be infused, but this occasionally exacerbates the angioedema.
• Icatibant, a synthetic peptidomimetic drug and bradykinin B2 receptor antagonist, can be used in emergencies for the symptomatic treatment of acute attacks of hereditary angioedema in adults with C1-esterase-inhibitor deficiency. It was approved by the FDA in 2011. In New Zealand, it is available for home use on Special Authority application.
• Ecallantide is a potent and selective human plasma kallikrein inhibitor that is also indicated for the symptomatic treatment of hereditary angioedema, approved for use by the FDA in 2009. It is a protease that is responsible for liberating bradykinin from its precursor kininogen. Ecallantide has been reported to cause anaphylaxis in 4% of cases and thus has a black box warning in the USA.

The chance of an attack can be reduced with the following medications:

• C1 inhibitor concentrate infused an hour before a surgical procedure
• Anabolic steroids (stanazolol, oxandrolone and danazol) to increase circulating levels of normal functional C1 inhibitor. These have 'male-like' hormonal activity, so may cause weight gain, menstrual irregularities and virilism.
• Tranexamic acid has been used in pre-pubertal children and may be effective in Type III hereditary angioedema.
• A monoclonal antibody, lanadelumab, which inhibits active plasma kallikrein, has been approved in the USA for the prevention of hereditary angioedema attacks.